Topotecan

Topotecan is a semi-synthetic derivative of camptothecin, a plant alkaloid, and it inhibits the nuclear enzyme topoisomerase I. In solution it undergoes a reversible, pH-dependent opening of its lactone ring; the lactone form is the pharmacologically active one, and the ring-opened carboxylate is inactive.

Mechanism of Action

• Topoisomerase I inhibition: the enzyme relieves the torsional strain that builds up ahead of the moving replication fork by making reversible single-strand breaks in DNA. Topotecan stabilises the covalent complex of the enzyme with the cut DNA strand, so the strand cannot be rejoined.
• DNA damage: the stabilised complexes cause protein-associated DNA single-strand breaks. When the replication fork meets them, replication stops and lethal double-strand breaks form, which mammalian cells cannot repair efficiently, leading to apoptosis. The effect is greatest during S phase.
• Binding: topotecan is thought to mimic a DNA base pair and to bind at the cleavage site, acting as an uncompetitive inhibitor of the enzyme–DNA complex.

Pharmacokinetics

• Distribution: after 30-minute infusions of 0.5–1.5 mg/m² daily for five days, plasma clearance was high (62 L/h, about two-thirds of liver blood flow) and the volume of distribution large (about 132 L), with a short half-life of 2–3 hours. Pharmacokinetics did not change over the five days, exposure rose about in proportion to the dose, and there was little or no accumulation. Plasma protein binding is low (35%), and distribution between blood cells and plasma is fairly even.
• Metabolism: the main route of clearance is hydrolysis of the lactone ring to the ring-opened carboxylate. Metabolism accounts for less than 10% of elimination; an N-desmethyl metabolite with similar or lower activity and O-glucuronides in urine have been found. In vitro, topotecan did not inhibit the main human cytochrome P450 enzymes or xanthine oxidase.
• Elimination: 71–76% of an intravenous dose was recovered after five daily doses. About 51% appeared in the urine as total topotecan and 3% as N-desmethyl topotecan; faecal elimination of total topotecan was 18% and of the N-desmethyl metabolite 1.7%.
• Special populations: in hepatic impairment (serum bilirubin 1.5–10 mg/dL), plasma clearance fell to about 67% of control and half-life rose by about 30%. In renal impairment with creatinine clearance of 41–60 mL/min, clearance fell to about 67% of control; in moderate renal impairment it fell to 34% of control and the mean half-life rose from 1.9 to 4.9 hours. Age, weight and ascites had no significant effect on clearance. Children, adolescents and young adults showed no apparent differences, but the data are limited.
• Capsules: the capsules may be taken with or without food. The oral pharmacokinetic data are in the SmPC of the capsules (section 5.2).

Powder for concentrate for solution for infusion

• Ovarian cancer (monotherapy): patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy.
• Small cell lung cancer (monotherapy): patients with relapsed SCLC for whom re-treatment with the first-line regimen is not considered appropriate.
• Cervical cancer (with cisplatin): patients with carcinoma of the cervix recurrent after radiotherapy, and patients with Stage IVB disease. Patients who have had cisplatin before need a sustained treatment-free interval to justify the combination.

Hard capsules

• Small cell lung cancer (monotherapy): adult patients with relapsed SCLC for whom re-treatment with the first-line regimen is not considered appropriate.

Another EU-authorised topotecan product, a concentrate for solution for infusion, carries the same infusion indications.

The same contraindications apply to the infusion and the capsules.

• Severe hypersensitivity to topotecan or to any of the excipients.
• Breastfeeding.
• Severe bone marrow depression before the first course, shown by baseline neutrophils below 1.5 × 10⁹/L and/or platelets below 100 × 10⁹/L.

In dose-finding studies with 523 patients with relapsed ovarian cancer and 631 with relapsed small cell lung cancer, the dose-limiting toxicity of topotecan monotherapy was haematological; it was predictable and reversible, with no sign of cumulative haematological or other toxicity. With cisplatin in cervical cancer the profile is consistent with monotherapy; blood toxicity overall is lower than with topotecan alone but higher than with cisplatin alone, and the additional reactions are those of cisplatin (see its SmPC). The lists below are for the infusion.

