topotecan

Topotecan injection, as a single agent, is indicated for the treatment of patients with metastatic carcinoma of the ovary after disease progression on or after initial or subsequent chemotherapy.

Topotecan injection, as a single agent, is indicated for the treatment of patients with small cell lung cancer with platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy.

Topotecan injection in combination with cisplatin is indicated for the treatment of patients with Stage IV-B, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment.

Topotecan injection is a cytotoxic drug. Follow applicable special handling and disposable procedures.¹

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of topotecan. Neutropenia is not cumulative over time. Severe myelotoxicity has been reported when topotecan is used in combination with cisplatin [see Drug Interactions (7)].

• The following data on myelosuppression are based on an integrated safety database from 8 trials (N = 879) using topotecan injection at 1.5 mg/m² by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course in patients with ovarian cancer and small cell lung cancer and from one trial in patients with cervical cancer (N = 147) using topotecan 0.75 mg/m² by intravenous infusion over 30 minutes daily on Days 1, 2, and 3 repeated every 21 days in combination with cisplatin 50 mg/m² on Day 1.

Neutropenia

• Monotherapy: Grade 4 neutropenia (less than 500 cells/mm³) occurred in 78% of patients, with a median duration of 7 days and was most common during Course 1 of treatment (58% of patients). Grade 4 neutropenia associated with infection occurred in 13% of patients and febrile neutropenia occurred in 5% of patients. Sepsis occurred in 4% of patients and was fatal in 1% of patients. Pancytopenia has been reported.
• Combination with cisplatin: Grade 4 neutropenia occurred in 48% of patients.

Thrombocytopenia

• Monotherapy: Grade 4 thrombocytopenia (less than 25,000/mm³) occurred in 27% of patients, with a median duration of 5 days.
• Combination with cisplatin: Grade 4 thrombocytopenia occurred in 7% of patients.

Anemia

• Monotherapy: Grade 3 or 4 anemia (less than 8 g/dL) occurred in 37% of patients.
• Combination with cisplatin: Grade 3 or Grade 4 anemia occurred in 40% of patients.

Administer topotecan only to patients with a baseline neutrophil count of greater than or equal to 1,500 cells/mm³ and a platelet count greater than or equal to 100,000/mm³. Monitor peripheral blood counts frequently during treatment with topotecan. Refer to Section 2.4 for dose modification guidelines for hematological toxicities in subsequent courses. Do not treat patients with subsequent courses of topotecan until neutrophils recover to greater than 1,000 cells/mm³, platelets recover to greater than 100,000 cells/mm³, and hemoglobin levels recover to 9 g/dL (with transfusion if necessary).

Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain.

Interstitial lung disease (ILD), including fatalities, has occurred with topotecan. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Monitor patients for pulmonary symptoms indicative of ILD (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue topotecan if a new diagnosis of ILD is confirmed.

Based on animal data, topotecan can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose of topotecan. Advise women of the potential risk to a fetus [see Use in Specific Populations (8.1, 8.3)].

Extravasation with topotecan has been observed; severe cases have been reported. If signs or symptoms of extravasation occur, immediately stop administration of topotecan and institute recommended management procedures [see Adverse Reactions (6)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following reactions have been identified during postmarketing use of topotecan. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to topotecan.

Blood and Lymphatic System Disorders

Severe bleeding (in association with thrombocytopenia) [see Warnings and Precautions (5.1)].

Immune System Disorders

Allergic manifestations, anaphylactoid reactions.

Gastrointestinal Disorders

Abdominal pain potentially associated with neutropenic enterocolitis [see Warnings and Precautions (5.2)].

Pulmonary Disorders

Interstitial lung disease [see Warnings and Precautions (5.3)].

Skin and Subcutaneous Tissue Disorders

Angioedema, severe dermatitis, severe pruritus.

General Disorders and Administration Site Conditions

Extravasation [see Warnings and Precautions (5.5)].

Concomitant administration with G-CSF can prolong the duration of neutropenia. If G-CSF is used, it should be started no sooner than 24 hours following the last dose of topotecan.

Safety and effectiveness in pediatric patients have not been established.

Of the 879 patients with metastatic ovarian cancer or small cell lung cancer in clinical trials of topotecan, 32% (n = 281) were aged 65 years and older, while 3.8% (n = 33) were aged 75 years and older. Of the 140 patients with Stage IV-B, relapsed, or refractory cervical cancer in clinical trials of topotecan who received topotecan plus cisplatin in the randomized clinical trial, 6% (n = 9) were aged 65 years and older, while 3% (n = 4) were aged 75 years and older.

No overall differences in effectiveness or safety were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger adult patients.

The systemic exposure to both topotecan lactone and total topotecan increased in patients with moderate renal impairment (Clcr = 20 to 39 mL/min) compared with patients with normal renal function (Clcr greater than 60 mL/min). Reduce the dose of topotecan in patients with moderate renal impairment (Clcr = 20 to 39 mL/min). No dosage adjustment of topotecan is recommended for patients with mild renal impairment (Clcr = 40 to 60 mL/min) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Insufficient data are available in patients with severe renal impairment (Clcr less than 20 mL/min) to provide a dosage recommendation for topotecan.

