STIVARGA- regorafenib tablet, film coated

Држава: Сједињене Америчке Државе

Језик: Енглески

Извор: NLM (National Library of Medicine)

Активни састојак:

REGORAFENIB (UNII: MGN125FS9D) (REGORAFENIB ANHYDROUS - UNII:24T2A1DOYB)

Доступно од:

Bayer HealthCare Pharmaceuticals Inc.

INN (Међународно име):

REGORAFENIB MONOHYDRATE

Састав:

REGORAFENIB 40 mg

Пут администрације:

ORAL

Тип рецептора:

PRESCRIPTION DRUG

Терапеутске индикације:

STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild- type, an anti-EGFR therapy. STIVARGA is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. STIVARGA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. None. Risk Summary Based on animal studies and its mechanism of action, STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Administration of regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations [see Data ] . Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively. Data Animal Data In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. Daily administration of regorafenib to pregnant rats during organogenesis resulted in fetal findings of delayed ossification at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) and dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis. In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies, as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies. Risk Summary There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production. In rats, regorafenib and its metabolites are excreted in milk. Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose. Contraception Females Use effective contraception during treatment and for 2 months after completion of therapy. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following the final dose of STIVARGA [see Nonclinical Toxicology (13.1)] . Infertility There are no data on the effect of STIVARGA on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology (13.1)]. The safety and efficacy of  STIVARGA in pediatric patients less than 18 years of age have not been established. Animal Data In 28-day repeat-dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings occurred at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat-dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate. Of the 1142 STIVARGA-treated patients enrolled in randomized, placebo-controlled trials, 40% were 65 years of age and over, while 10% were 75 and over. No overall differences in efficacy were observed between these patients and younger patients. There was an increased incidence of Grade 3 hypertension (18% versus 9%) in the placebo-controlled trials among STIVARGA-treated patients 65 years of age and older as compared to younger patients. In addition, one Grade 4 hypertension event has been reported in the 65 years and older age group and none in the younger age group. No dose adjustment is recommended in patients with mild (total bilirubin ≤ULN and AST >ULN, or total bilirubin >ULN to ≤1.5 times ULN) or moderate (total bilirubin >1.5 to ≤3 times ULN and any AST) hepatic impairment, [see Clinical Pharmacology (12.3)] . Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)] . STIVARGA is not recommended for use in patients with severe hepatic impairment (total bilirubin >3x ULN) as STIVARGA has not been studied in this population. No dose adjustment is recommended for patients with renal impairment. The pharmacokinetics of regorafenib have not been studied in patients who are on dialysis and there is no recommended dose for this patient population [see Clinical Pharmacology (12.3)] . Based on pooled data from three placebo-controlled trials (CORRECT, GRID and CONCUR), a higher incidence of HFSR and liver function test abnormalities occurred in Asian patients treated with STIVARGA as compared with Whites [see Warnings and Precautions (5.1, 5.5)] . No starting dose adjustment is necessary based on race.

Резиме производа:

How Supplied Tablets are supplied in the following: Packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03). Packages containing four bottles, with each bottle containing 21 tablets, for a total of 84 tablets per package (NDC 50419-171-06). Storage and Handling Store STIVARGA at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening. Discard any unused tablets 7 weeks after opening the bottle. Dispose of unused tablets in accordance with local requirements.

Статус ауторизације:

New Drug Application

Карактеристике производа

STIVARGA- REGORAFENIB TABLET, FILM COATED
BAYER HEALTHCARE PHARMACEUTICALS INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
STIVARGA SAFELY AND EFFECTIVELY. SEE FULL
PRESCRIBING INFORMATION FOR STIVARGA.
STIVARGA® (REGORAFENIB) TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 2012
WARNING: HEPATOTOXICITY
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
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INDICATIONS AND USAGE
STIVARGA is a kinase inhibitor indicated for the treatment of patients
with:
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DOSAGE AND ADMINISTRATION
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DOSAGE FORMS AND STRENGTHS
Tablets: 40 mg (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
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ADVERSE REACTIONS
The most common adverse reactions (≥20%) are pain (including
gastrointestinal and abdominal pain), HFSR,
SEVERE AND SOMETIMES FATAL HEPATOTOXICITY HAS OCCURRED IN CLINICAL
TRIALS. (5.1)
MONITOR HEPATIC FUNCTION PRIOR TO AND DURING TREATMENT. (5.1)
INTERRUPT AND THEN REDUCE OR DISCONTINUE STIVARGA FOR HEPATOTOXICITY
AS MANIFESTED BY ELEVATED
LIVER FUNCTION TESTS OR HEPATOCELLULAR NECROSIS, DEPENDING UPON
SEVERITY AND PERSISTENCE. (2.2)
Metastatic colorectal cancer (CRC) who have been previously treated
with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS
wild-type, an anti-EGFR therapy. (1.1)
Locally advanced, unresectable or metastatic gastrointestinal stromal
tumor (GIST) who have been previously
treated with imatinib mesylate and sunitinib malate. (1.2)
Hepatocellular carcinoma (HCC) who have been previously treated with
sorafenib (1.3)
Recommended dose: 160 mg orally, once daily for the first 21 days of
each 28-day cycle. (2.1)
Take STIVARGA after a low-fat meal. (2.1, 12.3)
Hepatotoxicity: Monitor liver function tests. Withhold and then reduce
or discontinue STIVARGA based on severity
and duration. (5.1)
Infections: Withhold STIVARGA in patients with worsening or severe
infections. (5.2)
Hemorrhage: Permanently discont