Tafinlar (dabrafenib mesylate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Dabrafenib, an inhibitor of b-Raf serine-threonine kinase (BRAF) with V600E or V600K mutation, is an antineoplastic agent.
Dabrafenib, a potent inhibitor of b-Raf serine-threonine kinase (BRAF) with V600E or V600K mutation, is an antineoplastic agent. Approximately 50% of cutaneous melanomas carry a BRAF mutation. The most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E); a less frequently occurring BRAF mutation is the substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K).
The mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis). In vitro studies indicate that dabrafenib also inhibits BRAF with V600D mutation. Paradoxical activation of MAPK and increased cell proliferation have been observed in BRAF wild-type cells exposed to BRAF inhibitors.
Clinical resistance to monotherapy with a BRAF inhibitor, generally occurring 6-7 months following initiation of therapy, has been attributed to several possible resistance mechanisms mostly relying on reactivation of the MAPK/ERK pathway. Complete inhibition of the MAPK/ERK pathway resulting in durable responses may be achieved with the use of combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib). Use of dabrafenib and trametinib in combination resulted in greater growth inhibition of melanoma cell lines testing positive for BRAF V600 mutations in vitro.
In addition, combination therapy was associated with prolonged inhibition of tumor growth in melanoma xenografts testing positive for BRAF V600 mutations compared with either drug alone.
Following administration, the absolute bioavailability of dabrafenib is 95% for the capsules and 76% for the tablets for oral suspension. The median time to peak plasma concentrations of dabrafenib is 2 hours after oral administration. Following administration of a single dabrafenib dose within the dosage range of 12-300 mg, the drug exhibits dose-proportional increases in peak plasma concentrations and AUC; however, these increases are less than dose proportional after repeated twice-daily dosing.
Administration of dabrafenib capsules with a high-fat meal (approximately 1000 calories) decreased peak plasma concentrations and AUC of the drug by 51 and 31%, respectively, and delayed the rate of absorption (time to reach peak concentrations delayed by 3.6 hours). Dabrafenib is more than 99% bound to plasma proteins; in vitro studies suggest that dabrafenib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Dabrafenib is principally metabolized by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C8.
Dabrafenib is an inducer of CYP3A4 and 2C19 and may induce other CYP isoenzymes. The metabolites hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib. The mean terminal half-life of dabrafenib is 8 hours.
Following oral administration of a radiolabeled dose of dabrafenib, about 71% of the dose is recovered in feces and 23% is recovered in urine.
The pharmacokinetics of dabrafenib in pediatric patients (1 to <18 years of age) with glioma and other solid tumors following single or multiple doses are with range of values observed in adults given the same dose based on weight. Weight (6 to 156 kg) had a statistically significant effect of dabrafenib oral clearance in this population.
USES: Dabrafenib is used to treat various cancers (such as skin, thyroid, lung, solid tumors, brain). It belongs to a class of drugs known as kinase inhibitors. Dabrafenib works by slowing or stopping the growth of cancer cells.
Generic name: dabrafenib mesylate
Pronunciation: (da-BRAF-e-nib)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Tafinlar:
- Anaplastic Thyroid Carcinoma With Braf V600e Mutation
- Low Grade Glioma With Braf V600e Mutation
- Malignant Melanoma With Braf V600e Mutation
- Malignant Melanoma With Braf V600k Mutation
- Malignant Solid Tumor With Braf V600e Mutation
- Non-Small Cell Lung Cancer With Braf V600e Mutation
Also known as: Anaplastic Thyroid Cancer With Braf V600e Mutation, Melanoma With Braf V600e Genetic Mutation, Nsclc With Braf V600e Mutation.
Dosing
Dosage of dabrafenib mesylate is expressed in terms of dabrafenib. Refer to the trametinib prescribing information for recommended trametinib dosage regimens.
Dosage of dabrafenib may be reduced or therapy temporarily interrupted or discontinued in patients who develop adverse effects. Dosage reductions for dabrafenib capsules and dabrafenib tablets for oral suspension for adverse reactions are presented in Tables 2 and 3, respectively. Permanently discontinue dabrafenib capsules if a patient is unable to tolerate the 50 mg twice daily dosage regimen.
Table 2. Recommended Dosage Reductions for Dabrafenib Capsules for Adverse Reactions
Recommended 75 mg orally 100 mg orally 150 mg orally Dosage twice daily twice daily twice daily First Dose 50 mg orally 75 mg orally 100 mg orally Reduction twice daily twice daily twice daily Second Dose Not applicable 50 mg orally 75 mg orally Reduction twice daily twice daily Third Dose Not applicable Not applicable 50 mg orally Reduction twice daily
Table 3. Recommended Dosage Reductions for Dabrafenib Tablets for Oral Suspension for Adverse Reactions
Body Weight First Dose Second Dose Third Dose (Recommended Reduction Reduction Reduction Dosage) 8 to 9 kg (20 mg 10 mg twice daily Not applicable Not applicable twice daily) 10 to 13 kg (30 20 mg twice daily 10 mg twice daily Not applicable mg twice daily) 14 to 17 kg (40 30 mg twice daily 20 mg twice daily 10 mg twice daily mg twice daily) 18 to 21 kg (50 30 mg twice daily 20 mg twice daily 10 mg twice daily mg twice daily) 22 to 25 kg (60 40 mg twice daily 30 mg twice daily 20 mg twice daily mg twice daily) 26 to 29 kg (70 50 mg twice daily 40 mg twice daily 20 mg twice daily mg twice daily) 30 to 33 kg (80 50 mg twice daily 40 mg twice daily 30 mg twice daily mg twice daily) 34 to 37 kg (90 60 mg twice daily 50 mg twice daily 30 mg twice daily mg twice daily) 38 to 41 kg (100 70 mg twice daily 50 mg twice daily 30 mg twice daily mg twice daily) 42 to 45 kg (110 70 mg twice daily 60 mg twice daily 40 mg twice daily mg twice daily) 46 to 50 kg (130 90 mg twice daily 70 mg twice daily 40 mg twice daily mg twice daily) >=51 kg (150 mg 100 mg twice 80 mg twice daily 50 mg twice daily twice daily) daily
Administer dabrafenib orally twice daily (as capsules or tablets for oral suspension), approximately every 12 hours.
