da-BRAF-e-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

• 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).

• Inhibits kinase, an enzyme that promotes cell proliferation.

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

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

Distribution: Unknown.

Protein Binding: 99.7%.

Metabolism/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.

(progression-free survival)

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).

CV: HF, THROMBOEMBOLISM.

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.

Resp: cough, nasopharyngitis.

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

Drug-Drug:

• Concurrent use of strong CYP3A4 inhibitors or strong CYP2C8 inhibitors, including ketoconazole, nefazodone, clarithromycin, and gemfibrozil, may ↑ levels and ↑ the risk of toxicity and should be avoided.
• Concurrent use of 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 may ↓ effectiveness; concurrent use should be avoided.

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

• PO (Adults): 150 mg twice daily until disease progression or unacceptable toxicity.
Tablets for Oral Suspension
• PO (Adults 51 kg): 150 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 46–50 kg): 130 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 42–45 kg): 110 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 38–41 kg): 100 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 34–37 kg): 90 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 30–33 kg): 80 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 26–29 kg): 70 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 22–25 kg): 60 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 18–21 kg): 50 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 14–17 kg): 40 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 10–13 kg): 30 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults 8–9 kg): 20 mg twice daily until disease progression or unacceptable toxicity.

Adjuvant Treatment of Unresectable/Metastatic Melanoma

• 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 until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 46–50 kg): 130 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 42–45 kg): 110 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 38–41 kg): 100 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 34–37 kg): 90 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 30–33 kg): 80 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 26–29 kg): 70 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 22–25 kg): 60 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 18–21 kg): 50 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 14–17 kg): 40 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 10–13 kg): 30 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.
• PO (Adults 8–9 kg): 20 mg twice daily until disease progression or unacceptable toxicity for up to 1 yr.

Treatment of Unresectable/Metastatic Solid Tumors

• PO (Adults): 150 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 51 kg): 150 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 38–50 kg): 100 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 26–37 kg): 75 mg twice daily until disease progression or unacceptable toxicity.
Tablets for Oral Suspension
• PO (Adults and Children 1 yr and 51 kg): 150 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 46–50 kg): 130 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 42–45 kg): 110 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 38–41 kg): 100 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 34–37 kg): 90 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 30–33 kg): 80 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 26–29 kg): 70 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 22–25 kg): 60 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 18–21 kg): 50 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 14–17 kg): 40 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 10–13 kg): 30 mg twice daily until disease progression or unacceptable toxicity.
• PO (Adults and Children 1 yr and 8–9 kg): 20 mg twice daily until disease progression or unacceptable toxicity.

Treatment of Low-Grade Glioma

• PO (Children 1 yr and 51 kg): 150 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 38–50 kg): 100 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 26–37 kg): 75 mg twice daily until disease progression or unacceptable toxicity.
Tablets for Oral Suspension
• PO (Children 1 yr and 51 kg): 150 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 46–50 kg): 130 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 42–45 kg): 110 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 38–41 kg): 100 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 34–37 kg): 90 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 30–33 kg): 80 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 26–29 kg): 70 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 22–25 kg): 60 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 18–21 kg): 50 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 14–17 kg): 40 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 10–13 kg): 30 mg twice daily until disease progression or unacceptable toxicity.
• PO (Children 1 yr and 8–9 kg): 20 mg twice daily until disease progression or unacceptable toxicity.

• Capsules: 50 mg; 75 mg;
• Tablets for oral suspension: 10 mg;

• Perform skin examinations before 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 temperature is >100.3°F, hold dabrafenib or dabrafenib and trametinib. Fever may include hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection, and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Dabrafenib and trametinib may be restarted if the patient has recovered from febrile reaction for 24 hr, either at the same or lower dose. Administer antipyretics as secondary prophylaxis when resuming dabrafenib. Administer corticosteroids (prednisone 10 mg daily) for 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, 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 toxicities (blurred vision, loss of vision, other vision changes, seeing colored dots, halos 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 left ventricular ejection fraction (LVEF) by ECG or multigated acquisition (MUGA) scan before starting therapy with dabrafenib with trametinib, 1 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 lower limit of normal (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 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 tarry stools) during therapy. If Grade 3 hemorrhagic event occurs, hold 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.

• 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. Confirm presence of BRAF V600E mutation in tumor specimens before starting treatment for solid tumors or low-grade gliomas with dabrafenib and trametinib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma and NSCLC is available at www.fda.gov/CompanionDiagnostics. No FDA-approved test for detection of BRAF V600E mutation in anaplastic thyroid cancer 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 G6PD deficiency.

