regorafenib (Rx)

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Brand and Other Names:Stivarga

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 40mg
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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

Safety and efficacy not established

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Interactions

Interaction Checker

and regorafenib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse 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

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            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 & 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
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            Pregnancy & 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.

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            Pharmacology

            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)

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            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

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            Images

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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