cabozantinib

cabozantinib

(ka-boe-zan-ti-nib) ,

Cometriq

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: kinase inhibitors
Pregnancy Category: D

Indications

Treatment of progressive, metastatic medullary thyroid cancer (MTC).

Action

Inibits tyrosine kinase, resulting in disruption of cellular function including tumor formation and progression.

Therapeutic effects

Decreased spread of MTC.

Pharmacokinetics

Absorption: Well absorbed following oral administration; food significantly enhances absorption.
Distribution: Unknown.
Protein Binding: >99.7%.
Metabolism and Excretion: Highly metabolized, mostly by the CYP3A4 system. 54% excreted in feces, 27% in urine (as metabolites).
Half-life: 55 hr.

Time/action profile (improved survival)

ROUTEONSETPEAKDURATION
POwithin 2 mounknown14.7 mos

Contraindications/Precautions

Contraindicated in: Moderate to severe hepatic impairment; Concurrent foods/nutritional supplements that are CYP3A4 inhibitors; Obstetric / Lactation: Pregnancy or lactation.
Use Cautiously in: Concurrent medications that are CYP3A4 inhibitors/inducers should be avoided if possible; if unavoidable, dosage adjustments are necessary; Elective surgical procedures (discontinue 28 days prior if possible); Reproductive potential; Hypertension (control prior to treatment); Pediatric: Safe and effective use in children has not been established.

Adverse Reactions/Side Effects

Central nervous system

  • fatigue (most frequent)
  • reversible posterior leukoencephalopathy syndrome

Cardiovascular

  • thrombotic events (life-threatening)
  • hypertension

Gastrointestinal

  • gastrointestinal perforation/fistula (life-threatening)
  • abdominal pain (most frequent)
  • ↓ appetite (most frequent)
  • altered taste (most frequent)
  • diarrhea (most frequent)
  • nausea (most frequent)
  • oral pain (most frequent)
  • stomatitis (most frequent)
  • ↑ transaminases (most frequent)
  • constipation

Dermatologic

  • hair color changes (most frequent)
  • palmar-plantar erythrodysesthesia syndrome
  • wound complications

Fluid and Electrolyte

  • hypocalcemia (most frequent)
  • hypophosphatemia (most frequent)

Genitourinary

  • nephrotic syndrome

Hematologic

  • bleeding (life-threatening)
  • lymphopenia (most frequent)
  • neutropenia (most frequent)
  • thrombocytopenia (most frequent)

Musculoskeletal

  • osteonecrosis of the jaw

Interactions

Drug-Drug interaction

Levels and risk of toxicity are ↑ by CYP3A4 inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazdone, nelfinavirritonavir, saquinavir, telithromycin, and voriconazole ; concurrent use should be avoided if possible. If unavoidable, cabozantinib daily dose should be ↓ by 40 mg; routine dose may be resumed 4 days following discontinuation of inhibitor.Levels and effectiveness may be ↓ by chronic concurrent use of CYP3A4 inducers including carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine and should be avoided. If unavoidable, daily dose should be ↑ by 40 mg; routine dose may be resumed 2–3 days following discontinuation of inducer.St. John's wort ↓ levels and effectiveness, concurrent use should be avoided.

Route/Dosage

Oral (Adults) 140 mg once daily; adjustments required for hematologic toxicity and/or interacting medications. Concurrent CYP3A4 inhibitors— ↓ daily dose by 40 mg, resume full dose 4 days after discontinuing inhibitor. Concurrent CYP3A4 inducers— ↑ daily dose by 40 mg, resume full dose 2–3 days after discontinuing inducer. Daily dose should not exceed 180 mg.

Availability

Capsules: 20 mg, 80 mg

Nursing implications

Nursing assessment

  • Monitor BP prior to and periodically during therapy. Withhold cabozantinib if BP is not adequately controlled with medications; resume at a reduced dose. Discontinue carbozantinib for uncontrolled hypertension.
  • Monitor for symptoms of perforations and fistulas (severe abdominal pain, coughing, gagging, choking especially when eating or drinking). Discontinue cabozantinib if symptoms occur.
  • Perform an oral examination for inflammation, infection, or ulceration prior to and periodically during therapy.
  • Evaluate patients with seizures, headache, visual disturbances, confusion, or altered mental status for reversible posterior leukoencephalopathy syndrome via MRI. Discontinue therapy if confirmed.
  • Lab Test Considerations: Monitor urine protein periodically during therapy; discontinue therapy in patients with nephrotic syndrome.
    • May cause ↑AST, ↑ALT, ↑ALP, hypocalcemia, hypophosphatemia, hyperbilirubinemia, hypomagnesemia, hypokalemia, hyponatremia, lymphopenia, neutropenia, and thrombocytopenia.

Potential Nursing Diagnoses

Diarrhea (Adverse Reactions)

Implementation

  • Stop treatment at least 28 days before scheduled surgery. Resume therapy postoperatively based on clinical judgement of adequate wound healing. Withhold in patients with dehiscence or wound healing complications.
  • Oral: Administer 140 mg dose as one 80-mg and 3 20-mg capsules, on an empty stomach at least 1hr before or 2 hr after meals. Swallow capsules whole; do not open, crush, or chew. Avoid foods or nutritional supplements that inhibit cytochrome P450 during therapy.
    • Withhold dose for Grade 4 hematologic, ≥Grade 3 non-hematologic or intolerable Grade 2 adverse reactions. Upon return to baseline or resolution to Grade 1, reduce dose. If previously receiving 140 mg daily, resume at 100 mg daily (one 80-mg and one 20-mg capsule). If previously receiving 100 mg daily, resume at 60 mg daily (3 20-mg capsules). If previously receiving 60 mg daily, resume at 60 mg daily if tolerated, otherwise, discontinue.
    • Permanently discontinue if development of visceral perforation or fistula formation, severe hemorrhage, serious arterial thrombotic event (MI, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite medical management, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome occur.

