Tafinlar

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

Dosage Forms & Strengths

capsule

• 50mg
• 75mg

Melanoma

BRAF protein kinase inhibitor indicated as a single agent for unresectable or metastatic melanoma with BRAF V600E mutation, or in combination with trametinib for BRAF V600E or V600K mutations

Single agent: 150 mg PO BID

Combination regimen: 150 mg PO BID plus trametinib 2 mg PO qDay

Also see Administration

Non-small cell lung cancer (NSCLC)

BRAF protein kinase inhibitor indicated in combination with trametinib for metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation

150 mg PO BID plus trametinib 2 mg PO qDay

Also see Administration

Dosage Modifications

Dose reductions for dabrafenib (single agent or in combination with trametinib)

• First dose reduction: 100 mg PO BID
• Second dose reduction: 75 mg PO BID
• Third dose reduction: 50 mg PO BID
• If unable to tolerate 50 mg BID: Permanently discontinue

Dose reductions for trametinib when administered with dabrafenib

• First dose reduction: 1.5 mg PO qDay
• Second dose reduction: 1 mg PO qDay
• Subsequent modification: Permanently discontinue if unable to tolerate trametinib 1 mg/day

Febrile drug reaction

• Fever of 101.3-104°F: Withhold dabrafenib until fever resolves, then resume at same or lower dose; do not modify trametinib
• Fever >104°F or complicated by rigors, hypotension, dehydration, or renal failure: Withhold trametinib until fever resolves, then resume at same or lower dose; withhold dabrafenib, then resume at same or lower dose (or permanently discontinue)

Cutaneous reactions

• Intolerable Grade 2 skin toxicity, or Grades 3 or 4:
• Withhold for up to 3 weeks; if improved, resume at lower dose level
• If not improved after withholding 3 weeks, permanently discontinue
• Applies to both trametinib and dabrafenib

Asymptomatic LVEF

• Asymptomatic, absolute decrease in LVEF ≥10% from baseline, but is below LLN from pretreatment value:
• Trametinib: Withhold for up to 4 weeks; if improved to normal LVEF value, resume at a lower dose level; if not improved to normal, permanently discontinue
• Dabrafenib: Do not modify dose

Symptomatic CHF

• Symptomatic congestive heart failure (absolute decrease in LVEF >20% from baseline that is below LLN:
• Trametinib: Permanently discontinue
• Dabrafenib: Withhold, if improved, then resume at the same dose

Uncomplicated DVT or PE

• Trametinib: Withhold trametinib for up to 3 weeks; if improved to Grade 0-1, resume at a lower dose level, if not improved, permanently discontinue
• Dabrafenib: Do not modify dose

Life-threatening PE

• Trametinib: Permanently discontinue
• Dabrafenib: Permanently discontinue

RPED

• Grade 2-3 retinal pigment epithelia detachments (RPED):
• Trametinib: Withhold for up to 3 weeks; if improved to Grade 0-1, resume at a lower dose level, if not improved, permanently discontinue
• Dabrafenib: Do not modify dose

Retinal vein occlusion

• Trametinib: Permanently discontinue
• Dabrafenib: Do not modify dose

Uveitis and iritis

• Trametinib: Do not modify dose
• Dabrafenib: Withhold for up to 6 weeks; if improved to Grade 0-1, resume at same dose, if not improved, permanently discontinue

Pulmonary reactions

• Interstitial lung disease/pneumonitis
• Trametinib: Permanently discontinue
• Dabrafenib: Do not modify dose

Other

• Applies to both trametinib and dabrafenib
• Intolerable Grade 2 or any Grade 3 adverse reactions: Withhold for up to 3 weeks; if improved to Grade 0-1, resume at lower dose level, if not improved, permanently discontinue
• First occurrence of any Grade 4 reaction: Withhold until improves to Grade 0-1, then resume at lower dose level, or permanently discontinue
• Recurrent Grade 4 reactions: Permanently discontinue

Dosing Considerations

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with THxID BRAF Kit

Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at http://www.fda.gov/CompanionDiagnostics

Not indicated for treatment of patients with wild-type BRAF melanoma

Glioma (Orphan)

Orphan designation for treatment of malignant glioma with BRAF V600 mutation

Sponsor

• Novartis Pharmaceuticals Corporation; 1 Health Plaza, Bldg 337; East Hanover, New Jersey 07936

Thyroid Cancer (Orphan)

Orphan designation for treatment of anaplastic thyroid cancer and locally advanced or metastatic papillary thyroid cancer with BRAF V600 mutation in combination with trametinib

Sponsor

• Novartis Pharmaceuticals Corp; One Health Plaza; East Hanover, New Jersey 07936

Safety and efficacy not established

Mechanism of Action

Inhibits some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively

Absorption

Bioavailability: 95%

Peak plasma time: 2 hr

High-calorie meal decreased AUC by 31%, Cmax by 51%, and delayed Tmax by 3.6 hr compared with fasted state

Distribution

Protein Bound: 99.7%

Vd: 70.3 L

Metabolism

Primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib

Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine

Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut

Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites

Elimination

Half-life: 8 hr (parent); 10 hr (hydroxy-dabrafenib); 21-22 hr (carboxy- and desmethyl-dabrafenib)

Clearance: 17 L/hr (single dose); 34.4 L/hr (after 2 wk of BID dosing)

Excretion: 71% feces; 23% urine (as metabolites only)

