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Topotecan

Medically reviewed on Nov 15, 2018

Pronunciation

(toe poe TEE kan)

Index Terms

  • Hycamptamine
  • SKF 104864
  • SKF 104864-A
  • Topotecan HCl
  • Topotecan Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Hycamtin: 0.25 mg, 1 mg

Solution, Intravenous [preservative free]:

Generic: 4 mg/4 mL (4 mL)

Solution Reconstituted, Intravenous:

Generic: 4 mg (1 ea [DSC])

Solution Reconstituted, Intravenous [preservative free]:

Hycamtin: 4 mg (1 ea)

Generic: 4 mg (1 ea)

Brand Names: U.S.

  • Hycamtin

Pharmacologic Category

  • Antineoplastic Agent, Camptothecin
  • Antineoplastic Agent, Topoisomerase I Inhibitor

Pharmacology

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.

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)

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%

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 AUCinf 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 AUCinf of 70% and 34%, respectively; white patients with CrCl 30 to 49 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUCinf of 108% and 80%, respectively; white patients with CrCl <30 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUCinf 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 AUCinf of 26% and 34%, respectively; Asian patients with CrCl 30 to 49 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUCinf of 153% and 121%, respectively; Asian patients with CrCl <30 mL/minute had a mean dose-normalized total topotecan and topotecan lactone AUCinf 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 resistant: Injection: Treatment of recurrent or resistant (stage IVB) cervical cancer (in combination with cisplatin) which 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

Off Label Uses

Acute myeloid leukemia (induction in older adults)

Data from a retrospective study suggest that topotecan induction may be beneficial for the treatment of AML in older adults [Kantarjian 2006].

CNS malignancy, relapsed/refractory

Data from a limited number of patients studied suggest that topotecan may be beneficial for the treatment of recurrent/refractory CNS malignancy in children [Minturn 2011].

Ewing sarcoma

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].

Neuroblastoma, relapsed/refractory

Data from both prospective and retrospective analyses support the use of topotecan in the management of relapsed/refractory neuroblastoma [Ashraf 2013], [ London 2010].

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

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 refractory

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

Rhabdomyosarcoma

Data from a phase II trial supports the use of topotecan in the treatment of metastatic rhabdomyosarcoma [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

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 resistant: 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 non-responders) or until disease progression or unacceptable toxicity (Long 2005)

Ovarian cancer, metastatic: IV: 1.5 mg/m2/day for 5 consecutive days every 21 days (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)

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.

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)

Primary CNS lymphoma, relapsed or refractory (off-label use): 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). Additional data may be necessary to further define the role of topotecan in this condition.

Rhabdomyosarcoma, metastatic (off-label use): Adults <21 years: 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)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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.

CNS malignancy, relapsed/refractory (off-label use; based on limited data): Oral: 0.8 mg/m2/day for 21 consecutive days every 4 weeks for ≥12 cycles (Minturn 2011); additional data may be necessary to further define the role of topotecan in this condition

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)

Neuroblastoma, relapsed/refractory (off-label use): IV: 0.75 mg/m2/day for 5 days every 21 days (in combination with cyclophosphamide) (Ashraf 2013; London 2010) or 2 mg/m2/day for 5 days every 21 days (monotherapy) (London 2010)

Rhabdomyosarcoma, metastatic (off-label use): 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)

Dosing: Renal Impairment

Manufacturer's labeling:

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).

Oral:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 49 mL/minute: Reduce dose to 1.5 mg/m2/day; may increase after the 1st cycle by 0.4 mg/m2/day if no severe hematologic or gastrointestinal toxicities occur.

CrCl <30 mL/minute: Reduce dose to 0.6 mg/m2/day; may increase after the 1st cycle by 0.4 mg/m2/day if no severe hematologic or gastrointestinal toxicities occur.

