1.1 Ovarian Cancer

Topotecan hydrochloride for 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

1.2 Small Cell Lung Cancer

Topotecan hydrochloride for 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.

1.3 Cervical Cancer

Topotecan hydrochloride for 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.

2.1 Ovarian Cancer

Recommended Dose and Schedule

The recommended dose of topotecan hydrochloride for injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course.

2.2 Small Cell Lung Cancer

Recommended Dose and Schedule

The recommended dose of topotecan hydrochloride for injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course.

2.3 Cervical Cancer

Recommended Dose and Schedule
The recommended dose of topotecan hydrochloride for injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on Days 1, 2, and 3 in combination with cisplatin 50 mg/m2 on Day 1, repeated every 21 days.

2.4 Dose Modifications

Hematologic Toxicities

For single-agent use, dose reduce topotecan hydrochloride for injection to 1.25 mg/m2 for:

• neutrophil counts of less than 500 cells/mm3, or administer granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours following the last dose of topotecan hydrochloride for injection.

• platelet counts less than 25,000 cells/mm3 during previous cycle.

For combination use with cisplatin, dose reduce topotecan hydrochloride for injection to 0.60 mg/m2 (and further to 0.45 mg/m2 if necessary) for:

• febrile neutropenia (defined as neutrophil counts less than 1,000 cells/mm3 with temperature of greater than or equal to 38.0°C (100.4°F), or administer G-CSF starting no sooner than 24 hours following the last dose of topotecan hydrochloride for injection.

• platelet counts less than 25,000 cells/mm3 during previous cycle.

Renal Impairment
For single-agent use, dose reduce topotecan hydrochloride for injection to 0.75 mg/m2 in patients with moderate renal impairment (creatinine clearance [Clcr] = 20 to 39 mL/min). Insufficient data are available in patients with severe renal impairment (Clcr less than 20 mL/min) to provide a dosage recommendation for topotecan hydrochloride for injection [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.5 Preparation and Intravenous Administration

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

Preparation and Administration

Topotecan hydrochloride for Injection, 4 mg (base)/vial, the lyophilized powder is reconstituted by adding 4 mL of Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration. Because the lyophilized dosage form contains no antibacterial preservative, the reconstituted product should be used immediately.

Stability
Unopened vials of topotecan hydrochloride for injection are stable until the date indicated on the package when stored between 20°C and 25°C (68°F and 77°F) [see USP] and protected from light in the original carton. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of topotecan hydrochloride for injection diluted for infusion are stable at approximately 20°C to 25°C (68°F to 77°F) and ambient lighting conditions for 24 hours.

5.1 Bone Marrow Suppression

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of topotecan hydrochloride for injection. Neutropenia is not cumulative over time. Severe myelotoxicity has been reported when topotecan hydrochloride for injection 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 hydrochloride for 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 hydrochloride for injection 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 hydrochloride for injection 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 hydrochloride for injection. Refer to Section 2.4 for dose modification guidelines for hematological toxicities in subsequent courses. Do not treat patients with subsequent courses of topotecan hydrochloride for injection until neutrophils recover to greater than 1,000 cells/mm3, platelets recover to greater than 100,000 cells/mm3, and hemoglobin levels recover to 9.0 g/dL (with transfusion if necessary).

5.2 Neutropenic Enterocolitis

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

5.3 Interstitial Lung Disease

Interstitial lung disease (ILD), including fatalities, has occurred with topotecan hydrochloride for injection. 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 hydrochloride for injection if a new diagnosis of ILD is confirmed.

5.4 Embryofetal Toxicity

Based on animal data, topotecan hydrochloride for injection 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 hydrochloride for injection. Advise women of the potential risk to a fetus [see Use in Specific Populations (8.1, 8.3)].

5.5 Extravasation and Tissue Injury

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

6.1 Clinical Trials Experience

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.

Ovarian Cancer
Table 1 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/paclitaxel comparator trial in ovarian cancer.