Dabrafenib capsules: Administer capsules on an empty stomach (at least 1 hour before or 2 hours after a meal). Do not open, crush, or break the capsules.
Dabrafenib tablets for oral suspension: Do not chew or crush tablets and do not swallow whole. Prepare the suspension by dissolving the tablets with approximately 5 mL (1 to 4 tablets) or 10 mL (5 to 15 tablets) of water in the provided cup. Gently stir the mixture with the handle of a teaspoon; full dissolution may take at least 3 minutes. The resulting suspension should be cloudy white in appearance. Administer the suspension immediately after preparation from the cup, oral dosing syringe, or feeding tube (10 French gauge or larger for 1 to 3 tablets; 12 French gauge or larger for 4 to 15 tablets). Administer the suspension on an empty stomach (at least 1 hour before or 2 hours after a meal). If a pediatric patient is unable to tolerate the fasting conditions, breastfeeding and/or baby formula may be administered on demand. Discard the suspension if not administered within 30 minutes after preparation.
If a dose of dabrafenib is missed, take the dose as soon as it is remembered, but only if it can be taken at least 6 hours prior to the next scheduled dose.
If vomiting occurs after administration, do not take an additional dose. Take the next dose at its scheduled time.
Store dabrafenib capsules and tablets for oral suspension in the original bottle with the dessicant at 20-25degreesC (excursions permitted between 15-30degreesC).
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Dabrafenib is metabolized primarily by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C8.
Dabrafenib is an inducer of CYP isoenzymes 3A4, 1A2, and 2C9. In vitro studies show that dabrafenib induces CYP3A4 and CYP2B6 via activation of the pregnane X receptor and constitutive androstane receptor. Dabrafenib also may induce CYP2C isoenzymes via this same mechanism of action.
Dabrafenib and its metabolites, hydroxyl-dabrafenib and desmethyldabrafenib, are substrates of human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Dabrafenib and its hydroxy, carboxy, and desmethyl metabolites are inhibitors of organic anion-transporting polypeptide (OATP) 1B1 and 1B3 as well as organic anion transporters (OAT) 1 and 3 in vitro.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*None.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in >=20% of adult patients receiving dabrafenib monotherapy include hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome).
Adverse effects reported in >=20% of adult patients receiving dabrafenib in combination with trametinib for the treatment of previously untreated unresectable or metastatic melanoma include pyrexia, rash, chills, headache, arthralgia, and cough.
Adverse effects reported in >=20% of adult patients receiving dabrafenib in combination with trametinib for the adjuvant treatment of melanoma include pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.
Adverse effects reported in >=20% of adult patients receiving dabrafenib in combination with trametinib for the treatment of metastatic NSCLC include pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.
Adverse effects reported in >=20% of adult patients receiving dabrafenib in combination with trametinib for the treatment of solid tumors include: pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema.
Adverse effects reported in >=20% of pediatric patients receiving dabrafenib in combination with trametinib for the treatment of solid tumors include: pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.
Adverse effects reported in >=20% of pediatric patients receiving dabrafenib in combination with trametinib for the treatment of low-grade glioma incude pyrexia, rash, headache, vomiting, musculokeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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The safety and efficacy of dabrafenib in combination with trametinib have been established in pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfatory alternative treatment options, or with low-grade glioma with BRAF V600E mutation who require systemic therapy. Dabrafenib in combination with trametinib for these indications is supported by evidence from 2 studies that enrolled 171 patients (between the ages of 1 to <18 years) with BRAF V600 mutation-positive advanced solid tumors. Safety and efficacy of dabrafenib in combination with trametinib have not been established in pediatric patients younger than 1 year of age.
Safety and efficacy of dabrafenib as monotherapy have not been established in pediatric patients.
Dabrafenib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings. If dabrafenib is used during pregnancy, the patient should be informed of the potential hazard to the fetus.
It is not known whether dabrafenib is distributed into human milk. Because of the potential for serious adverse reactions to dabrafenib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 2 weeks after the last dose. The effects of the drug on breast-fed infants or on the production of milk are unknown.
The manufacturer makes no specific dosage recommendations for geriatric patients.
No substantial differences in safety and efficacy of dabrafenib monotherapy have been observed in patients >=65 years of age relative to younger adults.
In clinical trials evaluating dabrafenib in combination with trametinib in patients with melanoma, 21% of patients were >=65 years of age and 5% were >=75 years of age. No overall differences in efficacy were observed between geriatric patients and younger adults, but some adverse effects (i.e., peripheral edema, anorexia) occurred more frequently in geriatric patients with metastatic melanoma.
Clinical experience with dabrafenib and trametinib combination therapy in patients >=65 years of age with non-small cell lung cancer (NSCLC) is insufficient to determine whether geriatric patients respond differently than younger adults.
In clinical trials evaluating dabrafenib and trametinib combination therapy in patients with anaplastic thyroid cancer, 77% of patients were >=65 years of age. An insufficient number of younger adults were included in the study to determine whether geriatric patients respond differently than younger adults.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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