FULL PRESCRIBING INFORMATION
Do not give Hycamtin to patients with baseline neutrophil counts less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood counts frequently on all patients receiving Hycamtin [see Warnings and Precautions (5.1)].
Indications and Usage for Hycamtin
Hycamtin is indicated for the treatment of:
- metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy.
- small cell lung cancer sensitive disease after failure of first-line chemotherapy. In clinical studies submitted to support approval, sensitive disease was defined as disease responding to chemotherapy but subsequently progressing at least 60 days (in the Phase 3 study) or at least 90 days (in the Phase 2 studies) after chemotherapy [see Clinical Studies(14)].
Hycamtin in combination with cisplatin is indicated for the treatment of:
- stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy.
Hycamtin Dosage and Administration
Prior to administration of the first course of Hycamtin, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.
Ovarian Cancer and Small Cell Lung Cancer
Recommended Dosage:
- The recommended dose of Hycamtin 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.
- In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 3 ovarian clinical trials was 9 to 12 weeks, and median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.
- In the event of severe neutropenia (defined as <500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses.
- Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration).
- In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses.
Cervical Cancer
Recommended Dosage:
The recommended dose of Hycamtin is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).
Dosage Modification Guidelines:
Dosage adjustments for subsequent courses of Hycamtin in combination with cisplatin are specific for each drug. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.
- In the event of severe febrile neutropenia (defined as <500 cells/mm3 with temperature of 38.0°C or 100.4°F), reduce the dose of Hycamtin to 0.60 mg/m2 for subsequent courses.
- Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of Hycamtin).
- If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of Hycamtin to 0.45 mg/m2 for subsequent courses.
- In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses.
Dosage Adjustment in Specific Populations
Renal Impairment:
No dosage adjustment of Hycamtin appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min.). Dosage adjustment of Hycamtin to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for Hycamtin [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Hycamtin in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with Hycamtin after cisplatin discontinuation in patients with cervical cancer.
Instructions for Handling, Preparation and Intravenous Adminstration
Handling:
Hycamtin is a cytotoxic anticancer drug. Prepare Hycamtin under a vertical laminar flow hood while wearing gloves and protective clothing. If Hycamtin solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Hycamtin contacts mucous membranes, flush thoroughly with water.
Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published.1-4
Preparation and Administration:
Each 4-mg vial of Hycamtin is reconstituted with 4 mL 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.
Stability:
Unopened vials of Hycamtin are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.
Reconstituted vials of Hycamtin diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.
Dosage Forms and Strengths
4-mg (free base) single-dose vial, light yellow to greenish powder.
Contraindications
Hycamtin is contraindicated in patients who have a history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients. Hycamtin should not be used in patients with severe bone marrow depression.
Warnings and Precautions
Bone Marrow Suppression
Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of Hycamtin. Neutropenia is not cumulative over time. In ovarian cancer, the overall treatment-related death rate was 1%. In the comparative study in small cell lung cancer, however, the treatment-related death rates were 5% for Hycamtin and 4% for CAV (cyclophosphamide-doxorubicin-vincristine).
Neutropenia:
- Ovarian and small cell lung cancer experience: Grade 4 neutropenia (<500 cells/mm3) was most common during course 1 of treatment (60% of patients) and occurred in 39% of all courses, with a median duration of 7 days. The nadir neutrophil count occurred at a median of 12 days. Therapy-related sepsis or febrile neutropenia occurred in 23% of patients, and sepsis was fatal in 1%. Pancytopenia has been reported.
- Cervical cancer experience: Grade 3 and grade 4 neutropenia affected 26% and 48% of patients, respectively.
- Ovarian and small cell lung cancer experience: Grade 4 thrombocytopenia (<25,000/mm3) occurred in 27% of patients and in 9% of courses, with a median duration of 5 days and platelet nadir at a median of 15 days. Platelet transfusions were given to 15% of patients in 4% of courses.
- Cervical cancer experience: Grade 3 and grade 4 thrombocytopenia affected 26% and 7% of patients, respectively.
- Ovarian and small cell lung cancer experience: Grade 3/4 anemia (<8 g/dL) occurred in 37% of patients and in 14% of courses. Median nadir was at day 15. Transfusions were needed in 52% of patients in 22% of courses.
- Cervical cancer experience: Grade 3 and grade 4 anemia affected 34% and 6% of patients, respectively.
Administer Hycamtin only in patients with adequate bone marrow reserves, including baseline neutrophil count of at least 1,500 cells/mm3 and platelet count at least 100,000/mm3. Monitor peripheral blood counts frequently during treatment with Hycamtin. Do not treat patients with subsequent courses of Hycamtin until neutrophils recover to >1,000 cells/mm3, platelets recover to >100,000 cells/mm3, and hemoglobin levels recover to 9.0 g/dL (with transfusion if necessary). Severe myelotoxicity has been reported when Hycamtin is used in combination with cisplatin [see Drug Interactions (7.1)].
Neutropenic Colitis
Topotecan-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with Hycamtin. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, consider the possibility of neutropenic colitis.
