HYCAMTIN

HYCAMTIN- topotecan hydrochloride capsule
Novartis Pharmaceuticals Corporation

WARNING: MYELOSUPPRESSION

HYCAMTIN can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm3 and platelet counts greater than or equal to 100,000/mm3. Monitor blood cell counts [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

HYCAMTIN® capsules are indicated for the treatment of relapsed small cell lung cancer (SCLC) in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of HYCAMTIN capsules is 2.3 mg/m2 /day orally once daily, with or without food, for 5 consecutive days, starting on Day 1 of a 21-day cycle. Round the dose to the nearest 0.25 mg and prescribe the minimum number of 1 mg and 0.25 mg capsules. Prescribe the same number of capsules for each of the 5 dosing days.

Swallow capsules whole. Do not chew, crush, or divide the capsules.

If a dose of HYCAMTIN capsules is missed or vomiting occurs after taking a dose, do not administer an additional dose and take the next dose at the scheduled time.

2.2 Dosage Modifications for Adverse Reactions

Diarrhea

Do not administer HYCAMTIN capsules to patients with Grade 3 or 4 diarrhea. After recovery to Grade 1 or less, reduce the dose by 0.4 mg/m2 /day for subsequent courses [see Warnings and Precautions (5.2)].

Hematologic

Do not administer subsequent cycles of HYCAMTIN capsules until neutrophils recover to greater than 1,000/mm3 , platelets recover to greater than 100,000/mm3 , and hemoglobin levels recover to greater than or equal to 9 g/dL (with transfusion if necessary) [see Warnings and Precautions (5.1)].

Reduce dose by 0.4 mg/m2 /day for:

  • neutrophil counts of less than 500/mm3 associated with fever or infection or lasting for 7 days or more;
  • neutrophil counts of 500 to 1,000/mm3 lasting beyond day 21 of the treatment course; or
  • platelet counts less than 25,000/mm3.

2.3 Dosage Modifications for Renal Impairment

Reduce the dose of HYCAMTIN capsules in patients with the following creatinine clearance (CLcr), calculated with the Cockcroft-Gault method using ideal body weight.

  • CLcr 30 to 49 mL/min: Administer 1.5 mg/m2 /day.
  • CLcr less than 30 mL/min: Administer 0.6 mg/m2 /day.

3 DOSAGE FORMS AND STRENGTHS

Capsules

  • 0.25 mg: opaque white to yellowish-white and imprinted with HYCAMTIN and 0.25 mg.
  • 1 mg: opaque pink and imprinted with HYCAMTIN and 1 mg.

4 CONTRAINDICATIONS

HYCAMTIN is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

HYCAMTIN can cause severe myelosuppression. The following safety data are based on an integrated safety database from four trials in patients with lung cancer (N = 682) who received HYCAMTIN capsules at a dose of 2.3 mg/m2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day cycle.

The median day for neutrophil and platelet nadirs occurred on Day 15. Grade 4 neutropenia occurred in 32% of the 682 patients, with a median duration of 7 days. Grade 4 neutropenia most commonly occurred during cycle 1 (20% of patients). Clinical sequelae of neutropenia included infection (17%), febrile neutropenia (4%), sepsis (2%), and septic death (1%). Grade 4 thrombocytopenia occurred in 6%, with a median duration of 3 days. Grade 3 or 4 anemia occurred in 25%.

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

Administer the first cycle of HYCAMTIN capsules only to patients with a baseline neutrophil count greater than or equal to 1,500/mm3 and a platelet count greater than or equal to 100,000/mm3. Monitor blood cell counts frequently during treatment. Withhold and reduce dose of HYCAMTIN capsules based on neutrophil counts, platelet counts and hemoglobin levels [see Dosage and Administration (2.2)].

5.2 Diarrhea

Diarrhea, including severe and life-threatening diarrhea requiring hospitalization, can occur with HYCAMTIN capsules. Diarrhea can occur at the same time as drug-induced neutropenia and its sequelae. In the 682 patients who received HYCAMTIN capsules in the four lung cancer trials, the incidence of diarrhea caused by HYCAMTIN capsules was 22%, including Grade 3 (4%) and Grade 4 (0.4%). The incidence of Grade 3 or 4 diarrhea proximate (within 5 days) to Grade 3 or 4 neutropenia was 5%. The median time to onset of Grade 2 to 4 diarrhea was 9 days in the group receiving HYCAMTIN capsules.

Monitor patients for diarrhea and treat with antidiarrheals at the first sign of diarrhea. Withhold and dose reduce as recommended based on severity [see Dosage and Administration (2.2)].

5.3 Interstitial Lung Disease

Interstitial lung disease (ILD), including fatalities, can occur with HYCAMTIN. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs or colony stimulating factors.

Monitor for pulmonary symptoms indicative of ILD. Permanently discontinue HYCAMTIN capsules if ILD is confirmed.

5.4 Embryo-Fetal Toxicity

Based on animal data, 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. Advise women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose of HYCAMTIN capsules. Advise males with a female partner of reproductive potential to use effective contraception during treatment with HYCAMTIN capsules and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclincial Toxicology (13.1)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

  • Myelosuppression [see Warnings and Precautions (5.1)]
  • Diarrhea [see Warnings and Precautions (5.2)]
  • Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.3)]

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.

The data in the Warnings and Precautions and below reflects exposure to HYCAMTIN capsules in 682 patients with recurrent lung cancer enrolled in four randomized, open label trials, including 275 patients with small lung cell lung cancer (SCLC) (Studies 478, 065 and 396), and 407 patients with non-small cell lung cancer (NSCLC) (Study 387), who received at least one dose of HYCAMTIN capsules. Patients in these trials had advanced lung cancer and received prior chemotherapy in the first-line setting. Patients received HYCAMTIN capsules 2.3 mg/m2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. The median number of cycles was 3 (range: 1 to 20).

The safety of HYCAMTIN capsules was evaluated in a randomized trial (Study 478) conducted in 70 patients with recurrent SCLC [see Clinical Studies (14)].

In the 682 patients who received HYCAMTIN capsules in the four lung cancer trials, 39 deaths (6%) occurred within 30 days after the last dose for a reason other than progressive disease: 13 due to hematologic toxicity, 5 due to non-hematologic toxicity (2 from diarrhea), and 21 due to other causes.

Table 1 describes the hematologic and non-hematologic adverse reactions that occurred in greater than 5% of patients treated with HYCAMTIN capsules in these trials.

Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Lung Cancer
a Adverse reactions were graded using National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0.

Adverse Reactionsa

HYCAMTIN Capsules With BestSupportive Care (Study 478)

HYCAMTIN CapsulesLung Cancer Population (Studies 478, 065, 396 and 387)

N = 70

N = 682

All Grades

(%)

Grade 3

(%)

Grade 4

(%)

All Grades

(%)

Grade 3

(%)

Grade 4

(%)

Hematologic

Anemia

94

15

10

98

18

7

Neutropenia

91

28

33

83

24

32

Thrombocytopenia

81

30

7

81

29

6

Non-hematologic

Nausea

27

1

0

33

3

0

Vomiting

19

1

0

21

3

0.4

Diarrhea

14

4

1

22

4

0.4

Fatigue

11

0

0

19

4

0.1

Alopecia

10

0

0

20

0.1

0

Pyrexia

7

1

0

5

1

1

Anorexia

7

0

0

14

2

0

Asthenia

3

0

0

7

2

0

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