- Treatment of metastatic/unresectable melanoma in patients with the BRAF V600E mutation.
- Treatment of metastatic/unresectable melanoma in patients with the BRAF V600E or V600K mutation (in combination with trametinib).
Inhibits kinase, an enzyme that promotes cell proliferation
Decreased spread/progression of melanoma
Absorption: Well absorbed (95%) following oral administration.
Protein Binding: 99.7%.
Metabolism and Excretion: Mostly metabolized by CYP 2C8 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|
- OB: Pregnancy (may cause fetal harm);
- Lactation: Breast feeding should be avoided;
- Concurrent use of CYP 3A4/CYP2C8 inhibitors or inducers (may significantly alter levels and effects).
Use Cautiously in:
- BRAF Wild-type melanoma (may ↑ proliferation);
- History of glucose-6–phosphate dehydrogenase deficiency (may cause hemolytic anemia);
- Moderate to severe hepatic impairment (blood levels may be ↑);
- Moderate to severe renal impairment;
- OB: Patients with reproductive potential (hormonal contraceptives may be less effective, additional methods required);
- Pedi: Safety and effectiveness not established.
Adverse Reactions/Side Effects
CNS: headache, fatigue
CV: HF, THROMBOEMBOLISM
EENT: iritis, retinal detachment, uveitis
Resp: cough, nasopharyngitis
GI: constipation, pancreatitis
Derm: alopecia, hyperkeratosis, palmar-plantar erythrodysesthesia, papilloma, cutaneous squamous cell carcinoma
F and E: hypophosphatemia, hyponatremia
MS: arthralgia, back pain, myalgia
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 ↑ blood 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 ↓ blood 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 ↓ blood levels and effectiveness
- May ↓ effectiveness of other CYP3A4 substrates and CYP2C9 substrates, including midazolam, warfarin, dexamethasone, and hormonal contraceptives.
St. John's wort ↓ blood levels and may ↓ effectiveness; concurrent use should be avoided.
PO: (Adults) 150 mg twice daily, continued until disease progression or unacceptable toxicity. Dose modifications recommended for various levels of related toxicities.
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, withhold dabrafenib for up to 3 wks; if used with trametinib, withhold trametinib for up to 3 wks. If improved, resume at a lower dose. If not improved, permanently discontinue.
- Monitor temperature. If fever is 101.3°F to 104°F, withhold dabrafenib until fever resolves, then resume at same dose. If fever is >104°F or complicated by rigors, hypotension, dehydration, or renal failure, withhold until fever resolves, then resume at a reduced dose. For first reduction, decrease dose to 100 mg twice daily. For second dose reduction, decrease dose to 75 mg twice daily. For third dose reduction, decrease dose to 50 mg twice daily. If unable to tolerate 50 mg twice daily, discontinue dabrafenib.
- 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 Grade 2-3 retinal pigment epithelial detachments (RPED) occur, do not modify dabrafenib dose. Withhold trametinib for up to 3 weeks. If improved to Grade 0-1, resume at lower dose. If not improved, permanently discontinue. If retinal vein occlusion occurs, do not modify dabrafenib dose. Discontinue trametinib permanently. If uveitis and iritis occur, withhold dabrafenib for up to 6 weeks. If improved to Grade 0-1, resume at same dose. If not improved, permanently discontinue dabrafenib. Do not modify trametinib dose.
- Monitor cardiac function during therapy. If asymptomatic, absolute decrease in LVEF ≥10% from baseline occurs and is below institutional lower limits of normal (LLN) from pretreatment value, do not modify dose if only taking dabrafenib. If also taking trametinib, withhold trametinib for up to 4 wks. If improved to normal LVEF, resume at lower dose. If not improved to normal LVEF value, permanently discontinue trametinib. If symptomatic congestive heart failure occurs with absolute decrease in LVEF >20% from baseline that is below LLN, withhold dabrafenib, if improved, resume at same dose. Permanently discontinue trametinib.
- 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) occur, do not modify dabrafenib dose. Withhold trametinib for up to 3 weeks. 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 wks, if improved resume at lower level. If Grade 4 hemorrhagic event occurs, permanently discontinue dabrafenib and trametinib.
Lab Test Considerations: 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.
- PO: Administer twice daily about 12 hrs apart. Administer on an empty stomach at least 1 hr before or 2 hrs after a meal. 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.
- 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 female patient to use a highly effective form of contraception during and for at least 2 wks after dabrafenib alone or 4 mo after treatment with dabrafenib and trametinib. 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. Advise patients to seek counseling on fertility and family planning prior to beginning therapy; may impair fertility in females and may cause spermatogenesis in males.
Decrease in progression of malignant melanoma.
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