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Hycamtin

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Hycamtin

WARNINGS

Included as part of the PRECAUTIONS section.

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 trial 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.
Thrombocytopenia
  • 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.
Anemia
  • 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.
Monitoring of Bone Marrow Function

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].

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]. 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].

Inadvertent Extravasation

Inadvertent extravasation with HYCAMTIN has been observed; most reactions have been mild, but severe cases have been reported.

Nonclinical Toxicology

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 1/4th 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.

Use In Specific Populations

Pregnancy

Pregnancy Category D

[see WARNINGS AND PRECAUTIONS].

HYCAMTIN can cause fetal harm when administered to a pregnant woman. In rabbits, a dose of 0.10 mg/kg/day (about equal to the clinical dose on a mg/m 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. A 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.

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 WARNINGS AND PRECAUTIONS].

Nursing Mothers

Rats excrete high concentrations of topotecan into milk. Lactating female rats given 4.72 mg/m² IV (about twice the clinical dose on a mg/m² basis) excreted topotecan into milk at concentrations up to 48-fold higher than those in plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from HYCAMTIN, discontinue breastfeeding when women are receiving HYCAMTIN.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the 879 patients with metastatic ovarian cancer or small cell lung cancer in clinical trials of HYCAMTIN, 32% (n = 281) were 65 years of age and older, while 3.8% (n = 33) were 75 years of age and older. Of the 140 patients with Stage IV-B, relapsed, or refractory cervical cancer in clinical trials of HYCAMTIN who received HYCAMTIN plus cisplatin in the randomized clinical trial, 6% (n = 9) were 65 years of age and older, while 3% (n = 4) were 75 years of age 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, but greater sensitivity of some older individuals cannot be ruled out.

There were no apparent differences in the pharmacokinetics of topotecan in elderly patients, once the age-related decrease in renal function was considered [see CLINICAL PHARMACOLOGY].

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see DOSAGE AND ADMINISTRATION].

Renal Impairment

No dosage adjustment of HYCAMTIN appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min). Dosage reduction is recommended for patients with moderate renal impairment (Clcr 20 to 39 mL/min). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for HYCAMTIN [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 3/18/2014
This monograph has been modified to include the generic and brand name in many instances.

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