Interstitial Lung Disease
Hycamtin has been associated with reports of interstitial lung disease (ILD), some of which have been fatal [see Adverse Reactions (6.2)]. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Monitor patients for pulmonary symptoms indicative of interstitial lung disease (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue Hycamtin if a new diagnosis of ILD is confirmed.
Pregnancy
Pregnancy Category D
Hycamtin can cause fetal harm when administered to a pregnant woman.
Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. There are no adequate and well controlled studies of Hycamtin in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Hycamtin, the patient should be apprised of the potential hazard to the fetus. [see Use in Specific Populations, Pregnancy (8.1)].
Inadvertent Extravasation
Inadvertent extravasation with Hycamtin has been observed, most reactions have been mild but severe cases have been reported.
Adverse Reactions
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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Ovarian Cancer and Small Cell Lung Cancer:
Data in the following section are based on the combined experience of 453 patients with metastatic ovarian carcinoma, and 426 patients with small cell lung cancer treated with Hycamtin. Table 1 lists the principal hematologic adverse reactions and Table 2 lists non-hematologic adverse reactions occurring in at least 15% of patients.
| Hematologic Adverse Reaction | Patients (n = 879) % Incidence |
| Neutropenia | |
| <1,500 cells/mm3 | 97 |
| <500 cells/mm3 | 78 |
| Leukopenia | |
| <3,000 cells/mm3 | 97 |
| <1,000 cells/mm3 | 32 |
| Thrombocytopenia | |
| <75,000/mm3 | 69 |
| <25,000/mm3 | 27 |
| Anemia | |
| <10 g/dL | 89 |
| <8 g/dL | 37 |
Non-hematologic Adverse Reaction | Percentage of Patients with Adverse Reaction (879 Patients) | ||
| All Grades | Grade 3 | Grade 4 | |
| Infections and infestations | |||
| Sepsis or pyrexia/infection with neutropenia a | 43 | NR | 23 |
| Metabolism and nutrition disorders | |||
| Anorexia | 19 | 2 | <1 |
| Nervous system disorders | |||
| Headache | 18 | 1 | <1 |
| Respiratory, thoracic, and mediastinal disorders | |||
| Dyspnea | 22 | 5 | 3 |
| Coughing | 15 | 1 | 0 |
| Gastrointestinal disorders | |||
| Nausea | 64 | 7 | 1 |
| Vomiting | 45 | 4 | 1 |
| Diarrhea | 32 | 3 | 1 |
| Constipation | 29 | 2 | 1 |
| Abdominal pain | 22 | 2 | 2 |
| Stomatitis | 18 | 1 | <1 |
| Skin and subcutaneous tissue disorders | |||
| Alopecia | 49 | NA | NA |
| Rashb | 16 | 1 | 0 |
| General disorders and administrative site conditions | |||
| Fatigue | 29 | 5 | 0 |
| Pyrexia | 28 | 1 | <1 |
| Painc | 23 | 2 | 1 |
| Asthenia | 25 | 4 | 2 |
NA = Not applicable
NR = Not reported separately
a Does not include Grade 1 sepsis or pyrexia.
b Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash.
c Pain includes body pain, back pain, and skeletal pain.
Nervous System Disorders:
Paresthesia occurred in 7% of patients but was generally grade 1.
Hepatobiliary Disorders:
Grade 1 transient elevations in hepatic enzymes occurred in 8% of patients. Greater elevations, grade 3/4, occurred in 4%. Grade 3/4 elevated bilirubin occurred in <2% of patients.
Table 3 shows the grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/paclitaxel comparator trial in ovarian cancer.
| Adverse Reaction | Hycamtin (n = 112) | Paclitaxel (n = 114) |
| Hematologic Grade 3/4 | % | % |
| Grade 4 neutropenia (<500 cells/mm3) | 80 | 21 |
| Grade 3/4 anemia (Hgb <8 g/dL) | 41 | 6 |
| Grade 4 thrombocytopenia (<25,000 plts/mm3) | 27 | 3 |
| Pyrexia/Grade 4 neutropenia | 23 | 4 |
| Non-hematologic Grade 3/4 | % | % |
| Infections and infestations | ||
| Documented sepsisa | 5 | 2 |
| Respiratory, thoracic, and mediastinal disorders | ||
| Dyspnea | 6 | 5 |
| Gastrointestinal disorders | ||
| Abdominal pain | 5 | 4 |
| Constipation | 5 | 0 |
| Diarrhea | 6 | 1 |
| Intestinal obstruction | 5 | 4 |
| Nausea | 10 | 2 |
| Vomiting | 10 | 3 |
| General disorders and administrative site conditions | ||
| Fatigue | 7 | 6 |
| Asthenia | 5 | 3 |
| Painb | 5 | 7 |
a Death related to sepsis occurred in 2% of patients receiving Hycamtin, and 0% of patients receiving paclitaxel.
b Pain includes body pain, skeletal pain, and back pain.
