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.
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 (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; 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 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 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 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) (Kasow 2012).
Neuroblastoma: 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: 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).
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 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 (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.
Infants, 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).
There are no pediatric specific recommendations; based on experience in adult patients, no adjustment may be necessary
(For additional information see "Topotecan: Drug information")
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Manufacturer's labeling (calculate CrCl with Cockcroft-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/dose
CrCl <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 patients
CrCl <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)
IV: 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 pharmacokinetic 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Hycamtin: 0.25 mg, 1 mg
Solution, 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)
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, 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)
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]).
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).
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).
Hazardous 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).
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.
Treatment of metastatic ovarian cancer, relapsed or refractory small cell lung cancer, and recurrent or resistant (stage IVB) cervical cancer (in combination with cisplatin) (All indications: FDA approved in adults); has also been used in pediatric solid tumors (including Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and neuroblastoma) and relapsed or refractory acute leukemias.
Hycamtin may be confused with Mycamine
Topotecan may be confused with irinotecan
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.
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.
The 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, typhlitis
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
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).
• 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.
Substrate of BCRP/ABCG2, P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCRP/ABCG2 Inhibitors: May increase the serum concentration of Topotecan. Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: 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. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Fosphenytoin-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 modification
Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Gilteritinib: May increase the serum concentration of BCRP/ABCG2 Substrates BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Lasmiditan: May increase the serum concentration of BCRP/ABCG2 Substrates BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk X: 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. Risk D: 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. Risk D: Consider therapy modification
Lumacaftor 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 therapy
Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: 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. Risk D: Consider therapy modification
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Topotecan. Risk X: Avoid combination
Platinum 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 modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon 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 modification
Velpatasvir: May increase the serum concentration of Topotecan. Risk X: Avoid combination
Voxilaprevir: May increase the serum concentration of BCRP/ABCG2 Substrates BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
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.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to topotecan may cause fetal harm.
CBC with differential and platelet count; renal function tests; bilirubin; monitor for signs and symptoms of interstitial lung disease; diarrhea symptoms/hydration status.
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.
Note: Pharmacokinetic 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 metabolite
Bioavailability: 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 hours
Time 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, 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)
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.
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.
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.
Capsules (Hycamtin Oral)
0.25 mg (per each): $120.59
1 mg (per each): $482.36
Solution (Topotecan HCl Intravenous)
4 mg/4 mL (per mL): $32.07 - $129.81
Solution (reconstituted) (Hycamtin Intravenous)
4 mg (per each): $1,389.00
Solution (reconstituted) (Topotecan HCl Intravenous)
4 mg (per each): $168.00 - $358.25
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