• Dose reduction recommendations: Adults: If taking 75 mg twice daily, 1st dose reduction, 50 mg PO twice daily. Permanently discontinue if unable to tolerate 50 mg twice daily. If taking 100 mg twice daily, 1st dose reduction, 75 mg PO twice daily; 2nd dose reduction, 50 mg PO twice daily. Permanently discontinue if unable to tolerate 50 mg twice daily. If taking 150 mg twice daily, 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. Pediatric Patients: If 8–9 kg, taking 20 mg twice daily, discontinue dabrafenib if unable to tolerate 10 mg PO twice daily. If 10–13 kg, taking 30 mg twice daily, 1st dose reduction, 20 mg PO twice daily; 2nd dose reduction, 10 mg PO twice daily. If 14–17 kg, taking 40 mg twice daily, 1st dose reduction, 30 mg PO twice daily; 2nd dose reduction, 20 mg PO twice daily; 3rd dose reduction, 10 mg PO twice daily. If 18–21 kg, taking 50 mg twice daily, 1st dose reduction, 30 mg PO twice daily; 2nd dose reduction, 20 mg PO twice daily; 3rd dose reduction, 10 mg PO twice daily. If 22–25 kg, taking 60 mg twice daily, 1st dose reduction, 40 mg PO twice daily; 2nd dose reduction, 30 mg PO twice daily; 3rd dose reduction, 20 mg PO twice daily. If 26–29 kg, taking 70 mg twice daily, 1st dose reduction, 50 mg PO twice daily; 2nd dose reduction, 40 mg PO twice daily; 3rd dose reduction, 20 mg PO twice daily. If 30–33 kg, taking 80 mg twice daily, 1st dose reduction, 50 mg PO twice daily; 2nd dose reduction, 40 mg PO twice daily; 3rd dose reduction, 30 mg PO twice daily. If 34–37 kg, taking 90 mg twice daily, 1st dose reduction, 60 mg PO twice daily; 2nd dose reduction, 50 mg PO twice daily; 3rd dose reduction, 30 mg PO twice daily. If 38–41 kg, taking 100 mg twice daily, 1st dose reduction, 70 mg PO twice daily; 2nd dose reduction, 50 mg PO twice daily; 3rd dose reduction, 30 mg PO twice daily. If 42–45 kg, taking 110 mg twice daily, 1st dose reduction, 70 mg PO twice daily; 2nd dose reduction, 60 mg PO twice daily; 3rd dose reduction, 40 mg PO twice daily. If 46–50 kg, taking 130 mg twice daily, 1st dose reduction, 90 mg PO twice daily; 2nd dose reduction, 70 mg PO twice daily; 3rd dose reduction, 40 mg PO twice daily. If 51 kg, taking 150 mg twice daily, 1st dose reduction, 100 mg PO twice daily; 2nd dose reduction, 80 mg PO twice daily; 3rd dose reduction, 50 mg PO twice daily.
• PO: Administer capsules twice daily about 12 hr apart. Administer on an empty stomach at least 1 hr before or 2 hr 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.
  • For tablets for oral suspension, use only dosing cups provided. Add cool drinking water to markings on cup. If dose is 1–4 tablets, use 5 mL of water; if dose is 5–15 tablets, use 10 mL of water. Put tablets in cup with water and gently stir with the handle of a teaspoon until tablets break apart; may take up to 3 min. Suspension is cloudy white and may contain small pieces. Administer suspension within 30 min of preparing; if outside 30 min, dispose of suspension and begin the process again. 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, the minimum size feeding tube that may be used is 10 French. If dose is 4 to 15 tablets, the minimum size feeding tube that may be used is 12 French. Flush feeding tube before administering suspension. Draw up all oral suspension from dosing cup into a syringe. If giving the dose through a feeding tube, give oral suspension into the feeding tube according to feeding tube manufacturer’s instructions. If giving dose of oral suspension using an oral syringe, place the open end of the oral syringe inside the mouth with the tip pointing toward the inside of either cheek. If giving dose of oral suspension to a child, make sure they are sitting upright. Slowly push the plunger all the way down on the plunger to give the full dose. Add 5 mL of water to empty dosing cup. Stir to loosen medicine residue inside the cup. Draw up water and medicine residue mixture. Give water and medicine residue mixture into the feeding tube or into the inside of the cheek. Repeat procedure 3 times.

• Instruct patient to take dabrafenib as directed at least 1 hr before or 2 hr after meals. Take missed doses as soon as remembered unless within 6 hr of next dose; then skip missed dose and take regularly scheduled dose. If vomiting occurs after administration, do not take an additional dose. Take next dose at the scheduled time. 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.
• Caution patient to use sunscreen and protective clothing to prevent photosensitivity reactions.
• 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 (blurred vision, loss of vision, vision changes, see color dots, halo [see blurred outline around objects], eye pain, swelling, redness), bleeding (headaches, dizziness, or feeling weak, cough up blood or blood clots, vomit blood or vomit looks like coffee grounds, red or black stool that looks like tar), skin reactions (blisters or peeling of skin, blisters on lips, or around mouth or eyes, mouth sores, high fever or flu-like symptoms, enlarged lymph nodes), thromboembolism, HF (heart pounding or racing, shortness of breath, swelling of ankles and feet, feeling light-headed) occur.
• Rep: Advise females of reproductive potential and males (including those who have had vasectomies) with female partners 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 nonhormonal form of contraception; dabrafenib may decrease effectiveness of hormonal contraceptives. Advise patient to notify health care professional if pregnancy is suspected and to avoid breastfeeding during therapy 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 females and males.

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

Tafinlar

NDC Code^*

• 0078- Novartis Pharmaceuticals Corporation
  • 0078-0681- Tafinlar
    • 0078-0681-66- 120 CAPSULE in 1 BOTTLE (0078-0681-66)

• 0078- Novartis Pharmaceuticals Corporation
  • 0078-0682- Tafinlar
    • 0078-0682-66- 120 CAPSULE in 1 BOTTLE (0078-0682-66)