Very common (≥1/10): infection; febrile neutropenia, neutropenia, thrombocytopenia, anaemia, leucopenia; anorexia (which may be severe); nausea, vomiting and diarrhoea (all of which may be severe), constipation, abdominal pain, mucositis; alopecia; pyrexia, asthenia, fatigue.

Common (≥1/100 to <1/10): sepsis; pancytopenia; hypersensitivity reaction including rash; hyperbilirubinaemia; pruritus; malaise.

Rare (≥1/10,000 to <1/1,000): anaphylactic reaction, angioedema, urticaria; interstitial lung disease (some cases fatal).

Very rare (<1/10,000): extravasation (reactions have been mild and have not generally needed specific treatment).

Not known: severe bleeding associated with thrombocytopenia; gastrointestinal perforation; mucosal inflammation.

Deaths from sepsis have been reported, and neutropenic colitis, including fatal cases, can complicate topotecan-induced neutropenia.

Capsules: the SmPC for the capsules lists similar reactions, with some frequency differences. Constipation, abdominal pain and mucositis are common rather than very common, dyspepsia is also listed as common, asthenia, pyrexia and malaise are common, and fatigue is very common. In 682 patients with relapsed lung cancer given 2,536 courses of oral topotecan, grade 4 neutropenia occurred in 32% of patients (13% of courses), grade 4 thrombocytopenia in 6% and moderate to severe anaemia (haemoglobin below 8.0 g/dL) in 25%; sepsis-related death occurred in 1%. The most frequent non-haematological reactions, whatever the cause, were nausea (37%), diarrhoea (29%), fatigue (26%), vomiting (24%), alopecia (21%) and anorexia (18%). Drug-related diarrhoea occurred in 22% (4% grade 3, 0.4% grade 4) and was more frequent over 65 years (28%) than under 65 (19%); the median time to grade 2 or worse diarrhoea was nine days.

• General: no in vivo human pharmacokinetic interaction studies have been done. Topotecan does not inhibit human cytochrome P450 enzymes. In a population study of intravenous topotecan, granisetron, ondansetron, morphine and corticosteroids given at the same time did not appear to affect the pharmacokinetics of total topotecan.
• Other chemotherapy: when topotecan is combined with other chemotherapy, the dose of each medicine may need to be lowered to improve tolerability.
• Platinum agents (cisplatin, carboplatin): there is a distinct sequence-dependent interaction. If the platinum agent is given on day 1 of the topotecan course, a lower dose of each medicine must be used than when the platinum agent is given on day 5. In 13 patients with ovarian cancer given topotecan 0.75 mg/m² for 5 days with cisplatin 60 mg/m² on day 1, exposure on day 5 rose slightly (AUC 12%, Cmax 23%), which is unlikely to be clinically relevant.
• Growth factors: neutropenia can be managed by giving G-CSF with topotecan or by lowering the dose; colony stimulating factors are among the risk factors listed for interstitial lung disease.
• Food: the capsules may be taken with or without food.

Topotecan infusion should be confined to units specialised in giving cytotoxic chemotherapy and given under the supervision of a physician experienced in chemotherapy. The capsules should only be prescribed, and treatment supervised, by a physician experienced in chemotherapy. Before the first course, patients need a neutrophil count of at least 1.5 × 10⁹/L, platelets of at least 100 × 10⁹/L and haemoglobin of at least 9 g/dL (after transfusion if necessary). When topotecan is used with cisplatin, the full prescribing information for cisplatin must also be consulted.

