regorafenib (Stivarga)

Dosing and uses of Stivarga (regorafenib)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 40mg

 

Colorectal Cancer

Indicated for the treatment of metastatic colorectal cancer in patients who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy (eg, bevacizumab, ziv-aflibercept), and, if KRAS wild type, an anti-EGFR therapy (eg, cetuximab, panitumumab)

160 mg PO qDay for the first 21 days of each 28-day cycle

Continue treatment until disease progression or unacceptable toxicity

 

Gastrointestinal Stromal Tumors

Indicated for locally advanced, unresectable gastrointestinal stromal tumors (GIST) that no longer respond to other treatments (eg, imatinib, sunitinib)

160 mg PO qDay for the first 21 days of each 28-day cycle

Continue treatment until disease progression or unacceptable toxicity

 

Dosage modifications

Interrupt dose

• Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia] 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

Reduce dose to 120 mg/day

• For the first occurrence of Grade 2 HFSR of any duration
• After recovery of any Grade 3 or 4 adverse reaction
• For Grade 3 AST/ALT elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity

Reduce dose to 80 mg/day

• For reoccurrence of Grade 2 HFSR at the 120 mg dose
• After recovery of any Grade 3 or 4 adverse reactions at the 120 mg dose (except hepatotoxicity)

Discontinue permanently

• Failure to tolerate 80 mg dose
• Any occurrence of AST/ALT >20 x ULN
• Any occurrence of AST/ALT >3 x ULN with concurrent bilirubin >2 x ULN
• Reoccurrence of AST/ALT >5 x ULN despite dose reduction to 120 mg
• For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

 

Hepatocellular Carcinoma (Orphan)

Orphan designation for treatment of hepatocellular carcinoma

Sponsor

• Bayer HealthCare Pharmaceuticals, Inc; 100 Bayer Blvd, P. O. Box 915; Whippany, NJ 07981-0915

 

Renal Impairment

No dose adjustment is needed for patients with mild, moderate, or severe renal impairment

 

Hepatic Impairment

No dose adjustment is needed for patients with mild or moderate hepatic impairment

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Stivarga (regorafenib) adverse (side) effects

>10%

Anemia (79%)

Increased AST (65%)

Asthenia (64%)

Proteinuria (60%)

Hypocalcemia (59%)

Hypophosphatemia (57%)

Lymphopenia (54%)

Decreased appetite and food intake (47%)

Increased lipase (46%)

Hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia] (45%)

Hyperbilirubinemia (45%)

Increased ALT (45%)

Diarrhea (43%)

Thrombocytopenia (41%)

Mucositis (33%)

Weight loss (32%)

Infection (31%)

Hypertension (30%)

Dysphonia (30%)

Hyponatremia (30%)

Pain (29%)

Fever (28%)

Rash (26%)

Hypokalemia (26%)

Increased amylase (26%)

Increased INR (24%)

Hemorrhage (21%)

Nausea (20%)

 

1-10%

Headache (10%)

Alopecia (7.6%)

Taste disorder (7.6%)

Musculoskeletal stiffness (6%)

Xerostomia (4.8%)

Hypothyroidism (4.2%)

Neutropenia (3%)

Tremor (2%)

GERD (1.4%)

Myocardial ischemia and infarction (1.2%)

 

<1%

Gastrointestinal fistula (0.8%)

Keratoacanthoma/squamous cell carcinoma of the skin (0.09%)

Hypersensitivity reactions

 

Warnings

Black box warnings

Severe and sometimes fatal hepatotoxicity observed in clinical trials

Monitor hepatic function prior to and during treatment

Interrupt and then reduce or discontinue for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence (see Dosing Modifications)

 

Contraindications

None

 

Cautions

May cause severe drug-induced liver injury with fatal outcome (see Black box warnings)

Increases risk for hemorrhage; discontinue therapy for severe or life-threatening hemorrhage

Increases risk for hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia] and rash; a higher incidence of HFSR reported in Asian patients; interrupt and then reduce or discontinue regorafenib depending on severity and persistence of dermatologic toxicity

Hypertension may occur, typically during the first treatment cycle; temporarily or permanently discontinue regorafenib for severe or uncontrolled hypertension

Myocardial ischemia and infarction observed in clinical trials; withhold regorafenib for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events

One case report of reversible posterior leukoencephalopathy syndrome (RPLS) reported (1 of 1100 treated patients); discontinue therapy if RPLS occurs

Discontinue therapy if gastrointestinal perforation or fistula occur

May impair wound healing (class effect of VEGFR inhibitors); discontinue at least 2 weeks before scheduled surgery; discontinue therapy in patients with wound dehiscence

Embryo-fetal toxicity likely if taken while pregnant (see Pregnancy and lactation)

Control hypertension before initiating treatment; monitor blood pressure regularly during treatment

Taper dose when possible and monitor for discontinuation symptoms

Advise females of reproductive potential to use effective contraception during treatment and for 2 months after final dose; advise males with female partners of reproductive potential to use effective contraception during treatment and for 2 months after final dose

Interaction overview

• CYP3A4 substrate; avoid coadministration with strong CYP3A4 inducers or inhibitors
• Regoragenib competitively inhibits UGT1A9 and UGT1A1 substrates
• Regorafenib inhibits BCRP substrates (eg, methotrexate, rosuvastatin, fluvastatin, atorvastatin); monitor BCRP susbstrates for potential increased toxicity and systemic exposure

 

Pregnancy and lactation

Based on its mechanism of action, can cause fetal harm

There are no adequate and well-controlled studies in pregnant women; 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

Lactation: Unknown whether distributed in breast milk; decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Stivarga (regorafenib)

Mechanism of action

Tyrosine kinase inhibitor; shown to inhibit activity of membrane-bound and intracellular kinases involved in normal cellular functions and in pathological processes (eg, oncogenesis, tumor angiogenesis) RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and AbL

 

Absorption

Bioavailability: 69-83% (with low fat meal)

Peak Plasma Time: 4 hr

Peak Plasma Concentration: 2.5 mcg/mL (single dose); 3.9 mcg/mL (steady-state)

AUC: 70.4 mcg•h/mL (single dose); 58.3 mcg•h/mL (steady-state)

 

Distribution

Protein Bound: 99.5% (regorafenib); 99.8% (M-2 active metabolite); 99.95% (M-5 active metabolite)

Undergoes enterohepatic circulation with multiple plasma concentration peaks observed during 24-hr intervaL

 

Metabolism

Metabolized by CYP3A4 and UGT1A9

Metabolites (active): 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

 

Elimination

Half-life: 28 hr (regorafenib); 25 hr (M-2 active metabolite); 51 hr (M-5 active metabolite)

Excretion: 71% feces; 19% urine (within 12 days of single dose)

 

Administration

Instructions

Take at same time each day

Swallow table whole with water, do not split, chew, or crush

Take after a low-fat meal that contains <600 calories and <30% fat

Do not take 2 doses on the same day to make up for a missed dose from the previous day