Search "مطالعات درس 21 هشتم" (2024)

Wound complications are important causes of early and late postoperative morbidity following laparotomy. Surgical wounds in normal, healthy individuals heal through an orderly sequence of physiologic events that includes inflammation, epithelialization, fibroplasia, and maturation. Mechanical failur

The primary effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is to inhibit cyclo-oxygenase (prostaglandin H synthase, or PGHS), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Two related isoforms of the cyclo-oxygenase (COX

All patients with coronary heart disease, including those with an acute coronary syndrome (ACS), should receive long-term, intensive lipid-lowering therapy starting with a statin irrespective of baseline low density lipoprotein cholesterol (LDL-C) level. In addition, all such patients should receive

The term cardiac preexcitation was originally used to describe premature activation of the ventricle prior to activation via the normal atrioventricular (AV) node His-Purkinje system in patients with the Wolff-Parkinson-White syndrome (WPW). This term has been broadened to include all conditions in

Nail pigmentation is most commonly caused by deposits of melanin or hemosiderin within the nail plate. It is rarely due to deposits of other pigments of endogenous or exogenous origin. Melanin deposits result from activation or proliferation of nail matrix melanocytes and in most cases present as a

ClosePanobinostat (United States: Withdrawn from market): Drug informationPanobinostat (United States: Withdrawn from market): Drug information(For additional information see "Panobinostat (United States: Withdrawn from market): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningGastrointestinal events:Severe diarrhea occurred in 25% of panobinostat treated patients. Monitor for symptoms, institute antidiarrheal treatment, interrupt panobinostat, and then reduce dose or discontinue panobinostat.Cardiovascular events:Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred in patients receiving panobinostat. Arrhythmias may be exacerbated by electrolyte abnormalities. Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated.Brand Names: USFarydak [DSC]Pharmacologic CategoryAntineoplastic Agent, Histone Deacetylase (HDAC) InhibitorDosing: AdultNote: In December 2021, the manufacturer voluntarily withdrew the approval of panobinostat for the treatment of relapsed or refractory multiple myeloma (in combination with bortezomib and dexamethasone) from the US market.Baseline ANC should be ≥1,500/mm3 and platelets ≥100,000/mm3 prior to treatment. Do not initiate panobinostat in patients with a QTcF >450 msec, clinically significant baseline ST-segment depression or T-wave abnormalities, or a history of recent myocardial infarction or unstable angina.Multiple myeloma, relapsed or refractoryMultiple myeloma, relapsed or refractory: Oral: 20 mg once every other day for 3 doses each week during weeks 1 and 2 of a 21-day treatment cycle (eg, Monday, Wednesday, and Friday of weeks 1 and 2 only, rest during week 3) for up to 8 cycles (in combination with bortezomib and dexamethasone); treatment may continue (the same schedule for panobinostat; bortezomib and dexamethasone schedules are modified) for an additional 8 cycles in patients experiencing clinical benefit and acceptable toxicity (San-Miguel 2014). The total duration of therapy may be up to 16 cycles (48 weeks) orHeavily pretreated bortezomib-refractory patients: Oral: 20 mg three days/week on weeks 1 and 2 of a 3-week treatment cycle for up to 8 cycles (in combination with bortezomib and dexamethasone); treatment may continue (the same schedule for panobinostat; bortezomib and dexamethasone schedules are modified) until disease progression or unacceptable toxicity (Richardson 2013).Off-label combinations: Oral: 20 mg on days 1, 3, 5, 15, 17, and 19 of a 28-day cycle (in combination with carfilzomib) until disease progression or unacceptable toxicity (Berdeja 2021) or 20 mg on days 1, 3, 5, 15, 17, and 19 of a 28-day cycle (in combination with lenalidomide and dexamethasone) (Chari 2017).Missed doses: A missed dose may be taken up to 12 hours after the scheduled time. If vomiting occurs, do not repeat the dose; resume with the next usual scheduled dose.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult Drug Interactions database for more information.Dosing: Kidney Impairment: AdultCrCl <80 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling. However, no need for dosage adjustment is expected (Krens 2019). Based on a pharmaco*kinetic study of a single 30 mg dose, renal impairment does not appear to impact panobinostat exposure in patients with mild, moderate, and severe renal impairment (excluding dialysis patients), and initial dosage adjustment is not necessary (Sharma 2015).End-stage renal disease (ESRD) and ESRD on dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). No need for dosage adjustment is expected (Krens 2019). Per the manufacturer, the dialyzability of panobinostat is unknown.Dosing: Hepatic Impairment: AdultHepatic impairment prior totreatment:Mild impairment (bilirubin ≤1 times ULN and AST >1 times ULN or bilirubin >1 to 1.5 times ULN and any AST): Reduce initial dose to 15 mg; monitor frequently for adverse events and adjust dose as needed for toxicity.Moderate impairment (bilirubin >1.5 to 3 times ULN and any AST): Reduce initial dose to 10 mg; monitor frequently for adverse events and adjust dose as needed for toxicity.Severe impairment: Avoid use.Hepatic impairment during treatment: If liver function tests are abnormal, consider dosage adjustments and monitor until liver function returns to normal or baseline.Dosing: Older AdultRefer to adult dosing.Dosing: Adjustment for Toxicity: AdultIf dose reductions are necessary, keep the same treatment schedule and reduce panobinostat dose in increments of 5 mg (from 20 mg to 15 mg, from 15 mg to 10 mg); if dose reduction below 10 mg 3 times a week is necessary, discontinue treatment.Panobinostat Recommended Dose Modifications for Adverse ReactionsAdverse reactionSeverityDose modificationHematologic toxicityThrombocytopeniaGrade 3 (platelets <50,000/mm3)No dosage adjustments are necessary; monitor platelets at least weekly.Grade 3 (platelets <50,000/mm3) with bleedingInterrupt panobinostat treatment, monitor platelets at least weekly until ≥50,000/mm3 and then restart panobinostat at a reduced dose.Interrupt bortezomib until platelets ≥50,000/mm3; if only 1 bortezomib dose omitted, restart bortezomib at the same dose; if ≥2 consecutive doses or doses within the same cycle are omitted, then restart bortezomib at a reduced dose.Grade 4 (platelets <25,000/mm3)Interrupt panobinostat treatment, monitor platelets at least weekly until ≥50,000/mm3 and then restart panobinostat at a reduced dose.Interrupt bortezomib until platelets ≥50,000/mm3; if only 1 bortezomib dose omitted, restart bortezomib at the same dose; if ≥2 consecutive doses or doses within the same cycle are omitted, then restart bortezomib at a reduced dose.Severe thrombocytopeniaConsider platelet transfusions. Discontinue panobinostat if thrombocytopenia does not improve despite treatment modifications or if repeated platelet transfusions are required.NeutropeniaGrade 3 (ANC 750 to 1,000/mm3)No dosage adjustments are necessary.Grade 3 (ANC 500 to 750/mm3 [2 or more occurrences])Interrupt panobinostat treatment until ANC ≥1,000/mm3 and then restart at the same dose.Bortezomib dosage adjustment is not necessary.Grade 3 (ANC <1,000/mm3) with neutropenic feverInterrupt panobinostat treatment until neutropenic fever resolves and ANC ≥1,000/mm3 and then restart at a reduced dose.Interrupt bortezomib until neutropenic fever resolves and ANC ≥1,000/mm3; if only 1 bortezomib dose omitted, restart bortezomib at the same dose; if ≥2 consecutive doses or doses within the same cycle are omitted, then restart bortezomib at a reduced dose.Grade 4 (ANC <500/mm3)Interrupt panobinostat treatment until ANC ≥1,000/mm3 and then restart at a reduced dose.Interrupt bortezomib until ANC ≥1,000/mm3; if only 1 bortezomib dose omitted, restart bortezomib at the same dose; if ≥2 consecutive doses or doses within the same cycle are omitted, then restart bortezomib at a reduced dose.Neutropenia, grade 3 or 4Consider growth factor support and/or dose modification; if neutropenia does not improve despite dose modification or growth factor support, or if severe infection occurs, discontinue panobinostat.AnemiaGrade 3 (hemoglobin <8 g/dL)Interrupt panobinostat until hemoglobin ≥10 g/dL and then restart at a reduced dose.Nonhematologic toxicityCardiovascularQTcF increase to ≥480 msecInterrupt panobinostat treatment; correct electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue panobinostat.DiarrheaFirst sign of abdominal cramping, loose stools, or onset of diarrheaBegin antidiarrheal medication (eg, loperamide).Grade 2 (moderate diarrhea; 4 to 6 stools per day)Interrupt panobinostat until resolved and then restart at the same dose.Consider interruption of bortezomib until resolved and then restart at the same dose.Grade 3 (severe diarrhea; ≥7 stools per day, IV fluids or hospitalization required)Interrupt panobinostat treatment until resolved and then restart at a reduced dose.Interrupt bortezomib until resolved and then restart at a reduced dose.Grade 4 (life-threatening)Permanently discontinue panobinostat.Permanently discontinue bortezomib.InfectionAnyConsider interrupting or discontinuing panobinostat. Do not initiate panobinostat if active infection is present.SevereDiscontinue panobinostat.Nausea or vomitingSevere nausea (grades 3/4)Interrupt panobinostat treatment until resolved and then restart at a reduced dose.Severe/life-threatening vomiting (grades 3/4)Interrupt panobinostat treatment until resolved and then restart at a reduced dose.Other toxicitiesGrade 3 or 4 toxicity or recurrent grade 2 toxicityWithhold panobinostat treatment until recovery to grade 1 or less and then restart at a reduced dose.Recurrent grade 3 or 4 toxicityWithhold panobinostat treatment until recovery to grade 1 or less and then restart at a reduced dose.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productCapsule, Oral: Farydak: 10 mg [DSC] [contains fd&c blue #1 (brilliant blue)]Farydak: 15 mg [DSC], 20 mg [DSC]Generic Equivalent Available: USNoMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM436377.pdf, must be dispensed with this medication.Administration: AdultOral: Administer at approximately the same time on scheduled days. May administer with or without food. Swallow capsule whole with a cup of water. Do not open, crush, or chew the capsules. Avoid exposure to crushed and/or broken capsules. Avoid direct skin or mucous membrane contact with powder inside the capsules; if contact occurs, wash thoroughly.Hazardous Drugs Handling ConsiderationsHazardous agent (NIOSH 2016 [group 1]).Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).Use: Labeled IndicationsMultiple myeloma, relapsed or refractory: Treatment of multiple myeloma (in combination with bortezomib and dexamethasone) in patients who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.Note: In December 2021, the manufacturer voluntarily withdrew the approval of panobinostat for the treatment of relapsed or refractory multiple myeloma (in combination with bortezomib and dexamethasone) from the US market.Medication Safety IssuesSound-alike/look-alike issues:Panobinostat may be confused with belinostat, palbociclib, pazopanib, ponatinib, tazemetostat, vorinostatHigh alert medication:This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not always defined.>10%:Cardiovascular: Abnormal T waves on ECG (40%), peripheral edema (29%; grades 3/4: 2%), depression of ST segment on ECG (22%), cardiac arrhythmia (12%; grades 3/4: 3%)Central nervous system: Fatigue (≤60%, grades 3/4: ≤25%), lethargy (≤60%; grades 3/4: ≤25%), malaise (≤60%; grades 3/4: ≤25%)Endocrine & metabolic: Hypocalcemia (67%; grades 3/4: 5%), hypoalbuminemia (63%; grades 3/4: 2%), hypophosphatemia (63%; grades 3/4: 20%), hypokalemia (52%; grades 3/4: 18%), hyponatremia (49%; grades 3/4: 13%), hyperphosphatemia (29%; grades 3/4: 2%), hypermagnesemia (27%; grades 3/4: 5%), weight loss (12%; grades 3/4: 2%)Gastrointestinal: Diarrhea (68%; grades 3/4: 25%), nausea (36%; grades 3/4: 6%), decreased appetite (28%; grades 3/4: 3%), vomiting (26%; grades 3/4: 7%)Hematologic & oncologic: Thrombocytopenia (97%; grades 3/4: 67%), lymphocytopenia (82%; grades 3/4: 53%), leukopenia (81%; grades 3/4: 23%), neutropenia (75%; grades 3/4: 34%), anemia (62%; grades 3/4: 18%)Hepatic: Hyperbilirubinemia (21%; grades 3/4: 1%)Infection: Severe infection (31%; includes bacterial, fungal, and viral infections)Neuromuscular & skeletal: Weakness (≤60%; grades ≥3: ≤25%)Renal: Increased serum creatinine (41%; grades 3/4: 1%)Miscellaneous: Fever (26%)1% to 10%:Cardiovascular: Hypertension (>2% to <10%), hypotension (>2% to <10%), orthostatic hypotension (>2% to <10%), palpitations (>2% to <10%), syncope (>2% to <10%), ischemic heart disease (4%), ECG changes, prolonged QT interval on ECGCentral nervous system: Chills (>2% to <10%), dizziness (>2% to <10%), headache (>2% to <10%), insomnia (>2% to <10%)Dermatologic: Cheilitis (>2% to <10%), erythema (>2% to <10%), skin lesion (>2% to <10%), skin rash (>2% to <10%)Endocrine & metabolic: Dehydration (>2% to <10%), fluid retention (>2% to <10%), hyperglycemia (>2% to <10%), hyperuricemia (>2% to <10%), hypomagnesemia (>2% to <10%), hypothyroidism (>2% to <10%)Gastrointestinal: Abdominal distention (>2% to <10%), abdominal pain (>2% to <10%), colitis (>2% to <10%), dysgeusia (>2% to <10%), dyspepsia (>2% to <10%), flatulence (>2% to <10%), gastritis (>2% to <10%), gastrointestinal pain (>2% to <10%), xerostomia (>2% to <10%), gastrointestinal toxicityGenitourinary: Urinary incontinence (>2% to <10%)Hematologic & oncologic: Hemorrhage (grades 3/4: 4%)Hepatic: Hepatitis B (>2% to <10%), increased serum alkaline phosphatase (>2% to <10%), increased serum transaminases, increased serum bilirubinInfection: Sepsis (6%)Neuromuscular & skeletal: Joint swelling (>2% to <10%), tremor (>2% to <10%)Renal: Increased blood urea nitrogen (>2% to <10%), mean glomerular filtration rate decreased (>2% to <10%), renal failure (>2% to <10%)Respiratory: Cough (>2% to <10%), dyspnea (>2% to <10%), rales (>2% to <10%), respiratory failure (>2% to <10%), wheezing (>2% to <10%)ContraindicationsThere are no contraindications listed in the manufacturer’s labeling.Warnings/PrecautionsConcerns related to adverse events:• Bone marrow suppression: Hematologic toxicities, including severe thrombocytopenia, neutropenia, and anemia have occurred. Patients >65 years of age may require more frequent monitoring.• Cardiovascular events: Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred in patients receiving panobinostat. Arrhythmias may be exacerbated by electrolyte abnormalities. ECG abnormalities, including ST-segment depression and T-wave abnormalities, have been observed. Panobinostat may prolong the QT interval. Concomitant use with medications known to prolong the QT interval is not recommended.• GI events: Severe diarrhea occurred in one-fourth of panobinostat-treated patients. Diarrhea (of any grade) was reported in over two-thirds of patients and may occur at any time. Patients should have antidiarrheal medications available for use; begin antidiarrheal medications at the first sign of diarrhea, loose stools, or abdominal cramping. If antiemetics are needed, some antiemetics known to prolong the QT interval (eg, dolasetron, ondansetron) may be used with frequent ECG monitoring.• Hemorrhage: Serious and fatal hemorrhage has occurred, including grade 3 or higher hemorrhage. All patients with hemorrhage also experienced thrombocytopenia at the time of hemorrhage.• Hepatotoxicity: Hepatic dysfunction (transaminase and total bilirubin elevations) has been reported.• Infection: Localized and systemic infections (including pneumonia, bacterial infections, invasive fungal infections, and viral infections) have been observed; infections may be severe (or fatal).Metabolism/Transport EffectsSubstrate of CYP2C19 (minor), CYP2D6 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (weak)Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combinationBaricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib.Risk X: Avoid combinationBCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of BCG Products.Risk X: Avoid combinationBrincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir.Risk C: Monitor therapyCladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine.Risk X: Avoid combinationClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCoccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test.Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modificationConivaptan: May increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with conivaptan. Monitor patient response to therapy closely for evidence of more severe adverse effects related to panobinostat therapy. Risk D: Consider therapy modificationCOVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector).Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modificationCOVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus).Risk C: Monitor therapyCOVID-19 Vaccine (mRNA): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA).Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modificationCOVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit).Risk C: Monitor therapyCOVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles).Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of Panobinostat. Risk X: Avoid combinationCYP3A4 Inhibitors (Moderate): May increase the serum concentration of Panobinostat. Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Monitor patient response to therapy closely for evidence of more severe adverse effects related to panobinostat therapy. Risk D: Consider therapy modificationDengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live).Risk X: Avoid combinationDenosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modificationDesmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin.Risk C: Monitor therapyDeucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combinationDolasetron: May enhance the arrhythmogenic effect of Panobinostat. Risk C: Monitor therapyFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFilgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combinationFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationGranisetron: May enhance the arrhythmogenic effect of Panobinostat. Risk C: Monitor therapyGrapefruit Juice: May increase the serum concentration of Panobinostat. Risk X: Avoid combinationHaloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol.Risk C: Monitor therapyInebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab.Risk C: Monitor therapyInfluenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Influenza Virus Vaccines.Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modificationLeflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide.Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modificationNatalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab.Risk X: Avoid combinationOcrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab.Risk C: Monitor therapyOfatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab.Risk C: Monitor therapyOndansetron: May enhance the arrhythmogenic effect of Panobinostat. Risk C: Monitor therapyPidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod.Risk C: Monitor therapyPimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combinationPneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines.Risk C: Monitor therapyPoliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral).Risk X: Avoid combinationPolymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate.Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modificationPomegranate: May increase the serum concentration of Panobinostat. Risk X: Avoid combinationQT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyRabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine.Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modificationRubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combinationRuxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical).Risk X: Avoid combinationSipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T.Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modificationSphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapyStar Fruit: May increase the serum concentration of Panobinostat. Risk X: Avoid combinationTacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical).Risk X: Avoid combinationTalimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased.Risk X: Avoid combinationTaurursodiol: Histone Deacetylase Inhibitors may enhance the adverse/toxic effect of Taurursodiol.Risk X: Avoid combinationTertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide.Risk X: Avoid combinationThioridazine: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Thioridazine.Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider therapy modificationTofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib.Risk X: Avoid combinationTyphoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Typhoid Vaccine.Risk X: Avoid combinationUpadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib.Risk X: Avoid combinationVaccines (Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating).Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modificationVaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live).Risk X: Avoid combinationYellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Yellow Fever Vaccine.Risk X: Avoid combinationFood InteractionsStar fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice may interfere with panobinostat metabolism. Management: Avoid star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice.Reproductive ConsiderationsVerify pregnancy status prior to use in patients who may become pregnant; pregnancy testing is recommended prior to use and intermittently during panobinostat therapy. Patients who may become pregnant should avoid pregnancy and use an effective contraceptive during therapy and for at least 3 months after the last panobinostat dose. Patients with partners who may become pregnant should use condoms during therapy and for at least 6 months after the last dose of panobinostat.Pregnancy ConsiderationsBased on data from animal reproduction studies, in utero exposure to panobinostat may cause fetal harm.Breastfeeding ConsiderationsIt is not known if panobinostat is present in breast milk.Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the person who is breastfeeding.Dietary ConsiderationsAvoid star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice. Monitoring ParametersCBC with differential and platelets (prior to treatment initiation then weekly or more often if clinically indicated during treatment; monitor more frequently in patients ≥65 years of age); serum electrolytes, including potassium and magnesium prior to treatment and during treatment (in the clinical trial, electrolytes were monitored prior to the start of each cycle, after the fifth panobinostat dose in week 2 through cycle 8 and then at the beginning of cycles 9 to 16); liver function tests at baseline and regularly during treatment. Evaluate pregnancy status in patients who may become pregnant (rule out pregnancy prior to and intermittently during treatment). ECG (prior to treatment initiation and periodically as clinically indicated during treatment); monitor frequently if using concomitant medications known to prolong the QT interval). Monitor hydration status; monitor for gastrointestinal toxicity (eg, diarrhea, nausea, vomiting), signs/symptoms of hemorrhage and/or infection.The American Society of Clinical Oncology hepatitis B virus screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.Mechanism of ActionPanobinostat is a histone deacetylase (HDAC) inhibitor; it inhibits enzymatic activity of HDACs resulting in increased acetylation of histone proteins. Accumulation of acetylated histones and other proteins induces cell cycle arrest and/or apoptosis of some transformed cells. Panobinostat has minimal activity in multiple myeloma as a single-agent; however, synergistic activity is demonstrated when combined with bortezomib and dexamethasone (San-Miguel 2014).Pharmaco*kineticsProtein binding: ~90% to plasma proteins.Metabolism: Extensive via reduction, hydrolysis, oxidation, and glucuronidation; CYP3A accounts for ~40 % of elimination, CYP2D6 and CYP2C19 are minor pathways.Bioavailability: ~21%; AUC is 16% lower (compared with fasting) when administered with a high-fat meal.Half-life elimination: ~37 hours.Time to peak: Within 2 hours.Excretion: Feces (44% to 77%; <4% as unchanged drug); Urine (29% to 51%; <3% as unchanged drug).Clearance: ~160 L/hour.Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: In patients with mild, moderate, and severe renal impairment, the AUC was 64%, 99%, and 59% of the normal renal function group, respectively.Hepatic function impairment: In patients with mild and moderate hepatic impairment, the AUC was increased 43% and 105%, respectively (compared with patients with normal hepatic function).Pricing: USCapsules (Farydak Oral)10 mg (per each): $2,816.5015 mg (per each): $2,816.5020 mg (per each): $2,816.50Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalFarydak (BE, CZ, DE, DK, EE, GB, HR, IE, JP, LT, NL, NO, PL, RO, SE, SI, SK)For country code abbreviations (show table)<800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.Berdeja JG, Gregory TK, Faber EA, et al. A phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma: final analysis of second dose-expansion cohort. Am J Hematol. 2021;9(4):428-435. doi:10.1002/ajh.26088 [PubMed 33421178]Berdeja JG, Hart LL, Mace JR, et al. Phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Haematologica. 2015;100(5):670-676. doi:10.3324/haematol.2014.119735 [PubMed 25710456]Chari A, Cho HJ, Dhadwal A, et al. A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. Blood Adv. 2017;1(19):1575-1583. doi:10.1182/bloodadvances.2017007427 [PubMed 29296798]Farydak (panobinostat) [prescribing information]. Las Vegas, NV: Secura Bio, Inc; September 2019.Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]Krens SD, Lassche G, Jansman FGA, et al. Dose recommendations for anticancer drugs in patients with renal or hepatic impairment. Lancet Oncol. 2019;20(4):e200-e207. doi:10.1016/S1470-2045(19)30145-7 [PubMed 30942181]Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013;122(14):2331-2337. doi:10.1182/blood-2013-01-481325 [PubMed 23950178]San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195-1206. [PubMed 25242045]Sharma S, Witteveen PO, Lolkema MP, et al. A phase I, open-label, multicenter study to evaluate the pharmaco*kinetics and safety of oral panobinostat in patients with advanced solid tumors and varying degrees of renal function. Cancer Chemother Pharmacol. 2015;75(1):87-95. [PubMed 25377157]US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed October 5, 2016.Topic 100045 Version 191.0

CloseAmphotericin B cholesteryl sulfate complex (United States: Not available): Pediatric drug informationAmphotericin B cholesteryl sulfate complex (United States: Not available): Pediatric drug information(For additional information see "Amphotericin B cholesteryl sulfate complex (United States: Not available): Drug information" and see "Amphotericin B cholesteryl sulfate complex (United States: Not available): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Therapeutic CategoryAntifungal Agent, ParenteralDosing: NeonatalNote: Amphotec has been discontinued in the US for more than 1 year.Medication errors, including deaths, have resulted from confusion between lipid-based forms of amphotericin (Abelcet, Amphotec, AmBisome) and conventional amphotericin B for injection. Lipid-based and conventional formulations are not interchangeable and have different dosing recommendations. Overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products.Note: In neonates, lipid formulations of amphotericin have poorer penetration into the central nervous system, kidneys, urinary tract, and eyes than conventional amphotericin and are not preferred in most cases (IDSA [Pappas 2016]; Red Book [AAP 2015]; Turkova 2011).Candidiasis, invasiveCandidiasis, invasive: Limited data available: IV: 3 to 5 mg/kg/dose once daily; treatment should continue for at least 2 weeks after the first negative blood culture and signs and symptoms have resolved (IDSA [Pappas 2016])Dosing: PediatricNote: Amphotec has been discontinued in the US for more than 1 year.Medication errors, including deaths, have resulted from confusion between lipid-based forms of amphotericin (Abelcet, Amphotec, AmBisome) and conventional amphotericin B for injection. Lipid-based and conventional formulations are not interchangeable and have different dosing recommendations. Overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products.Note: Premedication for patients who experience fever, chills, hypotension, nausea, or other nonanaphylactic infusion-related immediate reactions may be given 30 to 60 minutes prior to drug administration: NSAIDs (with or without diphenhydramine) or acetaminophen with diphenhydramine or hydrocortisone may be given (Paterson 2008); if patient experiences rigors during infusion, meperidine may be administered. The manufacturer’s labeling advises a test dose be administered immediately preceding the first dose when a new course of treatment occurs. A small amount of drug (eg, 10 mL of final preparation containing between 1.6 and 8.3 mg of drug) should be infused over 15 to 30 minutes and patient should be carefully observed for the next 30 minutes.Aspergillosis, treatmentAspergillosis, treatment:Invasive: Infants, Children, and Adolescents: IV: Usual dose range: 3 to 4 mg/kg/dose once daily; doses as high as 7.5 mg/kg/dose have been described in open label studies (Sandler 2000)Endocarditis: Children and Adolescents: IV: 3 to 5 mg/kg/dose once daily with or without flucytosine (AHA [Baltimore 2015])Candidiasis, treatmentCandidiasis, treatment: Infants, Children, and Adolescents:Invasive: IV: 3 to 5 mg/kg/dose once daily (IDSA [Pappas 2016])Endocarditis: Infants, Children, and Adolescents: IV: 3 to 5 mg/kg/dose once daily with or without flucytosine (AHA [Baltimore 2015]; IDSA [Pappas 2016])Esophageal, HIV-exposed/-infected: Adolescents: IV: 3 to 4 mg/kg/dose once daily for 14 to 21 days (HHS [OI adult 2016])Coccidiodomycosis, disseminated or diffuse pulmonary diseaseCoccidiodomycosis, disseminated (non-CNS) or diffuse pulmonary disease: HIV-exposed/-infected:Infants and Children: IV: 5 mg/kg/dose once daily until clinical improvement; dose may be increased as high as 10 mg/kg/dose once daily for life-threatening infection (HHS [OI pediatric 2013])Adolescents: IV: 3 to 5 mg/kg/dose once daily until clinical improvement, then change to fluconazole or itraconazole (HHS [OI adult 2016])Histoplasmosis, disseminated diseaseHistoplasmosis, disseminated disease (moderately severe to severe): HIV-exposed/-infected: Adolescents: IV: 3 mg/kg/dose once daily for at least 2 week induction, followed by oral itraconazole (HHS [OI adult 2016])Dosing: Kidney Impairment: PediatricMild to moderate impairment: There are no dosage adjustments provided in manufacturer's labeling; however, no pharmaco*kinetic changes were noted in patients with mild to moderate impairment.Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Hepatic Impairment: PediatricMild to moderate impairment: There are no dosage adjustments provided in manufacturer's labeling; however, no pharmaco*kinetic changes were noted in patients with mild to moderate impairment.Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Adult(For additional information see "Amphotericin B cholesteryl sulfate complex (United States: Not available): Drug information")Note: Amphotec has been discontinued in the US for more than 1 year.Note: Lipid-based amphotericin formulations (Amphotec) may be confused with conventional formulations (desoxycholate [Amphocin, Fungizone]). Lipid-based and conventional formulations are not interchangeable and have different dosing recommendations. Overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products.Aspergillosis, treatmentAspergillosis (invasive), treatment: Usual dosage range: 3 to 4 mg/kg/day. Note: 6 mg/kg/day has been used for treatment of life-threatening invasive aspergillosis in immunocompromised patients (Bowden, 2002).Premedication: For patients who experience chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related immediate reactions, premedicate with the following drugs 30 to 60 minutes prior to drug administration: A nonsteroidal with or without diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone 50 to 100 mg with or without a nonsteroidal and diphenhydramine (Paterson, 2008).Test dose: For patients receiving their first dose in a new treatment course, a small amount (10 mL of the final preparation, containing between 1.6 to 8.3 mg) infused over 15 to 30 minutes is recommended. The patient should then be observed for an additional 30 minutes.Dosing: Kidney Impairment: AdultMild to moderate impairment: No dosage adjustment provided in manufacturer’s labeling. However, no pharmaco*kinetic changes were noted in patients with mild-to-moderate impairment.Severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied).Dosing: Hepatic Impairment: AdultNo dosage adjustment provided in manufacturer’s labeling (has not been studied).Generic Equivalent Available: USMay be product dependentProduct AvailabilityAmphotec has been discontinued in the US for more than 1 year.Administration: PediatricParenteral: IV: Do not filter or use an inline filter for administration. Flush line with D5W prior to and following infusion.Initially infuse diluted solution at 1 mg/kg/hour. Rate of infusion may be increased with subsequent doses as patient tolerance allows (minimum infusion time: 2 hours). If utilizing test dose as recommended by the manufacturer’s labeling, infuse over 15 to 30 minutes.Administration: AdultIV: Initially infuse at 1 mg/kg/hour. Rate of infusion may be increased with subsequent doses as patient tolerance allows (minimum infusion time: 2 hours). For a patient who experiences chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related reactions, premedicate with the following drugs 30-60 minutes prior to drug administration: A nonsteroidal with or without diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone 50-100 mg with or without a nonsteroidal and diphenhydramine (Paterson, 2008). If the patient experiences rigors during the infusion, meperidine may be administered. If severe respiratory distress occurs, the infusion should be immediately discontinued.Storage/StabilityStore intact vials at 15°C to 30°C (59°F to 86°F). After reconstitution, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F) and used within 24 hours. Concentrations of 0.1-2 mg/mL in D5W are stable for 24 hours at 2°C to 8°C (36°F to 46°F).UseTreatment of invasive aspergillosis in patients who have failed amphotericin B deoxycholate treatment, or who have renal impairment or unacceptable toxicity which precludes treatment with amphotericin B deoxycholate in effective doses (FDA approved in pediatric patients [age not specified] and adults); has also been used for treatment of candidiasis, coccidiodomycosis, and histoplasmosisMedication Safety IssuesHigh alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.Other safety concerns:Lipid-based amphotericin formulations (Amphotec) may be confused with conventional formulations (Amphocin, Fungizone) Large overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products. Single daily doses of conventional amphotericin formulation never exceed 1.5 mg/kg.Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Amphotericin B colloidal dispersion has an improved therapeutic index compared to conventional amphotericin B, and has been used safely in patients with amphotericin B-related nephrotoxicity; however, continued decline of renal function has occurred in some patients.>10%:Cardiovascular: Hypotension, tachycardiaCentral nervous system: ChillsEndocrine & metabolic: HypokalemiaGastrointestinal: VomitingHepatic: HyperbilirubinemiaRenal: Increased serum creatinineMiscellaneous: Fever5% to 10%:Cardiovascular: Chest pain, facial edema, hypertensionCentral nervous system: Abnormality in thinking, drowsiness, headache, insomniaDermatologic: Diaphoresis, pruritus, skin rashEndocrine & metabolic: Hyperglycemia, hypocalcemia, hypomagnesemia, hypophosphatemiaGastrointestinal: Abdominal pain, diarrhea, enlargement of abdomen, hematemesis, nausea, stomatitis, xerostomiaHematologic & oncologic: Anemia, hemorrhage, thrombocytopeniaHepatic: Abnormal hepatic function tests, increased serum alkaline phosphatase, jaundiceNeuromuscular & skeletal: Back pain, muscle rigidity, tremorRespiratory: Dyspnea, epistaxis, hypoxia, increased cough, rhinitis<5%, postmarketing, and/or case reports: Acidosis, atrial arrhythmia, cardiac arrest, cardiac failure, gastrointestinal hemorrhage, hepatic failure, injection site reaction, oliguria, pain at injection site, pleural effusion, renal failure, seizure, syncope, ventricular arrhythmiaContraindicationsHypersensitivity to amphotericin B or any component of the formulation (unless the benefits outweigh the possible risk to the patient)Warnings/PrecautionsConcerns related to adverse effects:• Anaphylaxis: Has been reported with amphotericin B-containing drugs; facilities for cardiopulmonary resuscitation should be available during administration due to the possibility of anaphylactic reaction. If severe respiratory distress occurs, the infusion should be immediately discontinued; the patient should not receive further infusions. During the initial dosing, the drug should be administered under close clinical observation.• Infusion reactions: Acute infusion reactions, sometimes severe, may occur 1-3 hours after starting infusion. These reactions are usually more common with the first few doses and generally diminish with subsequent doses. Pretreatment with antihistamines/corticosteroids and/or decreasing the rate of infusion can be used to manage reactions. Avoid rapid infusion.Disease-related concerns:• Heart failure: In a scientific statement from the American Heart Association, amphotericin has been determined to be an agent that may cause direct myocardial toxicity (magnitude: moderate/major) (AHA [Page 2016]).Warnings: Additional Pediatric ConsiderationsIn a multicenter study of pediatric patients (<16 years of age), amphotericin B cholestyrel sulfate complex (ABCD) use had a significantly lower incidence of renal toxicity (12%; 3/25 patients) than amphotericin B deoxycholate (52%; 11/21 patients).Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAlfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyAmifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine.Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modificationAminoglycosides: Amphotericin B may enhance the nephrotoxic effect of Aminoglycosides. Amphotericin B may enhance the neurotoxic effect of Aminoglycosides.Risk C: Monitor therapyAmisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapyAntifungal Agents (Azole Derivatives, Systemic): May diminish the therapeutic effect of Amphotericin B. Risk C: Monitor therapyAntipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]).Risk C: Monitor therapyArsenic Trioxide: Amphotericin B may enhance the hypotensive effect of Arsenic Trioxide. Amphotericin B may enhance the QTc-prolonging effect of Arsenic Trioxide.Management: When possible, avoid concurrent use of arsenic trioxide with drugs that can cause electrolyte abnormalities, such as amphotericin B. Risk D: Consider therapy modificationBarbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyBenperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyBlood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapyBrimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyBromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combinationCardiac Glycosides: Amphotericin B may enhance the adverse/toxic effect of Cardiac Glycosides.Risk C: Monitor therapyColistimethate: Amphotericin B may enhance the nephrotoxic effect of Colistimethate.Management: Avoid coadministration of colistimethate and amphotericin B whenever possible due to the potential for additive or synergistic nephrotoxicity. If coadministration cannot be avoided, closely monitor renal function. Risk D: Consider therapy modificationCorticosteroids (Systemic): May enhance the hypokalemic effect of Amphotericin B. Risk C: Monitor therapyCycloSPORINE (Systemic): Amphotericin B may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Amphotericin B may increase the serum concentration of CycloSPORINE (Systemic).Risk C: Monitor therapyDiazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyDichlorphenamide: Amphotericin B may enhance the hypokalemic effect of Dichlorphenamide.Risk C: Monitor therapyDronabinol: May increase the serum concentration of Amphotericin B. Specifically, dronabinol may displace amphotericin B from its protein-binding sites, leading to an increased concentration of active, unbound drug. Risk C: Monitor therapyDULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine.Risk C: Monitor therapyFlucytosine: Amphotericin B may enhance the adverse/toxic effect of Flucytosine. Amphotericin B may increase the serum concentration of Flucytosine.Risk C: Monitor therapyFoscarnet: May enhance the nephrotoxic effect of Amphotericin B. Risk X: Avoid combinationGanciclovir-Valganciclovir: May enhance the nephrotoxic effect of Amphotericin B. Risk C: Monitor therapyHerbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyHypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents.Risk C: Monitor therapyLevodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products.Risk C: Monitor therapyLormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyMethoxyflurane: May enhance the nephrotoxic effect of Amphotericin B. Risk X: Avoid combinationMolsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyNaftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyNicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyNicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyNitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside.Risk C: Monitor therapyObinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modificationPentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyPholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine.Risk C: Monitor therapyPhosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyProstacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapyQuinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapySaccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii.Risk X: Avoid combinationPregnancy ConsiderationsAmphotericin crosses the placenta and enters the fetal circulation. Amphotericin B is recommended for the treatment of serious systemic fungal diseases in pregnant women; refer to current guidelines (IDSA [Pappas 2016]; King 1998; Pilmis 2015).Monitoring ParametersLiver function tests, electrolytes, BUN, Cr, vital signs, CBC, I & O, prothrombin time, signs of hypokalemia (muscle weakness, cramping, drowsiness, ECG changes)Mechanism of ActionBinds to ergosterol altering cell membrane permeability in susceptible fungi and causing leakage of cell components with subsequent cell death. Proposed mechanism suggests that amphotericin causes an oxidation-dependent stimulation of macrophages (Lyman, 1992).Pharmaco*kinetics (Adult data unless noted)Distribution: Vd: Total volume increases with higher doses, reflects increasing uptake by tissues (with 4 mg/kg/day = 4 L/kg); predominantly distributed in the liver; concentrations in kidneys and other tissues are lower than observed with conventional amphotericin B (Walsh 2008)Half-life elimination: ~28 hours; prolonged with higher dosesAdditional InformationThe lipid portion of amphotericin B cholesteryl sulfate complex formulation does not contain phospholipids; for patients receiving parenteral nutrition, adjustment to the amount of lipids should not be needed (Sacks 1997).Pricing: USSuspension (reconstituted) (Amphotec Intravenous)50 mg (1): $93.33100 mg (1): $160.00Disclaimer: The pricing data provide a representative AWP and/or AAWP price from a single manufacturer of the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for reimbursem*nt or purchasing functions. Pricing data is updated monthly.Brand Names: InternationalAmphocil (AU, DK, HK, HN, HU, IT, MX, MY, SI, TH, TW)For country abbreviations used in Lexicomp (show table)American Academy of Pediatrics (AAP). In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.Amphotec (amphotericin b cholesteryl sulfate complex) [prescribing information]. Bedford, OH: Ben Venue Laboratories, Inc; July 2005.Baltimore RS, Gewitz M, Baddour LM, et al. Infective endocarditis in childhood: 2015 update: A scientific statement from the American Heart Association. Circulation. 2015;132(15):1487-1515. [PubMed 26373317]Bowden R, Chandrasekar P, White MH, et al, “A Double-Blind, Randomized, Controlled Trial of Amphotericin B Colloidal Dispersion versus Amphotericin B for Treatment of Invasive Aspergillosis in Immunocompromised Patients,” Clin Infect Dis, 2002, 35(4):359-66. [PubMed 12145716]Chapman SW, Dismukes WE, Proia LA, et al, "Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America," Clin Infect Dis, 2008, 46(12):1801-12. [PubMed 18462107]Edwards JE Jr, Bodey GP, Bowden RA, et al, “International Conference for the Development of a Consensus on the Management and Prevention of Severe Candidal Infections,” Clin Infect Dis, 1997, 25(1):43-59. [PubMed 9243032]Eggimann P, Francioli P, Bille J, et al, “Fluconazole Prophylaxis Prevents Intra-abdominal Candidiasis in High-Risk Surgical Patients,” Crit Care Med, 1999, 27(6):1066-72. [PubMed 10397206]Fichtenbaum CJ, Zackin R, Rajicic N, et al, “Amphotericin B Oral Suspension for Fluconazole-Refractory Oral Candidiasis in Persons With HIV Infection. Adult AIDS Clinical Trials Group Study Team 295,” AIDS, 2000, 14(7):845-52. [PubMed 10839593]HHS. Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. November 6, 2013. Available at http://aidsinfo.nih.govHiemenz JW and Walsh TJ, “Lipid Formulations of Amphotericin B: Recent Progress and Future Directions,” Clin Infect Dis, 1996, 22(Suppl 2):133-44. [PubMed 8824978]Kauffman CA, Bustamante B, Chapman SW, et al, "Clinical Practice Guidelines for the Management of Sporotrichosis: 2007 Update by the Infectious Diseases Society of America," Clin Infect Dis, 2007, 45(10):1255-65. [PubMed 17968818]King CT, Rogers PD, Cleary JD, et al, "Antifungal Therapy During Pregnancy," Clin Infect Dis, 1998, 27(5):1151-60. [PubMed 9827262]Linder N, Klinger G, Shalit I, et al. Treatment of candidaemia in premature infants: comparison of three amphotericin B preparations. J Antimicrob Chemother. 2003;52(4):663-667. [PubMed 12972450]Lister J, “Amphotericin B Lipid Complex (Abelcet®) in the Treatment of Invasive Mycoses: The North American Experience,” Eur J Haematol Suppl, 1996, 57:18-23. [PubMed 8706812]Lyman CA and Walsh TJ, “Systemically Administered Antifungal Agents. A Review of Their Clinical Pharmacology and Therapeutic Applications,” Drugs, 1992, 44(1):9-35. [PubMed 1379913]Mactal-Haaf C, Hoffman M, and Kuchta A, "Use of Anti-infective Agents During Lactation, Part 3: Antivirals, Antifungals, and Urinary Antiseptics," J Hum Lact, 2001, 17(2):160-6. [PubMed 11847833]Mora-Duarte J, Betts R, Rotstein C, et al, “Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis,” N Engl J Med, 2002, 347(25):2020-9. [PubMed 12490683]Page RL 2nd, O'Bryant CL, Cheng D, et al; American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association [published correction appears in Circulation. 2016;134(12):e261]. Circulation. 2016;134(6):e32-e69. [PubMed 27400984]Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50. doi: 10.1093/cid/civ933. [PubMed 26679628]10.1093/cid/civ933Patel R, “Antifungal Agents. Part I. Amphotericin B Preparations and Flucytosine,” Mayo Clin Proc, 1998, 73(12):1205-25. [PubMed 9868423]Paterson DL, David K, Mrsic M, et al, “Pre-medication Practices and Incidence of Infusion-related Reactions in Patients Receiving AMPHOTEC®: Data from the Patients Registry of Amphotericin B Cholesteryl Sulfate Complex for Injection Clinical Tolerability (PRoACT) Registry,” J Antimicrob Chemother, 2008, 62(6):1392-1400. [PubMed 18812423]Perfect JR, Dismukes WE, Dromer F, et al, "Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America," Clin Infect Dis, 2010, 50(3):291-322. [PubMed 20047480]Pilmis B, Jullien V, Sobel J, et al. Antifungal drugs during pregnancy: an updated review. J Antimicrob Chemother. 2015;70(1):14-22. doi: 10.1093/jac/dku355. [PubMed 25204341]10.1093/jac/dku355Prentice HG, Hann IM, Herbrecht R, et al, “A Randomized Comparison of Liposomal Versus Conventional Amphotericin B for the Treatment of Pyrexia of Unknown Origin in Neutropenic Patients,” Br J Haematol, 1997, 98(3):711-8. [PubMed 9332329]Rex JH, Bennett JE, and Sugar AM, “A Randomized Trial Comparing Fluconazole With Amphotericin B for the Treatment of Candidemia in Patients Without Neutropenia. Candidemia Study Group and the National Institute,” N Engl J Med, 1994, 331(20):1325-30. [PubMed 7935701]Rex JH, Pappas PG, Karchmer AW, et al, “A Randomized and Blinded Multicenter Trial of High-Dose Fluconazole Plus Placebo Versus Fluconazole Plus Amphotericin B as Therapy for Candidemia and Its Consequences in Nonneutropenic Subjects,” Clin Infect Dis, 2003, 36(10):1221-8. [PubMed 12746765]Sacks GS, Cleary JD. Nutritional impact of lipid-associated amphotericin B formulations. Ann Pharmacother. 1997;31(1):121-122. [PubMed 8997484]Sandler ES, Mustafa MM, Tkaczewski I, et al. Use of amphotericin B colloidal dispersion in children. J Pediatr Hematol Oncol. 2000;22(3):242-246. [PubMed 10864055]Slain D, “Lipid-Based Amphotericin B for the Treatment of Fungal Infections,” Pharmacotherapy, 1999, 19(3):306-23. [PubMed 10221369]Turkova A, Roilides E, Sharland M. Amphotericin B in neonates: deoxycholate or lipid formulation as first-line therapy - is there a 'right' choice? Curr Opin Infect Dis. 2011;24(2):163-171. [PubMed 21301335]Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327-360.Wheat LJ, Freifeld AG, Kleiman MB, et al, "Clinical Practice Guidelines for the Management of Patients With Histoplasmosis: 2007 Update by the Infectious Diseases Society of America," Clin Infect Dis, 2007, 45(7):807-25. [PubMed 17806045]Topic 100046 Version 103.0

Monitoring is an essential component of’ anesthesia care. Anesthesia clinicians must monitor patient physiologic variables and anesthesia equipment during all types of anesthesia, as anesthesia and surgery can cause rapid changes in vital functions. Patient and equipment monitoring is used to titrat

Peripheral nerve blocks of the upper extremity are used for operative anesthesia and/or postoperative analgesia for a variety of upper extremity surgeries.This topic will discuss the innervation of the upper extremity, techniques and drugs used for upper extremity nerve blocks, and complications spe

