Tafinlar: Indications, Dosage, Precautions, Adverse Effects
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Tafinlar - Product Information

Manufacture: GlaxoSmithKline
Country: Australia
Condition: Skin Cancer, Melanoma (Melanoma)
Class: Multikinase inhibitors
Form: Capsules
Ingredients: dabrafenib (as mesilate), cellulose - microcrystalline, magnesium stearate, silica - colloidal anhydrous, iron oxide red, titanium dioxide, hypromellose, iron oxide black, shellac, butan-1-ol, isopropyl alcohol, propylene glycol, ammonium hydroxide

Name of the Medicine

Dabrafenib mesilate


It has the molecular formula C23H20F3N5O2S2. CH4O3S and a molecular weight of 615.68. CAS Registry Number: 1195768-06-9

Description

Dabrafenib mesilate is a nitrogen and sulphur containing heterocycle possessing an aromatic sulphonamide.

The chemical name for dabrafenib mesilate is N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol -4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulphonamide, methanesulphonate salt.

Dabrafenib mesilate is a white to slightly coloured solid. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media. The pKa of the sulfonamide moiety is 6.6, the pKa of the pyrimidine moiety is 2.2 and the pKa of the thiazole moiety is -1.5. The partition coefficient (log P) is 2.9.

The TAFINLAR Capsules contain 50 or 75 mg of dabrafenib (as mesilate) as the active ingredient. The hard capsules also contain cellulose - microcrystalline, magnesium stearate, silica -colloidal anhydrous, iron oxide red, titanium dioxide, hypromellose, iron oxide black, shellac, butan-1-ol, isopropyl alcohol, propylene glycol, ammonium hydroxide

Pharmacology

Monotherapy:

Dabrafenib is an 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. Dabrafenib also inhibits a small number of other kinases, including wild-type BRAF and CRAF with IC50 values of 3.2 and 5.0nM, respectively. Mutations in BRAF 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 these cancers. A number of rare mutations also occur including V600D, V600G and V600R. Clinical inhibition of the MAPK pathway signalling depends on cellular and genotypic context (See PRECAUTIONS: Non-cutaneous malignancy).

Dabrafenib inhibits BRAFV600 mutant melanoma cell growth in vitro and in vivo.

Combination with trametinib:

Trametinib is a reversible allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are components of the extracellular signal-related kinase (ERK) pathway. Dabrafenib and trametinib inhibit two critical kinases in this pathway, BRAF and MEK, and the combination provides concomitant inhibition of the pathway. 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 BRAFV600 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.

Determination of BRAF mutation status

In the Phase II and III clinical trials, screening for eligibility required central testing for BRAF V600 mutation using a BRAF mutation assay conducted on the most recent tumour sample available. Primary tumour or tumour from a metastatic site was tested with an investigational use only assay (IUO) developed by Response Genetics Inc. (RGI). The RGI IUO is an allele-specific polymerase chain reaction (PCR) assay performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue. The assay was specifically designed to differentiate between the V600E and V600K mutations. Only subjects with BRAFV600E or V600K mutation positive tumours were eligible for study participation.

Pharmacokinetics

The pharmacokinetics of dabrafenib were determined in patients with BRAF mutation-positive metastatic melanoma after single dose and after repeat dosing at 150 mg twice daily with dosing approximately 12 hours apart.

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 75 and 150 mg following single-dose administration, but the increase was slightly 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 averaged 0.73. Following administration of 150 mg twice daily, geometric mean Cmax, AUC(0 -τ) and predose concentration (Cτ) at steady state were 1478 ng/ml, 4341 ng*hr/ml 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 microdose 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 metabolised by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hours 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.

Excretion

Terminal half-life following IV microdose is 2.6 hours. Dabrafenib terminal half-life is8 hours due to a prolonged terminal phase after oral administration. IV plasma clearance after single dose is 12 L/hr. Following repeat oral dose administration, the oral clearance (CL/F) is 35 L/hr.

Faecal excretion is the major route of elimination after oral dose, accounting for 71% of a radioactive dose while urinary excretion accounted for 23% of radioactivity as metabolites.

Special Patient Populations

Hepatic Impairment: A population pharmacokinetic analysis indicates that mildly elevated bilirubin and/or AST levels (based on National Cancer Institute [NCI] classification) do not significantly affect dabrafenib oral clearance. In addition, mild hepatic impairment as defined by bilirubin and AST did not have a significant effect on dabrafenib metabolite plasma concentrations. No data are available in patients with moderate to severe hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, administration of dabrafenib should be undertaken with caution in patients with moderate to severe hepatic impairment (see DOSAGE AND ADMINISTRATION).

Renal Impairment: A population pharmacokinetic analysis suggests that mild renal impairment does not affect oral clearance of dabrafenib. Although data in moderate renal impairment are limited these data may indicate no clinically relevant effect No data are available in subjects with severe renal impairment (see DOSAGE AND 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.

Clinical Trials

Monotherapy:

The efficacy of TAFINLAR in the treatment of adult patients with BRAFV600 mutation positive unresectable or metastatic melanoma has been evaluated in 3 studies (BRF113683 [BREAK-3], BRF113710 [BREAK-2] and BRF113929 [BREAK-MB]). Included in these studies were in total 402 subjects with BRAF V600E and 49 subjects with BRAF V600K mutation. Patients with evidence of active CNS disease (e.g. radiographically unstable or with symptomatic lesions) and those with disease progression in the brain in the last 3 months were excluded from the pivotal Phase III study.

Previously untreated patients (Results from the phase III study BREAK-3)

The efficacy and safety of dabrafenib were evaluated in a Phase III randomised, open-label study [BREAK-3] comparing dabrafenib to dacarbazine (DTIC) in previously untreated patients with BRAFV600E 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 randomised 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) per investigator assessment for patients with BRAFV600E mutation positive metastatic melanoma. Patients on the DTIC arm were allowed to cross over and 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.

At the pre-specified analysis with a 19 December 2011 data cut, a significant improvement in the primary endpoint of PFS (HR = 0.30; 95% CI 0.18, 0.51; p< 0.0001) was achieved. PFS from the primary analysis is shown in Figure 1. Efficacy results from a post-hoc analysis with 6-months additional follow-up are summarised in Table 1. Overall survival data from a further post-hoc analysis based on an 18 December 2012 data cut is provided in Table 2 and shown in Figure 2.

