"The US Food and Drug Administration (FDA) today granted accelerated approval for osimertinib (Tagrisso, AstraZeneca), previously known as AZD9291, for the treatment of a specific type of advanced non-small-cell lung cancer.
Bone Marrow Suppression
Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of HYCAMTIN. Neutropenia is not cumulative over time. Severe myelotoxicity has been reported when HYCAMTIN is used in combination with cisplatin [see DRUG INTERACTIONS].
- The following data on myelosuppression are based on an integrated safety database from 8 trials (N = 879) using HYCAMTIN injection at 1.5 mg/m² by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course in patients with ovarian cancer and small cell lung cancer and from one trial in patients with cervical cancer (N = 147) using HYCAMTIN 0.75 mg/m² by intravenous infusion over 30 minutes daily on Days 1, 2, and 3 repeated every 21 days in combination with cisplatin 50 mg/m² on Day 1.
- Monotherapy: Grade 4 neutropenia (less than 500 cells/mm³) occurred in 78% of patients, with a median duration of 7 days and was most common during Course 1 of treatment (58% of patients). Grade 4 neutropenia associated with infection occurred in 13% of patients and febrile neutropenia occurred in 5% of patients. Sepsis occurred in 4% of patients and was fatal in 1% of patients. Pancytopenia has been reported.
- Combination with cisplatin: Grade 4 neutropenia occurred in 48% of patients.
- Monotherapy: Grade 4 thrombocytopenia (less than 25,000/mm³) occurred in 27% of patients, with a median duration of 5 days.
- Combination with cisplatin: Grade 4 thrombocytopenia occurred in 7% of patients.
- Monotherapy: Grade 3 or 4 anemia (less than 8 g/dL) occurred in 37% of patients.
- Combination with cisplatin: Grade 3 or Grade 4 anemia occurred in 40% of patients.
Administer HYCAMTIN only to patients with a baseline neutrophil count of greater than or equal to 1,500 cells/mm³ and a platelet count greater than or equal to 100,000/mm³. Monitor peripheral blood counts frequently during treatment with HYCAMTIN. Refer to Section 2.4 for dose modification guidelines for hematological toxicities in subsequent courses. Do not treat patients with subsequent courses of HYCAMTIN until neutrophils recover to greater than 1,000 cells/mm³, platelets recover to greater than 100,000 cells/mm³, and hemoglobin levels recover to 9.0 g/dL (with transfusion if necessary).
Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain.
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 ILD (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue HYCAMTIN if a new diagnosis of ILD is confirmed.
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 females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose of HYCAMTIN. Advise women of the potential risk to a fetus [see Use in Specific Populations].
Extravasation And Tissue Injury
Extravasation with HYCAMTIN has been observed; severe cases have been reported. If signs or symptoms of extravasation occur, immediately stop administration of HYCAMTIN and institute recommended management procedures [see ADVERSE REACTIONS].
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 0.25 times 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
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 at doses similar to the clinical dose [see Data]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown; however, the background risk in the US general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Animal Data: In rabbits, a dose of 0.10 mg/kg/day (about equal to the clinical 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, 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. Administration of an intravenous 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.
It is not known whether this drug is present in human milk; however, topotecan is excreted in rat milk at high concentrations [see Data]. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants with HYCAMTIN, advise nursing mothers to discontinue breastfeeding during treatment with HYCAMTIN.
Animal Data: Following intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m² (about twice the clinical dose on a mg/m² basis), topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma.
Females And Males Of Reproductive Potential
Females: Advise female patients of reproductive potential to use effective contraception during treatment with HYCAMTIN and for one month after the last dose. Advise females 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 three months after treatment with HYCAMTIN [see Nonclinical Toxicology].
Females: 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 [see Nonclinical Toxicology].
Safety and effectiveness in pediatric patients have not been established.
Of the 879 patients with metastatic ovarian cancer or small cell lung cancer in clinical trials of HYCAMTIN, 32% (n = 281) were aged 65 years and older, while 3.8% (n = 33) were aged 75 years 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 aged 65 years and older, while 3% (n = 4) were aged 75 years 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.
The systemic exposure to both topotecan lactone and total topotecan increased in patients with moderate renal impairment (Clcr = 20 to 39 mL/min) compared with patients with normal renal function (Clcr greater than 60 mL/min). Reduce the dose of HYCAMTIN in patients with moderate renal impairment (Clcr = 20 to 39 mL/min). No dosage adjustment of HYCAMTIN is recommended for patients with mild renal impairment (Clcr = 40 to 60 mL/min) [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Insufficient data are available in patients with severe renal impairment (Clcr less than 20 mL/min) to provide a dosage recommendation for HYCAMTIN.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 6/19/2015
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