regorafenib

High Alert

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 gastrointestinal 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 effects:

Decreased progression of hepatocellular carcinoma and metastatic colorectal cancer with improved survival.
Decreased progression of gastrointestinal 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/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)

ROUTE	ONSET	PEAK	DURATION
PO	3 mo	3 mo	up to 10 mo

Contraind./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 (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.

Adv. 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, ↓weight, ↑lipase, diarrhea, mucositis, ↑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

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↓ levels and effectiveness; avoid concurrent use.

Grapefruit juice↑ 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 until disease progression or unacceptable toxicity.

Availability ⬆ ⬇

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 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 with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.
Monitor for signs and symptoms of 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 (ULN) 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 ⬆ ⬇

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 × ULN, any occurrence of ↑ AST or ALT >3 × ULN with concurrent bilirubin >2 × ULN, reoccurrence of ↑ AST or ALT >5 × ULN 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 breastfeeding during therapy.
Emphasize importance of monitoring lab values to monitor for adverse reactions.

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Pronunciation ⬇

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