Dabrafenib


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Adjuvant treatment of stage III BRAF V600E or BRAF V600K mutation-positive melanoma Combined with trametinib following complete resection: 150 mg 12 hourly, continued for up to 1 year in the absence of disease progression or unacceptable toxicity. Metastatic or unresectable melanoma Monotherapy in patients with BRAF V600E mutation, or combined with trametinib in patients with BRAF V600E or BRAF V600K mutation-positive case: 150 mg 12 hourly, continued until disease progression or unacceptable toxicity. BRAF V600E mutation-positive advanced or metastatic non-small cell lung carcinoma Combined with trametinib: 150 mg 12 hourly, continued until disease progression or unacceptable toxicity. BRAF V600E mutation-positive locally advanced or metastatic anaplastic thyroid carcinoma Combined with trametinib: 150 mg 12 hourly, continued until disease progression or unacceptable toxicity.
Dosage Details
Oral
Melanoma
Adult: As adjuvant treatment in combination with trametinib in patients with stage III BRAF V600E or BRAF V600K mutation-positive cases, following complete resection: 150 mg 12 hourly, continued for up to 1 year in the absence of disease progression or unacceptable toxicity. Missed dose can be taken up to 6 hours prior to the next dose, administer the next dose as scheduled. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability (refer to detailed product guideline).

Oral
Metastatic melanoma, Unresectable melanoma
Adult: As monotherapy in patients with BRAF V600E mutation, or in combination with trametinib in patients with BRAF V600E or BRAF V600K mutation-positive cases: 150 mg 12 hourly, continued until disease progression or unacceptable toxicity. Missed dose can be taken up to 6 hours prior to the next dose, administer the next dose as scheduled. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability (refer to detailed product guideline).

Oral
Advanced non-small cell lung cancer, Metastatic non-small cell lung carcinoma
Adult: In combination with trametinib in patients with BRAF V600E mutation-positive cases: 150 mg 12 hourly, continued until disease progression or unacceptable toxicity. Missed dose can be taken up to 6 hours prior to the next dose, administer the next dose as scheduled. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability (refer to detailed product guideline).