Table 1: Efficacy in previously untreated patients (BREAK-3 study, 25 June 2012)

Intention-to-Treat Population
Endpoints/ Assessment TAFINLAR N=187 DTIC N=63
Progression-free survival
Median, months (95% CI) 6.9 (5.2, 9.0) 2.7 (1.5, 3.2)
HR (95% CI) 0.37 (0.24, 0.58)
P<0.0001
Overall responsea
% (95% CI)b 59 (51.4, 66.0) 24 (21.4, 36.2)
P<0.0001
Duration of response
Median, months (95% CI) N=110 8.0 (6.6, 11.5) N=15 7.6 (5.0, 9.7)

Abbreviations: CI: confidence interval; DTIC: dacarbazine; HR: hazard ratio; NR-not reached; a. Defined as complete response+partial response; b. Confirmed response.

As of 25 June 2012, thirty-five subjects (55.6%) of the 63 randomised to DTIC crossed over to TAFINLAR. Median PFS after cross-over was 4.4 months.

Figure 1: Progression-Free Survival - previously untreated patients (BREAK 3 ITT population, 19 December 2011)


Table 2: Survival data from a post-hoc analysis (18 December 2012).

Treatment Number of deaths (%) 12-month OS rate Hazard Ratio (95% CI)
DTIC 28 (44%) 63% 0.76 (0.48, 1.21) (a)
dabrafenib 78 (42%) 70%

Patients were not censored at the time of cross-over.

Figure 2: Kaplan-Meier curves of overall survival (BREAK-3) (18 December 2012)


Patients with brain metastases (Results from the phase II study BREAK-MB)

BREAK-MB was a multi-centre, 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 primary endpoint of the study was overall intracranial response rate (OIRR), which is a measure of response (CR+PR) of intracranial lesions using modified RECIST criteria as assessed by investigators. The results are summarised in Table 3. Of note, the benefit risk, in terms of intracranial response, relative to surgery or stereotactic radio-surgery has not been studied directly however evidence from cohort B below suggests that prior local treatment does not preclude subsequent benefit from BRAF inhibition.

Table 3: Efficacy Data in Patients with Brain Metastases (BREAK-MB study)

All Treated Subjects Population
BRAFV600E (Primary) BRAFV600K
Endpoints/ Assessment Cohort A N=74 Cohort B N=65 Cohort A N=15 Cohort B N=18
Overall intracranial response rate,% (95% CI) a
39% (28.0, 51.2) P<0.001 31% (19.9, 43.4) P<0.001b 7% (0.2, 31.9) 22% (6.4, 47.6)
Duration of intracranial response, median months (95% CI)
N=29 4.6 (2.8, NR) N=20 6.5 (4.6, 6.5) N=1 2.9 (NR, NR) N=4 3.8 (NR, NR)
Overall response,% (95% CI) a
38% (26.8, 49.9) 31% (19.9, 43.4) 0 (0, 21.8) 28% (9.7, 53.5)
Duration of response, median months (95% CI)
N=28 5.1 (3.7, NR) N=20 4.6 (4.6, 6.5) NA N=5 3.1 (2.8, NR)
Progression-free survival, median months (95% CI)
3.7 (3.6, 5.0) 3.8 (3.6, 5.5) 1.9 (0.7, 3.7) 3.6 (1.8, 5.2)
Overall survival, median months (95% CI)
7.6 (5.9, NR) 7.2 (5.9, NR) 3.7 (1.6, 5.2) 5.0 (3.5, NR)

Abbreviations: CI: confidence interval; NR: not reached; NA: not applicable a - Confirmed response.b –This study was designed to support or reject the null hypothesis of OIRR ≤10% (based on historical results) in favour of the alternative hypothesis of OIRR ≥ 30% in BRAFV600E positive subjects.

Patients who were previously untreated or failed at least one prior systemic therapy (Results from the phase II study BREAK-2)

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 BRAFV600E or V600K mutation-positive melanoma. Subjects were treatment-naïve (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% CI: 3.7, 6.8). There were no complete responses in the V600K patient population. Although the evidence for the efficacy of dabrafenib is limited by the low number of patients, median OS appeared consistent with data in patients with BRAF V600E positive tumours.

Combination with trametinib

In an open- label study (BRF113220), the safety, pharmacokinetics, pharmacodynamics and clinical activity of TAFINLAR and trametinib in combination were evaluated in patients with BRAF V600 mutation-positive melanoma. This study had four parts, A-D:

  • Part A: drug / drug interaction study (n=8),
  • Part B: dose escalation and expansion study (n=135),
  • Part C: see description below
  • Part D: pharmacokinetic and safety evaluation of Hydroxy Propyl Methyl Cellulose (HPMC) TAFINLAR capsules (n=110).

The determination of BRAF mutation positive status was required and was established by institutional laboratory for all patients enrolled in Parts A-D.

Part C was an open-label randomised three- arm phase II study to assess safety and efficacy of TAFINLAR at 150 mg given twice daily in combination with two different doses of trametinib (1 mg once daily and 2 mg once daily) relative to TAFINLAR alone (150 mg twice daily) in 162 patients. The primary efficacy endpoints were PFS, ORR, and duration of response. Patients on the TAFINLAR monotherapy arm were permitted to cross-over to the full-dose combination arm (150 mg TAFINLAR plus 2 mg trametinib) upon progression. A total of 43 patients (81%) in the TAFINLAR monotherapy arm with disease progression crossed over to receive TAFINLAR 150 mg and trametinib 2 mg combination.

Baseline characteristics were balanced between treatment groups. The majority of patients were male (57%) and Caucasian (>99%) . The median age was 53 years, most patients (66%) had ECOG performance status of 0, and 13 patients (8%) had history of brain metastases in all treatment arms. Most patients (85%) in all treatment arms had BRAF V600E mutation and 15% of patients had BRAF V600K.

The results of efficacy endpoints for part C based on investigator assessment are presented in Table 2; with Kaplan-Meier curves of investigator-assessed progression-free survival presented in Figure 2.