Table 1. Adverse Reactions Experienced by ≥5% of Ovarian Cancer Patients Randomized to Receive Topotecan Hydrochloride for Injection or Paclitaxel

6.2 Postmarketing Experience

The following reactions have been identified during postmarketing use of topotecan hydrochloride for injection. 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 hydrochloride for injection.

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)].

7.1 G-CSF

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 hydrochloride for injection.

8.1 Pregnancy

Risk Summary

Based on animal data, topotecan hydrochloride for injection can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose [see Data]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown; however, the background risk in the US general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data: In rabbits, a dose of 0.10 mg/kg/day (about equal to the clinical dose on a mg/m2 basis) given on Days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, a dose of 0.23 mg/kg/day (about equal to the clinical dose on a mg/m2 basis) given for 14 days before mating through gestation Day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. Administration of an intravenous dose of 0.10 mg/kg/day (about half the clinical dose on a mg/m2 basis) given to rats on Days 6 through 17 of gestation caused an increase in post-implantation mortality. This dose also caused an increase in total fetal malformations. The most frequent malformations were of the eye (microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit), brain (dilated lateral and third ventricles), skull, and vertebrae.

8.2 Labor & Delivery

Risk Summary

It is not known whether this drug is present in human milk; however, topotecan is excreted in rat milk at high concentrations [see Data]. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants with topotecan hydrochloride for injection, advise nursing mothers to discontinue breastfeeding during treatment with topotecan hydrochloride for injection.

Data

Animal Data: Following intravenous administration of topotecan to lactating rats at a dose of  4.72 mg/m2 (about twice the clinical dose on a mg/m2 basis), topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma.

8.3 Nursing Mothers

Contraception

Females: Advise female patients of reproductive potential to use effective contraception during treatment with topotecan hydrochloride for injection and for one month after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking topotecan hydrochloride for injection [see Use in Specific Populations (8.1)].

Males: Topotecan hydrochloride for injection may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for three months after treatment with topotecan hydrochloride for injection [see Nonclinical Toxicology (13.1)].

Infertility

Females: Topotecan hydrochloride for injection may have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1)].

Males: Effects on spermatogenesis have been observed in animals administered topotecan for injection. Advise males of the potential risk for impaired fertility and to seek counseling on fertility and family planning options prior to starting treatment [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the 879 patients with metastatic ovarian cancer or small cell lung cancer in clinical trials of topotecan hydrochloride for injection, 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 hydrochloride for injection who received topotecan hydrochloride for injection 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.

8.6 Renal Impairment

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 hydrochloride for injection in patients with moderate renal impairment (Clcr = 20 to 39 mL/min). No dosage adjustment of topotecan hydrochloride for injection 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 hydrochloride for injection.

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

Following administration of topotecan hydrochloride for injection for injection 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.

Distribution

Binding of topotecan to plasma proteins is approximately 35%.

Metabolism

Topotecan undergoes a reversible pH-dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. At pH ≤4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. In vitro studies in human liver microsomes indicate topotecan is metabolized to an N-demethylated metabolite. The mean metabolite: parent AUC ratio was about 3% for total topotecan and topotecan lactone following IV administration.

Excretion

Renal clearance is the primary route of topotecan elimination.

In a mass balance/excretion trial in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4% ± 2.3% of the administered IV dose. Mean values of 50.8% ± 2.9% as total topotecan and 3.1% ± 1% as N-desmethyl topotecan were excreted in the urine following IV administration. Fecal elimination of total topotecan accounted for 17.9% ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7% ± 0.6%. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.

Specific Populations

Gender: Plasma clearance of topotecan lactone in male patients was approximately 24% higher than that in female patients, largely reflecting difference in body size.

Age: Population pharmacokinetic analysis in female patients did not identify age as a significant factor. Decreased renal clearance, which is common in the elderly, is a more important determinant of topotecan clearance [see Dosage and Administration (2.4), Use in Specific Populations (8.5)].

