Topotecan is a chemotherapeutic drug and acts by inhibiting Topoisomerase 1. It is used in the treatment of lung cancer, ovarian, and cervical cancer.

Indications of Topotecan:

• Recurrent or persistent cervical cancer:

  • It is indicated for treatment (in combination with cisplatin) of stage IVb, recurrent or persistent cervical cancer that is not amenable to curative treatment.

• Metastatic Ovarian cancer:

  • It is used for the treatment of metastatic ovarian cancer (as a single agent) after disease progression on or after initial or subsequent chemotherapy.

• Relapsed or progressive small cell lung cancer:

  • It is used for treating  small cell lung cancer (as a single agent) in patients with a platinum-sensitive disease which has progressed at least 60 days after initiation of first-line chemotherapy.
  • It is also used for 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 Use of Topotecan in Adults:

  • Ewing sarcoma;
  • High-risk Myelodysplastic syndromes;
  • Relapsed or refractory primary CNS lymphoma;
  • Rhabdomyosarcoma

Topotecan dose in Adults

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 and hemoglobin ≥9 g/dL. IV doses should generally not exceed 4 mg.

Topotecan dose in the treatment of recurrent or persistent Cervical cancer:

• 0.75 mg/m² intravenous for 3 days (days 1, 2, and 3; in combination with cisplatin on day 1 only with hydration every 3 weeks for a maximum of 6 cycles  or until disease progression or unacceptable toxicity.

Topotecan dose in the treatment of relapsed/refractory CNS malignancy:

• Adults ≤21 years of age:

  • 0.8 mg/m² per oral per day for 21 consecutive days every 4 weeks for ≥12 cycles.

Topotecan dose in the treatment of metastatic or relapsed/refractory Ewing sarcoma:

• 0.75 mg/m² intravenous for 5 consecutive days every 21 days in combination with cyclophosphamide.

Topotecan dose in the treatment of High-risk Myelodysplastic syndromes:

Induction: 1.25 mg/m²  intravenous as a continuous infusion for 5 days in combination with cytarabine.

Topotecan dose in the treatment of metastatic Ovarian cancer:

• 1.5 mg/m² intravenous for 5 consecutive days every 21 days, continue until disease progression or unacceptable toxicity  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  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.

Topotecan dose in the treatment of Primary relapsed or refractory CNS lymphoma:

• 1.5 mg/m² intravenous for 5 days every 21 days for a maximum of 10 cycles or until disease progression or unacceptable toxicity.

Topotecan dose in the treatment of metastatic Rhabdomyosarcoma:

• Adults <21 years of age:

  • 0.75 mg/m² intravenous 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).

Topotecan dose in the treatment of relapsed or progressive Small cell lung cancer:

• 1.5 mg/m² intravenous for 5 consecutive days every 21 days.
• 2.3 mg/m² per oral for 5 consecutive days (days 1 to 5) every 21 days for at least 4 cycles ;
• round the dose to the nearest 0.25 mg;
• if the patient vomits after the dose is administered, do not give a replacement dose.

Topotecan dose in Childrens

Note:

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.

Topotecan dose in the treatment of recurrent Acute lymphoblastic leukemia:

• Children and Adolescents:

  • Induction therapy: 2.4 mg/m² intravenous once daily for 7 to 9 days.

Topotecan dose in the treatment of recurrent or refractory Acute myeloid leukemia:

• Children and Adolescents:

  • Initial: 4 mg/m² intravenous 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/m /day (range: 1.7 to 6 mg/m² /day)

Topotecan dose in the treatment of CNS malignancies, including gliomas:

• Fixed dosing:

  • Using reconstituted lyophilized parenteral formulation: 0.8 mg/m² per oral 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)].

  • Dose escalation:

    • Children ≥3 years and Adolescents:

      • using reconstituted lyophilized parenteral formulation: Initial: 0.4 mg/m² /dose per oral 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.
      • median maximum tolerated dose: 0.9 mg/m /day (range: 0.6 to 2 mg/m /day)
      • median duration of therapy: 3 months (range: 21 days to 1 year).

Topotecan dose in the treatment of Neuroblastoma:

• Induction:

  • Patient weight ≤12 kg:

    • 04 mg/kg intravenous once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days for 6 cycles.

  • Patient weight >12 kg:

    • Initial: 1.2 mg/m /dose once daily for 5 days (in combination with cyclophosphamide); repeat cycle every 21 days for 6 cycles.

