Topotecan

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Hycamtin: 0.25 mg, 1 mg

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)

Pharmacology

Mechanism of Action

Topotecan 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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d:

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)

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 metabolite

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, pharmacokinetic 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)

Time to Peak

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 (1.5 to 4 hours)

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 hours

Protein Binding

~35%

Use in Specific Populations

Special Populations: Renal Function Impairment

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.

Special Populations: Race

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.

Use: Labeled Indications

Cervical cancer, recurrent or persistent: Injection: Treatment (in combination with cisplatin) of stage IVB, recurrent or persistent cervical cancer that is not amenable to curative treatment

Ovarian cancer, metastatic: Injection: Treatment of metastatic ovarian cancer (as a single agent) after disease progression on or after initial or subsequent chemotherapy

Small 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 chemotherapy

Oral: 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 chemotherapy

Use: Off Label

Ewing sarcomab

Data from a phase II study and a retrospective analysis support the use of topotecan in the treatment of Ewing sarcoma Hunold 2006, Saylors 2001.

Myelodysplastic syndromes, high-riskcyes

Data from 2 retrospective analyses suggest that induction therapy with topotecan (in combination with cytarabine) may be beneficial for the treatment of high-risk myelodysplastic syndromes (MDS) in older adults Kantarjian 2006a, Kantarjian 2006b.

Based on guidelines for treatment of MDS from the European Society for Medical Oncology and from the European LeukemiaNet, topotecan may be given as a component of induction therapy (in combination with cytarabine) in the management of MDS.

Ovarian cancer, metastatic (off-label [weekly] dosing)b

Data from a phase II trial supports the use of topotecan as a weekly administration (in addition to the conventional 5-day treatment course) in the treatment of metastatic ovarian cancer Sehouli 2011.

Primary CNS lymphoma, relapsed or refractoryc

Data from a phase II trial suggests that topotecan may be beneficial for the treatment of relapsed or refractory primary CNS lymphoma Voloschin 2008.

Rhabdomyosarcomab

Data from a phase II trial supports the use of topotecan in the treatment of metastatic rhabdomyosarcoma in patients ≤21 years of age Walterhouse 2004.

Contraindications

Severe hypersensitivity to topotecan or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Severe renal impairment (CrCl <20 mL/minute); pregnancy; breastfeeding; preexisting severe bone marrow depression

Dosage and Administration

Dosing: Adult

Note: 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 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/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 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-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, 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 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, 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 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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: In adults, baseline neutrophil count should be ≥1500/mm³ and platelets should be ≥100,000/mm³ prior to treatment; for retreatment, neutrophil count should be >1000/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.

Acute lymphoblastic leukemia; recurrent (first relapse): Children and Adolescents: Induction therapy: IV: 2.4 mg/m²/dose once daily for 7 to 9 days (Furman 2002; Hijiya 2008)

Acute myeloid leukemia; recurrent, refractory: Children and Adolescents: IV: Initial: 4 mg/m²/dose once on day 1; subsequent daily doses (days 2 to 5) determined by pharmacokinetic analysis (target AUC: 140 ± 20 ng/mL/hour) and administered once daily (in combination with cladribine); the median reported topotecan dose was 4 mg/m²/day (range: 1.7 to 6 mg/m²/day) (Inaba 2010)

CNS malignancies, including gliomas:

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)

Neuroblastoma:

Induction: Infants, Children, and Adolescents: IV:

Patient weight ≤12 kg: 0.04 mg/kg/dose once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days for 6 cycles (Park 2011)

Patient weight >12 kg: Initial: 1.2 mg/m²/dose once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days for 6 cycles (Park 2011)

Note: Pharmacokinetic 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)

Recurrent, refractory, or untreated metastatic disease:

IV: Children and Adolescents:

Combination therapy: 0.75 mg/m²/dose once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days (Ashraf 2013; Kretschmar 2004; London 2010; Saylors 2001; Zage 2008)

Monotherapy: 2 mg/m²/day for 5 days (London 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 I dose escalation trial of 20 pediatric patients (median age: 10.6 years) with refractory solid tumors including neuroblastoma, a daily dose of 1.8 mg/m² once daily for 5 days, followed by 2 days rest, then another 5 days of therapy (one cycle: 10 doses over 12 days); repeat cycle every 28 days was shown to stabilize disease in some patients (Daw, 2004).

Hematopoietic stem-cell transplant; conditioning: 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: 1-29 years) with refractory solid tumors (neuroblastoma: n=11) (Kushner, 2001). In a Phase I/II 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 pharmacokinetic 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) (Kaskow 2012)

Pediatric solid tumors; recurrent or refractory or untreated metastatic including rhabdosarcoma, Ewing sarcoma:

IV: Infants, Children, and Adolescents:

Combination therapy: 0.75 mg/m²/dose once daily for 5 days every 21 days in combination with cyclophosphamide (Bernstien 2006; Hunhold 2006; Saylors 2001; Waterhouse 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)

Single-agent therapy (window therapy): 2-2.4 mg/m²/dose once daily for 5 days every 21 days (Pappo 2001)

Oral [using reconstituted lyophilized parenteral formulation or oral capsules (for patients able to swallow)]: Children ≥3 years and Adolescents: 1.8 mg/m² once daily for 5 days, followed by 2 days rest, then another 5 days of therapy (one cycle: 10 doses over 12 days); repeat cycle every 28 days; when using oral capsules, doses were rounded to the nearest 0.25 mg; dosing based on a Phase I trial dose escalation trial of 20 pediatric patients (median age: 10.6 years) with refractory solid tumors (Daw 2004)

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.