Patient/Family Teaching

  • Instruct patient to take cabozantinib as directed on an empty stomach with at least 8 oz of water. Take missed doses as soon as remembered if within 12 hr-s of dose; take next dose at regularly scheduled time. If >12 hrs omit dose and text next dose at normal time; do not double doses.
  • Advise patient to avoid grapefruit, grapefruit juice and any foods or supplements that contain grapefruit during therapy.
  • Caution patient to notify health care professional immediately if signs and symptoms of hemorrhage (coughing up blood or blood clots, vomiting blood or coffee-ground like vomit, red or black tarry stools, menstrual bleeding heavier than usual, any unusual or heavy bleeding), perforation or fistula, stroke or heart attack (swelling or pain in hands, arms, feet, or legs; shortness of breath; unusual sweating; numbness or weakness of face, arm or leg especially on one side of body; sudden confusion, trouble speaking, or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking; dizziness, loss of balance or coordination; sudden severe headache) or reversible posterior leukoencephalopathy syndrome occur.
  • Instruct patient to notify health care professional if signs and symptoms of hand-foot skin reactions (progressive or intolerable rash, redness, pain, swelling, blisters on hands or soles of feet); severe diarrhea; mouth sores, oral pain, changes in taste, nausea or vomiting severe or preventing from eating or drinking; or weight loss occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Instruct patient to maintain good oral hygiene and regular dentist exams during therapy. If jaw pain, toothache, or sores on gums occur, notify health care professional.
  • Advise patient to notify health care professional of medication regimen prior to treatment or surgery. Therapy must be stopped 28 days before planned surgery, including dental procedures.
  • Cabozantinib is teratogenic. Advise female and male patients with female partners who may become pregnant to use effective contraception during and for at least 4 mo after completion of therapy and to avoid breastfeeeding.

Evaluation/Desired Outcomes

  • Decreased spread of metastatic MTC.
References in periodicals archive ?
The transaction is part of Exelixis' ongoing strategy to build a range behind the company's internally discovered, commercially available therapies, including its flagship product, CABOMETYX (cabozantinib).
Morrissey continued: 'Our clinical development efforts continue to accelerate with the initiation of COSMIC-313, a new phase 3 pivotal trial of the cabozantinib triplet combination with nivolumab and ipilimumab in renal cell carcinoma, as well as the recent expansion of COSMIC-021, our phase 1b trial of cabozantinib and atezolizumab across multiple tumor types.
Exelixis announced that two original cohorts are being expanded and four new cohorts are being added to the protocol for COSMIC-021, the phase 1b trial of cabozantinib, in combination with atezolizumab, in patients with locally advanced or metastatic solid tumors.
Recent randomized trials for mRCC in the first line setting have also demonstrated impressive responses, including OS, with newer targeted therapies such as cabozantinib (CABOSUN trial) (10) as well as immunotherapies with checkpoint blockade including ipilimumab with nivolumab (Checkmate 214 trial).
Ipsen (Euronext: IPN; ADR: IPSEY) today announced that The New England Journal of Medicine (NEJM) published results from the CELESTIAL phase 3 pivotal trial of cabozantinib in patients with previously treated advanced hepatocellular carcinoma (HCC).1 The data, originally presented at the 2018 American Society of Clinical Oncology's Gastrointestinal Cancers Symposium (ASCO-GI) in January, demonstrate that cabozantinib provided a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo.
FRIDAY, July 6, 2018 (HealthDay News) -- Cabozantinib results in significantly longer overall and progression-free survival than placebo among patients with advanced hepatocellular carcinoma, according to a study published in the July 5 issue of the New England Journal of Medicine.
Additional late-stage efforts include a Phase IE trial, in partnership with Exelixis, to evaluate Opdivo in combination with Cabometyx (cabozantinib) tablets, a small molecule inhibitor of receptor tyrosine kinases, or Opdivo andYervoy in combination with Cabometyx versus sunitinib in advanced or metastatic renal cell carcinoma.
These MET exon 14-skipped variants occur in 2% to 3% of all NSCLC with enrichment in the sarcomatoid subtype and mark a tumor subset with quite exquisite sensitivity to several MET inhibitors, most notably the already available compounds crizotinib and cabozantinib, with multiple other more potent MET inhibitors showing high-level activity in addition in phase 2-level studies.
After other treatments proved to be unsuccessful, he is receiving a new targeted form of chemotherapy called cabozantinib which was only approved in the US in 2016.
Wang et al., "Cabozantinib reverses multidrug resistance of human hepatoma HepG2/ adr cells by modulating the function of P-glycoprotein," Liver International, vol.
More recently, the results of another landmark trial (CELESTIAL study) comparing cabozantinib versus placebo as second-line treatment were published.
Significant advances have been made in the secondline treatment of mRCC and the options now include TKIs--axitinib and cabozantinib; an anti-PD1 monoclonal antibody--nivolumab; and an mTOR inhibitor, everolimus, either alone or in combination with lenvatinib, a TKI.