Stivarga (Regorafenib)

Check Drug InteractionsCheck known drug interactions.

Dosage & administration

* •Recommended dose: 160 mg orally, once daily for the first 21 days of each 28-day cycle. (

2.1 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.

)
* •Take STIVARGA after a low-fat meal. (

2.1 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.

12.3 Pharmacokinetics

Absorption

Following a single 160 mg dose of STIVARGA in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (C_max) of 2.5 µg/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 µg*h/mL. The AUC of regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean C_maxof 3.9 µg/mL and a geometric mean AUC of 58.3 µg*h/mL. The coefficient of variation of AUC and C_maxis between 35% and 44%.

The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.

In a food-effect study, 24 healthy men received a single 160 mg dose of STIVARGA on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. STIVARGA was administered with a low-fat meal in the CORRECT and GRID studies

[see Dosage and Administration , Clinical Studies ].

Distribution

Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.

Elimination

Following a single 160 mg oral dose of STIVARGA, the geometric mean (minimum to maximum) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (minimum to maximum) elimination half-life of 51 hours (32 to 70 hours).

Metabolism

Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl). Both metabolites have similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).

Excretion

Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.

Specific Populations

Age, sex, race and weight had no clinically meaningful effect on the pharmacokinetics of regorafenib.

Hepatic Impairment

Based on a population pharmacokinetic analysis, no clinically important differences in the mean total exposure of regorafenib, including M-2 and M-5, were noted amongst patients with normal liver function (total bilirubin and AST ≤ ULN, n=744), mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin >ULN to ≤1.5x ULN, n=437), and moderate hepatic impairment (total bilirubin >1.5x to ≤3x ULN and any AST, n=36). The pooled analysis included 391 patients with HCC of whom 116, 249, and 26 were categorized as having normal liver function, mild, and moderate hepatic impairment, respectively. The pharmacokinetics of regorafenib were not evaluated in patients with severe hepatic impairment (total bilirubin >3x ULN).

Renal Impairment

The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 6 patients with severe renal impairment (CLcr 15-29 mL/min) and 18 patients with normal/mild renal function (CLcr ≥60 mL/min) following the administration of STIVARGA at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with severe renal impairment compared to patients with normal renal function. The pharmacokinetics of regorafenib has not been studied in patients with end-stage renal disease on dialysis.

Drug Interaction Studies

Effect of Regorafenib on Cytochrome P450 Substrates: In vitro

studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, CYP3A4 and CYP2C19; M-2 is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and M-5 is an inhibitor of CYP2C8. In vitro studies suggested that regorafenib is not an inducer of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.

Patients with advanced solid tumors received single oral doses of CYP substrates, 2 mg of midazolam (CYP3A4), 40 mg of omeprazole (CYP2C19) and 10 mg of warfarin (CYP2C9) or 4 mg of rosiglitazone (CYP2C8) one week before and two weeks after STIVARGA at a dose of 160 mg once daily. No clinically meaningful effect was observed in the mean AUC of rosiglitazone (N=12) or the mean omeprazole (N=11) plasma concentrations measured 6 hours after dosing or the mean AUC of midazolam (N=15). The mean AUC of warfarin (N=8) increased by 25%

[see Warnings and Precautions ].

Effect of CYP3A4 Strong Inducers on Regorafenib:

Twenty-two healthy men received a single 160 mg dose of STIVARGA alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed

[see Drug Interactions ]

Effect of CYP3A4 Strong Inhibitors on Regorafenib:

Eighteen healthy men

received a single 160 mg dose of STIVARGA alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93%

[see Drug Interactions ]

Effect of Neomycin on Regorafenib:

Twenty-seven healthy men received a single 160 mg dose of STIVARGA and then 5 days after starting neomycin. Neomycin, a non-absorbable antibiotic, was administered at a dose of 1 gram three times daily for 5 days. No clinically meaningful effect on the mean AUC of regorafenib was observed; however, the mean AUC of M-2 decreased by 76% and the mean AUC of M-5 decreased by 86%. The decreased exposure of M-2 and M-5 may result in a decreased efficacy of STIVARGA. The effects of other antibiotics on the exposure of regorafenib and its active metabolites have not been studied.

Effect of Regorafenib on UGT1A1 Substrates:

In vitro studies showed that regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations

Eleven patients received irinotecan-containing combination chemotherapy with STIVARGA at a dose of 160 mg. The mean AUC of irinotecan increased by 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of STIVARGA.

Effect of Regorafenib on BCRP Substrates:

Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in C_max

[see Drug Interactions ]

)

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Stivarga prescribing information

•
Severe and sometimes fatal hepatotoxicity has occurred in clinical trials
[see Warnings and Precautions (
5.1 Hepatotoxicity
Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients in clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury.
In the CORRECT study, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm. In the GRID study
,
fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm. In the RESORCE study, there was no increase in the incidence of fatal hepatic failure as compared to placebo
[see Adverse Reactions ]
.
Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.
Temporarily hold and then reduce or permanently discontinue STIVARGA depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis
[see Dosage and Administration and Use in Specific Populations ]
.
)]
.
•
Monitor hepatic function prior to and during treatment
[see Warnings and Precautions (
5.1 Hepatotoxicity
Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients in clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury.
In the CORRECT study, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm. In the GRID study
,
fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm. In the RESORCE study, there was no increase in the incidence of fatal hepatic failure as compared to placebo
[see Adverse Reactions ]
.
Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.
Temporarily hold and then reduce or permanently discontinue STIVARGA depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis
[see Dosage and Administration and Use in Specific Populations ]
.
)].
•
Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence
[see Dosage and Administration (
2.2 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:
•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
•Symptomatic Grade 2 hypertension
•Any Grade 3 or 4 adverse reaction
•Worsening infection of any grade
Reduce the dose of STIVARGA to 120 mg:
•For the first occurrence of Grade 2 HFSR of any duration
•After recovery of any Grade 3 or 4 adverse reaction except infection
•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:
•For re-occurrence of Grade 2 HFSR at the 120 mg dose
•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:
•Failure to tolerate 80 mg dose
•Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)
•Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN
•Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg
•For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks
)]
.

