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TAFINLAR is a brand name for Dabrafenib, supplied as a capsule. The medicine, its uses, side effects and dosage are the same regardless of brand.
Verbatim from this product's HC label. Tap a section to expand.
3 Pharmacokinetics). 6 Drug-Herb Interactions Interactions with herbal products have not been established. 7 Drug-Laboratory Test Interactions Interactions with laboratory tests have not been established. 1 Mechanism of Action TAFINLAR monotherapy: Dabrafenib is a selective, ATP-competitive small molecule inhibitor of RAF kinases, including BRAF.
Oncogenic amino acid variants in BRAF lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway (including RAS/RAF/MEK/ERK) and may promote tumour cell growth. BRAF mutations have been identified in specific cancers, including approximately 50% of melanoma.
The most commonly observed BRAF mutation, V600E, and the next most common, V600K, account for approximately 95% of BRAF mutations found in patients with melanoma. A number of less common substitutions include V600D, V600G and V600R.
Tafinlar (dabrafenib) Page 49 of 106 Dabrafenib selectively inhibits BRAF V600E and other V600 mutations and with greater potency compared to wild-type BRAF in in vitro kinase inhibition assays. The concentration of dabrafenib required to inhibit 50% of enzyme activity (IC50) of each of the different BRAF proteins is shown in Table 21.
The inhibitory activity of dabrafenib has not been determined for BRAF variants V600R, V600G and V600M. 5 The results from the in vitro kinase assays were consistent with the inhibition of proliferation of melanoma cell lines. In addition, dabrafenib inhibited growth in a BRAF V600E positive NSCLC cell line with an IC50 value similar to those observed in BRAF mutation melanoma cell lines.
TAFINLAR in combination with trametinib:
Trametinib is a small molecule inhibitor of mitogen-activated extracellular signal-regulated kinase 1 and 2 (MEK1 and MEK2). MEK1 and MEK2 are components of the MAPK pathway (including RAS/RAF/MEK/ERK). Dabrafenib and trametinib provide concomitant inhibition of the pathway at the level of the RAF and MEK kinases, respectively.
The combination of dabrafenib with trametinib was synergistic in BRAF V600 mutation-positive melanoma and V600E mutated non-small cell lung carcinoma (NSCLC) cell lines and delayed the emergence of resistance in BRAF V600 mutation-positive melanoma xenografts.
2 Pharmacodynamics Cardiac Electrophysiology: In a phase I, open-label, multiple-dose, dose escalation, first time-in-human study of dabrafenib in patients with solid tumours, serial ECG data were collected pre-dose and at 1, 2, 4, 6, and 8 h post-dosing on days 1, 8, and 15 of cycle 1 in temporal association with pharmacokinetic sampling.
A statistically significant positive relationship was demonstrated between concentrations of the three major metabolites of dabrafenib and the QTc interval. 6 ms on day 15 for all patients (N = 110). 2 ms on day 15, in patients receiving a 150 mg twice daily dose (N = 20).
). In a pooled safety population of pediatric patients receiving TAFINLAR in combination with trametinib (n=171), no cases of pre-renal or intrinsic renal failure were reported. Monitor serum creatinine and other evidence of renal function routinely during treatment and in events of severe pyrexia.
Reproductive Health Reproduction:
Male patients (including those who have had a vasectomy) with sexual partners who are pregnant, or are of childbearing potential should use condoms during sexual intercourse while taking TAFINLAR and for at least 2 weeks following discontinuation of treatment and at least 16 weeks following the last dose of trametinib when taken in combination with TAFINLAR.
Women of childbearing potential should use effective methods of contraception during therapy (methods that result in less than 1% pregnancy rates) and for 2 weeks following discontinuation of TAFINLAR and at least 16 weeks following the last dose of trametinib when taken in combination with TAFINLAR.
Dabrafenib is likely to decrease the efficacy of oral or any systemic hormonal contraceptives and effective alternative methods of contraception should be used (see 9 Effect of Dabrafenib on Other Drugs). If TAFINLAR is used during pregnancy, or if the patient becomes pregnant while taking TAFINLAR, the patient should be advised of the potential risk to the foetus.
Fertility:
There are no fertility data in humans. Adverse effects of dabrafenib on male reproductive organs have been seen in animals (see 16 Reproductive and Developmental Toxicity). Male patients should be informed of the potential risk for impaired spermatogenesis, which may be irreversible.
Skin Severe cutaneous adverse reactions:
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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In a single-blind ECG assessment study in subjects with BRAF V600 mutation-positive tumours (N = 30), placebo was administered on Day -1 followed by a single dose of dabrafenib 300 mg on Day 1, dabrafenib 300 mg BID (twice the recommended dose) on Days 2 to 7, and a single dose of dabrafenib 300 mg on Day 8.