Renal Impairment: In patients with mild renal impairment (Clcr = 40 to 60 mL/min), plasma clearance of topotecan lactone was decreased by 33% compared with patients with normal renal function (Clcr greater than 60 mL/min). In patients with moderate renal impairment (Clcr = 20 to 39 mL/min), plasma clearance of topotecan lactone was reduced by 65% compared with patients with normal renal function. Dosage adjustment is recommended for patients with moderate renal impairment. No dosage adjustment is required in patients with mild renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6)].

Hepatic Impairment: Plasma clearance of topotecan lactone in patients with hepatic impairment serum bilirubin levels between 1.7 and 15.0 mg/dL) was decreased by 33% compared with patients with normal hepatic function (serum bilirubin levels less than 1.7 mg/dL).

Drug Interactions

Effects of Topotecan on Drug-Metabolizing Enzymes: In vitro inhibition studies using marker substrates for human P450 CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase indicate that the activities of these enzymes were not altered by topotecan.

Cisplatin: Administration of cisplatin (60 or 75 mg/m2 on Day 1) before topotecan (0.75 mg/m2/day on Days 1 to 5) in 9 patients with ovarian cancer had no significant effect on the Cmax and AUC of total topotecan.

Topotecan (0.3 mg/m2 IV daily on Days 2 to 6) had no effect on the pharmacokinetics of free platinum in 15 patients with ovarian cancer who were administered cisplatin 50 mg/m2 (n = 9) or 75 mg/m2 (n = 6) on Day 2 after paclitaxel 110 mg/m2 on Day 1. Topotecan (0.75 mg/mIV daily on Days 1 to 5) had no effect on dose-normalized (60 mg/m2) Cmax values of free platinum in 13 patients with ovarian cancer who were administered 60 mg/m2 (n = 10) or 75 mg/m2 (n = 3) cisplatin on Day 1.

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

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.

14.1 Ovarian Cancer

Topotecan hydrochloride for injection 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 hydrochloride for injection (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.

Table 4. Efficacy of Topotecan Hydrochloride for Injection versus Paclitaxel in Ovarian Cancer

14.2 Small Cell Lung Cancer

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

Randomized Comparative Trial

In a randomized, comparative, Phase 3 trial, 107 patients were treated with topotecan hydrochloride for injection (1.5 mg/m2/day × 5 days starting on Day 1 of a 21-day course) and 104 patients were treated with CAV (1,000 mg/m2 cyclophosphamide, 45 mg/m2 doxorubicin, 2 mg vincristine administered sequentially on Day 1 of a 21-day course). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed greater than or equal to 60 days after completion of first-line therapy). A total of 77% of patients treated with topotecan hydrochloride for injection and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy. The efficacy outcome measures were response rate and duration of response.

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 5.

Table 5. Efficacy of Topotecan Hydrochloride for Injection versus CAV (cyclophosphamide-doxorubicin-vincristine) in Small Cell Lung Cancer Patients Sensitive to First-Line Chemotherapy

HR = hazard-ratio; CI = confidence interval.

The calculation for duration of response was based on the interval between first response and time to progression.

The time to response was similar in both arms: topotecan hydrochloride for injection median of 6 weeks (range: 2.4 to 15.7) versus CAV median 6 weeks (range: 5.1 to 18.1).

Changes on a disease-related symptom scale in patients who received topotecan hydrochloride for injection or who received CAV are presented in Table 6. It should be noted that not all patients had all symptoms, nor did all patients respond to all questions. Each symptom was rated on a 4-category scale with an improvement defined as a change in 1 category from baseline sustained over 2 courses. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.

Table 6. Percentage of Patients with Symptom Improvementa: Topotecan Hydrochloride for Injection versus CAV in Patients with Small Cell Lung Cancer

14.3 Cervical Cancer

In a comparative trial, 147 eligible women were randomized to topotecan hydrochloride for injection (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 hydrochloride for injection 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 hydrochloride for injection 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 Hydrochloride for Injection plus Cisplatin versus Cisplatin Monotherapy in Cervical Cancer Patient

16.1 How Supplied

Topotecan hydrochloride for injection is supplied as a sterile, lyophilized, buffered, light yellow to greenish powder or cake. Topotecan hydrochloride for injection is supplied in 4-mg (free base) single-use vials.