Table 4. 2 Investigator-Assessed Efficacy Endpoints (ITT population)

Endpoint Dabrafenib 150 mg BID Monotherapy (N = 54) Dabrafenib 150 mg BID plus trametinib 1mg QD Combination (N = 54) Dabrafenib 150 mg BID plus trametinib 2mg QD Combination (N = 54)
Progression-Free Survival
Survival Median PFS (months) (95% CI) 5.8 (4.6, 7.4) 9.2 (6.4, 11.0) 9.4 (8.6, 16.7)
Hazard Ratio (95% CI) P value 0.56 (0.37, 0.87) 0.0057 0.39 (0.25, 0.62) <0.0001
Overall Response Rate (%) 54 50 76
(95% CI) (39.6, 67.4) (36.1, 63.9) (62.4, 86.5)
P value 0.7730 0.0264
CR 4 6 9
PR 50 44 67
Median Duration of Response (months) 5.6 9.5 10.5

BID = twice daily; QD = once daily; PFS = Progression-free survival; CI = confidence interval; CR = Complete response; PR = Partial response

Figure 3. Investigator-Assessed Progression-Free Survival (ITT population)


The investigator-assessed ORR, Duration of Response, and PFS were consistent in the subgroup of patients with BRAF V600E and BRAF V600K mutation positive melanoma receiving 150 mg TAFINLAR plus 2 mg trametinib combination.

A retrospective blinded independent committee review (BICR) was conducted and had the following results: 61% ORR (95 CI: 46.9%, 74.1%; P = 0.1486) for the 150 mg TAFINLAR plus 2 mg trametinib combination, 39% (95% CI: 25.9, 53.1; P = 0.5008) for the 150 mg TAFINLAR plus 1 mg trametinib combination, and 46% (95 % CI: 32.6%, 60.4%) for the TAFINLAR monotherapy group. The median PFS was 9.2 months (95% CI: 7.6, NR; P = 0.0121) and 8.3 months (95% CI: 5.6, 11.3; P = 0.1721) for patients treated with 150 mg TAFINLAR plus 2 mg trametinib combination and 150 mg TAFINLAR plus 1 mg trametinib combination arms respectively, and 7.3 months (95% CI: 5.5, 9.4) for patients treated with TAFINLAR monotherapy.

Prior BRAF inhibitor therapy

Part B of this open-label study included a cohort of 26 patients that had progressed on a BRAF inhibitor. The combination of 150 mg TAFINLAR with 2 mg trametinib demonstrated limited clinical activity in patients who had progressed on a BRAF inhibitor. The Investigator-assessed ORR was 15% (95% CI: 4.4, 34.9) and the median PFS was 3.6 months (95% CI: 1.9, 5.2). Similar results were seen in the 43 patients who crossed over from TAFINLAR monotherapy to the combination of 150 mg TAFINLAR plus 2 mg trametinib in Part C of this study. In these patients a 9 % (95% CI: 2.6, 22.1) ORR was observed with a median PFS of 3.6 months (95% CI: 1.8, 3.9).

Indications

TAFINLAR in combination with trametinib is indicated for the treatment of patients with BRAFV600 mutation positive unresectable Stage III or metastatic (Stage IV) melanoma.

TAFINLAR as monotherapy is indicated for the treatment of patients with BRAF V600 mutation positive unresectable Stage III or metastatic (Stage IV) melanoma.

Contraindications

TAFINLAR is contraindicated in patients with hypersensitivity to the active substance dabrafenib mesilate or any of the excipients (see DESCRIPTION).

Precautions

Before taking TAFINLAR, patients must have BRAF V600 mutation- positive tumour status confirmed by a validated test. The efficacy and safety of TAFINLAR have not been established in patients with wild-type BRAF melanoma (see CLINICAL TRIALS). Further around 40% of BRAF wild-type metastatic melanomas have oncogenic NRAS mutations which may result in paradoxical activation of MAP- kinase signalling in the presence of BRAF inhibitors such as TAFINLAR and may lead to accelerated tumour growth. TAFINLAR should not be used in patients with BRAF wild-type melanoma.

Pyrexia and serious non-infectious febrile events

Fever has been reported in clinical trials with TAFINLAR monotherapy and in combination with trametinib (see Adverse Reactions). The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with trametinib. In patients who received the combination dose of TAFINLAR 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 half of the patients who experienced pyrexia had a single event.

In 1% of patients in clinical trials, serious non-infectious febrile events were identified defined as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency (See RENAL FAILURE PRECAUTION and ADVERSE EFFECTS). The onset of these serious non-infectious febrile events was typically within the first month of therapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care.

Therapy with TAFINLAR should be interrupted if the patient’s temperature is ≥ 38.5ºC. Patients should be evaluated for signs and symptoms of infection. TAFINLAR can be restarted once the fever resolves with appropriate prophylaxis using non-steroidal anti-inflammatory medicinal products or paracetamol. If fever is associated with other severe signs or symptoms, TAFINLAR should be restarted at a reduced dose once fever resolves and as clinically appropriate.

For management of pyrexia see DOSAGE AND 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 TAFINLAR as monotherapy and in combination with trametinib (see ADVERSE EFFECTS). With TAFINLAR monotherapy, approximately 70% of events occurred within the first 12 weeks of treatment with a median time to onset of 8 weeks. In patients who received the combination dose of TAFINLAR in combination with trametinib, events occurred later with the median time to onset of 22 weeks. More than 90 % of patients on TAFINLAR monotherapy and all patients on combination therapy who developed cuSCC continued on treatment without dose modification.

Skin examination for cuSCC should be performed prior to initiation of TAFINLAR and every month throughout treatment with TAFINLAR and for up to 6 months after treatment. Monitoring should continue for 6 months following discontinuation of TAFINLAR or until initiation of another anti-neoplastic therapy.

Cases of cuSCC should be managed by dermatological excision and TAFINLAR 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 clinical trials. These were identified within the first 5 months of therapy, were managed with excision and did not require treatment modification. Monitoring for skin lesions should occur as described for cuSCC.

Non-cutaneous 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. This may lead to increased risk of non-cutaneous malignancies with TAFINLAR exposure, when RAS mutations are present. Cases of RAS-associated malignancies have been reported, both with another BRAF inhibitor (Chronic myelomonocytic leukemia and non-cutaneous SCC of the head and neck) and with TAFINLAR when administered in combination with the MEK inhibitor trametinib (colorectal cancer, pancreatic cancer). Patients should be monitored as clinically appropriate.

Following discontinuation of TAFINLAR, monitoring for non-cutaneous malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy.

Uveitis

Ophthalmologic reactions, including uveitis and iritis have been reported. Patients should be routinely monitored for visual signs and symptoms (such as, change in vision, photophobia and eye pain) during therapy.

