General

Genetic Implications:

Pronunciation:
re-goe-raf-e-nib

Trade Name(s)

• Stivarga

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

•  Metastatic colorectal cancer (CRC) that has failed previous treatment that included a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF therapy, and additional anti-EGFR therapy if tumor is of the RAS wild type.
• Locally advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST) in patients who have previously been treated with imatinib and sunitinib.
• Hepatocellular carcinoma (HCC) in patients who have previously been treated with sorafenib.

Action

Inhibits kinases, which are responsible for many phases of cell function and proliferation.

Therapeutic Effect(s):

• Decreased progression of HCC and metastatic CRC with improved survival.
• Decreased progression of GIST

Pharmacokinetics

Absorption: Well absorbed following oral administration (69–83%).

Distribution: Unknown.

Protein Binding: Regorafenib– >99.5%,  M-2 metabolite– 99.8%,  M-5 metabolite– 99.95%.

Metabolism and Excretion: Highly metabolized (by CYP3A4 and UGT1A9), 2 metabolites (M-2 and M-5) have antineoplastic activity. Undergoes enterohepatic circulation.

Half-life: Regorafenib– 28 hr (range 14–58 hr),  M-2 metabolite– 25 hr (range 14–32 hr),  M-5 metabolite– 51 hr (range 32–70 hr). 47% excreted in feces as parent compound, 24% as metabolites; 19% excreted in urine (mostly as inactive metabolites).

TIME/ACTION PROFILE (improved survival)

Contraindication/Precautions

Contraindicated in:

• Avoid strong CYP3A4 inducers/inhibitors;
• Severe hepatic impairment (Child-Pugh Class C);
• OB:  Pregnancy (may cause fetal harm);
• Lactation:  Lactation.

Use Cautiously in:

• History of hypertension/cardiovascular disease (BP should be controlled prior to treatment);
• Elective surgical procedures (discontinue 2 wk prior to surgery);
•   Asian patients (↑ risk of palmar-plantar erythrodysesthesia);
• Rep:   Women of reproductive potential and men with female partners of reproductive potential;
• Pedi:  Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: HYPERTENSION, MYOCARDIAL ISCHEMIA/INFARCTION

Derm: ERYTHEMA MULTIFORME (EM), PALMAR-PLANTAR ERYTHRODYSESTHESIA, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN), alopecia, impaired wound healing, rash

EENT: dysphonia

Endo: hypothyroidism

F and E: hypocalcemia, hypokalemia, hypophosphatemia, hyponatremia

GI: GASTROINTESTINAL FISTULA/PERFORATION, HEPATOTOXICITY, ↓ appetite, diarrhea, mucositis, altered taste, dry mouth, gastrointestinal reflux, ↑ transaminases

GU: proteinuria, ↓ fertility

Hemat: BLEEDING, THROMBOCYTOPENIA, anemia, lymphopenia

Metabolic: ↓ weight, ↑ lipase, ↑ amylase

MS: pain, musculoskeletal stiffness

Neuro: tremor, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), fatigue, headache

Misc: INFECTION, HYPERSENSITIVITY REACTIONS, fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  Strong CYP3A4 inhibitors  including  clarithromycin,  itraconazole,  ketoconazole,  posaconazole, and  voriconazole  ↑ levels and the risk of toxicity, avoid concurrent use.
•  Strong CYP3A4 inducers  including  carbamazepine,  phenobarbital,  phenytoin, and  rifampin  ↓ levels and effectiveness, avoid concurrent use.
• May ↑ risk of bleeding with  warfarin.
• May ↑ levels and risk of toxicity of  breast cancer resistance protein (BCRP) substrates, including  methotrexate,  fluvastatin, or  atorvastatin.

Drug-Natural Products:

 St. John's wort  ↓ blood levels and effectiveness, avoid concurrent use.

Drug-Food:

Grapefruit juice ↑ blood levels and the risk of toxicity, avoid concurrent use.

Route/Dosage

PO (Adults): 160 mg daily on days 1–21 of a 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.

Availability

Tablets: 40 mg

Assessment

• Monitor BP prior to and weekly during the first 6 wk, then every cycle of therapy. Do not initiate regorafenib until BP is well controlled.

• Assess for cardiac ischemia or infarction during therapy.

• Assess for bleeding during therapy. Interrupt therapy if severe hemorrhage occurs.

