dabrafenib

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications:

Pronunciation:
da-braf-e-nib

Trade Name(s)

• Tafinlar

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

•   Metastatic or unresectable melanoma in patients with the BRAF V600E mutation (as monotherapy).
•   Metastatic or 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 in patients with the BRAF V600E mutation and no satisfactory locoregional treatment options (in combination with trametinib).
•  Unresectable or metastatic solid tumors with the BRAF V600E mutation in patients who have progressed following prior treatment and have no satisfactory alternative treatment options (in combination with trametinib).
•  Low-grade glioma with a BRAF V600E mutation in patients who require systemic therapy (in combination with trametinib).

Action

Inhibits kinase, an enzyme that promotes cell proliferation.

Therapeutic Effect(s):

Decreased spread/progression of melanoma, NSCLC, anaplastic thyroid cancer, low-grade gliomas, and other solid tumors.

Pharmacokinetics

Absorption: Well absorbed (95%) following oral administration.

Distribution: Unknown.

Protein Binding: 99.7%.

Metabolism and Excretion: Mostly metabolized by the CYP2C8 and CYP3A4 isoenzymes; 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)

Contraindication/Precautions

Contraindicated in:

• BRAF wild-type solid tumors (may ↑ proliferation);
• OB:  Pregnancy;
• Lactation: Lactation.

Use Cautiously in:

•  History of glucose-6-phosphate dehydrogenase (G6PD) deficiency (may cause hemolytic anemia);
• Diabetes;
• 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 not established in children <18 yr (as monotherapy) or <1 yr (in combination with trametinib for unresectable or metastatic solid tumors or low-grade gliomas with BRAF V600E mutation).

Adverse Reactions/Side Effects

CV: HF

Derm: alopecia, hyperkeratosis, palmar-plantar erythrodysesthesia, papilloma, cutaneous squamous cell carcinoma, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), photosensitivity, STEVENS-JOHNSON SYNDROME

EENT: iritis, retinal detachment, uveitis

Endo: hyperglycemia

F and E: hypophosphatemia, hyponatremia

GI: constipation, PANCREATITIS

Hemat: BLEEDING, hemophagocytic lymphohistiocytosis

MS: arthralgia, back pain, myalgia

Neuro: headache, fatigue, peripheral neuropathy

Resp: cough, nasopharyngitis

Misc: fever (including serious febrile reactions), chills, MALIGNANCY

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  Strong CYP3A4 inhibitors  or  strong CYP2C8 inhibitors, including  ketoconazole,  nefazodone,  clarithromycin, and  gemfibrozil, may ↑ levels and ↑ risk of toxicity; avoid concurrent use.
•  Strong CYP3A4 inducers  or  strong CYP2C8 inducers, including  carbamazepine,  phenobarbital,  phenytoin, and  rifampin, may ↓ levels and effectiveness.
•  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.

Drug-Natural Products:

 St. John's wort  ↓ levels and effectiveness; avoid concurrent use.

Route/Dosage

Treatment of Unresectable/Metastatic Melanoma, Metastatic Non-Small Cell Lung Cancer, or Locally Advanced/Metastatic Anaplastic Thyroid Cancer

Capsules

PO (Adults): 150 mg twice daily; continue until disease progression or unacceptable toxicity.

Tablets for Oral Suspension

PO (Adults  ≥51 kg): 150 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  46–50 kg): 130 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  42–45 kg): 110 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  38–41 kg): 100 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  34–37 kg): 90 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  30–33 kg): 80 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  26–29 kg): 70 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  22–25 kg): 60 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  18–21 kg): 50 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  14–17 kg): 40 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  10–13 kg): 30 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults  8–9 kg): 20 mg twice daily; continue until disease progression or unacceptable toxicity.

Adjuvant Treatment of Unresectable/Metastatic Melanoma

Capsules

PO (Adults): 150 mg twice daily; continue until disease recurrence or unacceptable toxicity for up to 1 yr.

Tablets for Oral Suspension

PO (Adults  ≥51 kg): 150 mg twice daily continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  46–50 kg): 130 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  42–45 kg): 110 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  38–41 kg): 100 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  34–37 kg): 90 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  30–33 kg): 80 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  26–29 kg): 70 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  22–25 kg): 60 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  18–21 kg): 50 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  14–17 kg): 40 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  10–13 kg): 30 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

PO (Adults  8–9 kg): 20 mg twice daily; continue until disease progression or unacceptable toxicity for up to 1 yr.

Treatment of Unresectable/Metastatic Solid Tumors

Capsules

PO (Adults): 150 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and ≥51 kg): 150 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 38–50 kg): 100 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 26–37 kg): 75 mg twice daily; continue until disease progression or unacceptable toxicity.

Tablets for Oral Suspension

PO (Adults and Children  ≥1 yr and ≥51 kg): 150 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 46–50 kg): 130 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 42–45 kg): 110 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 38–41 kg): 100 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 34–37 kg): 90 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 30–33 kg): 80 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 26–29 kg): 70 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 22–25 kg): 60 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 18–21 kg): 50 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 14–17 kg): 40 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 10–13 kg): 30 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Adults and Children  ≥1 yr and 8–9 kg): 20 mg twice daily; continue until disease progression or unacceptable toxicity.

