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Dabrafenib mesilate

Monotherapy or in combination w/ trametinib in adults w/ unresectable or metastatic melanoma w/ BRAF V600 mutation. In combination w/ trametinib in adults w/ advanced NSCLC w/ BRAF V600 mutation; ped patients ≥6 yr w/ low-grade glioma (LGG) w/ BRAF V600E mutation who require systemic therapy; adult & ped patients ≥6 yr w/ unresectable or metastatic solid tumors w/ BRAF V600E mutation who have progressed following prior treatment & no satisfactory alternative treatment options; as adjuvant treatment in adults w/ stage III melanoma w/ BRAF V600 mutation following complete resection.

Adult Take 150 mg bid at similar times every day w/ approx 12-hr interval. Total daily dose: 300 mg. Dose reduction (starting dose of 150 mg bid): 1st dose reduction: 100 mg bid. 2nd dose reduction: 75 mg bid. 3rd dose reduction: 50 mg bid. Ped weighing ≥51 kg 150 mg bid, 38-50 kg 100 mg bid, 26-37 kg 75 mg bid. Dose reduction: Starting dose of 75 mg bid: 1st dose reduction: 50 mg bid. Starting dose of 100 mg bid: 1st dose reduction: 75 mg bid. 2nd dose reduction: 50 mg bid. Starting dose of 150 mg bid: 1st dose reduction: 100 mg bid. 2nd dose reduction: 75 mg bid. 3rd dose reduction: 50 mg bid. Treatment duration: Adjuvant melanoma 12 mth unless there is disease recurrence or unacceptable toxicity.

Should be taken on an empty stomach: Swallow whole, do not chew or open.

Hypersensitivity.

Permanently discontinue treatment for life-threatening pulmonary embolism. Discontinue treatment if hemophagocytic lymphohistiocytosis (HLH) is confirmed. Interrupt therapy if patient's temp is ≥38°C & in case of recurrence; if creatinine increases. Withhold therapy until resolution of ocular inflammation if uveitis does not respond to local ocular therapy. W/draw treatment if signs & symptoms suggestive of severe cutaneous adverse reactions (SCARs) appear. Not indicated in patients w/ CRC; wild-type BRAF solid tumors. SCARs including SJS & DRESS. Cutaneous squamous cell carcinoma (cuSCC) including keratoacanthoma; new primary melanomas; RAS-associated malignancies w/ another BRAF inhibitor (chronic myelomonocytic leukaemia & non-cutaneous SCC of head & neck), monotherapy (pancreatic adenocarcinoma, bile duct adenocarcinoma), & in combination w/ MEK inhibitor, trametinib (CRC, pancreatic cancer). Increased risk of non-cutaneous malignancies. Haemorrhagic events including major haemorrhagic & fatal haemorrhages. Uveitis, iridocyclitis & iritis. Retinal pigment epithelial detachment; retinal vein occlusion. Pyrexia; dehydration. Left ventricular ejection fraction reduction/left ventricular dysfunction; BP elevation in patients w/ or w/o pre-existing HTN. ILD/pneumonitis; rash; rhabdomyolysis; pancreatitis; HLH. DVT/pulmonary embolism; shortness of breath, chest pain, arm or leg swelling. Colitis & GI perforation. Sarcoidosis mostly involving skin, lung, eye & lymph nodes. Renal failure; hepatic adverse events. Patients taking combination of dabrafenib w/ trametinib who have progressed on prior BRAF inhibitor. Perform skin exam prior to treatment initiation & mthly throughout therapy, & continue for up to 6 mth after treatment for cuSCC; head & neck exam w/ minimal visual inspection of oral mucosa & lymph node palpation, & chest/abdomen CT scan prior to treatment initiation; CBC & blood chemistry. Continuously monitor patients for 6 mth following discontinuation or until initiation of another anti-neoplastic therapy; head & neck exam every 3 mth & chest/abdomen CT scan every 6 mth during treatment. Monitor for skin lesions; skin reactions; liver function every 4 wk for 6 mth after treatment initiation. Routinely monitor patients for visual signs & symptoms (eg, change in vision, photophobia & eye pain); serum creatinine while on therapy. Evaluate patients for signs & symptoms of infection. Promptly investigate unexplained abdominal pain including serum amylase & lipase measurement. Avoid concomitant use w/ potent CYP2C8 & CYP3A4 inducers; sensitive substrates of certain metabolising enzymes or transporters. Concomitant use w/ warfarin (additional INR monitoring); digoxin. May affect ability to drive & use machines. Renal insufficiency (creatinine >1.5x ULN). Severe renal & moderate or severe hepatic impairment. Women of childbearing potential should use effective methods of contraception during therapy & for 2 wk following discontinuation of dabrafenib & 16 wk following last dose of trametinib when given in combination. Risk for impaired spermatogenesis in male patients. Pregnancy & lactation. Childn <6 yr.

Papilloma; decreased appetite; headache, dizziness; cough; nausea, vomiting, diarrhoea, abdominal pain, constipation; hyperkeratosis, alopecia, rash, palmar-plantar erythrodysaesthesia syndrome, dry skin, pruritus, erythema; arthralgia, myalgia, pain in extremity, muscle spasms; pyrexia, fatigue, chills, asthenia, peripheral oedema, flu-like illness; nasopharyngitis; HTN, haemorrhage; increased ALT/AST. cuSCC, seborrhoeic keratosis, acrochordon (skin tags), basal cell carcinoma; hypophosphataemia, hyperglycaemia, dehydration, hyponatraemia; actinic keratosis, skin lesion & fissures, photosensitivity, acneiform dermatitis, night sweats, hyperhidrosis, panniculitis; UTI, cellulitis, folliculitis, paronychia, pustular rash; neutropenia, anaemia, thrombocytopenia, leukopenia; blurred vision, visual impairment, uveitis; decreased ejection fraction, AV block; hypotension, lymphoedema; dyspnoea; dry mouth, stomatitis; mucosal inflammation, face oedema; increased blood alkaline phosphatase & creatine phosphokinase, & γ-glutamyltransferase.

Increased conc w/ strong CYP2C8 or CYP3A4 inhibitors eg, ketoconazole, gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir. Decreased conc w/ CYP2C8 or CYP3A4 inducers eg, rifampin, phenytoin, carbamazepine, phenobarb or St. John's wort. Increased AUC & C_max w/ ketoconazole. Decreased AUC & C_max w/ rifampin. Decreased AUC & C_max of midazolam. Decreased AUC & increased C_max of warfarin. Risk of liver injury w/ paracetamol. Concomitant use w/ analgesics (eg, fentanyl, methadone), antibiotics (eg, clarithromycin, doxycycline), anticancer agents (eg, cabazitaxel), anticoagulants (eg, acenocoumarol, warfarin), antiepileptic (eg, carbamazepine, phenytoin, primidone, valproic acid), antipsychotics (eg, haloperidol), Ca channel blockers (eg, diltiazem, felodipine, nicardipine, nifedipine, verapamil), cardiac glycosides (eg, digoxin), corticosteroids (eg, dexamethasone, methylprednisolone), HIV antivirals (eg, amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir), hormonal contraceptives), hypnotics (eg, diazepam, midazolam, zolpidem), immunosuppressants (eg, cyclosporin, tacrolimus, sirolimus), statins metabolised by CYP3A4 (eg, atorvastatin, simvastatin).

Targeted Cancer Therapy

L01EC02 - dabrafenib ; Belongs to the class of B-Raf serine-threonine kinase (BRAF) inhibitors. Used in the treatment of cancer.

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