Pancreatitis

Pancreatitis has been reported in < 1% of TAFINLAR-treated subjects. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting TAFINLAR after an episode of pancreatitis.

Hyperglycaemia

Hyperglycaemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycaemic 68 agent therapy can occur with TAFINLAR. In the pivotal study, five of 12 patients with a history of diabetes required more intensive hypoglycaemic therapy while taking TAFINLAR. The incidence of Grade 3 hyperglycaemia based on laboratory values was 6% (12/187) in patients treated with TAFINLAR compared to none of the dacarbazine- treated patients. Monitor serum glucose levels as clinically appropriate during treatment with TAFINLAR in patients with pre-existing diabetes or hyperglycaemia. Advise patients to report symptoms of severe hyperglycaemia such as excessive thirst or any increase in the volume or frequency of urination.

Renal failure

Renal failure has been identified in <1% of patients treated with TAFINLAR as monotherapy. Renal failure was reported in 7% of patients who received the combination dose of TAFINLAR150 mg twice daily and trametinib 2 mg once daily, a higher frequency than observed in TAFINLAR monotherapy patients (<1%). Observed cases were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has been reported. Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, TAFINLAR may need to be interrupted as clinically appropriate. TAFINLAR has not been studied in patients with renal insufficiency (defined as creatinine >1.5 x ULN) therefore caution should be used in this setting.

Dabrafenib in combination with trametinib

See the full Mekinist Product Information for trametinib Precautions.

Effects on Fertility

There are no data in humans. Dabrafenib may impair male and female fertility as adverse effects on male and female reproductive organs have been seen in animals. Male patients should be informed of the potential risk for impaired spermatogenesis, which may be irreversible.

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.

Male fertility studies with dabrafenib have not been conducted. However, in repeat dose studies, testicular degeneration/depletion or spermatid retention was seen in mice, rats and dogs (≥ 0.2 times the human clinical exposure based on AUC). Testicular changes in rats and dogs were still present following a 4-week recovery period.

Use in Pregnancy (Category D)

There are no adequate and well-controlled studies of TAFINLAR in pregnant women. Animal studies have shown embryofetal development toxicity, including teratogenic effects. In adult female rats dosed with dabrafenib before mating and during gestation embryofetal toxicities included embryo-lethality and fetal ventricular septal defects at 300 mg/kg/day, and delayed skeletal development and reduced fetal body weight at ≥ 20 mg/kg/day (≥ 0.5 times human clinical exposure based on AUC). TAFINLAR should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus.

Women of childbearing potential should use effective methods of contraception during therapy and for 4 weeks following discontinuation of TAFINLAR. TAFINLAR may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used (see Interactions).

If the patient becomes pregnant while taking TAFINLAR, the patient should be informed of the potential hazard to the fetus.

Use in Lactation

It is not known whether TAFINLAR 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 TAFINLAR, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Paediatric Usev

The safety and efficacy of TAFINLAR has not been yet established in children and adolescents (< 18 years). 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), testicular toxicity (degeneration and tubular dilation) and earlier vaginal opening (with no associated effects on ovarian weights or morphologic changes in female reproductive tissues) were observed.

Use in the Elderly

No initial dose adjustment is required in patients over 65 years (see DOSAGE AND ADMINISTRATION and PHARMACOKINETICS).

For clinical trials of TAFINLAR monotherapy, compared with younger subjects (< 65), more subjects over 65 years old had adverse reactions that led to study drug dose reductions (22% versus 12%) or interruptions (39% versus 27%) . In addition, older patients experienced more serious adverse reactions compared to younger patients (41% versus 22%). No overall differences in efficacy were observed between these subjects and younger subjects.

Across clinical trials of TAFINLAR administered in combination with trametinib (n = 202), adverse events resulting in dose interruption were reported for 71% of those aged ≥65 years as compared to 60% of those <65 years, while adverse events resulting in dose reduction occurred in 64% of those aged ≥65 years as compared to 44% of those <65 years.

Genotoxicity

Dabrafenib was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay.

Carcinogenicity

Carcinogenicity studies with dabrafenib have not been conducted. An increase in cutaneous malignancies has been observed with BRAF inhibitors with preliminary evidence suggesting this occurs in patients harbouring other MAPK pathway mutations, including RAS, in skin (see PRECAUTIONS for cuSCC, new primary melanoma and non-cutaneous malignancy ).

Ability to perform tasks that require judgement, motor or cognitive skills

There have been no studies to investigate the effect of TAFINLAR on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of TAFINLAR. The clinical status of the patient and the adverse event profile of TAFINLAR should be borne in mind when considering the patient’s ability to perform tasks that require judgment, motor and cognitive skills.

Interactions with Other Medicines

Effect of Other Medicines on TAFINLAR

Dabrafenib is a substrate of CYP2C8 and CYP3A4, while hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Co-administration of ketoconazole (CYP3A4 inhibitor) and gemfibrozil (CYP2C8 inhibitor) increased the AUC of dabrafenib by 71 and 47%, respectively. Pharmacokinetic data showed increases in hydroxy- and desmethyl-dabrafenib AUC with ketoconazole (increases of 82 and 68% respectively while a decrease in AUC was noted for carboxy-dabrafenib (decrease of 16%). No clinically relevant changes were noted in the AUC of the metabolites during co-administration with gemfibrozil. 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, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir, gemfibrozil) are coadministered with dabrafenib. Avoid coadministration of TAFINLAR with potent inducers of CYP2C8 or CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s wort (Hypericum perforatum).

Dabrafenib solubility is pH-dependent with decreased solubility at higher pH. Medicinal products such as proton pump inhibitors that inhibit gastric acid secretion to elevate gastric pH may decrease the solubility of dabrafenib and reduce its bioavailability. No clinical study has been conducted to evaluate the effect of pH on dabrafenib pharmacokinetics. Due to the theoretical risk that pH-elevating agents may decrease oral bioavailability and exposure to dabrafenib, these medicinal products that increase gastric pH should be used with caution when administered with dabrafenib.