Treatment of Low-Grade Glioma

Capsules

PO (Children  ≥1 yr and ≥51 kg): 150 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 38–50 kg): 100 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 26–37 kg): 75 mg twice daily; continue until disease progression or unacceptable toxicity.

Tablets for Oral Suspension

PO (Children  ≥1 yr and ≥51 kg): 150 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 46–50 kg): 130 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 42–45 kg): 110 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 38–41 kg): 100 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 34–37 kg): 90 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 30–33 kg): 80 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 26–29 kg): 70 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 22–25 kg): 60 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 18–21 kg): 50 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 14–17 kg): 40 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 10–13 kg): 30 mg twice daily; continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and 8–9 kg): 20 mg twice daily; continue until disease progression or unacceptable toxicity.

Availability

Capsules: 50 mg, 75 mg

Tablets for oral suspension: 10 mg

Assessment

• Perform skin examination at baseline, every 2 mo during therapy, and for 6 mo after completion of therapy.  If intolerable Grade 2–4 skin toxicity occurs,  hold dabrafenib for up to 3 wk. If improved, resume at ↓ dose. If not improved, permanently discontinue dabrafenib.
• Monitor temperature.  If temperature >100.3°F , hold dabrafenib or dabrafenib and trametinib. Evaluate for signs and symptoms of infection and renal impairment during and following pyrexia. Restart dabrafenib and trametinib when pyrexia resolved for ≥24 hr, either at the same or ↓ dose. Administer antipyretics as secondary prophylaxis when resuming therapy. Administer prednisone 10 mg once daily for ≥5 days for 2nd or subsequent episode of pyrexia if fever does not resolve within 3 days of onset or for pyrexia associated with complications (dehydration, hypotension, renal failure, severe chills/rigors) and with no evidence of active infection.
• Monitor for signs and symptoms of ocular toxicity (blurred or ↓ vision, seeing colored dots or halos, swelling, redness, photophobia, eye pain). May require steroid and mydriatic ophthalmic drops.  If iritis occurs,  administer ocular therapy; do not modify dose.  If severe uveitis or mild to moderate uveitis that does not respond to ocular therapy occurs,  hold and treat as indicated for up to 6 wk. If improved to Grade ≤1, resume at same or ↓ dose.  If Grade ≥2 uveitis persists for >6 wk, permanently discontinue dabrafenib.
• Monitor left ventricular ejection fraction (LVEF) by ECG or MUGA scan before starting therapy with dabrafenib and trametinib, 1 mo after initiation, and then every 2–3 mo during therapy.  If symptomatic HF occurs with absolute ↓ in LVEF >20% from baseline that is below lower limit of normal (LLN),  hold dabrafenib until improved to LLN and absolute ↓ to ≤10% of baseline; then resume at same dose.
• Assess for bleeding (headache, dizziness, weakness, hemoptysis, hematemesis, red or black tarry stool) during therapy.  If Grade 3 hemorrhagic event occurs,  hold dabrafenib and trametinib for up to 3 wk; if improved, resume at ↓ dose.  If Grade 4 hemorrhagic event occurs,  permanently discontinue dabrafenib and trametinib.

Lab Test Considerations:

Verify negative pregnancy test prior to initiation.

 Confirm presence of BRAF V600E mutation in tumor specimens prior to therapy with dabrafenib, and confirm 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 V600E mutations in ATC, melanoma, and NSCLC is available at https://www.fda.gov/CompanionDiagnostics.

• May cause hyperglycemia, requiring ↑ dose of or initiation of insulin or oral hypoglycemic. Monitor serum glucose in patients with pre-existing diabetes or hyperglycemia.
• May cause hypophosphatemia, ↑ alkaline phosphatase, and hyponatremia.
• Monitor for hemolytic anemia in patients with G6PD deficiency.