• Recurrent, refractory, or untreated metastatic disease:

  • Combination therapy:

    • 75 mg/m² intravenous once daily for 5 days (in combination with cyclophosphamide);
    • repeat cycle every 21 days.

  • Monotherapy:

    • 2 mg/m² /day for 5 days.

  •  (using reconstituted lyophilized parenteral formulation):

    • Children ≥2 years and Adolescents:

      • 8 mg/m² per oral once daily for 14 days (in combination with oral cyclophosphamide); repeat cycle every 21 to 28 days.

Topotecan dose in the conditioning of Hematopoietic stem-cell transplant:

• Children and Adolescents:

  • 2 mg/m² intravenous on days -8 through -4 prior to stem cell transfusion (total dose: 10 mg/m²), in combination with carboplatin and thiotepa.

Topotecan dose in the treatment of Pediatric solid tumors, recurrent or refractory or untreated metastatic including rhabdomyosarcoma and Ewing sarcoma:

• Combination therapy:

  • 75 mg/m² intravenous once daily for 5 days every 21 days in combination with cyclophosphamide or with cyclophosphamide and vincristine (VTC regimen),
  • This dosing has also been administered in combination with temozolomide in 28-day cycles (TOTEM regimen)

• Single-agent therapy (window therapy):

  • 2-2.4 mg/m² /dose once daily for 5 days every 21 day.

• Oral [using reconstituted lyophilized parenteral formulation or oral capsules (for patients able to swallow)]:

  • Children ≥3 years and Adolescents:

    • 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;

Topotecan Dosing adjustment for toxicity in Adults:  

• 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/m /day for subsequent cycles (may consider the same dosage reduction for grade 2 diarrhea if clinically indicated).

Pregnancy Risk Category: D

• Studies on animal reproduction have shown that fetal harm can be caused by it.
• It can lead to impaired spermatogenesis for males.
• Effective contraception should be used by females during treatment, for at least 6 month, and for three months after the last dose of topotecan.

Use of topotecan while breastfeeding

• It is not known if breast milk contains topotecan.
• According to the manufacturer, breastfeeding should be avoided during therapy as well as for one week after the last dose of topotecan.

Topotecan Dose adjustment in renal disease:

• Manufacturer's labeling (calculate CrCl with Cockcroft-Gault method using ideal body weight):

  • Single-agent topotecan):

    • Creatinine clearance≥40 mL/minute:

      • No dosage adjustment required.

    • Creatinine clearance 20 to 39 mL/minute:

      • Reduce dose to 0.75 mg/m /dose

    • Creatinine clearance <20 mL/minute:

      • There are no dosage adjustments provided in the manufacturer's labeling

  • IV (when used in combination with cisplatin):

    • There are no dosage adjustments provided in the manufacturer's labeling.

  • Oral Topotecan :

    • Creatinine clearance≥50 mL/minute:

      • No dosage adjustment is necessary.

    • Creatinine clearance 30 to 49 mL/minute:

      • Reduce dose to 1.5 mg/m /dose.

    • Creatinine clerance <30 mL/minute:

      • Reduce dose to 0.6 mg/m /dose.

  • The following adjustments have also been recommended (for IV topotecan):

    • Creatinine clearance 46 to 60 mL/minute:

      • Administer 80% of the usual dose.

    • Creatinine clearance 31 to 45 mL/minute:

      • Administer 75% of the usual dose.

    • Creatinine clearance ≤30 mL/minute:

      • Administer 70% of the usual dose.

    • Creatinine clearance ≥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/m to 1 mg/m² in heavily pretreated patients.

    • Creatinine clearance 20 to 39 mL/minute:

      • Reduce dose from 1.5 mg/m to 0.75 mg/m in minimally pretreated patients or to 0.5 mg/m in heavily pretreated patients

    • Creatinine clerance <20 mL/minute:

      • Data was insufficient to make a recommendation.

    • Hemodialysis:

      • Avoid use.

    • Continuous ambulatory peritoneal dialysis (CAPD):

      • Avoid use.

    • Continuous renal replacement therapy (CRRT):

      • 75 mg/m².

Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer's labeling for both intravenous or oral formulation.

