Dabrafenib
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Handling and access
NIOSH hazardous drug
Table 2NIOSH lists dabrafenib as a hazardous drug. AHFS class: 10:00 antineoplastic agents.
- Meets the NIOSH definition of a hazardous drug (carcinogenicity, developmental or reproductive toxicity, organ toxicity at low doses, or genotoxicity) without MSHI or a Group 1 or 2A carcinogen classification.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
Dosing in kidney impairment
Resume TAFINLAR at the same or lower dose if improves to Grade 0 or 1. Permanently discontinue TAFINLAR for persistent Grade 2 or greater uveitis of > 6 weeks [see Dosage and Administration] . 5.6 Serious Febrile Reactions Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur with TAFINLAR.
Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 6% of patients. TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population [see Adverse Reactions] , fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure occurred in 5% of patients.
Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in < 1% of patients. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population [see Adverse Reactions] , pyrexia occurred in 66% of patients. Withhold TAFINLAR when used as monotherapy, and both TAFINLAR and trametinib when used in combination, if the patient’s temperature is ≥ 100.4°F.
In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia [see Adverse Reactions] . Fever may be complicated by 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.
Administer corticosteroids (e.g., prednisone 10 mg daily) for at least 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, such as dehydration, hypotension, renal failure, or severe chills/rigors, and there is no evidence of active infection. 5.7 Serious Skin Toxicities Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with TAFINLAR administered with trametinib [see Adverse Reactions] .
| a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Tables 3 and 4 for recommended dose reductions of TAFINLAR. c Dose modifications are not recommended for TAFINLAR when administered with trametinib for the following adverse reactions of trametinib: retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism. Dose modification of TAFINLAR is not required for new primary cutaneous malignancies. | |
| Severity of Adverse Reactiona | Dosage Modification for TAFINLARb |
| New Primary Malignancies [see Warnings and Precautions (5.1)] | |
| Non-Cutaneous RAS Mutation-positive Malignancies | Permanently discontinue TAFINLAR. |
| Cardiomyopathy [see Warnings and Precautions (5.4)] | |
| Symptomatic cardiomyopathy Absolute decrease in left ventricular ejection fraction (LVEF) of greater than 20% from baseline that is below the institutional lower limit of normal (LLN) | Withhold TAFINLAR until LVEF improves to at least the institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, then resume TAFINLAR at same dose. |
| Uveitis [see Warnings and Precautions (5.5)] | |
| Uveitis, including iritis and iridocyclitis | For mild or moderate uveitis that does not respond to ocular therapy, or for severe uveitis, withhold TAFINLAR for up to 6 weeks.If improved to Grade 0-1, then resume TAFINLAR at same or lower dose. If not improved, permanently discontinue TAFINLAR. |
| Febrile Reactions [see Warnings and Precautions (5.6)] | |
| Fever of 100.4°F to 104°F (or first symptoms in case of recurrence) | Withhold TAFINLAR until fever resolves, then resume TAFINLAR at same or lower dose. |
| Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure | Withhold TAFINLAR until febrile reactions resolve for at least 24 hours, then resume TAFINLAR at lower dose.OrPermanently discontinue TAFINLAR. |
| Skin Toxicities [see Warnings and Precautions (5.7)] | |
| Intolerable Grade 2 Grade 3 or 4 | Withhold TAFINLAR for up to 3 weeks.If improved, resume TAFINLAR at lower dose. If not improved, permanently discontinue TAFINLAR. |
| Severe cutaneous adverse reactions (SCARs) | Permanently discontinue TAFINLAR. |
| Other Adverse Reactionsc, including Hemorrhage [see Warnings and Precautions (5.3)] | |
| Intolerable Grade 2 Any Grade 3 | Withhold TAFINLAR.If improved to Grade 0-1, resume TAFINLAR at lower dose. If not improved, permanently discontinue TAFINLAR. |
| First occurrence of any Grade 4 | Withhold TAFINLAR until improves to Grade 0-1, then resume TAFINLAR at lower dose.OrPermanently discontinue TAFINLAR. |
| Recurrent Grade 4 | Permanently discontinue TAFINLAR. |
Dosing in liver impairment
Hepatic Impairment Dose adjustment is not recommended for patients with mild (bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or bilirubin > 1x to 1.5x ULN and any AST) hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate (bilirubin > 1.5x to 3x ULN and any AST) to severe (bilirubin > 3x to 10x ULN and any AST) hepatic impairment may have increased exposure.
An appropriate dosage has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology] .
Preparation and administration
Administration Take TAFINLAR at the same time each day, approximately 12 hours apart. Do not take a missed dose of TAFINLAR within 6 hours of the next dose of TAFINLAR. If vomiting occurs after TAFINLAR administration, do not take an additional dose. Take the next dose at its scheduled time. TAFINLAR Capsules Take TAFINLAR capsules on an empty stomach (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology] .
Do not open, crush, or break TAFINLAR capsules. TAFINLAR Tablets for Oral Suspension Prior to use of the oral suspension, instruct caregivers (and if appropriate, patients) on proper dosing and administration of TAFINLAR tablets for oral suspension. Take the oral suspension on an empty stomach (at least 1 hour before or 2 hours after a meal).
Breastfeeding and/or baby formula may be given on demand if a pediatric patient is unable to tolerate the fasting conditions [see Clinical Pharmacology] . Do not swallow whole, chew or crush TAFINLAR tablets for oral suspension. Preparation and Administration Prepare the oral suspension with approximately 5 mL of water for 1 to 4 tablets, and approximately 10 mL of water for 5 to 15 tablets in the provided dosing cup.
Gently stir the water and prescribed number of tablets with the handle of a teaspoon until the tablets are fully dissolved. It may take at least 3 minutes to fully dissolve the tablets. Once the tablets are dissolved, the oral suspension will be cloudy white. Administer the oral suspension immediately after preparation from a dosing cup, oral syringe or feeding tube (10 French gauge or larger for 1 to 3 tablets; 12 French gauge or larger for 4 to 15 tablets).
Discard the oral suspension if not administered within 30 minutes after preparation.
Drug interactions
Check dabrafenib against a medication listLabel text (4 paragraphs)
Avoid concurrent administration of strong inhibitors of CYP3A4 or CYP2C8. ( 7.1 ) Concomitant use with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents. ( 7.2 )
7.1 Effects of Other Drugs on TAFINLAR Strong inhibitors of CYP3A4 or CYP2C8 may increase the concentration of dabrafenib [see Clinical Pharmacology (12.3)] . Substitution of strong inhibitors of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors.
7.2 Effects of TAFINLAR on Other Drugs Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)] . Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives , can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8. 3 )] .
Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.
Contraindications
None. None. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
E*Likelihood score E*: Unproven but suspected cause of clinically apparent liver injury.
Dabrafenib is a selective inhibitor of mutated forms of BRAF kinase and is used alone or in combination with trametinib in the treatment of advanced malignant melanoma. Dabrafenib therapy is associated with transient elevations in serum aminotransferase during therapy, but has not been linked to instances of clinically apparent acute liver injury.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)] , TAFINLAR can cause fetal harm when administered to a pregnant woman. There is insufficient data in pregnant women exposed to TAFINLAR to assess the risks. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended adult clinical dose of 150 mg twice daily (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a combined female fertility and embryo-fetal development study in rats conducted during the period of organogenesis, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day [approximately three times the human exposure at the recommended adult dose based on area under the curve (AUC)].
At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended adult dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.
Breastfeeding (LactMed)
No information is available on the clinical use of dabrafenib during breastfeeding. Because dabrafenib is more than 99% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during dabrafenib therapy and for 2 weeks after the last dose.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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