Effect of TAFINLAR on Other Medicines

Dabrafenib induces CYP3A4- and CYP2C9-mediated metabolism and may induce other enzymes including CYP2B6, CYP2C8, CYP2C19, UDP glucuronosyl transferase (UGT) and transporters. The single dose AUC of midazolam (CYP3A4 substrate) and S-warfarin (CYP2C9 substrate) was decreased by 74 and 37%, respectively with co-administration of dabrafenib. Co-administration of dabrafenib and medicinal products which are affected by the induction of these enzymes or transporters such as hormonal contraceptives (see PRECAUTIONS -PREGNANCY AND LACTATION), dexamethasone, antiretroviral agents, or immunosuppressants may result in decreased concentrations and loss of efficacy. Concomitant use of dabrafenib with these medicinal products should generally be avoided if monitoring for efficacy and dose adjustment is not possible.

Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib. Transient inhibition of CYP3A4 may be observed during the first few days of treatment. Upon discontinuation of dabrafenib, concentrations of sensitive CYP3A4 substrates may increase and subjects should be monitored for toxicity and dosage of these agents may need to be adjusted.

Exercise caution and consider additional INR (International Normalized Ratio) monitoring when dabrafenib is used concomitantly with warfarin.

Effects of dabrafenib on substance transport systems

Dabrafenib is an in vitro inhibitor of of human organic anion transporting polypeptide (OATP) 1B1 (OATP1B1) and OATP1B3 and clinical relevance cannot be excluded. Therefore caution is recommended at co-administration of dabrafenib and OATB1B1 or OATP1B3 substrates such as statins.

Although dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib and desmethyl-dabrafenib, were inhibitors of human 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 also 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.

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.

Adverse Effects

Clinical Trial Data TAFINLAR Monotherapy

Safety data were 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. The following convention has been utilised for the classification of frequency:

Very common: ≥ 1 in 10

Common: ≥ 1 in 100 to < 1 in 10

Uncommon: ≥ 1 in 1,000 to < 1 in 100

Neoplasms benign and malignant (including cysts and polyps)

Very common: Papilloma

Common: Acrochordon (skin tags), cutaneous squamous cell carcinoma (SCC) including SCC of the skin, SCC in situ (Bowen’s disease) and keratoacanthoma, seborrhoeic keratosis, basal cell carcinoma

Uncommon: New primary melanoma

Immune System Disorders

Uncommon: Hypersensitivity, panniculitis

Infections and infestations

Common: Nasopharyngitis

Metabolism and nutrition disorders

Very common: Decreased appetite

Common: Hypophosphataemia, hyperglycaemia

Nervous system disorders

Very common: Headache

Eye disorders

Uncommon: Uveitis

Respiratory, thoracic and mediastinal disorders

Very common: Cough

Gastrointestinal disorders

Very common: Nausea, vomiting, diarrhoea

Common: Constipation

Uncommon: Pancreatitis

Skin and subcutaneous tissue disorders

Very common: Skin effects (rash, hyperkeratosis), alopecia, palmar-plantarerythrodysaesthesia syndrome

Common: Skin effects (actinic keratosis, skin lesion, dry skin, erythema, pruritus)

Musculoskeletal and connective tissue disorders

Very common: Arthralgia, myalgia, pain in extremity

Renal disorders

Uncommon: Renal failure, acute renal failure, nephritis

General disorders and administration site conditions

Very common: Asthenia, chills, fatigue, pyrexia

Common: Influenza-like illness

Investigations

Common: LVEF decrease

Uncommon: QT prolongation

Table 5 lists the very common (≥10% of subjects) adverse events reported in the Phase III randomised, open-label study [BREAK-3].

Table 5: Adverse events reported in at Least 10% of subjects receiving TAFINLAR or Placebo in BREAK-3 (Safety Population) by maximum grade.

Preferred term Number (%) of Subjects
Dabrafenib (N=187) DTIC (N=59)
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Any event 185 (99) 55 (29) 7 (4) 54 (92) 16 (27) 8 (14)
Hyperkeratosis 69 (37) 1 (<1) 1 (<1) 0 0 0
Headache 59 (32) 0 0 5 (8) 0 0
Pyrexia 52 (28) 6 (3) 0 6 (10) 0 0
Arthralgia 51 (27) 2 (1) 0 1 (2) 0 0
Skin papilloma 45 (24) 0 0 1 (2) 0 0
Alopecia 41 (22) 0 0 1 (2) 0 0
PPE syndrome 37 (20) 4 (2) 0 1 (2) 0 0
Fatigue 36 (19) 2 (1) 0 14 (24) 0 0
Nausea 35 (19) 0 1 (<1) 30 (51) 0 0
Asthenia 33 (18) 1 (<1) 0 9 (15) 1 (2) 0
Rash 31 (17) 0 0 0 0 0
Vomiting 23 (12) 1 (<1) 1 (<1) 15 (25) 0 0
Cough 23 (12) 0 0 3 (5) 0 0
Back pain 22 (12) 5 (3) 0 4 (7) 0 0
Constipation 21 (11) 2 (1) 1 (<1) 8 (14) 0 0
Diarrhoea 20 (11) 1 (<1) 0 7 (12) 0 0
Myalgia 20 (11) 0 0 0 0 0
Nasopharyngitis 19 (10) 0 0 2 (3) 0 0
Pain in extremity 16 (9) 1 (<1) 0 7 (12) 0 0
Abdominal pain 7 (4) 1 (<1) 0 8 (14) 0 1 (2)
Anaemia 7 (4) 1 (<1) 0 7 (12) 1 (2) 1 (2)
Neutropenia 2 (1) 1 (<1) 0 10 (17) 4 (7) 4 (7)
Leukopenia 1 (<1) 0 0 6 (10) 2 (3) 0

DTIC = dacarbazine, PPE = palmar-plantar erythrodysaesthesia

Table 6 Incidence of Laboratory Abnormalities Increased from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in BRF113683 [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 or 4)]

Dabrafenib (n=187) DTIC (n=59)
All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%)
Hyperglycemia 50 6 43 0
Hypophosphatemia 37 6* 14 2
Increased Alkaline phosphatase 19 0 14 2
Hyponatremia 8 2 3 0

*Grade 4 laboratory abnormality limited to hypophosphatemia (n=1).

Description of selected adverse reactions

Pyrexia

Fever has been reported in clinical trials. In 1% of patients in clinical trials, serious non-infectious febrile events were identified defined as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency. The onset of these serious non-infectious febrile events was typically within the first month of therapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care (see DOSAGE AND ADMINISTRATION and PRECAUTIONS).

Cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinomas (including those classified as keratoacanthoma or mixed keratoacanthoma subtype) occurred in 9% (52/578) of patients treated with TAFINLAR. Approximately 70% of events occurred within the first 12 weeks of treatment with a median time to onset of 8 weeks. Ninety-six percent of patients who developed cuSCC continued on treatment without dose modification.

