Topotecan

FDA-Approved Indications:

• Metastatic ovarian cancer: For patients who have failed or relapsed following initial chemotherapy.
• Small cell lung cancer (SCLC): For patients with recurrent disease after first-line chemotherapy failure.
• Cervical cancer: In combination with cisplatin for stage IVB, recurrent, or persistent cervical cancer not amenable to curative treatment (e.g., surgery and/or radiation).

Clinically Accepted Off-Label Uses:

• Breast cancer: In metastatic or advanced stages unresponsive to standard agents.
• Glioblastoma multiforme: As part of salvage regimens.
• Pediatric cancers: Including neuroblastoma and Ewing's sarcoma in investigational or compassionate use settings.

Route of Administration:

• Intravenous (IV) infusion
• Oral capsule formulation

Adult Dosage:

• Ovarian Cancer (IV):
  1.5 mg/m²/day as a 30-minute IV infusion once daily for 5 consecutive days every 21 days.
• SCLC (IV):
  Same as ovarian cancer OR 1.25 mg/m²/day for 5 days every 21 days.
• Cervical Cancer (IV):
  0.75 mg/m²/day as a 30-minute IV infusion on days 1–3, with cisplatin 50 mg/m² IV on day 1 every 21 days.

Oral Topotecan (SCLC only):
2.3 mg/m² orally once daily for 5 consecutive days every 21 days.

Pediatric Dosage:
Not FDA-approved; doses vary based on clinical protocols (typically 0.75–1.5 mg/m²/day).

Dose Adjustments:

• Renal Impairment:
• CrCl 40–60 mL/min: Reduce dose to 0.75–1.25 mg/m².
• CrCl < 40 mL/min: Use is not recommended.
• Hepatic Impairment: Use with caution; limited data available.
• Elderly: No specific adjustments, but monitor for increased toxicity due to reduced organ function.

Topotecan is a topoisomerase I inhibitor. It binds reversibly to the topoisomerase I-DNA complex, stabilizing the cleavable complex and preventing re-ligation of single-strand breaks. This leads to the accumulation of DNA damage during replication, resulting in apoptosis of rapidly dividing tumor cells. Its cytotoxic effect is S-phase specific, maximizing impact on actively replicating cells.

• Absorption:
  Oral bioavailability ≈ 40%; peak plasma levels occur within 1–2 hours (oral), immediately post-infusion (IV).
• Distribution:
  Widely distributed; volume of distribution ~130 L/m²; plasma protein binding ~35%.
• Metabolism:
  Undergoes pH-dependent hydrolysis to an inactive carboxylate form; minimal CYP450 involvement.
• Elimination:
• Half-life: 2–3 hours (IV and oral)
• Excretion: Primarily renal (20–30% as unchanged drug); also fecal

• Pregnancy:
  Category D (old FDA system) – positive evidence of human fetal risk; use only if potential benefits outweigh risks. May cause fetal harm including teratogenicity and embryotoxicity.
• Lactation:
  Excreted in breast milk (based on animal data); breastfeeding is not recommended during treatment and for at least 1 week after the last dose due to potential serious adverse effects on the infant.

• Primary Class: Antineoplastic agent
• Subclass: Topoisomerase I inhibitor
• Chemical Class: Camptothecin derivative

• Known hypersensitivity to topotecan or any formulation components
• Severe bone marrow suppression (baseline neutrophils <1,500/mm³ or platelets <100,000/mm³)
• Pregnancy (due to teratogenic risk)
• Severe renal impairment (especially CrCl < 20 mL/min for oral formulation)

• Myelosuppression: Major dose-limiting toxicity. Monitor CBCs frequently; delay or reduce dose if neutropenia, thrombocytopenia, or anemia occur.
• Infection risk: Increased susceptibility to bacterial, viral, or fungal infections; febrile neutropenia may be life-threatening.
• Pulmonary toxicity: Rare but severe interstitial lung disease (ILD) has been reported; discontinue immediately if symptoms develop.
• Gastrointestinal effects: Severe diarrhea and mucositis possible; supportive care necessary.
• Pregnancy risk: Embryotoxic and teratogenic.
• Secondary malignancies: Rare reports of therapy-related leukemia or myelodysplastic syndromes.

Common (>10%)

• Hematologic: Neutropenia, anemia, thrombocytopenia
• Gastrointestinal: Nausea, vomiting, diarrhea, mucositis, constipation
• General: Fatigue, fever, weakness
• Hepatic: Elevated AST/ALT

Serious

• Febrile neutropenia
• Sepsis
• Interstitial lung disease (rare)
• Severe myelosuppression requiring hospitalization
• Secondary leukemia or MDS (long-term use)

Timing: Most adverse effects emerge during or shortly after treatment cycles and are dose-related.

• Myelosuppressive agents: Additive bone marrow toxicity; use with caution.
• Live vaccines: Avoid during and shortly after therapy due to immunosuppression risk.
• CYP450 interactions: Minimal involvement; few hepatic metabolism-based interactions.
• P-gp substrates/inhibitors: May influence oral absorption and distribution; monitor if co-administered.

• NCCN Guidelines: Still includes topotecan as an option for relapsed SCLC and ovarian cancer when platinum-based therapy fails.
• EMA Update: Reinforced pulmonary toxicity warnings based on post-marketing data.
• FDA: Updated boxed warnings regarding severe bone marrow suppression and the need for hematologic monitoring.

• IV formulation:
  Store vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C.
  Protect from light. Reconstituted solution stable for 24 hours at 2°C–8°C (refrigerated).
• Oral capsules:
  Store at 20°C to 25°C. Keep in original blister packaging until use.
  Avoid excessive moisture and heat.