Bone Marrow Suppression
Bone marrow suppression (primarily neutropenia) is a dose-limiting toxicity of HYCAMTIN. Neutropenia is not cumulative over time. The following data on myelosuppression are based on an integrated safety database from 4 thoracic malignancy studies (N = 682) using HYCAMTIN capsules at 2.3 mg/m²/day for 5 consecutive days. The median day for neutrophil, red blood cell, and platelet nadirs occurred on day 15.
Grade 4 neutropenia ( < 500 cells/mm³) occurred in 32% of patients with a median duration of 7 days and was most common during course 1 of treatment (20% of patients). Infection, sepsis, and febrile neutropenia occurred in 17%, 2%, and 4% of patients, respectively. Death due to sepsis occurred in 1% of patients. Pancytopenia has been reported. Topotec an-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered. [See DOSAGE AND ADMINISTRATION.]
Grade 4 thrombocytopenia ( < 10,000 cells/mm³) occurred in 6% of patients, with a median duration of 3 days.
Grade 3 or 4 anemia ( < 8 g/dL) occurred in 25% of patients.
Monitoring of Bone Marrow Function
HYCAMTIN should be administered only in patients with adequate bone marrow reserves, including a baseline neutrophil count of ≥ 1,500 cells/mm³ and a platelet count ≥ 100,000 cells/mm³. Frequent monitoring of peripheral blood cell counts should be instituted during treatment with HYCAMTIN.
Diarrhea, including severe diarrhea requiring hospitalization, has been reported during treatment with HYCAMTIN capsules. Diarrhea related to HYCAMTIN capsules can occur at the same time as drug-related neutropenia and its sequelae. Communication with patients prior to drug administration regarding these side effects and proactive management of early and all signs and symptoms of diarrhea is important. Treatment-related diarrhea is associated with significant morbidity and may be life-threatening. Should diarrhea occur during treatment with HYCAMTIN capsules, physicians are advised to aggressively manage diarrhea. Clinical guidelines describing the aggressive management of diarrhea include specific recommendations on patient communication and awareness, recognition of early warning signs, use of anti diarrheals and antibiotics, changes in fluid intake and diet, and need for hospitalization.
Of the 682 patients who received HYCAMTIN capsules in the 4 thoracic cancer studies, the overall incidence of drug-related diarrhea was 22%, including 4% with Grade 3 and 0.4% with Grade 4. Drug-related diarrhea was more frequent in patients ≥ 65 years of age (28%) compared to those < 65 years of age (19%). [See ADVERSE REACTIONS and Use In Specific Populations.]
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. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease (e.g., cough, fever, dyspnea, and/or hypoxia), and HYCAMTIN should be discontinued if a new diagnosis of ILD is confirmed.
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 taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use In Specific Populations, Pregnancy].
P-glycoprotein inhibitors (e.g., cyclosporine A, elacridar, ketoconazole, ritonavir, and saquinavir) can cause significant increases in topotecan exposure. The concomitant use of P glycoprotein inhibitors with HYCAMTIN capsules should be avoided. [See DRUG INTERACTIONS.]
Patient Counseling Information
See FDA-approved patient labeling.
Bone Marrow Suppression
Patients should be informed that HYCAMTIN decreases blood cell counts such as white blood cells, platelets, and red blood cells. Patients who develop fever or other signs of infection such as chills, cough, or burning pain on urination while on therapy should notify their physician promptly. Patients should be told that frequent blood tests will be performed while taking HYCAMTIN to monitor for the occurrence of bone marrow suppression.
Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breastfeeding during treatment with HYCAMTIN.
Patients should be informed that HYCAMTIN capsules cause diarrhea which may be severe in some cases. Patients should be told how to manage and/or prevent diarrhea and to inform their physician if severe diarrhea occurs during treatment with HYCAMTIN capsules.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity testing of topotecan has not been done. Nevertheless, 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 3/5th of the oral 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 1/6th the oral 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 Category D. [See WARNINGS AND PRECAUTIONS]
HYCAMTIN can cause fetal harm when administered to a pregnant woman. In rabbits, an IV dose of 0.10 mg/kg/day (about equal to the clinical IV 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, an IV dose of 0.23 mg/kg/day (about equal to the clinical IV 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. An IV dose of 0.10 mg/kg/day (about half the clinical IV 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 taking this drug, the patient should be apprised of the potential hazard to the fetus.
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.
Safety and effectiveness in pediatric patients have not been established.
Of the 682 patients with thoracic cancer in 4 clinical studies who received HYCAMTIN capsules, 33% (n = 225) were 65 years of age and older, while 4.8% (n = 33) were 75 years of age and older. Treatment-related diarrhea was more frequent in patients ≥ 65 years of age (28%) compared to those < 65 years of age (19%). [See WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.] Among patients ≥ 65 years of age, those receiving HYCAMTIN capsules plus BSC showed a survival benefit compared to those receiving BSC alone. There were no apparent differences in the pharmacokinetics of topotecan in elderly patients with creatinine clearance of ≥ 60 mL/minute [see CLINICAL PHARMACOLOGY].
A cross-study analysis of data collected from 217 patients with advanced solid tumors Topotecan hydrochloride has the following structural formula: indicated that exposure (AUC0-∞) to topotecan lactone, the pharmacologically active moiety, was 10% and 20% higher in patients with mild renal (CLcr = 50-80 mL/min) and moderate renal (CLcr = 30-49 mL/min) impairment, respectively, than in patients with normal renal function (CLcr > 80 mL/min) [see DOSAGE AND ADMINISTRATION].
In a population pharmacokinetic analysis involving oral topotecan administered at doses of 0.15-2.7 mg/m²/day to 118 cancer patients, the pharmacokinetics of total topotecan did not differ significantly based on patient serum bilirubin, ALT, or AST. No dosage adjustment appeared to be required for patients with impaired hepatic function (serum bilirubin of > 1.5 mg/dL).
Last reviewed on RxList: 10/28/2011
This monograph has been modified to include the generic and brand name in many instances.
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