"Jan. 13, 2015 -- Drug-maker Bristol-Myers Squibb says a trial of nivolumab (Opdivo) has been stopped early because the drug improves how long people with a type of advanced lung cancer live compared to chemotherapy.
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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 trials (N = 682) using HYCAMTIN capsules at 2.3 mg/m²/day for 5 consecutive days. The median day for neutrophil 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). Clinical sequelae of neutropenia included infection (17%), febrile neutropenia (4%), sepsis (2%), and septic death (1%). Pancytopenia has been reported.
Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain [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.
Administer the first course of HYCAMTIN only to patients with a neutrophil count of ≥ 1,500 cells/mm³ and a platelet count ≥ 100,000 cells/mm³. Monitor peripheral blood cell counts frequently during treatment with HYCAMTIN. Refer to Section 2.2 for dose modification guidelines for hematological toxicities in subsequent courses.
Diarrhea, including severe and life-threatening diarrhea requiring hospitalization, can occur during treatment with HYCAMTIN capsules. Diarrhea caused by HYCAMTIN capsules can occur at the same time as drug-induced neutropenia and its sequelae. In the 682 patients who received HYCAMTIN capsules in the 4 lung cancer trials, the incidence of diarrhea caused by HYCAMTIN capsules was 22%, with 4% Grade 3 and 0.4% Grade 4. The incidence of Grade 3 or 4 diarrhea proximate (within 5 days) to Grade 3 or 4 neutropenia events in the group receiving HYCAMTIN capsules was 5%. The median time to onset of Grade 2 or worse diarrhea was 9 days in the group receiving HYCAMTIN capsules. Manage diarrhea caused by HYCAMTIN capsules aggressively. Do not administer HYCAMTIN capsules to patients with Grade 3 or 4 diarrhea. Reduce the dose of HYCAMTIN after recovery to Grade 1or less [see DOSAGE AND ADMINISTRATION].
Interstitial Lung Disease
Interstitial lung disease (ILD), including fatalities, has occurred with HYCAMTIN. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic 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.
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. 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 a fetus [see Use in Specific Populations].
Advise females of reproductive potential to use highly effective contraception during treatment and for at least 1 month after the last dose of HYCAMTIN. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION)
- Bone Marrow Suppression
Inform patients that HYCAMTIN decreases blood cell counts such as white blood cells, platelets, and red blood cells. Instruct patients to notify their healthcare provider promptly for fever or other signs of infection such as chills, cough, or burning pain on urination. Advise patients that frequent blood tests will be performed while taking HYCAMTIN to monitor for bone marrow suppression [see WARNINGS AND PRECAUTIONS].
- Embryofetal Toxicity
Advise patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during treatment and for 1 month following treatment with HYCAMTIN [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 3 months after treatment [see Nonclinical Toxicology].
- Nursing Mothers
Advise patients to discontinue nursing during treatment with HYCAMTIN [see Use in Specific Populations].
Advise male and female patients of the potential risk for impaired fertility and possible family planning options.
Inform patients that HYCAMTIN capsules cause diarrhea which may be severe and lifethreatening. Instruct patients how to manage and/or prevent diarrhea and to inform their physician if severe diarrhea occurs during treatment with HYCAMTIN capsules [see WARNINGS AND PRECAUTIONS].
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 0.6 times 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 0.2 times 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
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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to a fetus.
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. Administration of an IV dose of 0.10 mg/kg/day (about half the clinical IV dose on a mg/m² basis) 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.
It is not known whether topotecan is present in human milk. Lactating rats excrete high concentrations of topotecan into milk. 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. Because many drugs are present in human milk, and because of the potential for serious adverse reactions in nursing infants from HYCAMTIN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established.
Of the 682 patients with thoracic cancer in 4 clinical trials who received HYCAMTIN capsules, 33% (n = 225) were aged 65 years and older, while 4.8% (n = 33) were aged 75 years and older. Treatment-related diarrhea was more frequent in patients aged ≥ 65 years (28%) compared with those younger than 65 years (19%). [See WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]
No overall differences in effectiveness were observed between patients 65 years and older and younger patients.
The systemic exposure to both topotecan lactone and total topotecan increased in patients with renal impairment compared with that in patients with normal renal function. No dosage adjustment is recommended for patients with mild renal impairment (CLcr = 50-79 mL/min). Adjust the dose of HYCAMTIN capsules in patients with moderate (CLcr = 30-49 mL/min) and severe (CLcr < 30 mL/min) renal impairment [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Females And Males Of Reproductive Potential
Females: Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during and for 1 month following treatment with HYCAMTIN. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking HYCAMTIN [see Use in Specific Populations].
Males: HYCAMTIN may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 3 months after treatment with HYCAMTIN [see Nonclinical Toxicology].
Females: In females of reproductive potential, HYCAMTIN may have both acute and long-term effects on fertility [see Nonclinical Toxicology].
Males: Effects on spermatogenesis have been observed in animals administered HYCAMTIN. Advise males of the potential risk for impaired fertility and to seek counseling on fertility and family planning options prior to starting treatment.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/7/2014
Additional Hycamtin Capsules Information
- Hycamtin Capsules Drug Interactions Center: topotecan oral
- Hycamtin Capsules Side Effects Center
- Hycamtin Capsules in detail including Side Effects and Drug Images
- Hycamtin Capsules FDA Approved Prescribing Information including Dosage
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