Implementation

•  Dose reduction recommendations: Adults:   If taking 75 mg twice daily,  1st dose reduction, 50 mg twice daily. Permanently discontinue if unable to tolerate 50 mg twice daily.  If taking 100 mg twice daily,  1st dose reduction, 75 mg twice daily; 2nd dose reduction, 50 mg twice daily. Permanently discontinue if unable to tolerate 50 mg twice daily.  If taking 150 mg twice daily,  1st dose reduction, 100 mg twice daily; 2nd dose reduction, 75 mg twice daily; 3rd dose reduction, 50 mg twice daily. Permanently discontinue if unable to tolerate 50 mg twice daily. Pediatric Patients:  If 8–9 kg, taking 20 mg twice daily,  1st dose reduction, 10 mg twice daily.  If 10–13 kg, taking 30 mg twice daily,  1st dose reduction, 20 mg twice daily; 2nd dose reduction, 10 mg twice daily.  If 14–17 kg, taking 40 mg twice daily,  1st dose reduction, 30 mg twice daily; 2nd dose reduction, 20 mg twice daily; 3rd dose reduction, 10 mg twice daily.  If 18–21 kg, taking 50 mg twice daily,  1st dose reduction, 30 mg twice daily; 2nd dose reduction, 20 mg twice daily; 3rd dose reduction, 10 mg twice daily.  If 22–25 kg, taking 60 mg twice daily,  1st dose reduction, 40 mg twice daily; 2nd dose reduction, 30 mg twice daily; 3rd dose reduction, 20 mg twice daily.  If 26–29 kg, taking 70 mg twice daily,  1st dose reduction, 50 mg twice daily; 2nd dose reduction, 40 mg twice daily; 3rd dose reduction, 20 mg twice daily.  If 30–33 kg, taking 80 mg twice daily,  1st dose reduction, 50 mg twice daily; 2nd dose reduction, 40 mg twice daily; 3rd dose reduction, 30 mg twice daily.  If 34–37 kg, taking 90 mg twice daily,  1st dose reduction, 60 mg twice daily; 2nd dose reduction, 50 mg twice daily; 3rd dose reduction, 30 mg twice daily.  If 38–41 kg, taking 100 mg twice daily,  1st dose reduction, 70 mg twice daily; 2nd dose reduction, 50 mg twice daily; 3rd dose reduction, 30 mg twice daily.  If 42–45 kg, taking 110 mg twice daily,  1st dose reduction, 70 mg twice daily; 2nd dose reduction, 60 mg twice daily; 3rd dose reduction, 40 mg twice daily.  If 46–50 kg, taking 130 mg twice daily,  1st dose reduction, 90 mg twice daily; 2nd dose reduction, 70 mg twice daily; 3rd dose reduction, 40 mg twice daily.  If ≥51 kg, taking 150 mg twice daily,  1st dose reduction, 100 mg twice daily; 2nd dose reduction, 80 mg twice daily; 3rd dose reduction, 50 mg twice daily.
• PO Administer capsules about 12 hr apart at the same time each day. Administer on empty stomach ≥1 hr before or 2 hr after food.  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.
  • For tablets for oral suspension, only use dosing cups provided. Administer on an empty stomach ≥1 hr before or 2 hr after food.  DNC: Do not swallow tablets for oral suspension whole; do not open, crush, break, or chew.  Breast milk or infant formula may be given on demand if infant is unable to tolerate fasting conditions. Add cool drinking water to markings on cup. For 1–4 tablets, use 5 mL water; for 5–15 tablets, use 10 mL water. Put tablets in cup with water and gently stir until tablets break apart; may take 3 min. Suspension is cloudy white and may contain small pieces. Administer suspension within 30 min of preparing; if >30 min, dispose of suspension. To access medicine residue in cup, add 5 mL of drinking water, stir, and drink the water and residual mixture. If 1–4 tablets were used, rinse and drink once; if 5–15 tablets used, repeat rinse procedure twice.
  • For tablets for oral suspension for use with oral syringe or feeding tube, use directions for oral suspension above. If dose is 1–3 tablets, use ≥10 French. If dose is 4–15 tablets, use ≥12 French. Flush feeding tube before administering; then draw up all suspension from dosing cup with syringe and administer according to manufacturer's instructions. If using an oral syringe, place the tip pointing toward the inside of the cheek. Slowly push the plunger until full dose administered. Add 5 mL water to dosing cup and stir to loosen medicine residue. Draw up mixture and administer via feeding tube or orally. Repeat procedure 3 times.

Patient/Family Teaching

• Explain purpose and side effects of medication. Advise patient to read  Patient Information  before starting therapy.
• Take missed dose as soon as remembered unless within 6 hr of next dose; then omit and take regularly scheduled dose. If vomiting occurs after administration, do not take additional dose.
• Inform patient that dabrafenib ↑ risk of developing new cutaneous malignancies and to notify health care provider 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.
• Caution patient to use sunscreen and protective clothing to prevent photosensitivity reactions.
• Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care provider before taking other medications, especially St. John's wort.
• Advise patient to notify health care provider if fever; ↑ thirst, appetite, or urination; fruity breath; visual changes; eye pain or swelling; ↑ bleeding; skin blisters, sores, or peeling; high fever; flu-like symptoms; enlarged lymph nodes; or HF occur.
• Rep:  Advise women of reproductive potential and men (including those who have had vasectomies) with female partners of reproductive potential to use a highly effective nonhormonal contraception during and for ≥2 wk after last dose. Dabrafenib may ↓ effectiveness of hormonal contraceptives. Advise patient to notify health care provider if pregnancy is suspected and to avoid breastfeeding during and for 2 wk after last dose. Advise patients to seek counseling on fertility and family planning before beginning therapy; may permanently impair fertility in both sexes.

Evaluation/Desired Outcomes

Decrease in progression of malignant melanoma, NSCLC, anaplastic thyroid cancer, low-grade gliomas, and other solid tumors.