Table 4 shows the grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV comparator trial in small cell lung cancer.
| Adverse Reaction | Hycamtin (n = 107) | CAV |
| (n = 104) | ||
| Hematologic Grade 3/4 | % | % |
Grade 4 neutropenia (<500 cells/mm3) | 70 | 72 |
Grade 3/4 anemia (Hgb <8 g/dL) | 42 | 20 |
Grade 4 thrombocytopenia (<25,000 plts/mm3) | 29 | 5 |
| Pyrexia/Grade 4 neutropenia | 28 | 26 |
| Non-hematologic Grade 3/4 | % | % |
| Infections and infestations | ||
| Documented sepsisa | 5 | 5 |
| Respiratory, thoracic, and mediastinal disorders | ||
| Dyspnea | 9 | 14 |
| Pneumonia | 8 | 6 |
| Gastrointestinal disorders | ||
| Abdominal pain | 6 | 4 |
| Nausea | 8 | 6 |
| General disorders and administrative site conditions | ||
| Fatigue | 6 | 10 |
| Asthenia | 9 | 7 |
| Painb | 5 | 7 |
a Death related to sepsis occurred in 3% of patients receiving Hycamtin, and 1% of patients receiving CAV.
b Pain includes body pain, skeletal pain, and back pain.
Cervical Cancer:
In the comparative trial with Hycamtin plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression. Table 5 shows the hematologic adverse reactions and Table 6 shows the non-hematologic adverse reactions in patients with cervical cancer.
| Hematologic Adverse Reaction | Hycamtin Plus Cisplatin (n = 140) | Cisplatin (n = 144) |
| Anemia | ||
| All grades (Hgb <12 g/dL) | 131 (94%) | 130 (90%) |
| Grade 3 (Hgb <8-6.5 g/dL) | 47 (34%) | 28 (19%) |
| Grade 4 (Hgb <6.5 g/dL) | 9 (6%) | 5 (3%) |
| Leukopenia | ||
| All grades (<3,800 cells/mm3) | 128 (91%) | 43 (30%) |
| Grade 3 (<2,000-1,000 cells/mm3) | 58 (41%) | 1 (1%) |
| Grade 4 (<1,000 cells/mm3) | 35 (25%) | 0 (0%) |
| Neutropenia | ||
| All grades (<2,000 cells/mm3) | 125 (89%) | 28 (19%) |
| Grade 3 (<1,000-500 cells/mm3) | 36 (26%) | 1 (1%) |
| Grade 4 (<500 cells/mm3) | 67 (48%) | 1 (1%) |
| Thrombocytopenia | ||
| All grades (<130,000 cells/mm3) | 104 (74%) | 21 (15%) |
| Grade 3 (<50,000-10,000 cells/mm3) | 36 (26%) | 5 (3%) |
| Grade 4 (<10,000 cells/mm3) | 10 (7%) | 0 (0%) |
a Includes patients who were eligible and treated.
| Hycamtin Plus Cisplatin | Cisplatin | |||||
| (n = 140) | (n = 144) | |||||
| Adverse Reaction | All Gradesb | Grade 3 | Grade 4 | All Gradesb | Grade 3 | Grade 4 |
| General disorders and administrative site conditions | ||||||
| Constitutionalc | 96 (69%) | 11 (8%) | 0 | 89 (62%) | 17 (12%) | 0 |
| Paind | 82 (59%) | 28 (20%) | 3 (2%) | 72 (50%) | 18 (13%) | 5 (3%) |
| Gastrointestinal disorders | ||||||
| Vomiting | 56 (40%) | 20 (14%) | 2 (1%) | 53 (37%) | 13 (9%) | 0 |
| Nausea | 77 (55%) | 18 (13%) | 2 (1%) | 79 (55%) | 13 (9%) | 0 |
| Stomatitis-pharyngitis | 8 (6%) | 1 (<1%) | 0 | 0 | 0 | 0 |
| Other | 88 (63%) | 16 (11%) | 4 (3%) | 80 (56%) | 12 (8%) | 3 (2%) |
| Dermatology | 67 (48%) | 1 (<1%) | 0 | 29 (20%) | 0 | 0 |
| Metabolic-Laboratory | 55 (39%) | 13 (9%) | 7 (5%) | 44 (31%) | 14 (10%) | 1 (<1%) |
| Genitourinary | 51 (36%) | 9 (6%) | 9 (6%) | 49 (34%) | 7 (5%) | 7 (5%) |
| Nervous system disorders | ||||||
| Neuropathy | 4 (3%) | 1 (<1%) | 0 | 3 (2%) | 1 (<1%) | 0 |
| Other | 49 (35%) | 3 (2%) | 1 (<1%) | 43 (30%) | 7 (5%) | 2 (1%) |
| Infection-febrile neutropenia | 39 (28%) | 21 (15%) | 5 (4%) | 26 (18%) | 11 (8%) | 0 |
| Cardiovascular | 35 (25%) | 7 (5%) | 6 (4%) | 22 (15%) | 8 (6%) | 3 (2%) |
| Hepatic | 34 (24%) | 5 (4%) | 2 (1%) | 23 (16%) | 2 (1%) | 0 |
| Pulmonary | 24 (17%) | 4 (3%) | 0 | 23 (16%) | 5 (3%) | 3 (2%) |
| Vascular disorders | ||||||
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