CloseTopotecan: Drug informationTopotecan: Drug information(For additional information see "Topotecan: Patient drug information" and see "Topotecan: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningBone marrow suppression:Topotecan can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of ≥1,500/mm3 and a platelet count of ≥100,000/mm3. Monitor blood cell counts.Brand Names: USHycamtinBrand Names: CanadaHycamtin [DSC];TEVA-TopotecanPharmacologic CategoryAntineoplastic Agent, Camptothecin;Antineoplastic Agent, Topoisomerase I InhibitorDosing: AdultNote: Baseline neutrophil count should be ≥1,500/mm3 and platelets should be ≥100,000/mm3 prior to treatment; for re-treatment, neutrophil count should be >1,000/mm3; platelets >100,000/mm3 and hemoglobin ≥9 g/dL. IV doses should generally not exceed 4 mg; verify dose prior to administration.Cervical cancer, recurrent or persistentCervical cancer, recurrent or persistent: IV: 0.75 mg/m2/day for 3 days (days 1, 2, and 3; in combination with cisplatin on day 1 only [with hydration]) every 21 days for a maximum of 6 cycles (in nonresponders) or until disease progression or unacceptable toxicity (Long 2005).CNS malignancy, relapsed/refractoryCNS malignancy, relapsed/refractory (off-label use; based on limited data): Adults ≤21 years of age: Oral: 0.8 mg/m2/day for 21 consecutive days every 4 weeks for ≥12 cycles (Minturn 2011).Ewing sarcoma, relapsed/refractory or metastaticEwing sarcoma, relapsed/refractory or metastatic (off-label use): IV: 0.75 mg/m2/day for 5 consecutive days every 21 days (in combination with cyclophosphamide) (Hunold 2006; Saylors 2001).Myelodysplastic syndromes, high-riskMyelodysplastic syndromes, high-risk (off-label use; based on limited data): IV: Induction: 1.25 mg/m2/day as a continuous infusion for 5 days (in combination with cytarabine) (Kantarjian 2006a).Ovarian cancer, metastaticOvarian cancer, metastatic: IV: 1.5 mg/m2/day for 5 consecutive days every 21 days, continue until disease progression or unacceptable toxicity (ten Bokkel Huinink 2004) or (off-label dosing) 1.25 mg/m2/day for 5 days every 21 days until disease progression or unacceptable toxicity or a maximum of 12 months (Sehouli 2011) or (weekly administration; off-label dosing) 4 mg/m2 on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity or a maximum of 12 months (Sehouli 2011).Primary CNS lymphoma, relapsed or refractoryPrimary CNS lymphoma, relapsed or refractory (off-label use; based on limited data): IV: 1.5 mg/m2 for 5 days every 21 days for a maximum of 10 cycles or until disease progression or unacceptable toxicity (Voloschin 2008).Rhabdomyosarcoma, metastaticRhabdomyosarcoma, metastatic (off-label use): Adults <21 years of age: IV: 0.75 mg/m2/day for 5 consecutive days every 21 days for 2 cycles (window therapy; in combination with cyclophosphamide); if objective response occurred by week 6, follow with alternating cycles of vincristine, topotecan, and cyclophosphamide (VTC) with vincristine, dactinomycin, and cyclophosphamide (VAC) (Walterhouse 2004).Small cell lung cancer, relapsed or progressiveSmall cell lung cancer, relapsed or progressive:IV: 1.5 mg/m2/day for 5 consecutive days every 21 days.Oral: 2.3 mg/m2/day for 5 consecutive days (days 1 to 5) every 21 days for at least 4 cycles (O'Brien 2006); round dose to the nearest 0.25 mg; if patient vomits after dose is administered, do not give a replacement dose.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultManufacturer's labeling (calculate CrCl with co*ckcroft-Gault method using ideal body weight):IV (single agent topotecan):CrCl ≥40 mL/minute: No dosage adjustment necessary.CrCl 20 to 39 mL/minute: Reduce dose to 0.75 mg/m2/doseCrCl <20 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (insufficient data available for dosing recommendation).IV (when used in combination with cisplatin): There are no dosage adjustments provided in the manufacturer's labeling.Oral:CrCl ≥50 mL/minute: No dosage adjustment necessary.CrCl 30 to 49 mL/minute: Reduce dose to 1.5 mg/m2/dose.CrCl <30 mL/minute: Reduce dose to 0.6 mg/m2/dose.The following adjustments have also been recommended (for IV topotecan):Kintzel 1995:CrCl 46 to 60 mL/minute: Administer 80% of usual dose.CrCl 31 to 45 mL/minute: Administer 75% of usual dose.CrCl ≤30 mL/minute: Administer 70% of usual dose.O’Reilly 1996b:CrCl ≥40 mL/minute: No dosage adjustment necessary in minimally pretreated patients; however, due to an increased potential for dose-limiting toxicities, reduce the dose from 1.5 mg/m2 to 1 mg/m2 in heavily pretreated patients.CrCl 20 to 39 mL/minute: Reduce dose from 1.5 mg/m2 to 0.75 mg/m2 in minimally pretreated patients or to 0.5 mg/m2 in heavily pretreated patientsCrCl <20 mL/minute: Data was insufficient (too few patients) to make a recommendation.Hemodialysis: Avoid use (Aronoff 2007).Continuous ambulatory peritoneal dialysis (CAPD): Avoid use (Aronoff 2007).Continuous renal replacement therapy (CRRT): 0.75 mg/m2 (Aronoff 2007)Dosing: Hepatic Impairment: AdultIV: There are no dosage adjustments provided in the manufacturer's labeling. A small phase I study in patients with hepatic impairment (total bilirubin >1.2 mg/dL), found no pharmaco*kinetic or pharmacodynamic alterations and suggests that dosage adjustment is not likely necessary (O’Reilly 1996a).Oral: There is no dosage adjustment provided in the manufacturer's labeling.Dosing: Pediatric(For additional information see "Topotecan: Pediatric drug information")Note: In adults, baseline neutrophil count should be ≥1,500/mm3 and platelets should be ≥100,000/mm3 prior to treatment; for retreatment, neutrophil count should be >1,000/mm3, platelets >100,000/mm3, and hemoglobin ≥9 g/dL; consult individual pediatric protocols for details regarding baseline neutrophil and platelet counts and hemoglobin. Dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol. In pediatric patients, dosing may be based on either BSA (mg/m2) or weight (mg/kg); use extra precaution to verify dosing parameters during calculations. Oral topotecan is associated with a moderate emetic potential (depending on the dose) in pediatrics; antiemetics may be recommended to prevent nausea and vomiting (POGO [Paw Cho Sing 2019]).Acute leukemias, relapsed or refractoryAcute leukemias (acute lymphocytic leukemia or acute myeloid leukemia), relapsed or refractory: Limited data available: TVTC regimen:Infants: IV: 0.03 mg/kg/day as a continuous infusion on days 0 to 4 (120 hours total) of a 14-day treatment protocol (in combination with thiotepa, clofarabine, vinorelbine, and intrathecal cytarabine). Patients without disease progression or significant toxicity may receive additional cycles upon hematologic recovery until hematopoietic stem cell transplant (HSCT) is available (Steinherz 2010).Children and Adolescents: IV: 1 mg/m2/day as a continuous infusion on days 0 to 4 (120 hours total) of a 14-day treatment protocol (in combination with thiotepa, clofarabine, vinorelbine, and intrathecal cytarabine). Patients without disease progression or significant toxicity may receive additional cycles upon hematologic recovery until HSCT is available (Shukla 2014; Steinherz 2010).Acute lymphoblastic leukemia; recurrentAcute lymphoblastic leukemia; recurrent (first relapse): Limited data available: Children and Adolescents: Induction therapy: IV: 2.4 mg/m2/dose once daily for 7 to 9 days (Furman 2002; Hijiya 2008).CNS malignancies, including gliomasCNS malignancies, including gliomas: Limited data available:Fixed dosing: Infants, Children, and Adolescents: Oral (using reconstituted lyophilized parenteral formulation): 0.8 mg/m2/dose once daily for 21 days of a 28-day cycle was used in 25 pediatric patients (median age: 9.2 years; range: 0.8 to 23 years) with recurrent brain tumors, including gliomas, medulloblastoma, and ependymoma; the reported median number of cycles: 1.9 [range: 0.5 to 15 cycles (months)] (Minturn 2011).Dose escalation: Children ≥3 years and Adolescents: Oral (using reconstituted lyophilized parenteral formulation): Initial: 0.4 mg/m2/dose once daily was used in a trial of 32 pediatric patients (median age: 9.5 years; range: 3 to 18 years) with recurrent or progression of high-grade glioma; dosage was increased based upon patient tolerance and individual dose-limiting toxicity; doses were increased in 0.2 mg/m2 increments at weekly intervals for the first 2 weeks of therapy and then increased in 0.1 mg/m2 increments at weekly intervals up to the maximum dose of 2 mg/m2/day; once the patient's maximum tolerated dose was reached, the daily dose was decreased until toxicity became acceptable; reported final median maximum tolerated dose: 0.9 mg/m2/day (range: 0.6 to 2 mg/m2/day); median duration of therapy: 3 months (range: 21 days to 1 year) (Wagner 2004).Hematopoietic stem-cell transplant for neuroblastoma; autologous, conditioning regimenHematopoietic stem-cell transplant for neuroblastoma; autologous, conditioning regimen: Limited data available:Children and Adolescents: IV: 2 mg/m2/dose on days −8 through −4 prior to stem cell transfusion (total dose: 10 mg/m2), in combination with carboplatin and thiotepa, was used in 21 patients (median age: 4.1 years; range: 1 to 29 years) with refractory solid tumors (neuroblastoma: n=11) (Kushner 2001). In a phase 1/2 trial of 51 patients (median age: 5.1 years; range: 1.5 to 21 years), an initial dose of: 3 mg/m2/dose on day −11 was used with subsequent doses (days −10 through −2; 10 days total of topotecan therapy) determined by pharmaco*kinetic analysis (target AUC: 100 ± 20 ng/mL/hour) and administered once daily (in combination with cyclophosphamide on days −6 through −2); the median reported topotecan dose was 3.1 mg/m2/day (range: 1.1 to 4.6 mg/m2/day) (Kasow 2012).NeuroblastomaNeuroblastoma: Limited data available:Induction: Infants, Children, and Adolescents:Patient weight ≤12 kg: IV: Initial: 0.04 mg/kg/dose once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days for 2 cycles (Park 2011).Patient weight >12 kg: IV: Initial: 1.2 mg/m2/dose once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days for 2 cycles (Park 2011).Note: Pharmaco*kinetic analysis was used to guide topotecan therapy during the first 2 cycles using a target AUC: 50 to 70 ng/mL/hour; median dose for cycle 1 was 1.2 mg/m2/day (range: 0.75 to 2.1 mg/m2/day) and for cycle 2, the median dose was 1.3 mg/m2/day (range: 1.2 to 2.9 mg/m2/day) (Park 2011).Untreated metastatic disease:Monotherapy (window therapy): Children and Adolescents: IV: 2 mg/m2/dose once daily for 5 days; repeat cycle every 21 days for 2 cycles (Kretschmar 2004).Topotecan and cyclophosphamide regimen (window therapy): Children and Adolescents: IV: 0.75 mg/m2/dose once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days for 2 cycles (Kretschmar 2004).Recurrent or refractory:IV:Monotherapy: Children and Adolescents: IV: 2 mg/m2/dose once daily for 5 days (London 2010).Topotecan and cyclophosphamide regimen: Children and Adolescents:Patient weight ≤12 kg: IV: 0.025 mg/kg/dose once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days (Ashraf 2013; Morgenstern 2015).Patient weight >12 kg: IV: 0.75 mg/m2/dose once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days (Ashraf 2013; London 2010; Saylors 2001).Topotecan and etoposide regimen: Children and Adolescents: IV: 1 mg/m2/dose once daily on days 1 to 5 of a 28-day cycle (in combination with etoposide) or 1 mg/m2/day as a continuous infusion for days 1 to 7 (168 hour total infusion) of a 28-day cycle (in combination with etoposide) (Simon 2007).Topotecan/Vincristine/High-Dose Cyclophosphamide regimen (HD-CTV): Children and Adolescents: IV: 2 mg/m2/dose once daily on days 1 to 4 (total dose per cycle: 8 mg/m2) (in combination with cyclophosphamide and vincristine); in the trial, some patients received 2 courses (Kushner 2010).Oral (using reconstituted lyophilized parenteral formulation): Children ≥2 years and Adolescents: 0.8 mg/m2/dose once daily for 14 days (in combination with oral cyclophosphamide); repeat cycle every 21 to 28 days (Bowers 2004). In a phase 1 dose escalation trial of 20 pediatric patients (median age: 10.6 years) with refractory solid tumors including neuroblastoma, patients received a daily dose of 1.8 mg/m2 once daily for 5 days, followed by 2 days of rest, then another 5 days of therapy (one cycle: 10 doses over 12 days); repeating this cycle every 28 days was shown to stabilize disease in some patients (Daw 2004).Pediatric solid tumors; recurrent or refractory or untreated metastatic including rhabdomyosarcoma and Ewing sarcomaPediatric solid tumors; recurrent or refractory or untreated metastatic including rhabdomyosarcoma and Ewing sarcoma: Limited data available:IV:Monotherapy: (window therapy): Children and Adolescents: IV: 2 to 2.4 mg/m2/dose once daily for 5 days every 21 days; dosing from an uncontrolled study in which patients (n=48) received topotecan as initial therapy, prior to other treatment (Pappo 2001).Combination therapy: Children and Adolescents: IV: 0.75 mg/m2/dose once daily for 5 days every 21 days in combination with cyclophosphamide (Bernstein 2006; Hunold 2006; Saylors 2001; Walterhouse 2004) or with cyclophosphamide and vincristine (VTC regimen) (Pappo 2001); this dosing has also been administered in combination with temozolomide in 28-day cycles (TOTEM regimen) (Rubie 2010).Oral (using reconstituted lyophilized parenteral formulation or oral capsules [for patients able to swallow]): Note: When using oral capsules, doses were rounded to the nearest 0.25 mg:Monotherapy: Children ≥3 years and Adolescents: Oral: 1.8 mg/m2 once daily for 5 days, followed by 2 days of rest, then another 5 days of therapy (10 doses over 12 days [days 1 to 5 and days 8 to 12]) of a 28-day cycle; repeat cycle every 28 days; dosing based on a phase 1 dose escalation trial of 20 pediatric patients (median age: 10.6 years) with refractory solid tumors (Daw 2004).Combination therapy: Children ≥3 years and Adolescents: Oral: 1.4 mg/m2 once daily for 5 days, followed by 2 days of rest, then another 5 days of therapy (10 doses over 12 days [days 1 to 5 and days 8 to 12]) of a 28-day cycle (in combination with sorafenib). Combination dosing based on a phase 1 dose escalation trial of 12 pediatric patients (median age: 13 years [range: 8 to 18 years]) with relapsed or refractory solid tumors; number of cycles received ranged from 1 to 8 (Reed 2016).Solid tumors with leptomeningeal metastases, recurrent/refractorySolid tumors with leptomeningeal metastases (including neuroblastoma, leukemia, CNS tumors), recurrent/refractory: Limited data available:Intraventricular/Intra-Ommaya:Blaney 2013: Children ≥3 years and Adolescents: 0.2 mg daily for 5 days (with dexamethasone); repeat every other week for 2 courses for induction, every 3 weeks for 2 courses for consolidation, then every 4 weeks for up to 11 courses for maintenance.Groves 2008: Children ≥5 years and Adolescents: 0.4 mg twice weekly for 6 weeks (12 doses), then twice monthly for 4 months, then monthly thereafter until disease progression or unacceptable toxicity.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.Adults:Withhold subsequent cycles until neutrophils recover to >1,000/mm3, platelets recover to >100,000/mm3, and hemoglobin recovers to ≥9 g/dL (with transfusion if necessary).Combination therapy with cisplatin (cisplatin may also require dosage adjustment): IV:Febrile neutropenia (neutrophils <1,000/mm3 with temperature of ≥38°C): Reduce topotecan to 0.6 mg/m2/day for subsequent cycles or administer granulocyte-colony stimulating factor (G-CSF) support beginning at least 24 hours after the last topotecan dose. If necessary, may further reduce dose to 0.45 mg/m2/day for subsequent cycles.Platelets <25,000/mm3: Reduce topotecan to 0.6 mg/m2/day for subsequent cycles. If necessary, may further reduce dose to 0.45 mg/m2/day for subsequent cycles.Single-agent therapy:IV:Neutrophils <500/mm3: Reduce dose to 1.25 mg/m2/day for subsequent cycles or administer G-CSF support beginning at least 24 hours after the last topotecan dose.Platelets <25,000/mm3: Reduce dose to 1.25 mg/m2/day for subsequent cycles.Oral:Diarrhea (grade 3 or 4): Do not administer to patients with grade 3 or 4 diarrhea. Upon recovery to ≤ grade 1 toxicity, reduce dose by 0.4 mg/m2/day for subsequent cycles.Neutrophils <500/mm3 associated with fever or infection or lasting ≥7 days or neutrophils 500/mm3 to 1,000/mm3 lasting beyond day 21: Reduce dose by 0.4 mg/m2/day for subsequent cycles.Platelets <25,000/mm3: Reduce dose by 0.4 mg/m2/day for subsequent cycles.Pulmonary toxicity: Interstitial lung disease (ILD): Permanently discontinue if ILD is confirmed.Dosing: Kidney Impairment: PediatricInfants, Children, and Adolescents: Consult protocol for specific recommendations. Some centers have considered the following adjustments: IV:Baseline: Initial dosing:CrCl >40 mL/minute/1.73 m2: No adjustment necessary.CrCl 20 to 40 mL/minute/1.73 m2: Administer 50% of dose.CrCl <20 mL/minute/1.73 m2: Hold doses until renal function recovers (CrCl >20 mL/minute/1.73 m2).During therapy: CrCl >60 mL/minute/1.73 m2: No adjustment necessary.CrCl 40 to 60 mL/minute/1.73 m2: Administer 50% of dose.CrCl 20 to <40 mL/minute/1.73 m2: Administer 25% to 50% of dose.CrCl <20 mL/minute/1.73 m2: Hold doses until renal function recovers (CrCl >20 mL/minute/1.73 m2).Hemodialysis: Very limited data available; some data suggest that clearance of the lactone metabolite is similar to pediatric patients with normal renal function; a case report describes topotecan use in an anephric 6-year old diagnosed with Wilms tumor; the patient received 0.75 mg/m2/dose once daily for 5 days every 21 days with hemodialysis on day 2 and 4; on dialysis days, topotecan was administered ~2 hours before the start of the dialysis session; dosage reductions required for toxicity (myelosuppression) after cycle 4 (Aronoff 2007; Iacono 2004).Continuous renal replacement therapy (CRRT): Administer 50% of dose or reduce dose by 0.75 mg/m2/dose, if appropriate (Aronoff 2007).Dosing: Hepatic Impairment: PediatricThere are no pediatric specific recommendations; based on experience in adult patients, no adjustment may be necessaryDosing: Older AdultRefer to adult dosing.Dosing: Obesity: AdultAmerican Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (ASCO [Griggs 2021]).Dosing: Adjustment for Toxicity: AdultWithhold subsequent cycles until neutrophils recover to >1,000/mm3, platelets recover to >100,000/mm3, and hemoglobin recovers to ≥9 g/dL (with transfusion if necessary).Combination therapy with cisplatin(cisplatin may also require dosage adjustment): IV:Febrile neutropenia (neutrophils <1,000/mm3 with temperature of ≥38°C): Reduce topotecan to 0.6 mg/m2/day for subsequent cycles or administer granulocyte-colony stimulating factor support beginning at least 24 hours after the last topotecan dose. If necessary, may further reduce dose to 0.45 mg/m2/day for subsequent cycles.Platelets <25,000/mm3: Reduce topotecan to 0.6 mg/m2/day for subsequent cycles. If necessary, may further reduce dose to 0.45 mg/m2/day for subsequent cycles.Single-agent therapy:IV:Neutrophils <500/mm3: Reduce dose to 1.25 mg/m2/day for subsequent cycles or administer G-CSF support beginning at least 24 hours after the last topotecan dose.Platelets <25,000/mm3: Reduce dose to 1.25 mg/m2/day for subsequent cycles.Oral:Diarrhea (grade 3 or 4): Do not administer to patients with grade 3 or 4 diarrhea. Upon recovery to ≤ grade 1 toxicity, reduce dose by 0.4 mg/m2/day for subsequent cycles.Neutrophils <500/mm3 associated with fever or infection or lasting ≥7 days or neutrophils 500/mm3 to 1,000/mm3 lasting beyond day 21: Reduce dose by 0.4 mg/m2/day for subsequent cycles.Platelets <25,000/mm3: Reduce dose by 0.4 mg/m2/day for subsequent cycles.Pulmonary toxicity: Interstitial lung disease (ILD): Permanently discontinue if ILD is confirmed.