General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications:

Pronunciation:
re-goe-raf-e-nib

Trade Name(s)

• Stivarga

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

•  Metastatic colorectal cancer 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 GI stromal tumor in patients who have previously been treated with imatinib and sunitinib.
• Hepatocellular carcinoma 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 hepatocellular carcinoma and metastatic colorectal cancer with improved survival.
• Decreased progression of GI stromal tumor.

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: Primarily metabolized by the liver via the CYP3A4 isoenzyme and UGT1A9; 2 metabolites (M-2 and M-5) have antineoplastic activity. Undergoes enterohepatic circulation. 47% excreted in feces as parent compound, 24% as metabolites; 19% excreted in urine (mostly as inactive metabolites).

Half-life: Regorafenib:  28 hr,  M-2 metabolite:  25 hr,  M-5 metabolite:  51 hr.

TIME/ACTION PROFILE (improved survival)

Contraindication/Precautions

Contraindicated in:

• Severe hepatic impairment;
• OB:  Pregnancy;
• Lactation:  Lactation.

Use Cautiously in:

• History of hypertension or cardiovascular disease (BP should be controlled prior to treatment);
• Elective surgical procedures;
•  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: alopecia, ERYTHEMA MULTIFORME, impaired wound healing, PALMAR-PLANTAR ERYTHRODYSESTHESIA, rash, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

EENT: dysphonia

Endo: hypothyroidism

F and E: hypocalcemia, hypokalemia, hypophosphatemia, hyponatremia

GI: ↓ appetite, ↑ lipase, diarrhea, mucositis, weight loss, ↑ amylase, ↑ liver enzymes, dry mouth, GI FISTULA/PERFORATION, HEPATOTOXICITY, reflux

GU: proteinuria, ↓ fertility

Hemat: anemia, BLEEDING, lymphopenia, THROMBOCYTOPENIA

MS: pain, musculoskeletal stiffness

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

Misc: fever, INFECTION

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

Interactions

Drug-Drug

•  Strong CYP3A4 inhibitors, including  clarithromycin,  itraconazole,  ketoconazole,  posaconazole, and  voriconazole, may ↑ levels and risk of toxicity, avoid concurrent use.
•  Strong CYP3A4 inducers, including  carbamazepine,  phenobarbital,  phenytoin, and  rifampin, may ↓ 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  may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Route/Dosage

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

Availability (generic available)

Tablets: 40 mg

Assessment

• Monitor BP prior to and weekly during the 1st 6 wk and then every cycle of therapy. Do not initiate regorafenib until BP is well controlled.
• Assess for myocardial 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 by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, or eosinophilia.
• Monitor for signs and symptoms of PRES (seizures, headache, visual disturbances, confusion, altered mental function) during therapy. Diagnosis via MRI.  If PRES occurs, permanently discontinue regorafenib.

Lab Test Considerations:

Black Box:  Monitor liver function tests (ALT, AST, bilirubin) before starting, at least every 2 wk during 1st 2 mo of therapy, and monthly thereafter. Monitor liver function tests weekly in patients with ↑ liver function tests until improvement to <3 times the upper limit of normal (ULN) or baseline.

• May cause anemia, thrombocytopenia, neutropenia, and lymphopenia.
• May cause hypocalcemia, hypokalemia, hyponatremia, and hypophosphatemia.
• May cause proteinuria, ↑ lipase, and ↑ amylase.
• May ↑ 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 ≥2 wk before elective surgery and for ≥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 1st 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 ↓, Grade 3 HSFR ≥7 days; symptomatic Grade 2 hypertension, or any Grade 3 or 4 adverse reactions.

  • ↓ dose to 120 mg once daily for:  1st occurrence of Grade 2 HFSR of any duration, after 1st recovery of any Grade 3 or 4 adverse reaction, or Grade 3 ↑ AST or ALT; only resume if potential benefits outweigh risk of hepatotoxicity.
  • ↓ dose to 80 mg once daily for: Recurrence of Grade 2 HFSR at 120 mg once daily dose or after recovery of any Grade 3 or 4 adverse reaction (except hepatotoxicity) at 120 mg once daily dose.
  • Permanently discontinue regorafenib for:  Failure to tolerate 80-mg once-daily dose, any occurrence of ↑ AST or ALT >20 times ULN, any occurrence of ↑ AST or ALT >3 times ULN with concurrent bilirubin >2 times ULN, recurrence of ↑ AST or ALT >5 times ULN despite reduction to 120-mg once-daily dose, or any Grade 4 adverse reaction; only resume if the potential benefits outweigh 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 two 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 provider immediately if signs or symptoms of liver problems (yellowing of skin or white part of eyes, nausea, vomiting, dark tea-colored urine, change in sleep pattern) occur.
• Advise patient to notify health care provider immediately if signs or symptoms of bleeding, skin changes (redness, pain, blisters, bleeding, swelling), hypertension (severe headache, light-headedness, 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 of recent surgeries.
• Advise patient to maintain adequate hydration to minimize risk and to notify health care provider 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 provider of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care provider 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 ≥2 mo after completion of therapy. Notify health care provider immediately if pregnancy is planned or suspected and to avoid breastfeeding during therapy.
• Emphasize importance of monitoring lab values to monitor for adverse reactions.

Evaluation/Desired Outcomes

• Decreased progression of hepatocellular carcinoma and metastatic colorectal cancer.
• Decreased progression of gastrointestinal stromal tumor.