Adult:

Cervical cancer: IV: Severe febrile neutropenia (<1000/mm³ with temperature of 38°C) or platelet count <25,000/mm³: Reduce topotecan to 0.6 mg/m²/day for subsequent cycles [may consider GCSF support (beginning on day 4) prior to instituting dose reduction for neutropenic fever]. Note: Cisplatin may also require dose adjustment.

For neutropenic fever despite G-SCF use, reduce dose to 0.45 mg/m²/day for subsequent cycles.

Ovarian cancer: IV: Dosage adjustment for hematological effects: Severe neutropenia (<500/mm³) or platelet count <25,000/mm³: Reduce dose to 1.25 mg/m²/day for subsequent cycles [may consider G-CSF support (beginning on day 6) prior to instituting dose reduction for neutropenia]

Small cell lung cancer:

IV: Dosage adjustment for hematological effects: Severe neutropenia (<500/mm³) or platelet count <25,000/mm³: Reduce dose to 1.25 mg/m²/day for subsequent cycles [may consider G-CSF support (beginning on day 6) prior to instituting dose reduction for severe neutropenia]

Oral: Severe neutropenia (neutrophils <500/mm³ associated with fever or infection or lasting ≥7 days) or prolonged neutropenia (neutrophils ≥500/mm³ to ≤1000/mm³ lasting beyond day 21) or platelets <25,000/mm³ or grades 3 or 4 diarrhea: Reduce dose by 0.4 mg/m²/day for subsequent cycles (may consider same dosage reduction for grade 2 diarrhea if clinically indicated)

Dosing: Adjustment for Toxicity

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 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: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Reconstitute lyophilized powder with 4 mL SWFI. Reconstituted lyophilized powder and solution for injection should be further diluted in D5W or NS for infusion; some manufacturers recommend diluting in a minimum of 50 mL D5W or NS. Refer to specific product labeling for information.

Extemporaneously Prepared

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 NC, Santana VM, Iacono LC, et al. Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors. J Clin Oncol. 2004;22(5):829-837.14990638

Administration

IV: 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).

Storage

IV: Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.

Solution for injection: Store intact vials at 2°C to 8°C (36°F to 45°F). Store in original carton to protect from light. Single-use vials should be discarded after initial vial entry. Stability of solutions diluted for infusion is variable; refer to specific product information for details.

Lyophilized powder: Store intact vials at 20°C to 25°C (68°F to 77°F). Protect from light. Reconstituted solution should be used immediately after reconstitution. Solutions diluted in D5W or NS are stable for no more than 24 hours at ~20°C to 25°C (68°F to 77°F) protected from light (manufacturer's labeling) or up to 7 days under refrigeration (Craig 1997). Reconstituted solution for injection (reconstituted with bacteriostatic SWFI to 1 mg/mL) for oral administration is stable for 14 days at 4°C in plastic syringes (Daw 2004).

Oral: Store at 2°C to 8°C (36°F to 46°F). Protect from light.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCRP/ABCG2 Inhibitors: May increase the serum concentration of Topotecan. Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: 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. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosphenytoin-Phenytoin: May decrease the serum concentration of Topotecan. Management: Monitor topotecan response closely, and consider alternatives to phenytoin when possible. No specific guidelines for topotecan dose adjustment are available. Consider therapy modification

Granulocyte 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. Consider therapy modification

Lasmiditan: May increase the serum concentration of BCRP/ABCG2 Substrates. Avoid combination

Lenograstim: 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. Consider therapy modification

Lipegfilgrastim: 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. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Topotecan. Avoid combination

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Platinum Derivatives: May enhance the adverse/toxic effect of Topotecan. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tafamidis: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Tolvaptan: May increase the serum concentration of BCRP/ABCG2 Substrates. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Velpatasvir: May increase the serum concentration of Topotecan. Avoid combination

Voxilaprevir: May increase the serum concentration of BCRP/ABCG2 Substrates. Avoid combination

Adverse Reactions

>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, typhlitis

Warnings/Precautions

Concerns 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). Antiemetics may be recommended to prevent nausea and vomiting; oral topotecan is associated with a moderate emetic potential (depending on the dose) in pediatrics (Paw Cho Sing 2019).
• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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.

Monitoring Parameters

CBC with differential and platelet count, renal function tests, bilirubin; pregnancy test (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).

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to topotecan may cause fetal harm.

Verify 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.

Patient Education

What is this drug used for?

• It is used to treat cancer.

Frequently reported side effects of this drug

• Constipation
• Hair loss
• Lack of appetite

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Abdominal pain
• Abdominal cramps
• Severe nausea
• Vomiting
• Diarrhea
• Severe loss of strength and energy
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Severe injection site redness, burning, swelling, pain, or irritation
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.