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral: Hycamtin: 0.25 mg, 1 mgSolution, Intravenous: Generic: 4 mg/4 mL (4 mL)Solution, Intravenous [preservative free]: Generic: 4 mg/4 mL (4 mL)Solution Reconstituted, Intravenous [preservative free]: Hycamtin: 4 mg (1 ea)Generic: 4 mg (1 ea)Generic Equivalent Available: USMay be product dependentDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Intravenous: Generic: 1 mg/mL (1 mL, 3 mL, 4 mL); 4 mg/4 mL (4 mL)Solution Reconstituted, Intravenous: Hycamtin: 4 mg ([DSC])Generic: 4 mg (1 ea)Administration: AdultIV: Administer IV piggyback over 30 minutes. For combination chemotherapy with cisplatin, administer pretreatment hydration. IV topotecan is an irritant (Pérez Fidalgo 2012). Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation. If extravasation occurs, discontinue infusion immediately and manage appropriately.Oral: Administer with or without food. If a dose is missed or patient vomits after dose is administered, do not administer a replacement dose; administer the next dose at the scheduled time. Swallow whole; do not open, crush, chew, or divide capsule. For patients unable to swallow capsules whole, reconstituted topotecan solution for injection (1 mg/mL concentration) may be mixed with up to 30 mL of acidic fruit juice (eg, apple, orange, grape) immediately prior to oral administration (Daw 2004).Administration: PediatricOral topotecan is associated with a moderate emetic potential (depending on the dose) in pediatrics; antiemetics may be recommended to prevent nausea and vomiting (POGO [Paw Cho Sing 2019]).Parenteral:IV: Must be diluted prior to administration. Administer by intermittent IV infusion over 30 minutes or as a continuous infusion (over 1 or more days). Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation. If extravasation occurs, discontinue infusion immediately and manage appropriately.Intraventricular: Administer through an intraventricular or Ommaya reservoir at a rate of 2 mL/minute following removal of an isovolumetric amount of CSF; following administration, flush reservoir slowly with 2 mL of CSF or preservative-free NS (Blaney 2013).Oral:Capsules: May administer with or without food. Swallow capsule whole; do not crush, chew, or divide capsule.Parenteral formulation; lyophilized powder for oral use. After reconstitution, mix dose in 30 mL of an acidic medium (eg, apple, grape, orange juice); Note: The reconstituted injectable solution is tasteless; the acidic medium serves as the vehicle only, not to mask the taste (Bowers 2004; Daw 2004; Minturn 2001; Wagner 2004).Hazardous Drugs Handling ConsiderationsHazardous agent (NIOSH 2016 [group 1]).Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).Use: Labeled IndicationsCervical cancer, recurrent or persistent: Injection: Treatment (in combination with cisplatin) of stage IVB, recurrent or persistent cervical cancer that is not amenable to curative treatmentOvarian cancer, metastatic: Injection: Treatment of metastatic ovarian cancer (as a single agent) after disease progression on or after initial or subsequent chemotherapySmall cell lung cancer, relapsed or progressive:Injection: Treatment of small cell lung cancer (as a single agent) in patients with platinum-sensitive disease which has progressed at least 60 days after initiation of first-line chemotherapyOral: Treatment of relapsed small cell lung cancer in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapyUse: Off-Label: AdultEwing sarcoma; Myelodysplastic syndromes, high-risk; Ovarian cancer, metastatic (off-label [weekly] dosing); Primary CNS lymphoma, relapsed or refractory; RhabdomyosarcomaMedication Safety IssuesSound-alike/look-alike issues: Hycamtin may be confused with MycamineTopotecan may be confused with irinotecanHigh alert medication:This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error. Other safety concerns:Topotecan overdoses have been reported; potential causes include omission of the leading zero and missing the decimal point when prescribing, preparing, and administering. Recommended intravenous doses should generally not exceed 4 mg; verify dose prior to administration.Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Central nervous system: Fatigue (oral: 11% to 19%; intravenous: grades 3/4: 6% to 7%)Dermatologic: Alopecia (oral: 10% to 20%)Gastrointestinal: Nausea (oral: 27% to 33%; intravenous: grades 3/4: 8% to 10%), diarrhea (oral: 14% to 22%; intravenous: grades 3/4: 6%), vomiting (oral: 19% to 21%; intravenous: grades 3/4: 10%), anorexia (oral: 7% to 14%)Hematologic & oncologic: Anemia (oral: 94% to 98%; grades 3/4: 25%; grade 3: 15% to 18%; grade 4: 7% to 10%; intravenous: grades 3/4: 37% to 42%), neutropenia (oral: 83% to 91%; grade 3: 24% to 28%; grade 4: 32% to 33%; intravenous: grade 4: 70% to 80%; nadir 12 to 15 days; duration: 7 days), thrombocytopenia (oral: 81%; grade 3: 29% to 30%; grade 4: 6% to 7%; intravenous: grade 4: 27% to 29%; nadir: 15 days; duration: 3 to 5 days), febrile neutropenia (intravenous: grade 3/4: 23% to 28%; grade 4: 5%; oral: grade 4: 4%), neutropenic infection (13% to 17%)1% to 10%:Central nervous system: Pain (intravenous: grades 3/4: 5%)Gastrointestinal: Abdominal pain (intravenous: grades 3/4: 5% to 6%), constipation (intravenous: grades 3/4: 5%), intestinal obstruction (intravenous: grades 3/4: 5%)Hepatic: Increased serum alanine aminotransferase (intravenous: grades 3/4: ≤4%). increased serum aspartate aminotransferase (intravenous: grades 3/4: ≤4%), increased serum bilirubin (intravenous: grades 3/4: <2%)Neuromuscular & skeletal: Asthenia (intravenous: grades 3/4: 5% to 9%; oral: 3% to 7%)Respiratory: Dyspnea (intravenous: grades 3/4: 6% to 9%), pneumonia (intravenous: grades 3/4: 8%)Miscellaneous: Fever (oral: 5% to 7%), sepsis (2% to 4%)Frequency not defined:Hematologic & oncologic: Bone marrow depression<1%, postmarketing, and/or case reports: Angioedema, arthralgia, chest pain, dermatitis (severe), gastrointestinal perforation, headache, hemorrhage (severe, associated with thrombocytopenia), hypersensitivity reaction, interstitial pulmonary disease, leukopenia, myalgia, neutropenic enterocolitis, nonimmune anaphylaxis, pancytopenia, pruritus (severe), stomatitis, typhlitisContraindicationsSevere hypersensitivity to topotecan or any component of the formulationCanadian labeling: Additional contraindications (not in the US labeling): Severe renal impairment (CrCl <20 mL/minute); pregnancy; breastfeeding; preexisting severe bone marrow depressionWarnings/PrecautionsConcerns related to adverse effects:• Bone marrow suppression: [US Boxed Warning]: Topotecan may cause severe myelosuppression. Monitor blood counts frequently. Administer the first cycle only to patients with baseline neutrophils ≥1,500/mm3 and platelets ≥100,000/mm3. Single-agent IV topotecan resulted in a median duration of grade 4 neutropenia of 7 days; neutropenia was most common during cycle 1. Grade 4 neutropenia associated with infection, as well as neutropenic fever, occurred; sepsis (sometimes fatal) has been reported. Grade 4 thrombocytopenia occurred with single-agent IV topotecan at a median duration of 5 days. Grade 4 neutropenia, grade 4 thrombocytopenia, and grades 3 and 4 anemia have occurred when IV topotecan was used in combination with cisplatin. For oral topotecan, the median day for neutrophil and platelet nadirs occurred on day 15; grade 4 neutropenia occurred with a median duration of 7 days and most commonly occurred during cycle 1. Clinical complications of neutropenia included infection, neutropenic fever, and sepsis (sometimes fatal). Grade 4 thrombocytopenia with oral topotecan occurred with a median duration of 3 days. Anemia (grades 3 or 4) has also been reported (with oral and IV single-agent topotecan). In a clinical study comparing IV to oral topotecan, granulocyte-colony stimulating factor support was administered in a higher percentage of patients receiving oral topotecan (Eckardt 2007). Hematologic toxicity may require treatment interruption, dosage reduction, and/or growth factor support.• Extravasation: Topotecan IV is an irritant (Pérez Fidalgo 2012). Extravasation injuries (some severe) have been reported with IV topotecan; if extravasation occurs, discontinue infusion immediately and manage appropriately. Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.• Gastrointestinal toxicity: Diarrhea may occur; diarrhea associated with oral topotecan may be severe and life-threatening (requiring hospitalization) and may occur at the same time as neutropenia. Monitor for diarrhea and manage with antidiarrheals at the first sign of diarrhea. The median time to onset of grade 2 or worse diarrhea with oral topotecan was 9 days. The incidence of diarrhea due to oral topotecan may be higher in the elderly. Do not administer oral topotecan in patients with grade 3 or 4 diarrhea; reduce dose upon recovery to ≤ grade 1 toxicity. GI perforation has been reported (postmarketing reports).• Hypersensitivity: Hypersensitivity reactions, including allergic reaction, anaphylactoid reaction, and angioedema have been reported.• Neutropenic enterocolitis: Topotecan-induced neutropenia may lead to fatal typhlitis (neutropenic enterocolitis); consider the possibility of typhlitis in patients presenting with neutropenia, fever, and abdominal pain.• Pulmonary toxicity: Interstitial lung disease (ILD), including fatal ILD, has been reported. Monitor for pulmonary signs/symptoms indicative of ILD; discontinue topotecan permanently in patients with confirmed ILD diagnosis. Risk factors for ILD include a history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, or the use of colony-stimulating factors or medications associated with pulmonary toxicity.Disease-related concerns:• Renal impairment: Renal impairment may require dose adjustment.Other warnings/precautions:• Medication safety: Topotecan overdoses have been reported; potential causes include omission of the leading zero and missing the decimal point when prescribing, preparing, and administering. Recommended intravenous doses should generally not exceed 4 mg in adults; verify dose prior to administration.Metabolism/Transport EffectsSubstrate of BCRP/ABCG2, P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapyAdagrasib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: Avoid concomitant use of adagrasib and these narrow therapeutic/sensitive substrates of P-gp when possible. If combined, monitor for increased toxicities of these substrates. Risk D: Consider therapy modificationAsciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapyBCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCRP/ABCG2 Inhibitors: May increase the serum concentration of Topotecan. Risk X: Avoid combinationChloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapyCladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combinationCloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.Risk C: Monitor therapyDeferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone.Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modificationDipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combinationErdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: If coadministration with these narrow therapeutic index/sensitive P-gp substrates is unavoidable, separate erdafitinib administration by at least 6 hours before or after administration of these P-gp substrates. Risk D: Consider therapy modificationFexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole.Risk X: Avoid combinationFosphenytoin-Phenytoin: May decrease the serum concentration of Topotecan. Management: Monitor topotecan response closely, and consider alternatives to phenytoin when possible. Systemic concentrations and effects of topotecan may be reduced. No specific guidelines for topotecan dose adjustment are available. Risk D: Consider therapy modificationFutibatinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapyFutibatinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyGilteritinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapyGilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapyGranulocyte Colony-Stimulating Factors: May enhance the adverse/toxic effect of Topotecan. Specifically, the risk for the development of interstitial lung disease may be increased. Granulocyte Colony-Stimulating Factors may enhance the myelosuppressive effect of Topotecan. Management: Avoid use of granulocyte colony-stimulating factors 24 hours before (14 days for pegfilgrastim) and 24 hours after the last dose of topotecan. Additionally, monitor patients closely for the development of interstitial lung disease with this combination. Risk D: Consider therapy modificationLasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combinationLenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim.Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modificationLipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim.Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modificationLumacaftor and Ivacaftor: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Risk C: Monitor therapyMitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapyOlaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib.Risk C: Monitor therapyPacritinib: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combinationPacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combinationPalifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oralmucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modificationP-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Topotecan. Risk X: Avoid combinationPlatinum Derivatives: May enhance the adverse/toxic effect of Topotecan. Management: Consider administering platinum derivatives after topotecan when possible to minimize toxicity or using lower doses if administering platinum derivatives prior to topotecan. Monitor for hematologic toxicity (eg, neutropenia, thrombocytopenia). Risk D: Consider therapy modificationPromazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapyRopeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b.Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modificationTaurursodiol: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combinationTaurursodiol: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combinationVelpatasvir: May increase the serum concentration of Topotecan. Risk X: Avoid combinationVoxilaprevir: May increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combinationReproductive ConsiderationsVerify pregnancy status in females of reproductive potential prior to treatment initiation. Females of reproductive potential should use effective contraception during treatment and for at least 6 months after the last topotecan dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last topotecan dose.Pregnancy ConsiderationsBased on the mechanism of action and data from animal reproduction studies, in utero exposure to topotecan may cause fetal harm.Breastfeeding ConsiderationsIt is not known if topotecan is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends lactating females not breastfeed during therapy and for 1 week following the last topotecan dose.Monitoring ParametersCBC with differential and platelet count, renal function tests, bilirubin. Verify pregnancy status (prior to treatment initiation in females of reproductive potential). Monitor for symptoms of interstitial lung disease; diarrhea symptoms/hydration status; monitor infusion site. Monitor adherence (for oral therapy).The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.Mechanism of ActionTopotecan binds to topoisomerase I and stabilizes the cleavable complex so that religation of the cleaved DNA strand cannot occur. This results in the accumulation of cleavable complexes and single-strand DNA breaks. Topotecan acts in S phase of the cell cycle.Pharmaco*kineticsNote: Pharmaco*kinetic data in pediatric patients and young adults (0.4 to 22 years of age) demonstrated a high level of interpatient variability (43% to 57% dependent upon parameter evaluated) as well as intrapatient variability (20% to 22% dependent upon parameter evaluated) (Schaiquevich 2007)Distribution: Vd:Pediatric patients and young adults (0.4 to 22 years of age): Mean range: 32.2 to 32.7 L/m2 (Schaiquevich 2007)Adults: 25 to 75 L/m2 (Hartmann 2006)Protein binding: ~35%Metabolism: Undergoes a reversible, pH-dependent hydrolysis of the (active) lactone ring to yield a relatively inactive hydroxy acid in plasma (at pH of ≤4, the active ring is predominant; at physiologic pH, the ring-opened hydroxy acid form predominates); topotecan is metabolized in the liver to N-demethylated metaboliteBioavailability: Oral: Capsule: Adults: ~40%; data from pediatric patients (1 to 18 years of age) showed that, while highly variable, the reported median oral bioavailability with oral administration of the reconstituted parenteral solution is similar to adults (Daw 2004; Zamboni 1999)Half-life elimination:Pediatric patients (0 to 18 years of age): Lactone moiety: 2.58 hours ± 0.15 (range: 0.2 to 7.1 hours) (Santana 2005)Adults: IV: 2 to 3 hours; Oral: 3 to 6 hoursTime to peak, plasma:Pediatric patients (1 to 18 years of age): Parenteral formulation (reconstituted lyophilized formulation): 0.75 to 2 hours (Zamboni 1999)Adults: Oral: 1 to 2 hours; delayed with high-fat meal (3 to 4 hours)Excretion:IV: Urine (51%; ~3% as N-desmethyl topotecan); feces (18%; ~2% as N-desmethyl topotecan)Oral: Urine (20%; 2% as N-desmethyl topotecan); feces (33%; <2% as N-desmethyl topotecan)Clearance: Pediatric patients (0.4 to 18 years of age): GFR most significant determinant of clearance; a linear model with GFR has been observed; BSA is also a significant determinant of clearance and AUC more so than patient weight; infants <6 months have decreased clearance (Schaiquevich 2007). However, pharmaco*kinetic data from 6 pediatric patients with severe renal impairment (n=5: Unilateral nephrectomy; n=1: Anephric on hemodialysis) suggests that other mechanisms than GFR may assist with renal clearance; in these patients, overall systemic clearance was shown to be similar to matched controls (age, BSA, and Scr) despite decreased GFR (Iacono 2003; Iacono 2004)Pharmaco*kinetics: Additional ConsiderationsAltered kidney function:IV: The plasma clearance of topotecan lactone decreased by 33% in patients with CrCl 40 to 60 mL/minute and decreased 65% in patients with CrCl 20 to 39 mL/minute, compared to patients with CrCl >60 mL/minute.Oral: The mean dose-normalized total topotecan and topotecan lactone AUC∞ increased in advanced cancer patients with renal impairment compared to patients with CrCl >80 mL/minute. White patients with CrCl 50 to 79 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUC∞ of 70% and 34%, respectively; white patients with CrCl 30 to 49 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUC∞ of 108% and 80%, respectively; white patients with CrCl <30 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUC∞ of 227% and 114%, respectively, compared to patients with normal renal function. Asian patients with CrCl 50 to 79 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUC∞ of 26% and 34%, respectively; Asian patients with CrCl 30 to 49 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUC∞ of 153% and 121%, respectively; Asian patients with CrCl <30 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUC∞ of 331% and 247%, respectively, compared to patients with normal renal function.Race/ethnicity: Following oral topotecan administration in patients with normal renal function, the AUC of topotecan lactone and total topotecan was 30% higher in Asian patients as compared to white patients.Pricing: USCapsules (Hycamtin Oral)0.25 mg (per each): $120.591 mg (per each): $482.36Solution (Topotecan HCl Intravenous)4 mg/4 mL (per mL): $20.79 - $129.81Solution (reconstituted) (Hycamtin Intravenous)4 mg (per each): $1,389.00Solution (reconstituted) (Topotecan HCl Intravenous)4 mg (per each): $168.00 - $358.25Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalCamtoop (CR, DO, GT, HN, NI, PA, SV);Canol (LK, ZW);Cantoop (MX);Cantop (IN);Firotex (VN);Hycamtin (AE, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CY, CZ, DE, DK, EE, EG, ES, FI, FR, GB, GR, HK, HR, HU, IE, IL, IS, IT, JO, KR, KW, LB, LT, LU, MT, MY, NL, NO, PH, PK, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, TH, TR, TW, UY, VN, ZA, ZW);Hykamtin (UA);Oncotecan (CO, EC, PE);Potactasol (AT, BE, CZ, FR, HR, HU, IE, IL, LV, MT, NL);Potekam (PY);Tisogen (AR);Topodria (CO);Topokebir (AR);Topotacx (BR);Topotel (EG, IN, PH, ZW);Toranex (CR, DO, GT, HN, NI, PA, SV)For country code abbreviations (show table)<800> Hazardous Drugs—Handling in Healthcare Settings. 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Response to pacl*taxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a pediatric oncology group study. J Clin Oncol. 2004;22(20):4119-4126. [PubMed 15483021]Kushner BH, Cheung NK, Kramer K, et al. Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults. Bone Marrow Transplant. 2001;28(6):551-556. [PubMed 11607767]Kushner BH, Kramer K, Modak S, Qin LX, Cheung NK. Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer. 2010;116(12):3054-3060. doi:10.1002/cncr.25232 [PubMed 20564411]London WB, Frantz CN, Campbell LA, et al. Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol. 2010;28(24):3808-3815. doi: 10.1200/JCO.2009.27.5016. [PubMed 20660830]Long HJ 3rd, Bundy BN, Grendys EC Jr, et al; Gynecologic Oncology Group Study. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2005;23(21):4626-4633. doi: 10.1200/JCO.2005.10.021. [PubMed 15911865]Malcovati L, Hellström-Lindberg E, Bowen D, et al; European Leukemia Net. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964. doi: 10.1182/blood-2013-03-492884. [PubMed 15911865]Minturn JE, Janss AJ, Fisher PG, et al. A phase II study of metronomic oral topotecan for recurrent childhood brain tumors. Pediatr Blood Cancer. 2011;56(1):39-44. doi: 10.1002/pbc.22690. [PubMed 21108437]Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27(28):4649-4655. doi: 10.1200/JCO.2009.21.8909. [PubMed 19720909]Morgenstern DA, Barone G, Moreno L, et al. Children's Cancer and Leukaemia Group (CCLG). Options for the treatment of patients with relapsed/progressive high-risk neuroblastoma. Available at: https://www.cclg.org.uk/write/MediaUploads/Member%20area/Treatment%20guidelines/CCLG_Relapsed_Progressive_High_Risk_Neuroblastoma_Guidelines_March_2015_FINAL.pdf. Published March 2015. Accessed June 21, 2021.O'Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006;24(34):5441-5447. [PubMed 17135646]O'Reilly S, Rowinsky E, Slichenmyer W, et al. Phase I and pharmacologic studies of topotecan in patients with impaired hepatic function. J Natl Cancer Inst. 1996a;88(12):817-824. [PubMed 8637048]O’Reilly S, Rowinsky EK, Slichenmyer W, et al. Phase I and pharmacologic study of topotecan in patients with impaired renal function. J Clin Oncol. 1996b;14(12):3062-3073. doi: 10.1200/JCO.1996.14.12.3062. [PubMed 8955651]Pappo AS, Lyden E, Breneman J, et al. Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol. 2001;19(1):213-219. [PubMed 11134215]Park JR, Scott JR, Stewart CF, et al. Pilot induction regimen incorporating pharmaco*kinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study. J Clin Oncol. 2011;29(33):4351-4357. [PubMed 22010014]Paw Cho Sing E, Robinson PD, Flank J, et al. Classification of the acute emetogenicity of chemotherapy in pediatric patients: a clinical practice guideline. Pediatr Blood Cancer. 2019;66(5):e27646. doi: 10.1002/pbc.27646. [PubMed 30729654]Pérez Fidalgo JA, García Fabregat L, Cervantes A, et al. Management of chemotherapy extravasation: ESMO-EONS clinical practice guidelines. Ann Oncol. 2012;23(Suppl 7):167-173. doi: 10.1093/annonc/mds294. [PubMed 22997449]Reed DR, Mascarenhas L, Manning K, et al. Pediatric phase I trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies. Cancer Med. 2016;5(2):294-303. doi:10.1002/cam4.598 [PubMed 26714427]Rubie H, Geoerger B, Frappaz D, et al. Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours. Eur J Cancer. 2010;46(15):2763-2770. [PubMed 20558056]Santana VM, Furman WL, Billups CA, et al. Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmaco*kinetically guided dosing approach. J Clin Oncol. 2005;23(18):4039-4047. doi: 10.1200/JCO.2005.02.097. [PubMed 15961757]Santana VM, Zamboni WC, Kirstein MN, et al, “A Pilot Study of Protracted Topotecan Dosing Using a Pharmaco*kinetically Guided Dosing Approach in Children With Solid Tumors,” Clin Cancer Res, 2003, 9(2):633-640. [PubMed 12576429]Saylors RL 3rd, Stine KC, Sullivan J, et al; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001;19(15):3463-34639. [PubMed 11481351]Schaiquevich P, Panetta JC, Iacono LC, et al. Population pharmaco*kinetic analysis of topotecan in pediatric cancer patients. Clin Cancer Res. 2007;13(22, pt 1):6703-6711. [PubMed 18006771]Sehouli J, Stengel D, Harter P, et al. Topotecan weekly versus conventional 5-day schedule in patients with platinum-resistant ovarian cancer: a randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol. 2011;29(2):242-248. doi: 10.1200/JCO.2009.27.8911. [PubMed 21115872]Shukla N, Kobos R, Renaud T, Steinherz LJ, Steinherz PG. Phase II trial of clofarabine with topotecan, vinorelbine, and thiotepa in pediatric patients with relapsed or refractory acute leukemia. Pediatr Blood Cancer. 2014;61(3):431-435. doi:10.1002/pbc.24789 [PubMed 24115731]Simon T, Längler A, Berthold F, Klingebiel T, Hero B. Topotecan and etoposide in the treatment of relapsed high-risk neuroblastoma: results of a phase 2 trial. J Pediatr Hematol Oncol. 2007;29(2):101-106. doi:10.1097/MPH.0b013e3180320b48 [PubMed 17279006]Steinherz PG, Shukla N, Kobos R, Steinherz L. Remission re-induction chemotherapy with clofarabine, topotecan, thiotepa, and vinorelbine for patients with relapsed or refractory leukemia. Pediatr Blood Cancer. 2010;54(5):687-693. doi:10.1002/pbc.22321 [PubMed 20205253]ten Bokkel Huinink W, Lane SR, Ross GA; International Topotecan Study Group. Long-term survival in a phase III, randomised study of topotecan versus pacl*taxel in advanced epithelial ovarian carcinoma. Ann Oncol. 2004;15(1):100-103. [PubMed 14679127]Topotecan for injection [prescribing information]. Durham, NC: Accord Healthcare, Inc; April 2017.Topotecan for injection [prescribing information]. Lake Forest, IL: Hospira Inc; December 2019.Topotecan for injection [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc; June 2019.US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. https://www.cdc.gov/niosh/docs/2016-161/. Updated September 2016. Accessed January 23, 2020.Voloschin AD, Betensky R, Wen PY, Hochberg F, Batchelor T. Topotecan as salvage therapy for relapsed or refractory primary central nervous system lymphoma. J Neurooncol. 2008;86(2):211-215. doi: 10.1007/s11060-007-9464-6. [PubMed 17896078]Wagner S, Erdlenbruch B, Längler A, et al. Oral topotecan in children with recurrent or progressive high-grade glioma: a Phase I/II study by the German Society for Pediatric Oncology and Hematology. Cancer. 2004;100(8):1750-1757. [PubMed 15073866]Walterhouse DO, Lyden ER, Breitfeld PP, Qualman SJ, Wharam MD, Meyer WH. Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study [published correction appears in: J Clin Oncol. 2004;22(15):3205]. J Clin Oncol. 2004;22(8):1398-403. doi: 10.1200/JCO.2004.05.184. [PubMed 15007087]Wells RJ, Reid JM, Ames MM, et al, “Phase I Trial of Cisplatin and Topotecan in Children With Recurrent Solid Tumors: Children's Cancer Group Study 0942,” J Pediatr Hematol Oncol, 2002, 24(2):89-93. [PubMed 11990712]Zamboni WC, Bowman LC, Tan M, et al. Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors. Cancer Chemother Pharmacol. 1999;43(6):454-460. doi: 10.1007/s002800050923. [PubMed 10321504]Topic 10007 Version 325.0

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CloseTrazodone: Drug informationTrazodone: Drug information(For additional information see "Trazodone: Patient drug information" and see "Trazodone: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningSuicidal thoughts and behaviors:Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Trazodone is not approved for use in pediatric patients.Brand Names: CanadaAPO-TraZODone;APO-TraZODone D;JAMP-Trazodone;PMS-TraZODone;TEVA-TraZODone;TraZODone-100;TraZODone-150;TraZODone-50Pharmacologic CategoryAntidepressant, Serotonin Reuptake Inhibitor/AntagonistDosing: AdultNote: Oleptro, the extended-release formulation, has been discontinued in the United States for more than 1 year.Aggressive or agitated behavior associated with dementiaAggressive or agitated behavior associated with dementia (alternative agent) (off-label use): Based on limited data: Oral: Immediate release: Initial: 25 to 50 mg once daily at bedtime; may increase dose gradually based on response and tolerability up to 300 mg/day in 1 to 3 divided doses (Ref). Some experts target doses in the lower end of the dosing range, rarely using doses as high as 100 to 150 mg/day (Ref).Insomnia, sleep onset and sleep maintenanceInsomnia, sleep onset and sleep maintenance (alternative agent) (off-label use):Note: Limit long-term use (>4 weeks) to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (Ref).Immediate release: Oral: Usual dose: 50 mg to 100 mg at bedtime (Ref). Note: Lower initial doses of 12.5 to 50 mg at bedtime may be considered (eg, in palliative care patients) (Ref). May consider increasing dose based on response and tolerability up to 200 mg at bedtime (eg, in patients with substance use disorder) (Ref). In patients with substance use disorder, trazodone may be preferred due to its low abuse potential (Ref).Insomnia in patients with depression (as adjunct to other appropriate antidepressant treatment [eg SSRI]): Oral: Immediate release: Usual dose: 50 to 300 mg at bedtime. Doses up to 600 mg/day have been evaluated; however, evidence of greater benefit is uncertain and adverse effects may be increased (Ref).Major depressive disorderMajor depressive disorder (unipolar) (alternative agent): Oral:Immediate release: Initial: 50 mg twice daily; may increase in increments of 50 mg/day every 3 to 7 days to a target dose of 75 to 150 mg twice daily. Thereafter may further increase by 50 to 100 mg/day every 2 to 4 weeks based on response and tolerability; usual dosage range 200 to 400 mg/day; maximum 600 mg/day. Note: Adverse effects are increased with doses >400 mg/day and are not recommended in patients with cardiovascular disease; sedative effects may be better tolerated by dividing the daily dose to give a smaller dose in daytime and larger dose before bedtime (Ref).Manufacturer’s labeling: Dosing in prescribing information may not reflect current clinical practice. Initial: 150 mg/day in divided doses; maximum dose: 600 mg/day (inpatients); 400 mg/day (outpatients).Extended release: Initial: 150 mg once daily at bedtime; may increase by 75 mg/day at intervals no less than every 3 days based on response, tolerability, and severity of symptoms; maximum dose: 375 mg/dayDiscontinuation of therapy:Due to its short half-life, withdrawal symptoms are likely with abrupt discontinuation. When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). Reasons for a slower taper (eg, over 4 weeks) include history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (Ref).Switching to or from an MAOI:Allow 14 days to elapse between discontinuing an MAOI and initiation of trazodone.Allow 14 days to elapse between discontinuing trazodone and initiation of an MAOI.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Altered kidney function: Mild to severe impairment: No dosage adjustment necessary; titrate with caution (Ref).Hemodialysis, Intermittent (thrice weekly): Not significantly dialyzed (Doweiko 1984); no dosage adjustment necessary; titrate with caution (Ref).Peritoneal dialysis: No dosage adjustment necessary; titrate with caution (Ref).