New primary melanoma

New primary melanomas have been reported in clinical trials with TAFINLAR. Cases were managed with excision and did not require treatment modification (see PRECAUTIONS).

Non-cutaneous malignancy

Activation of MAP-kinase signalling in BRAF wild type cells which are exposed to BRAF inhibitors may lead to increased risk of non-cutaneous malignancies, including those with RAS mutations (see PRECAUTIONS).Cases of RAS-driven malignancies have been seen with TAFINLAR. Patients should be monitored as clinically appropriate.

TAFINLAR and trametinib Combination Therapy

In addition to adverse reactions observed with monotherapy treatments (see Table 3 above and the trametinib prescribing information), Table 5 lists adverse reactions which are specific to/much more common when TAFINLAR is used in combination with trametinib.

Frequencies in Table 6 are based on subjects receiving TAFINLAR (150 mg twice daily) + trametinib (2 mg once daily) combination therapy (n = 55) in Part C of study BRF113220 (data cut-off 31 May 2012).

The following convention has been utilised for the classification of frequency:

Very common: ≥ 1/10

Common: ≥ 1/100 and < 1/10

Note: As patient numbers are small the frequencies of uncommon or rare events could not be determined.

Table 7 Adverse Reactions Specific for TAFINLAR In Combination With Trametinib

Infections and infestations
Very common Urinary tract infection
Blood and lymphatic system disorders
Very common Neutropenia
Common Thrombocytopenia
Metabolism and nutrition disorders
Common Hyponatraemia
Nervous system disorders
Very common Dizziness
Vascular disorders
Very Common Haemorrhagea
Common Hypotension
Hepatobiliary disorders
Common Gamma-glutamyltransferase increased
Skin and subcutaneous tissue disorders
Very common Night sweats
Common Hyperhidrosis
Musculoskeletal and connective tissue disorders
Very Common Muscle spasms
Common Rhabdomyolysis

aEvents include: brain stem haemorrhage, cerebral haemorrhage, gastric haemorrhage, epistaxis, gingival haemorrhage, hematuria, vaginal haemorrhage, haemorrhage intracranial, eye haemorrhage, and vitreous haemorrhage

The common adverse events based on ≥ 15% of patients in the TAFINLAR 150mg twice daily in combination with trametinib 2 mg once daily are provided in Table 7.

Table 8 Adverse Events (%) Occurring in ≥ 10% of Patients in the TAFINLAR 150 mg BID/ trametinib 2mg QD Combination Arm (BRF113220)

Reactions TAFINLAR 150 mg BID
Monotherapy (N = 53) Trametinib 1mg QD Combination (N = 54) Trametinib 2mg QD Combination (N = 55)
All Grade sa Grade 3 Grade 4 All Grade sa Grade 3 Grade 4 All Grade sa Grade 3 Grade 4
Skin and subcutaneous tissue disorders
Rash 36 0 0 20 0 0 27 0 0
Night Sweats 6 0 0 15 0 0 24 0 0
Dry Skin 6 0 0 9 0 0 18 0 0
Dermatitis acneiform 4 0 0 11 0 0 16 0 0
Actinic keratosis 9 0 0 11 0 0 16 0 0
Actinic keratosis 9 0 0 7 0 0 15 0 0
Erythema 2 0 0 6 0 0 15 0 0
Pruritus 13 0 0 11 0 0 11 0 0
Rash generalized 8 0 0 4 2 0 11 0 0
Metabolism and nutritional disorders
Decreased appetite 19 0 0 30 0 0 22 0 0
Dehydration 2 0 0 6 2 0 11 0 0
Nervous system disorders
Headache 28 0 0 37 2 0 29 0 0
Dizziness 9 0 0 13 0 0 16 0 0
Vascular Disorders
Haemorrhageb 2 0 0 11 0 0 16 0 2
Respiratory, thoracic, and mediastinal disorders
Cough 21 0 0 11 0 0 29 0 0
Oropharyngeal pain 0 0 0 7 0 0 13 0 0
Gastrointestinal disorders
Diarrhea 28 0 0 26 0 0 36 2 0
Nausea 21 0 0 46 4 2 44 2 0
Vomiting 15 0 0 43 4 0 40 2 0
Constipation 11 0 0 17 2 0 22 0 0
Abdominal pain upper 8 0 0 7 0 0 16 0 0
Abdominal pain 13 2 0 15 2 0 15 2 0
Dry mouth 6 0 0 11 0 0 11 0 0
General disorders and administrative site conditions
Pyrexia 26 0 0 69 9 0 71 5 0
Chills 17 0 0 50 2 0 58 2 0
Fatigue 40 6 0 57 2 0 53 4 0
Edema peripheral 17 0 0 24 0 0 29 0 0
Musculoskeletal, connective tissue, and bone disorders
Arthralgia 34 0 0 44 0 0 27 0 0
Myalgia 23 2 0 24 0 0 22 2 0
Back pain 11 2 0 11 0 0 18 5 0
Muscle spasm 4 0 0 2 0 0 16 0 0
Pain in extremity 19 0 0 11 2 0 16 0 0
Renal and urinary disorders
Urinary tract infection 9 2 0 6 0 0 13 2 0
Blood and Lymphatic System Disorders
Neutropenia 2 2 0 9 2 0 15 5 5
Anemia 6 0 0 20 6 0 13 4 0
Psychiatric Disorders
Insomnia 8 2 0 11 0 0 18 2 0

aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.

bEvents include: brain stem haemorrhage, cerebral haemorrhage, gastric haemorrhage, epistaxis, gingival haemorrhage, hematuria, vaginal haemorrhage, haemorrhage intracranial, eye haemorrhage, and vitreous haemorrhage

BID = twice daily; QD = once daily

Table 7. Treatment Emergent Abnormalities in Liver Function Tests Occurring in Patients Treated With TAFINLAR in Combination with Trametinib

Test TAFINLAR 150 mg BID Monotherapy (N = 53) Trametinib 1mg QD Combination (N = 54) Trametinib 2mg QD Combination (N = 55)
All Gradesa Grade 3 Grade 4 All Gradesa Grade 3 Grade 4 All Gradesa Grade 3 Grade 4
Increased Alkaline phosphatase 26 2 0 67 6 0 60 2 0
Increased AST 15 0 0 54 0 0 60 5 0
Increased ALT 11 0 0 35 4 0 42 4 0
Hyperbilirubinemia 0 0 0 7 4 0 15 0 0

a No Grade 4 events were reported in dabrafenib arm.