Alternate recommendations:

Aronoff 2007: IV:

Adults:

CrCl >50 mL/minute: Administer 75% of dose

CrCl 10 to 50 mL/minute: Administer 50% of dose

CrCl <10 mL/minute: Administer 25% of dose

Hemodialysis: Avoid use

Continuous ambulatory peritoneal dialysis (CAPD): Avoid use

Continuous renal replacement therapy (CRRT): 0.75 mg/m2

Children:

CrCl 30 to 50 mL/minute: Administer 75% of dose

CrCl 10 to 29 mL/minute: Administer 50% of dose

CrCl <10 mL/minute: Administer 25% of dose

Continuous renal replacement therapy (CRRT): Administer 50% of dose

Kintzel 1995: IV:

CrCl 46 to 60 mL/minute: Administer 80% of dose

CrCl 31 to 45 mL/minute: Administer 75% of dose

CrCl ≤30 mL/minute: Administer 70% of dose

Dosing: Hepatic Impairment

Manufacturer's labeling:

IV: Bilirubin 1.7 to 15 mg/dL: There are no dosage adjustments provided in the manufacturer's labeling, although clearance is reduced up to 33%.

Oral: There is no dosage adjustment provided in the manufacturer's labeling; however, dosage adjustment is likely not necessary as the pharmacokinetics of topotecan do not differ significantly based on serum bilirubin, ALT, or AST.

Dosing: Adjustment for Toxicity

Do not administer 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).

Cervical cancer (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 (may consider G-CSF support [beginning on day 4] prior to instituting dose reduction). 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.

Ovarian cancer: IV:

Neutrophils <500/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).

Platelets <25,000/mm3: Reduce dose to 1.25 mg/m2/day for subsequent cycles.

Small cell lung cancer (SCLC):

IV:

Neutrophils <500/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).

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.

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.

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 IVPB over 30 minutes. For combination chemotherapy with cisplatin, administer pretreatment hydration.

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). 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

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. Avoid combination

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 (G-CSFs) until at least 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

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

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

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

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

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

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. 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%)

Dermatologic: Alopecia (oral: 10% to 20%)

Gastrointestinal: Nausea (oral: 27% to 33%), anorexia (intravenous: 32%; oral: 7% to 14%), diarrhea (oral: 14% to 22%, grade 3: 4%, grade 4: ≤1%; intravenous: grades 3/4: 6%), vomiting (oral: 19% to 21%)

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%; oral: grade 4: 4%), neutropenic infection (13% to 17%)

1% to 10%:

Gastrointestinal: Abdominal pain (intravenous: grades 3/4: 5% to 6%)

Hepatic: Increased liver enzymes (intravenous: 8%; transient)

Neuromuscular & skeletal: Weakness (3% to 7%)

Respiratory: Dyspnea (intravenous: 6% to 9%)

Miscellaneous: Fever (oral: 5% to 7%), sepsis (intravenous: grades 3/4: 5%; oral: 2%)

<1%, postmarketing, and/or case reports: Anaphylactoid reactions, angioedema, arthralgia, chest pain, cough, dermatitis (severe), extravasation, headache, hemorrhage (severe, associated with thrombocytopenia), hypersensitivity reaction, interstitial pulmonary disease, leukopenia, myalgia, neutropenic enterocolitis, pancytopenia, paresthesia, pruritus (severe), skin rash, stomatitis, typhlitis

ALERT: U.S. Boxed Warning

Bone marrow suppression:

Topotecan can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of ≥1,500 cells/mm3 and a platelet count of ≥100,000 cells/mm3. Monitor blood cell counts.

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 topotecan). In a clinical study comparing IV to oral topotecan, G-CSF 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.

• Interstitial lung disease: 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, and the use of colony-stimulating factors or medications associated with pulmonary toxicity.

• 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.

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 Considerations

Based on the mechanism of action and data from animal reproduction studies, topotecan may cause fetal harm if administered during pregnancy.

Females of reproductive potential should have a pregnancy test prior to treatment initiation and 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.

Topotecan may have both acute and long-term effects on fertility in women and spermatogenesis may be impaired in males (based on animal data).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience, constipation, hair loss, or lack of appetite. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; 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, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), or severe injection site redness, burning, edema, pain, or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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