STIVARGA is a kinase inhibitor 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. (
1.1 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.
)
•Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. (
1.2 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 (HCC) who have been previously treated with sorafenib (
1.3 Hepatocellular Carcinoma
STIVARGA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
)

•Recommended dose: 160 mg orally, once daily for the first 21 days of each 28-day cycle. (
2.1 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.
)
•Take STIVARGA after a low-fat meal. (
2.1 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.
,
12.3 Pharmacokinetics
Absorption
Following a single 160 mg dose of STIVARGA in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (C_max) of 2.5 µg/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 µg*h/mL. The AUC of regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean C_maxof 3.9 µg/mL and a geometric mean AUC of 58.3 µg*h/mL. The coefficient of variation of AUC and C_maxis between 35% and 44%.
The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.
In a food-effect study, 24 healthy men received a single 160 mg dose of STIVARGA on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. STIVARGA was administered with a low-fat meal in the CORRECT and GRID studies
[see Dosage and Administration , Clinical Studies ].
Distribution
Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.
Elimination
Following a single 160 mg oral dose of STIVARGA, the geometric mean (minimum to maximum) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (minimum to maximum) elimination half-life of 51 hours (32 to 70 hours).
Metabolism
Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl). Both metabolites have similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).
Excretion
Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.
Specific Populations
Age, sex, race and weight had no clinically meaningful effect on the pharmacokinetics of regorafenib.
Hepatic Impairment
Based on a population pharmacokinetic analysis, no clinically important differences in the mean total exposure of regorafenib, including M-2 and M-5, were noted amongst patients with normal liver function (total bilirubin and AST ≤ ULN, n=744), mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin >ULN to ≤1.5x ULN, n=437), and moderate hepatic impairment (total bilirubin >1.5x to ≤3x ULN and any AST, n=36). The pooled analysis included 391 patients with HCC of whom 116, 249, and 26 were categorized as having normal liver function, mild, and moderate hepatic impairment, respectively. The pharmacokinetics of regorafenib were not evaluated in patients with severe hepatic impairment (total bilirubin >3x ULN).
Renal Impairment
The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 6 patients with severe renal impairment (CLcr 15-29 mL/min) and 18 patients with normal/mild renal function (CLcr ≥60 mL/min) following the administration of STIVARGA at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with severe renal impairment compared to patients with normal renal function. The pharmacokinetics of regorafenib has not been studied in patients with end-stage renal disease on dialysis.
Drug Interaction Studies
Effect of Regorafenib on Cytochrome P450 Substrates: In vitro
studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, CYP3A4 and CYP2C19; M-2 is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and M-5 is an inhibitor of CYP2C8. In vitro studies suggested that regorafenib is not an inducer of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.
Patients with advanced solid tumors received single oral doses of CYP substrates, 2 mg of midazolam (CYP3A4), 40 mg of omeprazole (CYP2C19) and 10 mg of warfarin (CYP2C9) or 4 mg of rosiglitazone (CYP2C8) one week before and two weeks after STIVARGA at a dose of 160 mg once daily. No clinically meaningful effect was observed in the mean AUC of rosiglitazone (N=12) or the mean omeprazole (N=11) plasma concentrations measured 6 hours after dosing or the mean AUC of midazolam (N=15). The mean AUC of warfarin (N=8) increased by 25%
[see Warnings and Precautions ].
Effect of CYP3A4 Strong Inducers on Regorafenib:
Twenty-two healthy men received a single 160 mg dose of STIVARGA alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed
[see Drug Interactions ]
.
Effect of CYP3A4 Strong Inhibitors on Regorafenib:
Eighteen healthy men
received a single 160 mg dose of STIVARGA alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93%
[see Drug Interactions ]
.
Effect of Neomycin on Regorafenib:
Twenty-seven healthy men received a single 160 mg dose of STIVARGA and then 5 days after starting neomycin. Neomycin, a non-absorbable antibiotic, was administered at a dose of 1 gram three times daily for 5 days. No clinically meaningful effect on the mean AUC of regorafenib was observed; however, the mean AUC of M-2 decreased by 76% and the mean AUC of M-5 decreased by 86%. The decreased exposure of M-2 and M-5 may result in a decreased efficacy of STIVARGA. The effects of other antibiotics on the exposure of regorafenib and its active metabolites have not been studied.
Effect of Regorafenib on UGT1A1 Substrates:
In vitro studies showed that regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations
.
Eleven patients received irinotecan-containing combination chemotherapy with STIVARGA at a dose of 160 mg. The mean AUC of irinotecan increased by 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of STIVARGA.
Effect of Regorafenib on BCRP Substrates:
Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in C_max
[see Drug Interactions ]
.
)

Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of the drug to the mother. (

8.3 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 ].

)

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Stivarga (Regorafenib)

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