REGOPHAL

Regorafenib is an

Oral-administered inhibitor of multiple kinases.

It is used for the treatment of metastatic colorectal cancer, advanced gastrointestinal stromal tumours, and hepatocellular carcinoma.

FDA approved on

September 27, 2012.

Approved use of Regorafenib was expanded to treat Hepatocellular Carcinoma in April 2017.

Regorafenib 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 KRAS wild type, an anti-EGFR therapy.

Regorafenib is also indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumour (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.

Regorafenib is also indicated for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib.

Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity.

In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl and CSF1R at concentrations of regorafenib that have been achieved clinically.

In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model and inhibition of tumor growth in several mouse xenograft models including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma.

Regorafenib also demonstrated anti-metastatic activity in a mouse xenograft model and two mouse orthotopic models of human colorectal carcinoma. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of multiple doses of STIVARGA (160 mg once daily for 21 days) on the QTc interval was evaluated in an open-label, single-arm study in 25 patients with advanced solid tumors.

No large changes in the mean

QTc interval (i.e., > 20 msec) were detected in the study. 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.

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 max of 3.9 µg/mL and a geometric mean AUC of 58.3 µg*h/mL.

The coefficient of variation of AUC and C max is 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.

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.

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

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).

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.

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 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).

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% .

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.

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.

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.

AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93% .

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.

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.

Vascular endothelial growth factor receptor 1 Inhibitor Vascular endothelial growth factor receptor 2 Inhibitor Vascular endothelial growth factor receptor 3 Inhibitor + 16 more targets.

Cmax = 2.5 μg/mL Tmax = 4 hours AUC = 70.4 μg h/mL Cmax, steady-state = 3.9 μg/mL AUC, steady-state = 58.3 μg h/mL The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.

Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval.

Regorafenib is metabolized by

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 of them having 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).

Regorafenib is an inhibitor of P-glycoprotein

Label, while its active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) are substrates of P-glycoprotein 1.

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.

Regorafenib, 160 mg oral dose = 28 hours (14-58 hours) M2 metabolite, 160 mg oral dose = 25 hours (14-32 hours) M5 metabolite, 160 mg oral dose = 51 hours (32-72 hours).

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The most common adverse reactions (≥20%) are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, and infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea.

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

• 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.

Do not take two doses of

STIVARGA on the same day to make up for a missed dose from the previous day. 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.

• 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.

• For the first occurrence of Grade 2 HFSR of any duration.

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

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

• 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.

• 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).

STIVARGA at 25°C (77°F); excursions are permitted from to 30°C (59 to 86°F) .

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.

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.

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 to 4 % and to 20%, respectively.

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.

The safety and efficacy of

STIVARGA in pediatric patients less than 18 years of age have not been established.

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 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 and none in the younger.