- Metastatic/unresectable melanoma in patients with the BRAF V600E mutation.
- Metastatic/unresectable melanoma in patients with the BRAF V600E or V600K mutation (in combination with trametinib).
- Adjuvant treatment of melanoma in patients with the BRAF V600E or V600K mutation and lymph node involvement following complete resection (in combination with trametinib).
- Metastatic non-small-cell lung cancer (NSCLC) in patients with the BRAF V600E mutation (in combination with trametinib).
- Locally advanced or metastatic anaplastic thyroid cancer (ATC) in patients with the BRAF V600E mutation and no satisfactory locoregional treatment options (in combination with trametinib).
Inhibits kinase, an enzyme that promotes cell proliferation
Decreased spread/progression of melanoma, NSCLC, and ATC.
Absorption: Well absorbed (95%) following oral administration.
Protein Binding: 99.7%.
Metabolism and Excretion: Mostly metabolized by CYP2C8 and CYP3A4 enzyme systems; two metabolites (hydroxy-dabrafenib and desmethyl-1–dabrafenib) have antineoplastic activity. Excreted as metabolites in feces (72%) and urine (23%).
Half-life: Dabrafenib– 8 hr; hydroxy-dabrafenib– 10 hr, desmethyl-1–dabrafenib– 21–22 hr.
TIME/ACTION PROFILE (progression-free survival)
|PO||within 1 mo||1–2 mo||8 mo|
- Concurrent use of CYP3A4/CYP2C8 inhibitors or inducers (may significantly alter levels and effects);
- OB: Pregnancy (may cause fetal harm);
Use Cautiously in:
- BRAF Wild-type melanoma (may ↑ proliferation);
- History of glucose-6–phosphate dehydrogenase deficiency (may cause hemolytic anemia);
- Moderate or severe hepatic impairment;
- Moderate or severe renal impairment;
- Rep: Women of reproductive potential and men with female partners of reproductive potential;
- Pedi: Safety and effectiveness in children not established.
Adverse Reactions/Side Effects
CV: HF, THROMBOEMBOLISM
Derm: DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), STEVENS-JOHNSON SYNDROME, alopecia, hyperkeratosis, palmar-plantar erythrodysesthesia, papilloma, cutaneous squamous cell carcinoma
EENT: iritis, retinal detachment, uveitis
F and E: hypophosphatemia, hyponatremia
GI: constipation, pancreatitis
MS: arthralgia, back pain, myalgia
Neuro: headache, fatigue
Resp: cough, nasopharyngitis
Misc: MALIGNANCY, fever including serious febrile reactions, ↑ alkaline phosphatase, chills, tumor promotion
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- Concurrent use of strong inhibitors of CYP3A4 or CYP2C8, including ketoconazole, nefazodone, clarithromycin, and gemfibrozil ↑ levels and the risk of toxicity and should be avoided. Careful monitoring for toxicity is required.
- Concurrent use of strong inducers of CYP3A4 or CYP2C8 including carbamazepine, phenobarbital, phenytoin, and rifampin ↓ levels and may ↓ effectiveness. Careful monitoring for decreased results is required.
- Drugs that ↑ gastric pH including antacids, H2 –receptor antagonists and proton pump inhibitors may ↓ levels and effectiveness
- May ↓ effectiveness of other CYP3A4 substrates and CYP2C9 substrates, including midazolam, warfarin, dexamethasone, and hormonal contraceptives.
St. John's wort ↓ levels and may ↓ effectiveness; concurrent use should be avoided.
PO (Adults): 150 mg twice daily until disease progression or unacceptable toxicity.
Capsules: 50 mg, 75 mg
- Perform skin examinations prior to starting therapy and every 2 mo during and for 6 mo after completion of therapy. If intolerable Grade 2 skin toxicity, Grade 3 or Grade 4 occurs, hold dabrafenib for up to 3 wk. If improved, resume at a lower dose. If not improved, permanently discontinue.
- Monitor temperature. If fever is 101.3°F to 104°F , hold dabrafenib until fever resolves, then resume at same dose. If fever is >104°F or complicated by rigors, hypotension, dehydration, or renal failure , hold until fever resolves, then resume at a reduced dose.
- Monitor for signs and symptoms of ocular toxicities (blurred vision, loss of vision, other vision changes, see color dots, halo around objects, swelling, redness, photophobia, eye pain). May require steroid and mydriatic ophthalmic drops. If iritis occurs, do not modify dabrafenib dose. If severe uveitis or mild to moderate uveitis that does not respond to ocular therapy, hold dabrafenib for up to 6 wk. If improved to Grade 0–1, resume at same or lower dose. If not improved, permanently discontinue therapy.