• Assess for rash periodically during therapy. May cause SJS or TEN. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

• Monitor for signs and symptoms of posterior reversible encephalopathy syndrome (PRES) (seizures, headache, visual disturbances, confusion, altered mental function) during therapy. Diagnosis via MRI. Discontinue regorafenib in patients who develop PRES.

Lab Test Considerations:

Obtain liver function test (ALT, AST, bilirubin) before starting, at least every 2 wk during first 2 mo of therapy, and monthly thereafter. Monitor liver function tests weekly in patients with ↑ liver function tests until improvement to <3× the upper limit of normal or baseline.

• May cause anemia, thrombocytopenia, neutropenia, and lymphopenia.
• May cause hypocalcemia, hypokalemia, hyponatremia, and hypophosphatemia.
• May cause proteinuria, ↑ serum lipase, and ↑ serum amylase.
• May cause ↑ INR. Monitor INR levels more frequently in patients receiving warfarin.

Implementation

• High Alert: Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits. Therapy should be initiated by physician experienced in the treatment of patients with colorectal cancer.
• May impair wound healing. Hold therapy for at least 2 wk before elective surgery and for at least 2 wk after major surgery until adequate wound healing occurs.
• PO Administer four 40 mg tablets once daily at same time of day with a whole glass of water for the first 21 days of each 28-day cycle.  DNC: Swallow tablets whole with a low-fat meal that contains <30% fat and <600 calories. 
• Dose modifications:

  Interrupt therapy for  Grade 2 hand-foot skin reaction (HFSR) that is recurrent or does not improve in 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 reactions.

  • Reduce dose to 120 mg daily for  1st occurrence of Grade 2 HFSR of any duration, after 1st recovery of any Grade 3 or 4 adverse reaction, for Grade 3 ↑ AST or ALT; only resume if potential benefit outweighs risk of hepatotoxicity.
  • Reduce dose to 80 mg daily for reoccurrence of Grade 2 HFSR at 120 mg dose, after recovery of any Grade 3 or 4 adverse reaction at 120 mg dose (except hepatotoxicity).
  • Discontinue regorafenib permanently for  failure to tolerate 80 mg dose, any occurrence of ↑ AST or ALT >20 × upper limit of normal, any occurrence of ↑ AST or ALT >3 × upper limit of normal with concurrent bilirubin >2 × upper limit of normal, reoccurrence of ↑ AST or ALT >5 × upper limit of normal despite reduction to 120 mg dose, any Grade 4 adverse reaction; only resume if the potential benefits outweigh the risks.

Patient/Family Teaching

• Instruct patient to take tablets at the same time each day with a low-fat meal. Take missed doses on the same day as soon as remembered; do not take 2 doses on the same day to make up for a missed dose. Store medicine in original container; do not place in daily or weekly pill boxes. Discard remaining tablets 28 days after opening bottle. Tightly close bottle after each opening and keep desiccant in bottle. Advise patient to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
• Advise patient to avoid drinking grapefruit juice or eating grapefruit during regorafenib therapy.

• Advise patient to notify health care professional immediately if signs and symptoms of liver problems (yellowing of skin or white part of eyes, nausea, vomiting, dark tea-colored urine, change in sleep pattern), bleeding, skin changes (redness, pain, blisters, bleeding, swelling), hypertension (severe headache, lightheadedness, neurologic symptoms), myocardial ischemia or infarction (chest pain, shortness of breath, dizziness, fainting), or GI perforation or fistula (severe abdominal pain, persistent swelling of abdomen, high fever, chills, nausea, vomiting, severe diarrhea, dehydration) occur.

• Advise patient to notify health care provider of therapy prior to surgery or if had recent surgery.

• Advise patient to maintain adequate hydration to minimize risk and to notify health care professional promptly if signs and symptoms of PRES (headache, seizures, weakness, confusion, high BP, blindness or change in vision, problems thinking) occur.

• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
• Rep:  May cause fetal harm. Advise women of reproductive potential and men of the need for effective contraception during and for at least 2 mo after completion of therapy. Notify health care provider immediately if pregnancy is planned or suspected and to avoid breast feeding during therapy.
• Emphasize importance of monitoring lab values to monitor for adverse reactions.

Evaluation/Desired Outcomes

• Decreased progression of HCC and metastatic CRC.
• Decreased progression of GIST