QT Prolongation

In BRF113220, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with trametinib and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with trametinib and 2% (1/53) of patients treated with TAFINLAR as a single agent.

Special populations

Elderly population

Of the total number of patients in clinical studies of dabrafenib (N = 578), 22% were 65 years of age and older, and 6% were 75 years of age and older. Compared with younger subjects (< 65), more subjects ≥ 65 years old had adverse events that led to study drug dose reductions (22% versus 12%) or interruptions (39% versus 27%). In addition, older patients experienced more serious adverse events compared to younger patients (41% versus 22%). No overall differences in efficacy were observed between these subjects and younger subjects.

In the phase I/II study of TAFINLAR in combination with trametinib in patients with unresectable or metastatic melanoma (n = 202), 42 patients (21%) were ≥ 65 years of age, and 12 patients (6%) were ≥ 75 years of age. The proportion of subjects experiencing AEs was similar in the subjects aged < 65 years and those aged ≥ 65 years.

Patients ≥ 65 years were more likely to experience SAEs, fatal SAEs and AEs leading to permanent discontinuation of study drug, dose reduction and dose interruption than those < 65 years.

Dosage and Administration

Confirmation of BRAF V600 mutation using an approved/validated test is required for selection of patients appropriate for TAFINLAR monotherapy and in combination with trametinib (see CLINICAL TRIALS).

When TAFINLAR is used in combination with trametinib, refer to the full trametinib prescribing information, DOSAGE AND ADMINISTRATION, for trametinib dosing instructions

The efficacy and safety of TAFINLAR have not been established in patients with wild- type BRAF melanoma (see CLINICAL TRIALS). TAFINLAR should not be used in patients with BRAF wild-type melanoma (see PRECAUTIONS).

Adults

The recommended dose of TAFINLAR used as monotherapy or in combination with trametinib is 150 mg (two 75 mg capsules) twice daily (corresponding to a total daily dose of 300 mg).

TAFINLAR should be taken either at least one hour before, or at least two hours after a meal, leaving an interval of approximately 12 hours between doses. TAFINLAR should be taken at similar times every day.

Treatment should continue until disease progression or the development of unacceptable toxicity (see Table 9).

If a dose is missed, it should not be taken if it is less than 6 hours until the next dose.

Dose modifications

Monotherapy and in combination with dabrafenib

The management of adverse reactions may require treatment interruption, dose reduction, or treatment discontinuation (see Table 8 and Table 9).

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 8 and Table 9, respectively. Dose adjustments resulting in a dose lower than 50 mg twice daily are not recommended.

Table 9: Recommended TAFINLAR dose level reductions

Dose Level Dose/Schedule
Full dose 150 mg twice daily
First reduction 100 mg twice daily
Second reduction 75 mg twice daily
Third reduction 50 mg twice daily

Refer to the full trametinib prescribing information: DOSAGE AND ADMINISTRATION, for trametinib dosing instructions.

Table 10: TAFINLAR dose modification schedule

Grade (CTC-AE)* Recommended TAFINLAR Dose Modifications
Grade 1 or Grade 2 (Tolerable) Continue treatment and monitor as clinically indicated
Grade 2 (Intolerable) or Grade 3 Interrupt therapy until toxicity is grade 0 – 1 and reduce by one dose level when resuming therapy.
Grade 4 Discontinue permanently, or interrupt therapy until grade 0 – 1 and reduce by one dose level when resuming therapy

*The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events (CTC-AE) v4.0.

When an individual’s adverse reactions are under effective management, dose re-escalation following the same dosing steps as de-escalation may be considered. The dose should not exceed 150 mg twice daily.

If treatment related toxicities occur when TAFINLAR is used in combination with trametinib then both treatments should be simultaneously dose reduced, interrupted or discontinued with the exceptions shown below.

Exception where dose modification is necessary for only TAFINLAR:

  • New Primary Non-Cutaneous Malignancies
  • Pyrexia

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)
  • nterstitial lung disease/Pneumonitis

Detailed dosing modifications for selected adverse reactions

New Primary Malignancies:

For New Primary Cutaneous Malignancies no dose modifications are required. For New Primary Non-Cutaneous Malignancies, permanently discontinue TAFINLAR in patients who develop RAS mutation-positive non-cutaneous malignancies.

Haemorrhagic events:

Permanently discontinue TAFINLAR, and also permanently discontinue trametinib if administered in combination, for all Grade 4 haemorrhagic events and for any Grade 3 haemorrhagic events that do not improve. Withhold TAFINLAR for up to 3 weeks for Grade 3 haemorrhagic events; if improved resume at a lower dose level. If used in combination, withhold trametinib for Grade 3 haemorrhagic events; if improved resume at a lower dose level.

Pyrexia Management:

If the patient’s temperature is > 40ºC or if fever is complicated by rigors, hypotension, dehydration, or renal failure

When TAFINLAR is used in combination with trametinib, withhold TAFINLAR and trametinib.

Initiate treatment with anti-pyretics such as ibuprofen (preferred) or acetaminophen/paracetamol. Patients should be evaluated for signs and symptoms of infection (see PRECAUTIONS).

Upon resolution of pyrexia, therapy can be restarted with appropriate anti-pyretic prophylaxis either:

  • TAFINLAR at a lower dose level, trametinib at the same or lower dose level.
  • Or, permanently discontinue TAFINLAR

If the patient’s temperature is ≥ 38.5ºC and ≤ 40ºC

When TAFINLAR is used as monotherapy or incombination with trametinib, withhold TAFINLAR. Trametinib should be continued at the same dose.Initiate treatment with anti-pyretics such as ibuprofen (preferred) or acetaminophen/paracetamol. Patients should be evaluated for signs and symptoms of infection (see PRECAUTIONS).

Upon resolution of pyrexia, TAFINLAR can be restarted with appropriate anti-pyretic prophylaxis either:

  • At the same dose level.
  • Or, reduce one dose level, if pyrexia is recurrent

The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient.