ECG assessments performed on Days 1 and 8 showed an increase in heart rate, with statistically significant placebo-adjusted mean changes from baseline ranging from 3 to 12 bpm. , > 20 ms) were detected.
Blood Pressure:
TAFINLAR 150 mg BID was associated with decreases in systolic and diastolic blood pressure in the pivotal phase III study of patients with BRAF mutation-positive melanoma. 6 mm Hg. 3 Pharmacokinetics The pharmacokinetics (PK) of dabrafenib were determined in adult patients with BRAF mutation-positive metastatic melanoma after single dose and after repeat dosing with TAFINLAR capsules at 150 mg twice daily with dosing approximately 12 hours apart.
0) 1478 (1229, 1777) 4341 (3599, 5235) NA CI = confidence interval; NA = not applicable a AUC refers to AUC(0-) for single dose and AUC(0-) for repeat-dose b. Data from phase I food effect study (fasting conditions) c Data from steady-state phase III study (PK subset); d.
N = 14; e.
N = 13 Absorption:
Dabrafenib is absorbed orally with a mean absolute bioavailability of 95% (with a lower 90% CI of 81%) and with a median time to achieve peak plasma concentration of 2 hours post-dose in the fasted state. Across a range of doses there was less than a dose-proportional increase after repeat twice daily dosing.
There is a decrease in exposure observed with repeat dosing, due to induction of its own metabolism. 0, respectively. 7%, respectively. Single dose and steady-state PK parameters are shown in Table 22. In a single dose study in healthy volunteers, the administration of […]
Cases of 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 in combination with trametinib.
Before initiating treatment, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs appear, TAFINLAR and trametinib should be withdrawn. 1 Pregnancy TAFINLAR should not be administered to pregnant women.
Dabrafenib may cause foetal harm by interfering with BRAF function, which is essential for the developing embryo. There are no adequate and well-controlled studies of TAFINLAR in pregnant women (see 7 Reproductive Tafinlar (dabrafenib) Page 22 of 106 Health: Female and Male Potential).
Dabrafenib caused reproductive toxicity and teratogenicity in rats (see 16 Reproductive and Developmental Toxicity). 2 Breastfeeding No studies have been conducted with TAFINLAR in nursing mothers. TAFINLAR should not be used by nursing women.
It is not known whether dabrafenib is transferred into human milk. Because many drugs are transferred into human milk, and because of the potential for serious adverse reactions from dabrafenib in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
3 Pediatrics Pediatrics (< 1 year of age): The safety and efficacy of TAFINLAR in pediatric patients <1 year of age have not been established. TAFINLAR is not recommended in this age group.
Pediatrics (≥ 1 year to <18 years of age):
The safety and efficacy of TAFINLAR in combination with trametinib in pediatric patients 1 year of age and older with low-grade glioma are supported by evidence from the randomized LGG cohort of the G2201 study (N=73). The safety and efficacy of TAFINLAR in combination with trametinib in pediatric patients 1 year of age and older with high-grade glioma are supported by evidence from the single-arm HGG cohort of the G2201 study (N=41).
The warnings applicable to adults are also relevant to pediatric use. Adverse drug reactions occurring at a higher frequency category in a pooled safety population of pediatric patients (N=171) compared to adult patients were neutropenia, dermatitis acneiform, paronychia, anaemia, leukopenia (very common); bradycardia, dermatitis exfoliative generalised, hypersensitivity and pancreatitis (common).
Weight increase has only been reported in the pediatric population. 6% of patients. 5 months. 7% of patients. Please refer to pediatric Adverse Events Tables 12 and 13 Studies in juvenile animals have shown adverse effects, including effects on growth and renal toxicity, which had not been observed in adult animals (see 16 Juvenile Toxicity).
4 Geriatrics Geriatrics (≥ 65 years of age): Of the total number of patients in clinical studies of TAFINLAR monotherapy (N = 797), 23% were 65 years of age and older, and 6% were 75 years of age and older. Compared with younger patients (< 65 years), more patients ≥ 65 years old had adverse events that led to dabrafenib dose reductions (23% versus 14%) or interruptions (46% versus 30%).
In addition, older patients experienced more serious adverse events compared to Tafinlar (dabrafenib) Page 23 of 106 younger patients (46% versus 27%). Of the number of patients in a phase III clinical study in unresectable or metastatic melanoma receiving TAFINLAR in combination with trametinib (N = 209), 56 patients (27%) were 65 years of age and older, and 11 patients (5%) were 75 years of age and older.
Compared with younger patients (< 65 years), more patients ≥ 65 years old had adverse events that led to dose reductions (43% versus 23%) or interruptions (66% […]