Oral
Locally advanced anaplastic thyroid carcinoma, Metastatic anaplastic thyroid carcinoma
Adult: In combination with trametinib in patients with BRAF V600E mutation-positive cases, and with no satisfactory locoregional treatment options: 150 mg 12 hourly, continued until disease progression or unacceptable toxicity. Missed dose can be taken up to 6 hours prior to the next dose, administer the next dose as scheduled. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability (refer to detailed product guideline).
Administration
Should be taken on an empty stomach. Take at least 1 hr before or 2 hr after meals.
Special Precautions
Patient with G6PD deficiency; malignancy associated with RAS mutations; risk factors for arrhythmias, pre-existing diabetes mellitus or hyperglycaemia. Not indicated for treatment in patients with wild-type BRAF melanoma, wild-type BRAF NSCLC, or wild-type BRAF anaplastic thyroid cancer. Severe renal and moderate to severe hepatic impairment. Pregnancy and lactation.
Adverse Reactions
Significant: Cardiomyopathy, decreased LVEF, serious dermatologic toxicity (e.g. rash, dermatitis, acneiform rash, palmar-plantar erythrodysaesthesia syndrome, erythema), serious febrile reactions (e.g. fever complicated by hypotension, rigors or chills, dehydration, renal failure), granulomatous nephritis, hepatic events, hypertension, haemorrhage, hyperglycaemia, ILD or pneumonitis, rhabdomyolysis, pancreatitis, malignancy (e.g. cutaneous squamous cell carcinoma, keratoacanthoma, new primary melanoma, non-cutaneous malignancy), ocular toxicity (e.g. uveitis, iritis, iridocyclitis, RPED, RVO). Rarely, QT prolongation.
Blood and lymphatic system disorders: Anaemia, leucopenia, neutropenia, thrombocytopenia.
Eye disorders: Blurred vision, visual impairment.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, constipation, abdominal pain, dry mouth, stomatitis.
General disorders and admin site conditions: Fatigue, asthenia, influenza-like illness, peripheral or face oedema.
Immune system disorders: Hypersensitivity.
Infections and infestations: Cellulitis, folliculitis.
Investigations: Increased ALT/AST, blood alkaline phosphatase, creatine phosphokinase.
Metabolism and nutrition disorders: Decreased appetite, hypophosphataemia, hyponatraemia, dehydration.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, pain in extremity, muscle spasms.
Neoplasms benign, malignant and unspecified: Papilloma, seborrheic keratosis, acrochordon, basal cell carcinoma.
Nervous system disorders: Headache, dizziness.
Renal and urinary disorders: UTI.
Respiratory, thoracic and mediastinal disorders: Cough, nasopharyngitis, dyspnoea.
Skin and subcutaneous tissue disorders: Alopecia, hyperkeratosis, pruritus, dry skin, actinic keratosis, skin lesion or fissures, photosensitivity, hyperhidrosis, panniculitis.
Vascular disorders: Hypotension, lymphoedema.
Potentially Fatal: Intracranial, subarachnoid, retroperitoneal, or gastrointestinal haemorrhage; venous thromboembolism (e.g. DVT, pulmonary embolism), severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS); colitis, gastrointestinal perforation.
Patient Counseling Information
This drug may cause fatigue and eye problems, if affected, do not drive or operate machinery.
MonitoringParameters
Perform confirmatory tests to determine BRAF V600K or V600E mutation status, and pregnancy status prior to treatment initiation of therapy; dermatologic evaluation prior to, every 2 months during, and for up to 6 months after treatment discontinuation. Monitor serum glucose, electrolytes, renal function tests; febrile drug reactions, signs and symptoms of infection, uveitis, haemolytic anaemia, dermatologic toxicity, and non-cutaneous malignancies. For patients treated in combination with trametinib: Perform ophthalmic exams including retinal evaluation periodically. Monitor LFTs every 4 weeks after starting treatment and as clinically indicated; CBC at baseline and periodically during treatment. Assess LVEF by echocardiogram or MUGA scan at baseline, 1 month after initiation, then at every 2-3 months during therapy. Monitor for signs and symptoms of haemorrhage, venous thromboembolism, interstitial lung disease (ILD), retinal pigment epithelial detachments (RPED), or retinal vein occlusion (RVO).
Drug Interactions
May decrease exposure of warfarin, digoxin, midazolam. Increased plasma concentrations with strong CYP2C8 (e.g. gemfibrozil) or CYP3A4 inhibitors (e.g. ketoconazole). Decreased plasma concentrations with potent CYP2C8 inducers (e.g. rifampicin) and strong CYP3A4 inducers (e.g. carbamazepine, phenytoin).
Food Interaction
Decreased absorption and exposure, and delays time to peak plasma concentration with high fat meal. Decreased plasma levels with St. John’s wort.
Action
Description: Dabrafenib is a potent and selective inhibitor of some mutated forms of b-Raf kinases (BRAF), which prevents tumour growth of melanomas with BRAF V600 mutation.
Pharmacokinetics:
Absorption: Absorbed from the gastrointestinal tract. Food, particularly high-fat meal, may decrease absorption. Bioavailability: 95%. Time to peak plasma concentration: 2 hours.
Distribution: Volume of distribution: 70.3 L. Plasma protein binding: 99.7%.
Metabolism: Metabolised in the liver by CYP2C8 and CYP3A4 isoenzymes to active metabolite, hydroxy-dabrafenib; further metabolised via oxidation by CYP3A4 to active metabolite, desmethyl-dabrafenib.
Excretion: Mainly via faeces (71%); urine (23% as metabolites). Elimination half-life: 8 hours (dabrafenib); 10 hours (hydroxy-dabrafenib); 21-22 hours (desmethyl-dabrafenib).
Chemical Structure

Chemical Structure Image

Source: National Center for Biotechnology Information. PubChem Database. Dabrafenib, CID=44462760, https://pubchem.ncbi.nlm.nih.gov/compound/Dabrafenib (accessed on Jan. 20, 2020)

Storage
Store at 25°C. Protect from light and moisture.
This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal. Wear gloves during receiving, unpacking, and placing in storage.
ATC Classification
L01XE23 - dabrafenib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.
References
Anon. Dabrafenib. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 14/01/2020.

Anon. Dabrafenib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 14/01/2020.

Buckingham R (ed). Dabrafenib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 14/01/2020.

Joint Formulary Committee. Dabrafenib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 14/01/2020.

Tafinlar Capsule (GlaxoSmithKline LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 14/01/2020.

Disclaimer: This information is independently developed by MIMS based on Dabrafenib from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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