LVEF Reduction/Left Ventricular Dysfunction:

When receiving TAFINLAR in combination with trametinib, trametinib should be interrupted in patients who have an asymptomatic, absolute decrease of ≥10% in LVEF compared to baseline and the ejection fraction is below the institution’s lower limit of normal (LLN) (see PRECAUTIONS). TAFINLAR therapy may be continued at the same dose. If the LVEF recovers, treatment with trametinib may be restarted, but reduce dose by one dose level with careful monitoring.

Permanently discontinue trametinib with Grade 3 or 4 left ventricular cardiac dysfunction or if LVEF does not recover. If trametinib is being used in combination with TAFINLAR then therapy with TAFINLAR should be withheld and resumed at the same dose upon recovery of cardiac function.

Retinal Vein Occlusion and Retinal Pigment Epithelial Detachment:

When receiving TAFINLAR in combination with trametinib, if patients report new visual disturbances such as diminished central vision, blurry vision, or loss of vision at any time, a prompt ophthalmological assessment is recommended. In patients who are diagnosed with retinal vein occlusion (RVO), treatment with trametinib should be permanently discontinued. TAFINLAR treatment can continue at the same dose. If retinal pigment epithelial detachment (RPED) is diagnosed continue TAFINLAR at the same dose and follow the dose modification schedule in Table 9 below for trametinib (see PRECAUTIONS).

Table 10. Recommended dose modifications for trametinib for retinal pigment epithelial detachments (RPED)

Grade 1 RPED Continue treatment with retinal evaluation monthly until resolution. If RPED worsens follow instructions below and withhold trametinib for up to 3 weeks
Grade 2-3 RPED Withhold trametinib for up to 3 weeks
Grade 2-3 RPED that improves to Grade 0-1 within 3 weeks Resume trametinib at a lower dose (reduced by 0.5 mg) or discontinue trametinib in patients taking trametinib 1 mg daily
Grade 2-3 RPED that does not improve to at least Grade 1 within 3 weeks Permanently discontinue trametinib

Interstitial lung disease (ILD)/Pneumonitis

When receiving TAFINLAR in combination with trametinib, withhold trametinib in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue trametinib for patients diagnosed with treatment-related ILD or pneumonitis. Do not modify the dose of TAFINLAR.

Serious Skin Toxicity:

For dosing instructions for intolerable or severe skin toxicity for TAFINLAR and TAFINLAR in combination with trametinib, see Table 11. Dose reduction, interruption or discontinuation should be applied to both treatments.

Table 11. Guidelines for Cutaneous toxicity

Severity of Adverse Reaction TAFINLAR Trametinib (When Used in Combination)
Intolerable Grade 2 skin toxicity Grade 3 or 4 skin toxicity
Withhold TAFINLAR for up to 3 weeks. If improved, resume at a lower dose level. If not improved, permanently discontinue.
Withhold trametinib for up to 3 weeks. If improved, resume at a lower dose level. If not improved, permanently discontinue.

The following rash management guidance should be considered whether TAFINLAR is given as monotherapy or in combination with trametinib, and if dose reduction, interruption or discontinuation is necessary it should be applied to both treatments.

Treatment of rash has not been formally studied and should be based on rash severity. The following guidelines were used in clinical studies with TAFINLAR as monotherapy or in combination with trametinib and can be used to manage rash (see Table 12).

Table 12. Supportive Care Guidelines for Rash

Step Rash grading Rash severity Management of Rash
1 Mild Localised Initiate prophylactic regimena if not already started.
Minimally symptomatic
No impact on ADL Reassess after two weeks; if rash worsens or does not improve, proceed to step 2
No sign of superinfection
2 Moderate Generalised Initiate prophylactic regimena if not already started, using moderate strength topical steroids.
Mild symptoms (e.g. pruritus, tenderness)
Minimal impact on ADL Reassess after two weeks; if rash worsens or does not improve, proceed to step 3
No sign of superinfection
3 Severe Generalised Initiate prophylactic regimena if not already started, using moderate strength topical steroids PLUS systemic corticosteroids
Severe symptoms (e.g. pruritus, tenderness)
Significant impact on ADL
Sign of or potential for superinfection Manage rash per dermatologist’s recommendation.

a. broad-spectrum sunscreen (skin protection factor ≥ 15), alcohol-free emollient cream, mild-strength topical steroid, and oral antibiotics for first 2-3 weeks

ADL= Activity of Daily Living

Populations

Paediatric population

The safety and efficacy of TAFINLAR have not been established in children and adolescents (< 18 years). Studies in juvenile animals have shown effects of dabrafenib which had not been observed in adult animals (see PRECAUTIONS).

Elderly

No dose adjustment is required in patients over 65 years (see PHARMACOKINETICS).

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 PHARMACOKINETICS). There are no clinical data in subjects with severe renal impairment and the potential need for dose adjustment cannot be determined. TAFINLAR 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 PHARMACOKINETICS). 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. TAFINLAR 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 TAFINLAR. The maximum dose of TAFINLAR administered during clinical trials was 600 mg (300 mg twice daily).

Treatment

There is no specific antidote for overdosage of TAFINLAR. Patients who develop adverse reactions should receive appropriate symptomatic treatment. In case of suspected overdose, TAFINLAR should be withheld and supportive care instituted. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

Presentation and Storage Conditions

The TAFINLAR 50 mg capsules are, opaque, size 2 hard capsule composed of a dark red body and dark red cap containing a white to slightly coloured solid. The capsule shells are imprinted with GS TEW and 50 mg. The TAFINLAR 50 mg capsules are supplied in high-density polyethylene (HDPE) bottles with child resistant polypropylene closures containing 28 or 120 capsules*.

The TAFINLAR 75 mg capsules are opaque, size 1 hard capsule composed of a dark pink body and dark pink cap containing a white to slightly coloured solid. The capsule shells are imprinted with GS LHF and 75 mg. The TAFINLAR 75 mg capsule are supplied in high-density polyethylene (HDPE) bottles with child resistant polypropylene closures containing 28 or 120 capsules*.

*Not all pack sizes may be marketed.

Storage Conditions

Store below 30°C.

Name and Address of the Sponsor

GlaxoSmithKline Australia Pty Ltd,

Level 4, 436 Johnston Street,

Abbotsford, Victoria, 3067

Poison Schedule of the Medicine

Schedule 4 – Prescription Only Medicine

Date of First Inclusion in the Australian Register of Therapeutic Goods (The ARTG):

21 August 2013

Date of the Most Recent Amendment:

29 January 2015

TAFINLAR is a registered trade mark of the GlaxoSmithKline group of companies.