- Monitor cardiac function (LVEF) by ECG or multigated acquisition (MUGA) scan before starting therapy with dabrafenib with trametinib, one mo after initiation of therapy, and then at 2- to 3-mo intervals during therapy . If symptomatic HF occurs with absolute decrease in LVEF >20% from baseline that is below LLN, hold dabrafenib until improved to institutional LLN and absolute decrease to ≤10% compared to baseline, then resume at same dose.
- Monitor for signs and symptoms of venous thromboembolism (shortness of breath, chest pain, arm or leg swelling, cool or pale arm or leg) during therapy. If uncomplicated deep vein thrombosis (DVT) or pulmonary embolus (PE) occurs, do not modify dabrafenib dose. Withhold trametinib for up to 3 wk. If improved to Grade 0-1, resume at lower dose. If not improved, permanently discontinue. If life-threatening PE occurs, permanently discontinue dabrafenib and trametinib.
- Monitor for signs and symptoms of interstitial lung disease or pneumonitis (cough, dyspnea, hypoxia, pleural effusion, infiltrates) during therapy. If signs and symptoms occur, do not modify dabrafenib dose; permanently discontinue trametinib.
- Assess for bleeding (headaches, dizziness, feeling weak, coughing up blood or blood clots, vomiting blood or vomit looks like "coffee grounds," red or black stools that look like tar) during therapy. If Grade 3 hemorrhagic event occurs, withhold dabrafenib and trametinib for up to 3 wk, if improved resume at lower level. If Grade 4 hemorrhagic event occurs, permanently discontinue dabrafenib and trametinib.
Lab Test Considerations:
Verify negative pregnancy test prior to starting therapy.
Confirm presence of BRAF V600E mutation in tumor specimens prior to therapy with dabrafenib and confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to therapy with dabrafenib and trametinib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma and NSCLC is available at: http://www.fda.gov/CompanionDiagnostics. No FDA approved test for detection of BRAF V600E mutation in ATC is available.
May cause hyperglycemia requiring increase in dose of or initiation of insulin or oral hypoglycemic agents. Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia.
- May cause hypophosphatemia, ↑ alkaline phosphatase, and hyponatremia.
- Monitor for hemolytic anemia in patients with glucose-6–phosphate dehydrogenase (G6PD) deficiency.
- Impaired skin integrity (Indications)
- Evidence of BRAF V600E or V600K mutation status must be confirmed prior to starting therapy with dabrafenib for melanoma or NSCLC.
- Dose reduction recommendations: 1st dose reduction, 100 mg PO twice daily; 2nd dose reduction, 75 mg PO twice daily; 3rd dose reduction, 50 mg PO twice daily. If patient is unable to tolerate 50 mg twice daily, permanently discontinue dabrafenib.
Administer twice daily about 12 hrs apart. Administer on an empty stomach at least 1 hr before or 2 hrs after a meal. DNC: Swallow capsules whole; do not open, crush, break, or chew.
- When administered with trametinib, administer once-daily dose of trametinib at same time each day with either morning or evening dose of dabrafenib.
- Instruct patient to take dabrafenib as directed at least 1 hr before or 2 hrs after meals. Take missed doses as soon as remembered unless within 6 hrs of next dose, then skip missed dose and take regularly scheduled dose. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
- Inform patient that dabrafenib increases risk of developing new cutaneous malignancies. Notify health care professional immediately if new lesions (wart, skin sore or reddish bump that bleeds or does not heal) or changes in size or color of existing moles or lesions 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, especially St. John's wort.
- Inform patient of potential side effects. Advise patient to notify health care professional if fever, signs and symptoms of hyperglycemia (increased thirst, urinating more often than normal, breath smells like fruit), or eye problems, bleeding, thromboembolism, heart failure (heart pounding or racing, shortness of breath, swelling of ankles and feet, feeling lightheaded) occur.
- Rep: Advise females of reproductive potential and males (including those who have had vasectomies) with female partner of reproductive potential to use a highly effective form of contraception during and for at least 2 wk after last dose of dabrafenib. Use a non-hormonal form of contraception; dabrafenib may decrease effectiveness of hormonal contraceptives. Advise patient to notify health care professional if pregnancy is suspected and to avoid breast feeding during and for 2 wk after last dose. Advise patients to seek counseling on fertility and family planning prior to beginning therapy; may permanently impair fertility in females and males.
Decrease in progression of malignant melanoma, NSCLC, and ATC.
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