Infusion: Ovarian Cancer and Small Cell Lung Cancer

• Initial dose: 1.5 mg/m² of body surface area per day by intravenous infusion over 30 minutes, daily for five consecutive days, with a three-week interval between the starts of courses. If well tolerated, treatment may continue until disease progression.
• Later courses: do not repeat unless neutrophils are at least 1 × 10⁹/L, platelets at least 100 × 10⁹/L and haemoglobin at least 9 g/dL (after transfusion if necessary).
• Dose reduction: neutropenia can be managed by giving G-CSF or by lowering the dose. For neutrophils below 0.5 × 10⁹/L for seven days or more, severe neutropenia with fever or infection, or a delay in treatment because of neutropenia, reduce by 0.25 mg/m² per day to 1.25 mg/m², and then if necessary to 1.0 mg/m². Reduce in the same way if platelets fall below 25 × 10⁹/L. In studies, treatment was stopped if a further reduction was needed at 1.0 mg/m².

Infusion: Cervical Cancer with Cisplatin

• Initial dose: topotecan 0.75 mg/m² per day as a 30-minute infusion on days 1, 2 and 3; cisplatin 50 mg/m² on day 1, after the topotecan dose. The schedule is repeated every 21 days for six courses or until disease progression.
• Later courses: do not repeat unless neutrophils are at least 1.5 × 10⁹/L, platelets at least 100 × 10⁹/L and haemoglobin at least 9 g/dL (after transfusion if necessary).
• Dose reduction: for the neutropenia criteria above, reduce by 20% to 0.60 mg/m² per day for later courses, and then if necessary to 0.45 mg/m². Reduce in the same way if platelets fall below 25 × 10⁹/L.
• The infusion must be reconstituted and diluted before use (SmPC section 6.6).

Capsules: Relapsed Small Cell Lung Cancer

• Initial dose: 2.3 mg/m² of body surface area per day for five consecutive days, with a three-week interval between the starts of courses. If well tolerated, treatment may continue until disease progression. Capsules are swallowed whole, not chewed, crushed or divided, with or without food.
• Later courses: same blood-count criteria as for the infusion in ovarian and lung cancer (neutrophils at least 1 × 10⁹/L, platelets at least 100 × 10⁹/L, haemoglobin at least 9 g/dL).
• Dose reduction: for the neutropenia criteria above, reduce by 0.4 mg/m² per day to 1.9 mg/m², and then if necessary to 1.5 mg/m²; reduce in the same way if platelets fall below 25 × 10⁹/L. In studies, treatment was stopped if the dose needed to go below 1.5 mg/m². For grade 3 or 4 diarrhoea, reduce by 0.4 mg/m² per day for later courses; grade 2 diarrhoea may need the same approach.
• Diarrhoea: proactive treatment with anti-diarrhoeal medicines is important. Severe cases may need oral or intravenous electrolytes and fluids, and interruption of topotecan.

Special Populations

• Renal impairment, infusion monotherapy: not recommended with creatinine clearance below 20 mL/min (insufficient experience). With creatinine clearance of 20–39 mL/min, limited data indicate 0.75 mg/m² per day for five consecutive days.
• Renal impairment, cervical combination: treatment was started only if serum creatinine was 1.5 mg/dL or lower. If it rises above 1.5 mg/dL, the cisplatin information should be consulted on reducing or continuing cisplatin. If cisplatin is stopped, there are too few data on continuing topotecan alone in cervical cancer.
• Renal impairment, capsules: with creatinine clearance of 30–49 mL/min, 1.9 mg/m² per day for five consecutive days, which may be raised to 2.3 mg/m² in later cycles if well tolerated. Limited data in Korean patients with creatinine clearance below 50 mL/min suggest a still lower dose may be needed. There are too few data below 30 mL/min.
• Hepatic impairment: in a small number of patients with serum bilirubin 1.5–10 mg/dL given 1.5 mg/m² per day, clearance fell, but the data are too few for a dose recommendation. The infusion is not recommended in severely impaired liver function due to cirrhosis. The capsules have not been specifically studied in hepatic impairment.
• Elderly: with the capsules, effectiveness was similar in patients over 65 and in younger adults, but drug-related diarrhoea was more frequent over 65.
• Children and adolescents: the available data are described in the SmPC, but no dose recommendation can be made.

Missed Dose

The SmPC gives no rule for a missed capsule dose; the treating physician decides.

