regorafenib

regorafenib

(re-goe-raf-e-nib) ,

Stivarga

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: kinase inhibitors
Pregnancy Category: D

Indications

Metastatic colorectal cancer (CRC) that has failed previous treatment that included a fluoropyrimidine, oxiplatin, irinotecan, an anti-VEGF therapy, and additional anti-EGFR therapy if tumor is of the KRAS wild type.

Action

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

Therapeutic effects

Decreased progression of metastatic CRC with improved survival.

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)

ROUTEONSETPEAKDURATION
PO3 mo3 moup to 10 mo

Contraindications/Precautions

Contraindicated in: Avoid strong inducers/inhibitors of CYP3A4; Lactation: Breast feeding should be avoided; Obstetric: May cause fetal harm, pregnancy should be avoided;Severe hepatic impairment (Child-Pugh Class C).
Use Cautiously in: History of hypertension/cardiovascular disease (BP should be controlled prior to treatment);Elective surgical procedures (discontinue 2 wk prior to surgery);Patients with reproductive potential (effective contraception should be practiced during and for 2 mo following treatment); Pediatric: Safe and effective use in children <18 yr has not been established.

Adverse Reactions/Side Effects

Central nervous system

  • reversible posterior leukoencephalopathy (life-threatening)
  • fatigue (most frequent)
  • headache

Ear, Eye, Nose, Throat

  • dysphonia (most frequent)

Cardiovascular

  • cardiac ischemia/infarction (life-threatening)
  • hypertension

Gastrointestinal

  • gastrointestinal fistula/perforation (life-threatening)
  • hepatotoxicity (life-threatening)
  • ↓ appetite (most frequent)
  • diarrhea (most frequent)
  • mucositis (most frequent)
  • altered taste
  • dry mouth
  • gastrointestinal reflux
  • ↑ transaminases

Dermatologic

  • plantar erythrodysthesia (life-threatening)
  • alopecia
  • impaired wound healing
  • rash

Endocrinologic

  • hypothyroidism

Fluid and Electrolyte

  • hypocalcemia (most frequent)
  • hypokalemia (most frequent)
  • hypophosphatemia (most frequent)
  • hyponatremia

Genitourinary

  • proteinuria (most frequent)

Hematologic

  • bleeding
  • thrombocytopenia
  • anemia (most frequent)
  • lymphopenia (most frequent)

Metabolic

  • weight loss (most frequent)
  • ↑ lipase (most frequent)
  • ↑ amylase

Musculoskeletal

  • pain (most frequent)
  • musculoskeletal stiffness

Neurologic

  • tremor

Miscellaneous

  • infection
  • fever (most frequent)

Interactions

Drug-Drug interaction

Strong inhibitors of CYP3A4 including clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole ↑blood levels and the risk of toxicity, avoid concurrent use.Strong inducers of CYP3A4 including carbamazepine, phenobarbital, phenytoin, and rifampin ↓ blood levels and effectiveness, avoid concurrent use.May ↑ risk of bleeding with warfarin.St. John's wort ↓ blood levels and effectiveness, avoid concurrent use.Grapefruit juice ↑ blood levels and the risk of toxicity, avoid concurrent use.

Route/Dosage

Oral (Adults) 160 mg daily on days 1–21 of a 28-day cycle (with low-fat meal containing <30% fat). Dose modifications required for hematologic toxicity, dermatologic toxicity, or hypertension. Discontinuation may be necessary for life-threatening toxicities.

Availability

Tablets: 40 mg

Nursing implications

Nursing 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.
  • 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.

Potential Nursing Diagnoses

Risk for impaired skin integrity
Deficient knowledge, related to medication regimen (Patient/Family Teaching)

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; have second practitioner independently double check original order and dose calculations. Therapy should be initiated by physician experienced in the treatment of patients with colorectal cancer.
  • Oral: Administer four 40 mg tablets once daily for the first 21 days of the of each 28-day cycle. Swallow tablets whole with a low-fat breakfast that contains <30% fat such as 2 slices of white toast with 1 tbsp of low-fat margarine and 1 tbsp of jelly, and 8 oz of skim milk; or 1 cup of cereal, 8 oz skim milk, 1 slice toast with jam, apple juice, and 1 cup coffee or tea.
  • 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 first occurrence of Grade 2 HFSR of any duration, after first 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 re-occuuence 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, re-occurrence 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 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 reversible posterior leukoencephalopathy syndrome (RPLS) (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.
  • Inform female patient that regorafenib can cause fetal harm. Advise women with 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 or if breast feeding.
  • Emphasize importance of monitoring lab values to monitor for adverse reactions.

Evaluation/Desired Outcomes

  • Decreased progression of metastatic CRC.
References in periodicals archive ?
Regorafenib for previously treated metastatic colorectal cancer (mCRC): Results from 683 Italian patients treated in the open-label phase 3B CONSIGN study
But regorafenib only outperformed best supportive care (BSC) by 1 week of progression-free survival and 1.
demonstrated that the drugs sorafenib and regorafenib synergize with a class of drugs known as PI3K/AKT inhibitors to kill a variety of cancers.
The sixth kinase inhibitor is a multikinase inhibitor: regorafenib (Stivarga; colorectal cancer).
The approval of Stivarga was based on data from the pivotal Phase III CORRECT (Colorectal cancer treated with regorafenib or placebo after failure of standard therapy) trial.
Bayer said it has started to enroll patients in a phase III trial to test the drug, dubbed regorafenib or BAY 73-4506 by Bayer, to fight advanced bowel cancer after other treatments have failed.
He also led premarket activities for regorafenib for gastrointestinal stromal tumors and colon cancer and alpharadin for prostate cancer.
This review found that side effects from regorafenib like redness and swelling may be undertreated.
Bayer HealthCare today announced that it is suspending enrolment into a Phase III trial with regorafenib (Stivarga) in colorectal cancer patients with resected liver metastases due to insufficient patient recruitment.
Demetri refers to data from a sub-analysis of the phase III GIST-Regorafenib in Progressive Desease (GRID) trial, designed to assess the efficacy of regorafenib in patients with GIST.
The FDA-approved anti-cancer drugs sorafenib and regorafenib are also potent sEHIs.
Effects of regorafenib (REG) therapy on health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) in the phase III CONCUR trial