Hycamtin Capsules

Hycamtin Capsules are indicated for the treatment of 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.

HYCAMTIN is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan.

Overdoses (up to 5-fold of the prescribed dose) occurred in patients treated with Hycamtin Capsules. The primary complication of overdosage is bone marrow suppression. The observed signs and symptoms of overdose are consistent with the known adverse reactions associated with HYCAMTIN for oral use [see Adverse Reactions (6.1)]. Mucositis has also been reported in association with overdose.

There is no known antidote for overdosage with HYCAMTIN. If an overdose is suspected, monitor the patient closely for bone marrow suppression, and institute supportive-care measures (such as the prophylactic use of G-CSF and/or antibiotic therapy) as appropriate.

Small Cell Lung Cancer

The efficacy of Hycamtin Capsules was studied in 141 patients with relapsed SCLC in a randomized, controlled, open-label trial. The patients were prior responders (complete or partial) to first-line chemotherapy, were not considered candidates for standard intravenous chemotherapy, and had relapsed at least 45 days from the end of first-line chemotherapy. Seventy-one patients were randomized to Hycamtin Capsules (2.3 mg/m2/day administered for 5 consecutive days repeated every 21 days) and Best Supportive Care (BSC) and 70 patients were randomized to BSC alone. The primary objective was to compare the overall survival between the treatment arms. Patients in the arm receiving Hycamtin Capsules plus BSC received a median of 4 courses (range: 1 to 10) and maintained a median dose intensity of 3.77 mg/m2/week. The median patient age in the arm receiving Hycamtin Capsules plus BSC and the BSC-alone treatment arm was 60 years and 58 years while the percentage of patients aged >65 years was 34% and 29%, respectively. The majority of patients were Caucasian (99.3%) and male (73%). Eighty percent of patients receiving Hycamtin Capsules plus BSC previously received carboplatin or cisplatin, and 77% of patients in the BSC-alone arm received prior carboplatin or cisplatin. The arm receiving Hycamtin Capsules plus BSC included 68% of patients with extensive disease and 28% with liver metastasis. In the BSC- alone arm, 61% of patients had extensive disease and 20% had liver metastases. Both treatment arms recruited 73% males. In the arm receiving Hycamtin Capsules plus BSC, 18% of patients had prior carboplatin and 62% had prior cisplatin. In the BSC-alone arm, 26% of patients had prior carboplatin and 51% had prior cisplatin.

The arm receiving Hycamtin Capsules plus BSC showed a statistically significant improvement in overall survival compared with the BSC-alone arm (Log-rank P = 0.0104). Survival results are shown in Table 3 and Figure 1.

BSC = Best Supportive Care.

N = Total number of patients randomized.

CI = Confidence interval.

Figure 1. Kaplan-Meier Estimates for Survival

Small cell lung cancer or Ovarian cancer, IV formulation:
-Mild renal impairment (CrCl 40 to 60 mL/min): No adjustment recommended
-Moderate renal impairment (CrCl 20 to 39 mL/min): Decrease dose to 0.75 mg/m(2)
-Severe renal impairment: Insufficient data to provide a dosage recommendation

Small cell lung cancer, oral capsules:
-Mild renal impairment (CrCl 50 to 79 mL/min): No adjustment recommended
-Moderate renal impairment (CrCl 30 to 49 mL/min): Decrease dose to 1.5 mg/m(2)
-Severe renal impairment (CrCl less than 30): Decrease dose to 0.6 mg/m(2)
-Doses for moderate to severe renal impairment can be increased by 0.4 mg/m(2) after the first course if no severe hematologic or gastrointestinal toxicities occur.

Cervical cancer:
-Only initiate treatment if serum creatinine is less than 1.5 mg/dL
-Serum creatinine greater than 1.5 mg/dL on day 1 of first cycle: Delay initiation of treatment until renal recovery
-Serum creatinine greater than 1.5 mg/dL on day 1 of subsequent cycles: Delay cycle until renal recovery
-Serum creatinine greater than 1.5 mg/dL in subsequent cycles: Permanently discontinue

Data not available

All cancer types:
On day 1 of first cycle, delay therapy initiation until hematologic or renal recovery IF:
-Neutrophil count is less than 1,500 cells/mm(3) OR
-Platelet count 100,000 cells/mm(3) or less OR
-Serum creatinine less than 1.5 mg/dL

On day 1 of subsequent cycles, delay treatment cycle until hematologic or renal recovery IF:
-Neutrophil count is less than 1000 cells/mm(3) OR
-Platelet count 100,000 cells/mm(3) or less OR
-Serum creatinine less than 1.5 mg/dL OR
-Hemoglobin less than 9 gm/dL
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Small cell lung cancer or Ovarian cancer:
IV formulation:
Severe neutropenia [less than 500 cells/mm(3)] in preceding cycle:
-Permanently reduce IV dose by 0.25 mg [to 1.25 mg/m(2)] or oral dose by 0.4 mg/m(2) for subsequent courses OR
-Administer granulocyte-colony stimulating factor (G-CSF) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration).

Platelet count below 25,000 cells/mm(3): Reduce dose to 1.25 mg/m(2) for subsequent courses .

Oral capsules (Small cell lung cancer only):
Permanently reduce dose by 0.4 mg/m(2) for subsequent courses for:
-Neutrophil counts less than 500 cells/mm(3)] with fever or infection lasting 7 or more days
-Neutrophil counts of 500 to 1,000 cells/mm(3) lasting beyond day 21 of treatment course
-Platelet count below 25,000 cells/mm(3)
Do not give oral formulation to patients with Grade 3 or 4 diarrhea
-After recovery to Grade 1 or less, reduce dose by 0.4 mg/m(2) for subsequent courses
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Cervical cancer:
First occurrence of febrile neutropenia [less than 1,000 neutrophils/mm(3) with fever of 38 C/100.4F or higher] in preceding cycle:
-Permanently reduce dose to 0.60 mg/m(2) OR
-Administer prophylactic G-CSF during subsequent cycles

Re-occurrence of febrile neutropenia in preceding cycle despite use of G-CSF:
-Permanently reduce dose to 0.45 mg/m(2)

Platelet nadir less than 25,000 cells/mm(3) in preceding cycle:
-Permanently reduce dose to 0.60 mg/m(2)

Serum creatinine greater than 1.5 mg/dL in subsequent cycles:
-Permanently discontinue topotecan

US BOXED WARNING:
BONE MARROW SUPPRESSION
-Bone marrow suppression, primarily neutropenia, may be severe and result in infection and death.
-Do not initiate treatment in patients with bone marrow suppression (e.g. neutrophil counts less than 1,500 cells/mm(3).
-Monitor peripheral blood counts frequently during treatment.
-Reduce or withhold treatment dosing as recommended.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Data not available

Administration advice:
-Verify dose using body surface area.
-Oral capsules should be swallowed whole: do not crush, chew, or divide the capsules.
-Oral capsules can be taken with or without food.

Reconstitution/preparation techniques:
-Prepare in a laminar flow hood while wearing gloves and protective clothing.
-If solution contacts skin, wash skin immediately and thoroughly with soap and water.
-If solution contacts mucous membranes, flush thoroughly with water.