Blood Counts, Sepsis and Neutropenic Colitis

• Blood toxicity is dose-related, and full blood counts including platelets are needed regularly. Topotecan can cause severe myelosuppression, and sepsis and deaths from sepsis have been reported.
• Neutropenia can lead to neutropenic colitis, with deaths in clinical studies. Consider it in a patient with fever, neutropenia and a compatible pattern of abdominal pain.
• Clinically relevant thrombocytopenia is common, which matters when patients at higher risk of bleeding from the tumour are considered for treatment.
• Patients with poor performance status (above 1) respond less often and have more complications such as fever, infection and sepsis. Performance status must be assessed accurately when therapy is given, to make sure the patient has not worsened to status 3.

Interstitial Lung Disease

Interstitial lung disease, some of it fatal, has been reported. Risk factors are earlier interstitial lung disease, pulmonary fibrosis, lung cancer, radiation to the chest, and the use of pneumotoxic medicines and/or colony stimulating factors. Monitor for cough, fever, shortness of breath or low oxygen, and stop topotecan if a new diagnosis is confirmed.

Kidney and Liver Function

There is too little experience in severely impaired kidney function (creatinine clearance below 20 mL/min) or in severely impaired liver function due to cirrhosis, and topotecan is not recommended in these patients.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: topotecan caused embryo-foetal lethality and malformations in preclinical studies and may cause foetal harm. Women of childbearing potential should be advised to avoid becoming pregnant during treatment. If it is used in pregnancy, or the patient becomes pregnant, she must be warned of the possible risk to the foetus.
• Contraception: women of childbearing potential should use effective contraception during treatment and for 6 months after it ends. Men should use effective contraception and not father a child during treatment and for 3 months after it ends.
• Breastfeeding: contraindicated. Although it is not known whether topotecan passes into breast milk, breastfeeding should be stopped at the start of treatment.
• Fertility: no effect on male or female fertility was seen in rats, but topotecan is genotoxic, so effects on fertility, including male fertility, cannot be excluded.

Sodium and Ethanol

The infusion contains less than 1 mmol (23 mg) of sodium per dose, essentially sodium-free; the sodium dose is higher if 0.9% sodium chloride solution is used for dilution. The ink on the capsule sealing band contains anhydrous ethanol; see the package leaflet.

Effect on Driving

No studies on driving or using machines have been done. Take care when driving or using machines if fatigue and asthenia persist.

• Powder for infusion (Hycamtin 1 mg and 4 mg): keep the vial in the outer carton to protect it from light. The SmPC sets no temperature limit.
• Hard capsules (0.25 mg and 1 mg): store in a refrigerator at 2–8 °C, do not freeze, and keep the blister in the outer carton to protect it from light. This calls for cold-chain handling during delivery and storage.
• Other topotecan concentrate for infusion: the concentrate for solution for infusion from another marketing authorisation holder is stored in a refrigerator at 2–8 °C, not frozen, with the vial kept in the outer carton to protect it from light. Check the SmPC of the product actually supplied.
• Storage after reconstitution and dilution is described under Shelf Life.

• Powder vials and hard capsules: 3 years.
• Reconstituted and diluted infusion solutions: use immediately after reconstitution, because the product has no antibacterial preservative. If reconstitution and dilution are done under strict aseptic conditions (for example on a laminar air flow bench), the infusion should be completed within 12 hours at room temperature or within 24 hours if stored at 2–8 °C after the first puncture of the vial.
• Other topotecan concentrate for infusion: unopened vial 3 years; after first opening, chemical and physical in-use stability has been shown for 24 hours at 25 °C under normal light and at 2–8 °C protected from light.

Prescription only (Rx). Topotecan must be used under the supervision of a physician experienced in chemotherapy. The infusion is given in a unit specialised in cytotoxic chemotherapy, so it is supplied to the hospital or clinic that administers it. The hard capsules are taken by the patient, so they are supplied to the patient or to the treating clinic on prescription, with cold-chain delivery at 2–8 °C.