Common Side Effects of Topotecan:

• Central Nervous System:

  • Fatigue

• Dermatologic:

  • Alopecia

• Gastrointestinal:

  • Nausea
  • Diarrhea
  • Vomiting
  • Anorexia

• Hematologic & Oncologic:

  • Anemia
  • Neutropenia
  • Thrombocytopenia
  • Febrile Neutropenia
  • Neutropenic Infection

Rare Side Effects Of Topotecan:

• Central Nervous System:

  • Pain

• Gastrointestinal:

  • Abdominal Pain
  • Constipation
  • Intestinal Obstruction

• Hepatic:

  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Bilirubin

• Neuromuscular & Skeletal:

  • Asthenia

• Respiratory:

  • Dyspnea
  • Pneumonia

• Miscellaneous:

  • Fever
  • Sepsis

Uncommon side effects of Topotecan:

• Hematologic & Oncologic:

  • Bone Marrow Depression

Contraindications to Topotecan:

• Hypersensitivity to any component of the formulation or topotecan in severe cases
• Grave renal impairment
• Pregnancy
• Breastfeeding
• Pre-existing severe bone marrow depression

Warnings and precautions

• Suppression of bone marrow: [US Boxed Warning]

  • Topotecan can cause severe myelosuppression, including anemia, neutropenia, infection, sepsis, and thrombocytopenia.
  • Treatment interruption, dosage reduction or support for growth factor may be required in cases of hematologic toxicities.

• Extravasation

  • Topotecan IV can cause extravasation and is an irritant. Proper needle positioning is essential.

• Gastrointestinal toxicities:

  • Topotecan can cause severe diarrhea and GI perforation.
  • In severe cases, antidiarrhoeals and antiemetics may also be recommended. This is to prevent nausea/vomiting or diarrhea.

• Hypersensitivity

  • Reports of hypersensitivity reactions including anaphylaxis, allergic reaction and angioedema are common.

• Neutropenic enterocolitis

  • Topotecan-induced neutropenia can lead to neutropenic enterocolitis in which patients present with neutropenia, fever and abdominal pain.

• Toxicity in the lungs:

  • ILD can occur in patients with interstitial lung disease (ILD), especially if there are risk factors like a history of ILD or pulmonary fibrosis, lung cancer, lung malignancy, thoracic radiotherapy, or medications that cause pulmonary toxicities.

Topotecan: Drug Interaction

Monitoring parameters:

• Complete blood count
• Renal function tests
• Liver function test
• Pregnancy test
• Symptoms of interstitial lung disease
• Diarrhea symptoms/hydration status.

How to administer Topotecan?

• The intravenous piggyback should not be administered for more than half an hour. 
• Before starting therapy, it is important to hydrate properly.
• To avoid extravasation, it is important to properly position the catheter. 
• Infusions should be stopped immediately.
• Extravasation should be treated promptly.
• Orally administer the medication as a whole, with or without food. 
• If a dose is not taken, a replacement dose should not be given.
• However, the next dose should always be administered at the time scheduled.
• Patients who are unable to swallow whole capsules may mix reconstituted topotecan solution (1 mg/mL) with up to 30mL of acidic juice, such as grape, orange, or apple. 

Mechanism of action of Topotecan:

• Topotecan is active in the S phase. 
• Topotecan stabilizes the cleavable compound by binding to topoisomerase 1 to prevent religation. 
• This causes the formation of cleavable complicatedes and the breaking down of single-strand DNA.

Protein binding:

• 35%

Metabolism:

• It undergoes a pH-dependent, reversible hydrolysis of the (active), lactone ring to produce a relatively inactive form of hydroxy acid plasma. At pH =4, however, the active ring dominates; At physiologic pH the ring-opened form of hydroxy acid predominates; topotecan can be metabolized by the liver to N–demethylated metabolite

The Bioavailability of the oral capsules in adults is 40%.

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)
• Adults: IV: 2 to 3 hours Oral: 3 to 6 hours

The time to reach peak plasma concentration:

• Pediatric patients (1 to 18 years of age): Parenteral formulation (reconstituted lyophilized formulation): 0.75 to 2 hours.
• Adults: Oral: 1 to 2 hours; delayed with a high-fat meal (3 to 4 hours)

Excretion:

• Intravenous occurs in urine (51%; ~3% as N-desmethyl topotecan)
• feces (18%; ~2% as N-desmethyl topotecan)
• Oral
  • occurs in urine (20%; 2% as N-desmethyl topotecan)
  • feces (33%; <2% as N-desmethyl topotecan).

Topotecan Brand Names (International):

• Hycamtin
• ACT Topotecan
• Hycamtin
• PMS-Topotecan
• Camtoop
• Canol
• Firotex
• Hycamtin
• Hykamtin
• Oncotecan
• Potactasol
• Potekam
• Topocan
• Topodria
• Topokebir
• Topotel
• Toranex

Topotecan Brand Names in Pakistan: