Tafinlar

Tafinlar

dabrafenib

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Dabrafenib mesylate.
Description
Cap 50 mg (opaque, size 2 capsules composed of a dark red body and dark red cap containing a white to slightly coloured solid and capsule shells imprinted with GS TEW and 50 mg). 75 mg (opaque, size 1 capsules composed of a dark pink body and dark pink cap containing a white to slightly coloured solid and capsule shells imprinted with GS LHP and 75 mg).
Excipients/Inactive Ingredients: 50 mg and 75 mg capsules: Microcrystalline cellulose, Magnesium stearate, vegetable source, Colloidal silicone dioxide.
Shell composition: Red iron oxide, Titanium dioxide, Hypromellose.
Monogramming: Black iron oxide, Shellac, N-Butyl alcohol, Isopropyl alcohol, Propylene glycol, Ammonium hydroxide.
Action
Pharmacotherapeutic Group: Antineoplastic agents, protein kinase inhibitor.
Pharmacology: Pharmacodynamics:
Mechanism of Action: Monotherapy: Dabrafenib is a potent, selective, ATP-competitive inhibitor of RAF kinases with IC50 values of 0.65, 0.5 and 1.84 nM for BRAFV600E, BRAFV600K and BRAFV600D enzymes, respectively. Oncogenic mutations in BRAF V600 lead to constitutive activation of the RAS/RAF/MEK/ERK pathway and stimulation of tumour cell growth. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 50% of melanoma. The most commonly observed BRAF mutation, V600E, and the next most common, V600K, account for 95% of the BRAF mutations found in all patients with cancer. A number of rare substitutions also occur including V600D, V600G and V600R.
Dabrafenib also inhibits wild-type BRAF and CRAF enzymes with IC50 values of 3.2 and 5.0 nM, respectively. Dabrafenib inhibits BRAF V600 mutant melanoma cell growth in vitro and in vivo.
Combination with Trametinib: Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase I (MEK1) and MEK2 activation and kinase activity. MEK proteins are components of the extracellular signal-related kinase (ERK) pathway. Dabrafenib and trametinib inhibit two kinases in this pathway, BRAF and MEK, and the combination provides concomitant inhibition of the pathway. The combination of dabrafenib with trametinib is synergistic in BRAF V600 mutation positive melanoma cell lines in vitro and delays the emergence of resistance in vivo in BRAF V600 mutation positive melanoma xenografts.
Pharmacodynamic Effects: Dabrafenib demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated ERK) in BRAF V600 mutant melanoma cell lines, in vitro and in animal models.
In subjects with BRAF V600 mutant melanoma, administration of dabrafenib resulted in inhibition of tumour phosphorylated ERK relative to baseline.
QT Prolongation: The potential effect of dabrafenib on QT prolongation was assessed in a dedicated multiple dose QT study. A supratherapeutic dose of 300 mg dabrafenib BID was administered in 32 subjects with BRAF V600 mutation-positive tumors. No clinically relevant effect of dabrafenib or its metabolites on the QTc interval was observed.
Clinical Studies: Dabrafenib monotherapy: The efficacy of dabrafenib in the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma has been evaluated in 3 studies (BRF113683 [BREAK-3], BRF113929 [BREAK-MB], and BRF113710 [BREAK-2]) including patients with BRAF V600E and/or V600K mutations.
Previously untreated patients: The efficacy and safety of dabrafenib were evaluated in a Phase III randomized, open-label study [BREAK-3] comparing dabrafenib to dacarbazine (DTIC) in previously untreated patients with BRAF V600E mutation positive advanced (unresectable Stage III) or metastatic (Stage IV) melanoma. Screening included central testing of BRAF mutation V600E using a BRAF mutation assay conducted on the most recent tumour sample available.
The trial enrolled 250 patients randomized 3:1 to receive either dabrafenib 150 mg twice daily or intravenous DTIC 1000 mg/m2 every 3 weeks. The primary objective for this study was to evaluate the efficacy of dabrafenib compared to DTIC with respect to progression-free survival (PFS) for patients with BRAF V600E mutation positive metastatic melanoma. Patients on the DTIC arm were allowed to receive dabrafenib after independent radiographic confirmation of initial progression. Baseline characteristics were balanced between treatment groups. Sixty percent of patients were male and 99.6% were Caucasian; the median age was 52 years with 21% of patients being ≥65 years, 98.4% had ECOG status of 0 or 1, and 97% of patients had metastatic disease.
The primary analysis was based on a 118 events at the time of the data cut off. Efficacy results are summarized in Table 1 and Figure 1. (See Table 1 and Figure 1.)

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Twenty-eight subjects (44%) randomized to DTIC crossed over to dabrafenib following independently verified disease progression. Median time on dabrafenib after cross-over was 2.8 months and unconfirmed overall response rate (ORR) was 46%.

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Patients with brain metastases: BREAK-MB was a multi-center, open-label, two-cohort, Phase II study designed to evaluate the intracranial response of dabrafenib in subjects with histologically confirmed (Stage IV) BRAF-mutation positive (V600E or V600K) melanoma metastatic to the brain. Subjects were enrolled into Cohort A (subjects with no prior local therapy for brain metastasis) or Cohort B (subjects who received prior local therapy for brain metastasis).
The results are summarised in Table 2. (See Table 2.)

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Patients who were previously untreated or failed at least one prior systemic therapy: BRF113710 (BREAK-2) was a multi-centre, global, open-label, single-arm, Phase II study that enrolled 92 subjects with histologically confirmed metastatic melanoma (Stage IV) with confirmed BRAF V600E or V600K mutation-positive melanoma. Subjects were treatment-naive (n=15) or received prior treatment (n=77) in the metastatic setting (i.e., chemotherapy, immunotherapy, prior targeted therapy, etc.).
The investigator assessed confirmed response rate in the primary efficacy population of patients with BRAF V600E metastatic melanoma (n=76) was 59% (95% CI: 48.2, 70.3) including 7% complete response. Median PFS was 6.3 months (95% CI: 4.6, 7.7) and the median duration of response was 5.2 months (95% CI: 3.9, not calculable). Prior systemic therapy did not appear to significantly impact response. The investigator assessed confirmed response rate in a secondary efficacy population of patients with BRAF V600K mutation positive metastatic melanoma (n=16) was 13% (95% CI: 0.0, 28.7) with a median duration of response of 5.3 months (95% Cl: 3.7, 6.8). There were no complete responses in the V600K patient population.
Combination with trametinib: The efficacy and safety of the recommended dose of dabrafenib (150 mg twice daily) in combination with trametinib (2 mg once daily) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation was studied in two pivotal Phase III studies.
MEK115306 (COMBI-d): MEK115306 (COMBI-d) was a Phase III, randomized, double-blind study comparing the combination of dabrafenib and trametinib to dabrafenib and placebo as first-line therapy for subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The primary endpoint of the study was investigator assessed progression-free survival (PFS) with a key secondary endpoint of Overall Survival (OS). Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ ULN) and BRAF mutation (V600E versus V600K).
A total of 423 subjects were randomized 1:1 to either the combination therapy arm (dabrafenib 150 mg twice daily and trametinib 2 mg once daily) (N = 211) or dabrafenib monotherapy arm (150 mg twice daily) (N = 212). Baseline characteristics were balanced between treatment groups. Males constituted 53 % of patients and the median age was 56 years; Majority of patients had an ECOG performance score of 0 (72%) and had Stage IVM1c disease (66%). Most patients had the BRAF V600E mutation (85%); the remaining 15% of patients had the BRAF V600K mutation.
At the time of final OS analysis, a total of 222 deaths (52.5%) [combination 99 deaths (47%) and dabrafenib 123 deaths (58%)] out of the randomized (or ITT) population were reported. The median follow up time on study treatment was 20 months in the combination therapy arm and 16 months in the dabrafenib montherapy arm. Study MEK115306 showed a statistically significant 29% reduction in the risk of death for the combination therapy arm compared with the dabrafenib monotherapy arm (HR = 0.71, 95% CI: 0.55, 0.92; p=0.011). The median OS was 25.1 months for the combination therapy arm and 18.7 months for the dabrafenib monotherapy arm. The 12-month (74%) and 24-month (51.4%) OS estimates for the combination were also greater than those for dabrafenib monotherapy (67.6 and 42.1%, respectively). (See Figure 2 and Table 3.)

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MEK116513 (COMBI-v): Study MEK116513 was a 2-arm, randomized, open-label, Phase III study comparing dabrafenib and trametinib combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positive metastatic melanoma. The primary endpoint of the study was overall survival. Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K).
A total of 704 subjects were randomized 1:1 to either the combination therapy arm (dabrafenib 150 mg twice daily and trametinib 2 mg once daily) or the vemurafenib monotherapy arm (960 mg twice daily). Most subjects were White (>96%) and Male (55%), with a median age of 55 years (24% were ≥65 years). The majority of subjects had Stage IV M1c disease (61%). Most subjects had LDH ≤ULN (67%), ECOG performance status of 0 (70%), and visceral disease (78%) at baseline. Overall, 54% of subjects had <3 disease sites at Baseline. The majority of subjects had a BRAF V600E mutation (89%).
The OS analysis was conducted when 222 total deaths (77% of the required events for the final analysis) occurred. The Independent Data Monitoring Committee (IDMC) recommended stopping the study since the OS results crossed the pre-specified efficacy boundary. As a consequence the interim OS summary was considered the final comparative OS analysis.
The OS analysis for Study MEK116513 was based on 222 deaths (32%) [combination;100 deaths (28%) and vemurafenib 122 deaths (35%)]. The median follow up time on study treatment was 11 months for the combination arm and 9 months in the vemurafenib arm. Study MEK116513 showed a statistically significant 31% reduction in the risk of death for the combination therapy compared with vemurafenib (HR=0.69, 95% CI: 0.53, 0.89; p=0.005). The median OS was not yet reached for the combination arm, and was 17.2 months for vemurafenib monotherapy. (See Figure 3 and Table 4.)

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Pharmacokinetics: Absorption: Dabrafenib is absorbed orally with median time to achieve peak plasma concentration of 2 hours post-dose. Mean absolute bioavailability of oral dabrafenib is 95 % (90 % CI: 81, 110 %). Dabrafenib exposure (Cmax and AUC) increased in a dose proportional manner between 12 and 300 mg following single-dose administration, but the increase was less than dose-proportional after repeat twice daily dosing. There was a decrease in exposure observed with repeat dosing, likely due to induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. Following administration of 150 mg twice daily, geometric mean Cmax, AUC(0-τ) and predose concentration (Cτ) were 1478 ng/ml, 4341 ng*hr/m-1 and 26 ng/ml, respectively.
Administration of dabrafenib with food reduced the bioavailability (Cmax and AUC decreased by 51 % and 31 % respectively) and delayed absorption of dabrafenib capsules when compared to the fasted state.
Distribution: Dabrafenib binds to human plasma protein and is 99.7 % bound. The steady-state volume of distribution following intravenous microdosc administration is 46 L.
Metabolism: The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib, which is further oxidized via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenib can be decarboxylated via a non-enzymatic process to form desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut and reabsorbed. Desmethyl-dabrafenib is metabolized by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hrs while the carboxy- and desmethyl- metabolites exhibited longer half-lives (21-22 hours). Mean metabolite to parent AUC ratios following repeat-dose administration were 0.9, 11 and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib; while the activity of carboxy-dabrafenib is not likely to be significant.
Elimination: Terminal half-life following IV microdose is 2.6 hours. Dabrafenib terminal half-life is 8 hours due to a prolonged terminal phase after oral administration. IV plasma clearance is 12 L/hr.
Faecal excretion is the major route of elimination after oral dosing, accounting for 71 % of a radioactive dose while urinary excretion accounted for 23 % of radioactivity.
Special Populations: Hepatic Impairment: The pharmacokinetics of dabrafenib has been characterized in 65 patients with mild hepatic impairment (based on National Cancer Institute [NCI] classification) enrolled in clinical trials using a population analysis. Dabrafenib oral clearance was not significantly different between these subjects and subjects with normal hepatic function (4 % difference). In addition, mild hepatic impairment did not have a significant effect on dabrafenib metabolite plasma concentrations. Administration of dabrafenib should be undertaken with caution in patients with moderate to severe hepatic impairment (see Dosage & Administration).
Renal Impairment: The pharmacokinetics of dabrafenib were characterized in 233 patients with mild renal impairment (GFR 60-89 ml/min/1.73 m2) and 30 patients with moderate renal impairment (GFR 30-59 ml/min/1.73 m2) enrolled in clinical trials using a population analysis. The effect of mild or moderate renal impairment on dabrafenib oral clearance was small (< 6 % for both categories) and not clinically relevant. In addition, mild and moderate renal impairment did not have a significant effect on hydroxy-, carboxy-, and desmethyl-dabrafenib plasma concentrations. No data are available in subjects with severe renal impairment (see Dosage & Administration).
Age: Based on the population pharmacokinetic analysis, age had no significant effect on dabrafenib pharmacokinetics. Age greater than 75 years was a significant predictor of carboxy- and desmethyl-dabrafenib plasma concentrations with a 40 % greater exposure in subjects ≥75 years of age, relative to subjects <75 years old.
Body Weight and Gender: Based on the population pharmacokinetic analysis, gender and weight were found to influence dabrafenib oral clearance; weight also impacted oral volume of distribution and distributional clearance. These pharmacokinetic differences were not considered clinically relevant.
Race: There are insufficient data to evaluate the potential effect of race on dabrafenib pharmacokinetics.
Drug Interactions: Effect of dabrafenib on other drugs: Dabrafenib is an inducer of CYP3A4 and CYP2C9 and may induce other enzymes including CYP2B6, CYP2C8, CYP2C19, and UDP glucuronosyltransferases (UGT) and may induce transporters. In human hepatocytes, dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4 mRNA levels up to 32 times the control levels and was shown to be an inducer of CYP3A4 and CYP2C9 in vivo. In a clinical study in 12 subjects using a single-dose of midazolam, a CYP3A4 substrate, Cmax and AUC were decreased by 61 % and 74 %, respectively with co-administration of repeat dose dabrafenib 150 mg BID. In a separate trial in 14 subjects, repeat-dose dabrafenib decreased the single-dose AUC of S-warfarin (a substrate of CYP2C9) and of R-warfarin (a substrate of CYP3A4/CYP1A2) by 37 % and 33 %, respectively, with a small increase in Cmax (18 and 19 % respectively) (see Interactions). Although dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafeaib and desmethyl-dabrafenib, were inhibitors of human organic anion transporting polypeptide (OATP) 1B1 (OATP1B1), OATP1B3, organic anion transporter (OAT) 1 and OAT3 in vitro, the risk of a drug-drug interaction is minimal based on clinical exposure. Dabrafenib and desmethyl-dabrafenib were shown to be moderate inhibitors of human breast cancer resistance protein (BCRP); however, based on clinical exposure, the risk of a drug-drug interaction is minimal. Neither dabrafenib nor its 3 metabolites were demonstrated to be inhibitors of P-glycoprotein (Pgp) in vitro. Effect of other drugs on dabrafenib: Human liver microsome studies suggest that CYP2C8 and CYP3A4 are the primary CYP enzymes involved in the oxidative metabolism of dabrafenib in vitro while hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Pharmacokinetic data showed an increase in repeat dose dabrafenib Cmax (33 %) and AUC (71 %) with ketoconazole, and increases in hydroxy- and desmethyl-dabrafenib AUC (increases of 82 and 68 % respectively). A decrease in AUC was noted for carboxy-dabrafenib (decrease of 16 %). Coadministration of dabrafenib and gemfibrozil (a CYP2C8 inhibitor) resulted in an increase in repeat-dose dabrafenib AUC (47 %) and no relevant change in the concentrations of the metabolites (see Interactions). Dabrafenib is a substrate of human P-glycoprotein (Pgp) and BCRP1 in vitro. However, there transporters have minimal impact on dabrafenib oral bioavailability and elimination, and the risk of a drug-drug interaction is minimal. Combination with trametinib: Co-administration of repeat dosing of dabrafenib 150 mg twice daily and trametinib 2 mg once daily resulted in a 16 % increase in dabrafenib Cmax and a 23 % increase in dabrafenib AUC. A small decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12%, was estimated when trametinib is administered in combination with dabrafenib using a population pharmacokinetic analysis.
Toxicology: Non-Clinical Safety Data: Carcinogenesis/Mutagenesis: Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay.
Reproductive Toxicology: In combined female fertility, early embryonic and embryofetal development studies in rats numbers of ovarian corpora lutea were reduced in pregnant females at 300 mg/kg/day (approximately 3 times human clinical exposure based on AUC), but there were no effects on estrous cycle, mating or fertility. Developmental toxicity including embryo- lethality and ventricular septal defects were seen at 300 mg/kg/day, and delayed skeletal development and reduced foetal body weight at ≥20 mg/kg/day (≥ 0.5 times human clinical exposure based on AUC).
Male fertility studies with dabrafenib have not been conducted. However, in repeat dose studies, testicular degeneration/depletion was seen in rats and dogs (≥ 0.2 times the human clinical exposure based on AUC). Testicular changes in rat and dog were still present following a 4-week recovery period.
Animal Toxicology and/or Pharmacology: Cardiovascular effects, including coronary arterial degeneration/necrosis and/or haemorrhage, cardiac atrioventricular valve hypertrophy/haemorrhage and atrial fibrovascular proliferation were seen in dogs (≥ 2 times clinical exposure based on AUC). Focal arterial perivascular inflammation in various tissues was observed in mice and an increased incidence of hepatic arterial degeneration and spontaneous cardiomyocyte degeneration with inflammation (spontaneous cardiomyopathy) was observed in rats (≥0.5 and 0.6 times clinical exposure for rats and mice respectively). Hepatic effects, including hepatocellular necrosis and inflammation were observed in mice (≥0.6 times clinical exposure). Bronchoalveolar inflammation of the lungs was observed in several dogs at ≥20 mg/kg/day (≥9 times human clinical exposure based on AUC) and was associated with shallow and/or laboured breathing.
Reversible haematological effects have been observed in dogs and rats given dabrafenib. In studies of up to 13 weeks, decreases in reticulocyte counts and/or red cell mass were observed in dogs and rats (≥10 and 1.4 times clinical exposure, respectively).
In juvenile toxicity studies in rats, effects on growth (shorter long bone length), renal toxicity (tubular deposits, increased incidence of cortical cysts and tubular basophilia and reversible increases in urea and/or creatinine concentrations) and testicular toxicity (degeneration and tubular dilation) were observed (≥0.2 times adult human clinical exposure based on AUC).
Dabrafenib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay and in vivo at doses ≥100 mg/kg (>44 times clinical exposure based on Cmax) in an oral phototoxicity study in hairless mice. Although dabrafenib was phototoxic in nonclinical studies, based on clinical safety data, there is low risk for phototoxicity to patients taking dabrafenib.
Dabrafenib in combination with trametinib: Dogs given dabrafenib and trametinib in combination for 4 weeks demonstrated similar toxicities as observed in comparable monotherapy studies. Refer to the full prescribing information for trametinib.
Indications/Uses
Dabrafenib in combination with trarnetinib is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Dabrafenib as a monotherapy is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Dosage/Direction for Use
Confirmation of BRAF V600 mutation using an approved/validated test is required for selection of patients appropriate for dabrafenib monotherapy and in combination with trametinib (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). Dabrafenib should not be used in patients with BRAF wild-type melanoma.
When dabrafenib is used in combination with trametinib, refer to the full trametinib prescribing information: Dosage and administration, for trametinib dosing instructions.
General target population: Adults: The recommended dose of dabrafenib either as monotherapy or in combination with trametinib is 150 mg twice daily (corresponding to a total daily dose of 300 mg).
Dabrafenib should be taken either at least one hour before, or at least two hours after a meal (see Pharmacology under Actions), leaving an interval of approximately 12 hours between doses. Dabrafenib should be taken at similar times every day.
When dabrafenib and trametinib are taken in combination, take the once-daily dose of trametinib at the same time each day with either the morning dose or the evening dose of dabrafenib.
If a dose of dabrafenib is missed, it should not be taken if it is less than 6 hours until the next scheduled dose.
Dose modifications: Monotherapy and in combination with trametinib: The management of adverse reactions may require treatment interruption, dose reduction, or treatment discontinuation (see Tables 5 and 6).
Dose modifications or interruptions are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see Precautions).
Therapy should be interrupted if the patient's temperature is ≥38.5°C. Patients should be evaluated for signs and symptoms of infection (see Precautions).
Recommended dose level reductions and recommendations for dose modifications are provided in Table 5 and Table 6, respectively. Posology adjustments resulting in a dose lower than 50 mg twice daily are not recommended. (See Table 5 and 6.)

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Click on icon to see table/diagram/image

When an individual's adverse reactions are under effective management, dose reescalation following the same dosing steps as de-escalation may be considered. The dabrafenib dose should not exceed 150 mg twice daily.
If treatment related toxicities occur when dabrafenib is used in combination with trametinib then both treatments should be simultaneously dose reduced, interrupted or discontinued with the exceptions shown as follows.
Exceptions where dose modifications are necessary for only dabrafenib: Pyrexia; Uveitis.
Pyrexia Management: Therapy with dabrafenib should be interrupted when dabrafenib is used as monotherapy or in combination with trametinib, if the patient's temperature is ≥ 38.5°C; trametinib should be continued at the same dose. Initiate treatment with antipyretics such as ibuprofen or acetaminophen/paracetamol. Patients should be evaluated for signs and symptoms of infection (see Precautions).
Upon resolution of pyrexia, dabrafenib can be restarted with appropriate anti-pyretic prophylaxis either: At the same dose level; Or, reduce one dose level, if pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure.
The use of oral corticosteroids should be considered in those instances in which antipyretics are insufficient.
Uveitis Management: No dose modifications are required as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, withhold dabrafenib until resolution of ocular inflammation and then restart dabrafenib reduced by one dose level. No dose modification of trametinib is required when taken in combination with dabrafenib.
Exceptions where dose modifications are necessary for only trametinib: Left ventricular ejection fraction (LVEF) reduction; Retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED); Pneumonitis and Interstitial Lung Disease (ILD).
Special Populations: Children and adolescents: The safety and efficacy of dabrafenib have not been established in children and adolescents (<18 years).
Elderly: No dose adjustment is required in patients over 65 years (see Pharmacology: Pharmacokinetics under Actions).
Renal Impairment: No dose adjustment is required for patients with mild or moderate renal impairment. Based on the population pharmacokinetic analysis, mild and moderate renal impairment had no significant effect on dabrafenib oral clearance or on the concentrations of its metabolites (see Pharmacology: Pharmacokinetics under Actions). There are no clinical data in subjects with severe renal impairment and the potential need for dose adjustment cannot be determined. Dabrafenib should be used with caution in patients with severe renal impairment.
Hepatic impairment: No dose adjustment is required for patients with mild hepatic impairment. Based on the population pharmacokinetic analysis, mild hepatic impairment had no significant effect on dabrafenib oral clearance or on the concentrations of its metabolites (see Pharmacology: Pharmacokinetics under Actions). There are no clinical data in subjects with moderate to severe hepatic impairment and the potential need for dose adjustment cannot be determined. Hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites and patients with moderate to severe hepatic impairment may have increased exposure. Dabrafenib should be used with caution in patients with moderate or severe hepatic impairment.
Overdosage
Symptoms and Signs: There is currently very limited experience with overdosage with dabrafenib. The maximum dose of dabrafenib administered during clinical trials was 600 mg (300 mg twice daily).
Treatment: There is no specific antidote for overdosage of dabrafenib. Patients who develop adverse reactions should receive appropriate symptomatic treatment. In case of suspected overdose, dabrafenib should be withheld and supportive care instituted. Further management should be as clinically indicated or as recommended by the national poisons center, where available.
Contraindications
Hypersensitivity to the active substance or to any of the excipients in this product.
Special Precautions
Pyrexia: Pyrexia was reported in clinical trials with dabrafenib monotherapy and in combination with trametinib (see Adverse Reactions). In a Phase III clinical trial, the incidence and severity of pyrexia were increased when dabrafenib was used in combination with trametinib (57% [119/209], 7% Grade 3) as compared to dabrafenib monotherapy (33% [69/211], 2% Grade 3). In patients who received the combination dose of dabrafenib 150 mg twice daily and trametinib 2 mg once daily and developed pyrexia, approximately half of the first occurrences of pyrexia happened within the first month of therapy. About one-third of the patients receiving combination therapy who experienced pyrexia had 3 or more events. Pyrexia may be accompanied by severe rigors, dehydration and hypotension which in some cases can lead to acute renal insufficiency. Monitor serum creatinine and other evidence of renal function during and following severe events of pyrexia.
Serious non-infectious febrile events have been observed. These events responded well to dose interruption and/or dose reduction and supportive care in clinical trials.
For management of pyrexia, see Dose Modification Guidelines under Dosage & Administration.
Cutaneous Squamous Cell Carcinoma (cuSCC): Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with dabrafenib as monotherapy and in combination with trametinib (see Adverse Reactions). In a Phase III study, 10% (22/211) of patients receiving dabrafenib monotherapy developed cuSCC, with a median time to onset of the first occurrence of approximately 8 weeks. In patients who received dabrafenib in combination with trametinib, 3% (6/209) of patients developed cuSCC and events occurred later, with the median time to onset of the first occurrence of 20 to 32 weeks. More than 90 % of patients on dabrafenib who developed cuSCC continued on treatment without dose modification.
Skin examination should be performed prior to initiation of dabrafenib and during treatment with dabrafenib, every 2 months throughout therapy. Monitoring should continue every 2 to 3 months for 6 months following discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy.
Cases of cuSCC should be managed by dermatological excision and dabrafenib treatment should be continued without any dose adjustment. Patients should be instructed to immediately inform their physician if new lesions develop.
New primary melanoma: New primary melanomas have been reported in patients treated with dabrafenib. In clinical trials these were identified within the first 5 months of therapy and did not require treatment modification other than excision. Monitoring for skin lesions should occur as described for cuSCC.
Non-cutaneous secondary/recurrent malignancy: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signalling in BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors, which may lead to increased risk of non-cutaneous malignancies in patients treated with dabrafenib. Cases of RAS-driven malignancies have been seen with BRAF inhibitors. Patients should be monitored as clinically appropriate. Consider the benefits and risks before continuing treatment, with dabrafenib in patients with a non-cutaneous malignancy that has a RAS mutation. No dose modification of trametinib is required when taken in combination with dabrafenib.
Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy.
Pancreatitis: Pancreatitis has been reported in < 1 % of dabrafenib-treated subjects in clinical trials. One of the events occurred on the first day of dosing and recurred following re-challenge at a reduced dose. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting dabrafenib after an episode of pancreatitis.
Uveitis: Treatment with dabrafenib has been associated with the development of uveitis (including iritis). Monitor patients for visual signs and symptoms (such as, change in vision, photophobia and eye pain) during therapy (see Dosage & Administration).
Dabrafenib in combination with trametinib: Haemorrhage: Haemorrhagic events, including major haemorrhagic events have occurred in patients taking trametinib as monotherapy and in combination with dabrafenib (see Adverse Reactions). Three of 209 subjects (1%) receiving dabrafenib in combination with trametinib in a phase III trial had fatal intracranial haemorrhagic events.
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of dabrafenib on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of dabrafenib. The clinical status of the patient and the adverse event profile of dabrafenib should be borne in mind when considering the patient's ability to perform tasks that require judgment, motor and cognitive skills.
Fertility: There are no data in humans. Adverse effects on male reproductive organs have been seen in animals (see Pharmacology: Toxicology: Non-clinical Safety Data under Actions). Male patients should be informed of the potential risk for impaired spermatogenesis, which may be irreversible.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no adequate and well-controlled studies of dabrafenib in pregnant women. Animal studies with dabrafenib have shown reproductive toxicity (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions). Dabrafenib should not be administered to pregnant women or nursing mothers. Women of childbearing potential should use effective methods of contraception during therapy and for 4 weeks following discontinuation of dabrafenib and at least 4 months following the last dose of trametinib. Dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used (see Interactions). If dabrafenib is used during pregnancy, or if the patient becomes pregnant while taking dabrafenib the patient should be informed of the potential hazard to the foetus.
Use in Lactation: It is not known whether dabrafenib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the suckling child cannot be excluded. A decision should be made whether to discontinue breastfeeding or discontinue dabrafenib, taking into account the importance of the dabrafenib to the mother.
Adverse Reactions
Clinical Trial Data: Dabrafenib monotherapy: Safety data for dabrafenib monotherapy was integrated from five clinical monotherapy studies and included 578 patients with melanoma. Approximately 30% of patients received treatment with dabrafenib for more than 6 months.
In the integrated dabrafenib safety population, the most common (≥15%) adverse reactions were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, skin papilloma, alopecia, rash and vomiting. Adverse reactions are listed below by MedDRA body system organ class.
Adverse drug reactions are ranked by frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

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Dabrafenib and trametinib combination therapy: The safety of dabrafenib and trametinib combination therapy has been evaluated in 2 randomized Phase III studies of patients with BRAF V600 mutant unresectable or metastatic melanoma treated with dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). The most common adverse reactions (≥20%) for dabrafenib and trametinib combination therapy include pyrexia, fatigue, nausea, headache, chills, diarrhoea, rash, arthralgia, hypertension, vomiting and cough.
Table 8 lists adverse reactions when trametinib was used in combination with dabrafenib from the randomized double-blind Phase III study MEK115306 (N=209), and integrated safety data from MEK115306 (N=209) and from the randomized open-label Phase III study MEK 116513 (N=350).
The following convention has been utilised for the classification of frequency very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100). (See Table 8.)

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Click on icon to see table/diagram/image

Postmarketing Data with dabrafenib: The following adverse reactions have been reported during post-approval use of dabrafenib. These include spontaneous case reports as well as serious adverse events from registries, investigator sponsored studies, clinical pharmacology studies and exploratory studies in unapproved indications.
Skin and subcutaneous tissue disorder: Rare: Panniculitis.
Postmarketing Data with dabrafenib and trametinib in combination: Cardiac disorders: Common: Bradycardia*, heart rate decreased*.
* These terms are based mainly upon heart rate data collected in clinical trials for dabrafenib in combination with trametinib and not only upon case reports of serious adverse events.
Drug Interactions
Effect of other drugs on dabrafenib: Based on preclinical in vitro studies, dabrafenib was shown to be primarily metabolized by CYP2C8 and CYP3A4. Co-administration of ketoconazole (CYP3A4 inhibitor) or gemfibrozil (CYP2C8 inhibitor) increased the AUC of dabrafenib by 71 % and 47 % respectively (see Pharmacology: Pharmacokinetics under Actions). Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are likely to increase or decrease, respectively, dabrafenib concentrations. Alternative agents should be considered during administration with dabrafenib when possible. Use caution if strong inhibitors (e.g. ketoconazole, nefazodone, clarithromycin, ritonavir, gemfibrozil) or inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of CYP2C8 or CYP3A4 are coadministered with dabrafenib.
Drugs that affect gastric pH: Medicinal products that alter the pH of the upper GI tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib. When dabrafenib is coadministered with a proton pump inhibitor, H2 receptor antagonist, or antacid, systemic exposure of dabrafenib may be decreased and the effect on efficacy of dabrafenib is unknown.
Effect of dabrafenib on other drugs: Dabrafenib induces CYP3A4- and CYP2C9-mediated metabolism and may induce other enzymes including CYP2B6, CYP2C8, CYP2C19 and UDP glucuronosyltransferases (UGT) and may induce transporters (e.g. Pglycoprotein (P-gp)). AUC of midazolam (CYP3A4 substrate) and of S-warfarin (CYP2C9 substrate) was decreased with co-administration of dabrafenib (see Pharmacology: Pharmacokinetics under Actions). Co-administration of dabrafenib and medicinal products which are affected by the induction of these enzymes such as hormonal contraceptives, warfarin or dexamethasone may result in decreased concentrations and loss of efficacy (see Use in Pregnancy & Lactation). If co-administration of these medications is necessary, monitor subjects for loss of efficacy or consider substitutions of these medicinal products.
Combination with trametinib: Co-administration of repeat dosing dabrafenib 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically meaningful changes in dabrafenib or trametinib Cmax and AUC (see Pharmacology under Actions).
Caution For Usage
There are no special requirements for use or handling of this product.
Incompatibilities: Not applicable.
Storage
Do not store above 30°C. Protect from light and moisture. Store in the original container. Do not remove the desiccant.
ATC Classification
L01EC02 - dabrafenib ; Belongs to the class of B-Raf serine-threonine kinase (BRAF) inhibitors. Used in the treatment of cancer.
Presentation/Packing
Cap 50 mg (opaque, size 2 composed of a dark red body and dark red cap containing a white to slightly coloured solid. Capsule shells imprinted with GS TEW and 50 mg) x 28's. 75 mg (opaque, size 1 composed of a dark pink body and dark pink cap containing a white to slightly coloured solid. Capsule shells imprinted with GS LHP and 75 mg) x 28's.
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