Topoisomerase I relieves torsional strain in DNA by inducing reversible single-strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents re-ligation of these single-strand breaks. The cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double-strand breaks.

Following administration of topotecan at doses of 0.5 to 1.5 mg/m² administered as a 30-minute infusion to cancer patients, topotecan exhibited multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) is approximately dose-proportional.

Carcinogenicity testing of topotecan has not been performed. Topotecan is known to be genotoxic to mammalian cells and is a probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.

Topotecan given to female rats prior to mating at a dose of 1.4 mg/m² IV (about equal to the clinical dose on a mg/m² basis) caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. Studies in dogs given 0.4 mg/m² IV (about 0.25 times the clinical dose on a mg/m² basis) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes. Topotecan may impair fertility in women and men.

Another formulation of topotecan was studied in 2 clinical trials of 223 patients given topotecan with metastatic ovarian carcinoma. All patients had disease that had recurred on, or was unresponsive to, a platinum-containing regimen. Patients in these 2 trials received an initial dose of 1.5 mg/m² given by intravenous infusion over 30 minutes for 5 consecutive days, starting on Day 1 of a 21-day course.

One trial was a randomized trial of 112 patients treated with topotecan (1.5 mg/m²/day × 5 days starting on Day 1 of a 21-day course) and 114 patients treated with paclitaxel (175 mg/m² over 3 hours on Day 1 of a 21-day course). All patients had recurrent ovarian cancer after a platinum-containing regimen or had not responded to at least 1 prior platinum-containing regimen. Patients who did not respond to the trial therapy, or who progressed, could be given the alternative treatment. The efficacy outcome measures were response rate, response duration, and time to progression.

The results of the trial did not show statistically significant improvements in response rates, response duration, time to progression, and overall survival as shown in Table 4.

The median time to response was 7.6 weeks (range: 3.1 to 21.7) with topotecan compared with 6 weeks (range: 2.4 to 18.1) with paclitaxel. In the crossover phase, 8 of 61 (13%) patients who received topotecan after paclitaxel had a partial response and 5 of 49 (10%) patients who received paclitaxel after topotecan had a response (2 complete responses).

Topotecan was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within 6 months after completion of, a platinum-containing regimen. One complete and 6 partial responses were seen in 60 patients, for a response rate of 12%. In the same trial, there were no complete responders and 4 partial responders on the paclitaxel arm, for a response rate of 7%.

Topotecan was also studied in an open-label, non-comparative trial in 111 patients with recurrent ovarian cancer after treatment with a platinum-containing regimen, or who had not responded to 1 prior platinum-containing regimen. The response rate was 14% (95% CI: 7% to 20%). The median duration of response was 22 weeks (range: 4.6 to 41.9 weeks). The time to progression was 11.3 weeks (range: 0.7 to 72.1 weeks). The median survival was 67.9 weeks (range: 1.4 to 112.9 weeks).

Topotecan was studied in 426 patients with recurrent or progressive small cell lung cancer in 1 randomized, comparative trial and in 3 single-arm trials.

In a comparative trial, 147 eligible women were randomized to topotecan (0.75 mg/m²/day IV over 30 minutes × 3 consecutive days starting on Day 1 of a 21-day course) plus cisplatin (50 mg/m² on Day 1) and 146 eligible women were randomized to cisplatin (50 mg/m² IV on Day 1 of a 21-day course). All patients had histologically confirmed Stage IV-B, recurrent, or persistent carcinoma of the cervix considered not amenable to curative treatment with surgery and/or radiation. Fifty-six percent (56%) of patients treated with topotecan plus cisplatin and 56% of patients treated with cisplatin had received prior cisplatin with or without other agents as first-line chemotherapy.

Median survival of eligible patients receiving topotecan plus cisplatin was 9.4 months (95% CI: 7.9 to 11.9) compared with 6.5 months (95% CI: 5.8 to 8.8) among patients randomized to cisplatin alone with a log rank P-value of 0.033 (significance level was 0.044 after adjusting for the interim analysis). The unadjusted hazard ratio for overall survival was 0.76 (95% CI: 0.59 to 0.98).

Figure 1. Overall Survival Curves Comparing Topotecan plus Cisplatin versus Cisplatin Monotherapy in Cervical Cancer Patients

Topotecan Injection is supplied as follows:

Topotecan injection is supplied in 4 mg per 4 mL (1 mg per mL, topotecan free base equivalent) single-dose vials. Each vial contains 4 mL of the sterile, clear, light yellow to greenish solution.

Store refrigerated between 2°C and 8°C (36°F and 46°F). Handle and dispose of topotecan injection consistent with recommendations for the handling and disposal of hazardous drugs¹.

Protect from light. Retain in carton until time of use.
Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.