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in manufacturer's labeling (has not been studied). Use with caution.Dosing: Pediatric(For additional information see "Trazodone: Pediatric drug information")Insomnia; sleep disturbancesInsomnia; sleep disturbances: Limited data available; frequently used clinically in children with comorbid neuropsychiatric disorders (eg, autistic spectrum disorders [ASDs], neurogenetic disorders, mood disorders, anxiety disorders, developmental delay with attention-deficit hyperactivity disorder) (Ref). Due to possible risk of QT prolongation, it is suggested to avoid or use with caution in patients with Rett syndrome (Ref).Oral: Immediate-release formulation:Children 18 months to <3 years: Oral: Immediate release: Initial: 1 to 2 mg/kg/dose at bedtime; maximum dose: 25 mg/dose; may increase dose at 2-week intervals in 12.5 to 25 mg increments up to 3 mg/kg/dose once daily at bedtime, not to exceed a maximum dose: 100 mg/dose (Ref). Note: Pharmaco*kinetic analysis based on simulation reported that the following age-dependent pediatric doses resulted in exposures similar to adult doses of 30 to 150 mg/day: Children 2 to 6 years: 0.35 to 1.6 mg/kg/day; experiential data are needed to fully assess (Ref).Children 3 to 5 years: Oral: Immediate release: Initial: 1 to 2 mg/kg/dose at bedtime; maximum dose: 50 mg/dose; may increase dose at 2-week intervals in 12.5 to 25 mg increments up to 3 mg/kg/dose once daily at bedtime, not to exceed a maximum dose: 150 mg/dose (Ref). Note: Pharmaco*kinetic analysis based on simulation reported that the following age-dependent pediatric doses resulted in exposures similar to adult doses of 30 to 150 mg/day: Children 2 to 6 years: 0.35 to 1.6 mg/kg/day; experiential data are needed to fully assess (Ref).Children >5 years and Adolescents: Oral: Immediate release: Initial: 0.75 to 1 mg/kg/dose or 25 to 50 mg at bedtime; may increase at 2-week intervals in 12.5 to 25 mg increments up to a maximum dose of 200 mg/dose; reported range: 0.5 to 2 mg/kg/day (Ref). When used for palliative care, multiple daily doses may be necessary; in patients >18 years of age, 25 to 50 mg/dose increased gradually to twice or 3 times daily as needed (do not exceed adult dosing) (Ref). Note: Pharmaco*kinetic analysis based on simulation reported that the following age-dependent pediatric doses resulted in exposures similar to adult doses of 30 to 150 mg/day: Children >6 to 12 years: 0.4 to 1.9 mg/kg/day and Adolescents: 0.4 to 2.1 mg/kg/day (Ref); experiential data are needed to fully assess.Migraine, prophylaxisMigraine, prophylaxis: Limited data available: Note: Efficacy results variable; expert recommendations for migraine prevention in children and adolescents do not suggest trazodone as a routine therapeutic option (Ref).Children ≥7 years and Adolescents: Oral: Immediate-release formulation: 1 mg/kg/day in 3 divided doses; maximum dose: 150 mg/dose (Ref).Discontinuation of therapy: Due to short half-life of trazodone, avoid abrupt discontinuation to minimize the incidence of withdrawal symptoms, rebound insomnia, or increased nightmares as a result of REM sleep rebound. Evidence supporting ideal taper rates is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the drug; drugs with a shorter half-life may need to be tapered more conservatively. If intolerable withdrawal symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no specific pediatric dosage adjustments; in adult patients, no dosage adjustment is necessary for mild to moderate kidney impairment, and titration should be done with caution. Not significantly dialyzed (Ref).Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling. Use with caution.Dosing: Older AdultMajor depressive disorder (unipolar) (alternative agent):Immediate release: Oral: Initial: 25 to 50 mg at bedtime; may increase in increments of 25 to 50 mg/day every 3 days for inpatients and weekly for outpatients, if tolerated; usual dose: 75 to 150 mg/dayExtended release: Refer to adult dosing. Use with caution in the elderly; clinical experience is limited.Discontinuation of therapy: Refer to adult dosing.Switching antidepressants: Refer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral, as hydrochloride: Generic: 50 mg, 100 mg, 150 mg, 300 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Generic: 75 mgTablet, Oral, as hydrochloride: Generic: 50 mg, 100 mg, 150 mgProduct AvailabilityOleptro has been discontinued in the United States for more than 1 year.Medication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Desyrel: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf#page=13Oleptro extended release tablets: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM202202.pdfAntidepressant medications: http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/ucm100211.pdfAdministration: AdultOral:IR tablet: Administer shortly after a meal or light snack; swallow whole or as a half tablet by breaking along the score line.ER tablet: Take on an empty stomach; swallow whole or as a half tablet without food. Tablet may be broken along the score line, but do not crush or chew.Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet formulation is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.Administration: PediatricOral: Immediate release: Administer after meals or a snack to decrease lightheadedness, sedation, and postural hypotension; swallow whole or as a half tablet by breaking along the score line.Use: Labeled IndicationsMajor depressive disorder (unipolar): Treatment of unipolar major depressive disorderUse: Off-Label: AdultAggressive or agitated behavior associated with dementia; Insomnia, sleep onset and sleep maintenanceMedication Safety IssuesSound-alike/look-alike issues:Desyrel may be confused with deferoxamine, Demerol, Delsym, SEROquel, ZestrilTraZODone may be confused with traMADol, ziprasidoneAdverse Reactions (Significant): ConsiderationsActivation of mania or hypomaniaAntidepressants may precipitate a mixed/manic episode in patients with bipolar disorder. Treatment-emergent mania or hypomania in patients with unipolar major depressive disorder (MDD) have been reported, as many cases of bipolar disorder present in episodes of MDD (Ref).Mechanism: Non-dose-related; idiosyncratic; unclear to what extent mood switches represent an uncovering of unrecognized bipolar disorder or a more direct pharmacologic effect independent of diagnosis (Ref). May interfere with the balance of neurotransmitter systems when trazodone is added to other antidepressant therapies, like selective serotonin reuptake inhibitors (SSRIs) (eg, sertraline) (Ref).Onset: Varied; onset may vary from 4 days to 4 weeks (Ref). A systematic review observed that the risk of switching increased significantly within the initial 2 years of antidepressant treatment in patients with unipolar MDD receiving an antidepressant as monotherapy but not thereafter (up to 4.6 years) (Ref).Risk factors:• Family history of bipolar disorder (Ref)• Depressive episode with psychotic symptoms (Ref)• Younger age at onset of depression (Ref)• Antidepressant resistance (Ref)• Female sex (Ref)Bleeding riskTrazodone may increase the risk of bleeding, particularly if used concomitantly with antiplatelet and/or anticoagulants. Multiple observational studies with other drugs that interfere with serotonin reuptake (eg, selective serotonin reuptake inhibitors [SSRIs]) have found an association with use and a variety of bleeding complications. Similar to these agents, trazodone may increase the risk of bleeding; however, the risk may be lower (Ref).Mechanism: Possibly via inhibition of serotonin-mediated platelet activation and subsequent platelet dysfunction (Ref).Onset: Varied; per SSRI-derived literature (ie, trazodone not included), bleeding risk is likely delayed for several weeks until SSRI-induced platelet serotonin depletion becomes clinically significant (Ref).Risk factors:• Concomitant use of antiplatelets and/or anticoagulants (based on SSRI-derived literature) (Ref)• Preexisting platelet dysfunction or coagulation disorders (eg, von Willebrand factor) (Ref)Cardiac arrhythmiasCardiac arrhythmias, including prolonged QT interval on ECG (with or without torsades de pointes [TdP]) and ventricular tachycardia, have been reported. Other arrhythmias identified include ventricular premature contractions, ventricular couplets, tachycardia with syncope, sinus bradycardia, first-degree atrioventricular block, and complete atrioventricular block (Ref).Mechanism: Dose-related (generally, although may also occur at low to moderate doses); QT prolongation may be a result of the concentration-dependent inhibition of human ether-à-go-go (hERG) channel current (Ref). Risk factors:Risk factors for drug-induced QT prolongation (in general):• Females (Ref)• Age >65 years (Ref)• Structural heart disease (eg, history of myocardial infarction or heart failure with reduced ejection fraction) (Ref)• History of drug-induced TdP (Ref)• Genetic defects of cardiac ion channels (Ref)• Congenital long QT syndrome (Ref)• Baseline QTc interval prolongation (eg, >500 msec or lengthening of the QTc by ≥60 msec) (Ref)• Electrolyte disturbances (eg, hypokalemia, hypocalcemia, hypomagnesemia) (Ref)• Bradycardia (Ref)• Hepatic impairment (Ref)• Kidney impairment (Ref)• Coadministration of multiple medications (≥2) that prolong the QT interval or increase drug interactions that increase serum drug concentrations of QTc prolonging medications (Ref)• Substance use (Ref)Orthostatic hypotensionTrazodone may cause significant orthostatic hypotension, which may lead to syncope and subsequent falls and fracture (Ref).Mechanism: Orthostatic hypotension is due to alpha-1 adrenergic receptor blockade (Ref).Risk factors:• Cerebrovascular disease• Cardiovascular disease• Hypovolemia/dehydration (Ref)• Concurrent medication use that may predispose to hypotension/bradycardia (Ref)• Older adults, especially in those with preexisting heart conditions (Ref)PriapismPriapism has been reported rarely (Ref).Mechanism: Related to the blockade of alpha receptors in the absence of sufficient antimuscarinic activity (Ref).Onset: Intermediate; usually evident within 28 days of beginning treatment (Ref).Risk factors:• Sickle cell anemia• Multiple myeloma• Leukemia• Anatomical deformation of the penis (eg, angulation, cavernosal fibrosis, Peyronie disease)Serotonin syndromeSerotonin syndrome has been reported and typically occurs with coadministration of multiple serotonergic drugs but can occur following a single serotonergic agent at therapeutic doses (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).Mechanism: Dose-related; overstimulation of serotonin receptors by serotonergic agents (Ref).Onset: Rapid; in the majority of cases (74%), onset occurred within 24 hours of treatment initiation, overdose, or change in dose (Ref).Risk factors:• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism (eg, monoamine oxidase inhibitors [MAOIs]). Of note, concomitant use of some serotonergic agents, such as MAOIs, is contraindicated.Suicidal thinking and behaviorAntidepressants are associated with an increased risk of suicidal ideation and suicidal tendencies in pediatric and young adult patients (18 to 24 years) in short-term studies. In adults >24 years, short-term studies did not show an increased risk of suicidal thinking and behavior, and in older adults ≥65 years of age, a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, collective evidence shows a trend of an elevated risk of suicidality in younger age groups (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.Mechanism: Not established; one of several postulated mechanisms is antidepressants may energize suicidal patients to act on impulses; another suggests that antidepressants may produce a worsening of depressive symptoms leading to the emergence of suicidal thoughts and actions (Ref).Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether the risk extends to longer-term use (>4 months).Risk factors:• Children and adolescents (Ref)• Depression (risk of suicide associated with major depression and may persist until remission occurs)Withdrawal syndromeWithdrawal syndrome, consisting of both somatic symptoms (eg, dizziness, chills, lightheadedness, vertigo, shock-like sensations, paresthesia, fatigue, headache, nausea, tremor, diarrhea, visual disturbances) and psychological symptoms (eg, anxiety, agitation, confusion, insomnia, irritability), has been reported, primarily following the abrupt discontinuation of selective serotonin reuptake inhibitors (SSRIs) (including case reports with trazodone). Withdrawal symptoms may also occur following gradual tapering (Ref).Mechanism: Withdrawal; due to reduced availability of serotonin in the CNS with decreasing levels of the serotonergic agent. Other neurotransmission systems, including increased glutamine and dopamine, may also be affected, as well as effects on the hypothalamic-pituitary-adrenal axis (Ref).Onset: Intermediate; expected onset is 1 to 10 days (following either abrupt or tapered discontinuation) (Ref).Risk factors:• Abrupt discontinuation (rather than gradual dosage reduction) of an antidepressant treatment that has lasted >3 weeks, particularly a drug with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)• Prior history of antidepressant withdrawal symptoms (Ref)• High dose (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Gastrointestinal: Nausea and vomiting (10% to 13%), xerostomia (15% to 34%)Nervous system: Dizziness (20% to 28%), drowsiness (24% to 41%), fatigue (6% to 11%), headache (10% to 20%), nervousness (15%)Ophthalmic: Blurred vision (6% to 15%)1% to 10%:Cardiovascular: Chest pain, hypotension (4% to 7%) (table 1)Hypotension, palpitations, sinus bradycardia, syncope (3% to 5%) (table 2)Syncope, tachycardia (may include syncope)TraZODone: Adverse Reaction: HypotensionDrug (Trazodone)Placebo PopulationNumber of Patients (Trazodone)Number of Patients (Placebo)7%1%Inpatients142954%0%Outpatients157158TraZODone: Adverse Reaction: SyncopeDrug (Trazodone)Placebo PopulationNumber of Patients (Trazodone)Number of Patients (Placebo)3%2%Inpatients142955%1%Outpatients157158Endocrine & metabolic: Change in menstrual flow, increased libido, weight gain (1% to 5%), weight loss (6%)Gastrointestinal: Constipation (7% to 8%), diarrhea (5%), flatulence, gastrointestinal disease (6%), increased appetite, sialorrheaGenitourinary: Early menses, hematuria, impotence, retrograde ejacul*tion, urinary frequency, urinary hesitancyHematologic & oncologic: AnemiaHypersensitivity: Angioedema (3% to 7%), hypersensitivity reactionNervous system: Akathisia, ataxia (2% to 5%), confusion (5%), delusion, disorientation (2%), hallucination, heavy headedness (3%), hypomania, lack of concentration (1% to 3%), malaise (3%), memory impairment, numbness, paresthesia, speech disturbanceNeuromuscular & skeletal: Muscle twitching, myalgia (5% to 6%), tremor (3% to 5%)Ophthalmic: Asthenopia, eye pruritus, eye rednessRespiratory: Dyspnea, nasal congestion (≤6%), paranasal sinus congestion (≤6%)Frequency not defined:Cardiovascular: Hypertension, ventricular premature contractionsNervous system: Suicidal ideation, suicidal tendenciesPostmarketing:Cardiovascular: Acute myocardial infarction, atrial fibrillation (White 1985), bradycardia (Li 2011), cardiac arrhythmia, cardiac conduction disorder, cardiac failure, cerebrovascular accident, complete atrioventricular block (rare: <1%) (Rausch 1984), edema (Barnett 1985), first-degree atrioventricular block (rare: <1%) (Winkler 2006), orthostatic hypotension (common: ≥10%) (Poon 2005; Spivak 1987), prolonged QT interval on ECG (de Meester 2001; Levenson 1999), torsades de pointes (de Meester 2001; Levenson 1999), ventricular ectopy, ventricular tachycardia (rare: <1%) (Aronson 1986, Vittulo 1990)Dermatologic: Alopecia, leukonychia (Longstreth 1985), psoriasis (Barth 1986), skin rash, urticariaEndocrine & metabolic: Hirsutism, SIADHGastrointestinal: Cholestasis (Sheikh 1983), esophageal achalasiaGenitourinary: Breast engorgement, breast hypertrophy, lactation, priapism (rare: <1%) (Raskin 1985; Scher 1983), urinary incontinence, urinary retentionHematologic & oncologic: Hemolytic anemia, leukocytosis, methemoglobinemiaHepatic: Hepatotoxicity (Fernandes 2000; Rettman 2001)Nervous system: Abnormal dreams, anxiety, aphasia, delirium (Lennkh 1998), extrapyramidal reaction (Sotto 2015 ), female sexual disorder (Battaglia 2009; Purcell 1995), insomnia, mania (rare: <1%) (Hu 2017), paranoid ideation, psychosis (Mizoguchi 2005), seizure (Vanpee 1999), serotonin syndrome (rare: <1%) (Duignan 2019; Hudd 2010), stupor, tardive dyskinesia (Lin 2008), vertigoOphthalmic: DiplopiaRespiratory: ApneaContraindicationsHypersensitivity to trazodone or any component of the formulation; use of MAOIs intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing either trazodone or the MAOI); initiation of trazodone in a patient receiving linezolid or intravenous methylene blueWarnings/PrecautionsConcerns related to adverse effects:• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).• Falls: May cause falls and major osteoporotic fractures (eg, hip, pelvis, humerus, forearm) when used in elderly patients. The fall rate was found to be similar to the rates associated with antipsychotics and benzodiazepines (Bronskill 2018; Watt 2018).• Ocular effects: May cause mild pupillary dilation, which can lead to an episode of narrow-angle glaucoma in susceptible individuals. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.Disease-related concerns:• Coronary artery disease: Not recommended for use in a patient during the acute recovery phase of MI due to exacerbation of arrhythmias.• Hepatic impairment: Use with caution in patients with hepatic impairment; has not been studied in hepatic impairment.• Renal impairment: Use with caution in patients with renal impairment.• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications that may lower seizure threshold (Hill 2015).Metabolism/Transport EffectsSubstrate of CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Alcohol (Ethyl): May enhance the adverse/toxic effect of TraZODone. Specifically, effects on sleepiness, dizziness, and manual dexterity may be enhanced. Risk C: Monitor therapyAlizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyAlmotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyAlosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyAmphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapyAntiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyAntipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.Risk C: Monitor therapyAzelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBlonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin.Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modificationBrexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone.Risk C: Monitor therapyBrexanolone: Serotonin Reuptake Inhibitor/Antagonists may enhance the CNS depressant effect of Brexanolone.Risk C: Monitor therapyBrimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBuprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine.Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modificationBusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyCannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.Risk C: Monitor therapyCarBAMazepine: May decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of CarBAMazepine. Management: Consider increasing the trazodone dose during coadministration with strong CYP3A4 inducers, such as carbamazepine. In addition, monitor for increased carbamazepine concentrations and effects during coadministration with trazodone. Risk D: Consider therapy modificationChlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modificationChlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapyClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapyCyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyCYP3A4 Inducers (Moderate): May decrease the serum concentration of TraZODone. Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of TraZODone. Management: Consider increasing the trazodone dose during coadministration with strong CYP3A4 inducers. Risk D: Consider therapy modificationCYP3A4 Inhibitors (Moderate): May increase the serum concentration of TraZODone. Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase the serum concentration of TraZODone. Management: Consider the use of a lower trazodone dose and monitor for increased trazodone effects (eg, sedation, QTc prolongation) if combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationDapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combinationDaridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationDexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine.Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modificationDexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyDextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyDifelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDoxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants isnot recommended. Risk C: Monitor therapyDroperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modificationEletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyErgot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyEsketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyFenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapyFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFlunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine.Risk X: Avoid combinationFlunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modificationFosphenytoin: May decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Fosphenytoin. Management: Consider increasing the trazodone dose during coadministration with strong CYP3A4 inducers, such as fosphenytoin. In addition, monitor for increased phenytoin concentrations and effects during coadministration with trazodone. Risk D: Consider therapy modificationFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationHaloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol.Risk C: Monitor therapyHydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modificationKava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyKratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationLasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyLemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modificationLinezolid: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combinationLisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyLofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyLorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyMagnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMetaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyMethotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modificationMethylene Blue: Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome.Risk X: Avoid combinationMetoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMetoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyMetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE.Risk C: Monitor therapyMinocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMirtazapine: TraZODone may enhance the CNS depressant effect of Mirtazapine. TraZODone may enhance the serotonergic effect of Mirtazapine. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and CNS depression when these agents are combined. Risk C: Monitor therapyMonoamine Oxidase Inhibitors (Antidepressant): Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome.Risk X: Avoid combinationNefazodone: TraZODone may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of TraZODone.Management: Consider the use of a lower trazodone dose and monitor for increased trazodone effects such as sedation, QTc prolongation, and signs and symptoms of serotonin syndrome/serotonin toxicity when these agents are combined. Risk D: Consider therapy modificationOlopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOndansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyOpioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists.Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOrphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine.Risk X: Avoid combinationOxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyOxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products.Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modificationOxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE.Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOzanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapyParaldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde.Risk X: Avoid combinationPerampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyPhenytoin: May decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Phenytoin. Management: Consider increasing the trazodone dose during coadministration with strong CYP3A4 inducers, such as phenytoin. In addition, monitor for increased phenytoin concentrations and effects during coadministration with trazodone. Risk D: Consider therapy modificationPiribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil.Risk C: Monitor therapyPramipexole: CNS Depressants may enhance the sedative effect of Pramipexole.Risk C: Monitor therapyProcarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyQT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyRamosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyRasagiline: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combinationRopeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased.Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modificationROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole.Risk C: Monitor therapyRotigotine: CNS Depressants may enhance the sedative effect of Rotigotine.Risk C: Monitor therapyRufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapySafinamide: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combinationSaquinavir: May enhance the QTc-prolonging effect of TraZODone. Saquinavir may increase the serum concentration of TraZODone. Risk X: Avoid combinationSelective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySelegiline: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combinationSerotonergic Agents (High Risk, Miscellaneous): May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySerotonergic Opioids (High Risk): Serotonergic Non-Opioid CNS Depressants may enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome.Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modificationSerotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySerotonin/Norepinephrine Reuptake Inhibitors: TraZODone may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome.Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySt John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapySuvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant.Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary.Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationSyrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapyThalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide.Risk X: Avoid combinationTricyclic Antidepressants: May enhance the CNS depressant effect of Serotonergic Non-Opioid CNS Depressants. Tricyclic Antidepressants may enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and CNS depression when these agents are combined. Risk C: Monitor therapyTrimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyValerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyWarfarin: TraZODone may diminish the anticoagulant effect of Warfarin.Risk C: Monitor therapyZolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem.Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg formen who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modificationFood InteractionsTime to peak serum levels may be increased if immediate release trazodone is taken with food. Management: Administer immediate release after a meal or light snack. Administer extended release on an empty stomach.Pregnancy ConsiderationsTrazodone and the active metabolite 1-m-chlorophenylpiperazine cross the placenta and can be detected in cord blood at delivery (Saito 2021).Based on available data, an increased risk of adverse pregnancy outcomes has not been observed following use of trazodone during pregnancy (Anderson 2020; Einarson 2003; Einarson 2009). Long-term effects on neurodevelopment are not known (Korade 2021).Untreated or inadequately treated psychiatric illness may lead to poor adherence with prenatal care and adverse pregnancy outcomes. Therapy with antidepressants during pregnancy should be individualized; treatment with antidepressant medication is recommended for pregnant patients with severe major depressive disorder (ACOG 2008; CANMAT [MacQueen 2016]). Patients treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued (68%) as compared to pregnant patients who continue taking antidepressant medications (26%) (Cohen 2006). However, if treatment for major depressive disorder is initiated for the first time during pregnancy, trazodone is not one of the preferred medications (CANMAT [MacQueen 2016]; Larsen 2015; WFSBP [Bauer 2013]).Trazodone has also been evaluated for the treatment of insomnia. A randomized, placebo-controlled study in pregnant patients found trazodone (n = 18) to improve total sleep duration and sleep efficacy after 6 weeks of treatment compared to placebo (n = 17). In addition, the risk of postpartum depression was decreased. Treatment began during the third trimester and patients had no underlying sleep or mood disorders prior to pregnancy. Daytime sleepiness was a common adverse event (Khazaie 2013). In nonpregnant patients, trazodone is not the preferred treatment when cognitive behavioral therapies are not adequate because harm outweighs benefit (AASM [Sateia 2017]). Cognitive behavioral therapy is also effective in pregnant patients and is the currently preferred treatment (Bacaro 2020).Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Patients exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants. Pregnant patients 18 to 45 years of age or their health care providers may contact the registry by calling 1-844-405-6185. Enrollment should be done as early in pregnancy as possible.Breastfeeding ConsiderationsTrazodone and the active metabolite 1-m-chlorophenylpiperazine (mCPP) are present in breast milk (Saito 2021).Information related to the presence of trazodone in breast milk is available from a study that administered a single dose of trazodone 50 mg to 6 otherwise healthy breastfeeding women, 3 to 8 months postpartum. Breast milk was sampled over 24 hours. The presence of trazodone metabolites was not evaluated. Trazodone concentrations in breast milk peaked about 2 hours following administration, approximately the same time as in the plasma (Verbeeck 1986). Using data from this study, the relative infant dose (RID) of trazodone was calculated to be 2% of the weight-adjusted maternal dose, based on the highest breast milk concentration (100 ng/mL), providing an estimated daily infant dose via breast milk of 0.015 mg/kg/day.Information related to the presence of trazodone and mCPP in breast milk is available from a patient following use of trazodone 50 mg daily during pregnancy and postpartum. Breast milk was sampled after 5 days of therapy. The highest concentrations of trazodone (50.2 ng/mL) and mCPP (3.2 ng/mL) in breast milk were in the sample obtained 7.2 hours after a maternal dose. Using the highest breast milk concentration of trazodone, authors of this study calculated the RID to be 0.8% of the weight-adjusted maternal dose, providing an estimated daily infant dose via breast milk of 0.008 mg/kg/day. The infant was partially breastfed with >50% of nutrition from breast milk. Trazodone and mCPP were detected in infant serum 14.2 hours after birth (156.6 ng/mL and 9.8 ng/mL, respectively) and decreased significantly by postpartum day 5 (1.3 ng/mL and <0.2 ng/mL, respectively). This infant required oxygen due to a persistent respiratory disturbance for the first 4 days after birth (mother also taking etizolam); however, no drug-related adverse events were observed in the infant up to 6 months of age (Saito 2021).In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).Additional information related to the use of trazodone in breastfeeding women is limited (Misri 1991; Misri 2006).According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Infants exposed to antidepressants via breast milk should be monitored for changes in sleep, feeding patterns, and behavior as well as growth and development (Sachs 2013; WFSBP [Bauer 2013]).Psychotherapy or other nonmedication therapies are recommended for the initial treatment of mild depression in breastfeeding patients; antidepressant medication is recommended when psychotherapy is not an option or symptoms are moderate to severe. If a specific medication was used effectively during pregnancy, it can be continued while breastfeeding if no contraindications exist (ABM [Sriraman 2015]).When first initiating an antidepressant in a breastfeeding patient, agents other than trazodone are preferred (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]; Larsen 2015).Monitoring ParametersBaseline liver function prior to and periodically during therapy; closely monitor patients for depression, clinical worsening, suicidality, psychosis, or unusual changes in behavior (eg. anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania), particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); signs/symptoms of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile BP, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures; signs/symptoms of hypotension or orthostasis.Mechanism of ActionInhibits reuptake of serotonin, causes adrenoreceptor subsensitivity, acts as a 5HT2a receptor antagonist and induces significant changes in 5-HT presynaptic receptor adrenoreceptors. Trazodone also significantly blocks histamine (H1) and alpha1-adrenergic receptors.Pharmaco*kineticsOnset of action: Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).Absorption: Well absorbed. Food increases absorption, decreases peak concentration and delays time to peak concentration of immediate release tablet; Extended release: Cmax increases ~86% when taken shortly after ingestion of a high-fat meal compared to fasting conditionsProtein binding: 89% to 95%Metabolism: Hepatic via CYP3A4 (extensive) to an active metabolite (mCPP)Bioavailability: 100% (Hiemke 2018)Half-life elimination: 5 to 9 hours, prolonged in obese patientsTime to peak, serum:Immediate release: 30 to 100 minutes; delayed with food (up to 2.5 hours)Extended release: 9 hours; not significantly affected by foodExcretion: Primarily urine (74%, <1% excreted unchanged); secondarily feces (~21%)Pricing: USTablets (traZODone HCl Oral)50 mg (per each): $0.15 - $1.07100 mg (per each): $0.21 - $1.39150 mg (per each): $0.52 - $2.79300 mg (per each): $5.44Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAcraf (CH);Azonz (FI);Codipzona (CL);Deprel (PK);Depresil (PH);Depryl (IN);Desirel (TH);Desyrel (JP);Devidon (HR);Donaren (BR);Mei Su Yu (CN);Mesyrel (CN, TW);Mesyrol (HK);Molipaxin (GB, ZA);Nestrolan (BE);Oleptro (BM);Pragmarel (FR);Reslin (JP);Taxagon (AR);Taxagon AC (UY);Thombran (DE);Torlex (TW);Trazo (TH);Trazodil (IL);Trazodone-Continental (LU);Trazolan (BE, IN, LU, NL);Trazone (PT);Trazonil (IN);Trazopress (HK);Trittico (AE, AT, BG, BH, CH, CL, CO, CY, CZ, EG, GR, HK, HN, IL, IQ, IR, IT, JO, KR, KW, LB, LY, OM, PE, PL, PY, QA, RU, SA, SG, SI, SK, SY, UA, VE, YE);Trittico AC (CO, RO);Trittico CR (KR);Zodonrel (TH)For country code abbreviations (show table)ACOG Committee on Practice Bulletins--Obstetrics. 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CloseKeratin granulomaKeratin granuloma(A) A granulomatous inflammatory reaction surrounding eosinophilic keratinous material released into the dermis by a ruptured epidermoid cyst.(B) At higher magnification, foreign body-type giant cells and keratin flakes are visible.Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.Graphic 100143 Version 2.0

CloseLeg raises in all planes (around the world)Leg raises in all planes (around the world)Leg raises are an example of light resistance exercise and can be performed relatively early during rehabilitation, provided they do not cause pain: (A) hip flexion; (B) hip abduction; (C) hip adduction; (D) prone hip extension.Courtesy of Timothy J Von Fange, MD.Graphic 100182 Version 3.0