Stivarga

Colorectal Cancer

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.

Gastrointestinal Stromal Tumors

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.

Hepatocellular Carcinoma

STIVARGA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Recommended Dose

The recommended dose is 160 mg STIVARGA (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.

Take STIVARGA at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat [see Clinical Pharmacology ]. Do not take two doses of STIVARGA on the same day to make up for a missed dose from the previous day.

Dose Modifications

If dose modifications are required, reduce the dose in 40 mg (one tablet) increments; the lowest recommended daily dose of STIVARGA is 80 mg daily.

Interrupt STIVARGA for the following:

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Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR

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Symptomatic Grade 2 hypertension

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Any Grade 3 or 4 adverse reaction

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Worsening infection of any grade

Reduce the dose of STIVARGA to 120 mg:

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For the first occurrence of Grade 2 HFSR of any duration

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After recovery of any Grade 3 or 4 adverse reaction except infection

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For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation, only resume if the potential benefit outweighs the risk of hepatotoxicity

Reduce the dose of STIVARGA to 80 mg:

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For re-occurrence of Grade 2 HFSR at the 120 mg dose

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After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity or infection)

Discontinue STIVARGA permanently for the following:

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Failure to tolerate 80 mg dose

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Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)

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Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN

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Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg

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For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

Pregnancy

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.

Lactation

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.

Females and Males of Reproductive Potential

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 ].

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 ].

Pediatric Use

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.

Geriatric Use

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.

Hepatic Impairment

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 ]. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions ].

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.

 8.7 Renal Impairment

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 ].

 8.8 Race

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 ]. No starting dose adjustment is necessary based on race.