Before taking Tafinlar, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to this medication or to any of its ingredients
• have liver or kidney problems
• have diabetes
• plan to have surgery, dental, or other medical procedures
• have a deficiency of the glucose-6-phosphate dehydrogenase (G6PD) enzyme
• have any other medical conditions
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Using dabrafenib with trametinib may increase your risk of developing a certain type of skin cancer. Ask your doctor about your specific risk. Tell your doctor if you notice any new skin symptoms.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Storage

Oral

25°C (may be exposed to 15–30°C).1

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of dabrafenib in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of dabrafenib in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Amisulpride
• Bepridil
• Cisapride
• Dronedarone
• Fluconazole
• Ketoconazole
• Mesoridazine
• Pimozide
• Piperaquine
• Posaconazole
• Saquinavir
• Sparfloxacin
• Terfenadine
• Thioridazine
• Ziprasidone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abiraterone Acetate
• Alfuzosin
• Amiodarone
• Amitriptyline
• Anagrelide
• Apomorphine
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Asenapine
• Astemizole
• Azithromycin
• Bedaquiline
• Boceprevir
• Buserelin
• Ceritinib
• Chloroquine
• Chlorpromazine
• Ciprofloxacin
• Citalopram
• Clarithromycin
• Clomipramine
• Clozapine
• Cobicistat
• Conivaptan
• Crizotinib
• Cyclobenzaprine
• Dasatinib
• Degarelix
• Delamanid
• Desipramine
• Deslorelin
• Desogestrel
• Deutetrabenazine
• Dienogest
• Disopyramide
• Dofetilide
• Dolasetron
• Dolutegravir
• Domperidone
• Donepezil
• Doxepin
• Droperidol
• Drospirenone
• Ebastine
• Efavirenz
• Eribulin
• Erythromycin
• Escitalopram
• Estradiol
• Ethinyl Estradiol
• Ethynodiol
• Etonogestrel
• Famotidine
• Felbamate
• Fingolimod
• Flecainide
• Fluoxetine
• Formoterol
• Foscarnet
• Fosphenytoin
• Galantamine
• Gatifloxacin
• Gemfibrozil
• Gemifloxacin
• Gonadorelin
• Goserelin
• Granisetron
• Halofantrine
• Haloperidol
• Histrelin
• Hydroquinidine
• Hydroxychloroquine
• Hydroxyzine
• Ibutilide
• Idelalisib
• Iloperidone
• Imipramine
• Indinavir
• Itraconazole
• Ivabradine
• Lapatinib
• Leuprolide
• Levofloxacin
• Levonorgestrel
• Lopinavir
• Lumefantrine
• Medroxyprogesterone
• Mefloquine
• Mestranol
• Methadone
• Methotrimeprazine
• Metronidazole
• Mifepristone
• Mizolastine
• Moricizine
• Moxifloxacin
• Nafarelin
• Nefazodone
• Nelfinavir
• Netupitant
• Nilotinib
• Norelgestromin
• Norethindrone
• Norfloxacin
• Norgestimate
• Norgestrel
• Octreotide
• Ofloxacin
• Olanzapine
• Ondansetron
• Paliperidone
• Panobinostat
• Papaverine
• Paroxetine
• Pasireotide
• Pazopanib
• Pentamidine
• Perphenazine
• Pimavanserin
• Pipamperone
• Pitolisant
• Probucol
• Procainamide
• Prochlorperazine
• Progesterone
• Promethazine
• Propafenone
• Protriptyline
• Quetiapine
• Quinidine
• Quinine
• Ranolazine
• Ribociclib
• Rilpivirine
• Risperidone
• Ritonavir
• Sertindole
• Sevoflurane
• Sodium Phosphate
• Sodium Phosphate, Dibasic
• Sodium Phosphate, Monobasic
• Solifenacin
• Sorafenib
• Sotalol
• Sulpiride
• Sunitinib
• Tacrolimus
• Tamoxifen
• Telaprevir
• Telavancin
• Telithromycin
• Tetrabenazine
• Tizanidine
• Tolterodine
• Toremifene
• Trazodone
• Trimipramine
• Triptorelin
• Vandetanib
• Vardenafil
• Vemurafenib
• Venlafaxine
• Vilanterol
• Vinflunine
• Voriconazole
• Vorinostat
• Warfarin
• Zuclopenthixol

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Opicapone

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Dehydration or
• Hypotension (low blood pressure) or
• Kidney failure—Use with caution. May cause side effects to become worse.

• Diabetes or
• Hyperglycemia (high blood sugar) or
• Iritis (eye problem) or
• Uveitis (eye problem)—Use with caution. May make these conditions worse.

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency (a hereditary metabolic disorder affecting red blood cells)—May cause hemolytic anemia (blood disorder) in patients with this condition.

• Liver disease, moderate to severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

      Patient Selection

Melanoma

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with Tafinlar as a single agent [see Warnings and Precautions (5.2) and Clinical Studies (14.1)]. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with Tafinlar and trametinib [see Warnings and Precautions (5.2) and Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

NSCLC

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with Tafinlar and trametinib [see Clinical Studies (14.2)]. Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

      Recommended Dosing

The recommended dosage regimen of Tafinlar is 150 mg orally taken twice daily, approximately 12 hours apart as a single agent or with trametinib. Continue treatment until disease progression or unacceptable toxicity occurs.

Take Tafinlar at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)]. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or break Tafinlar capsules.

      Dose Modifications

Review the Full Prescribing Information for trametinib for recommended dose modifications. Dose modifications are not recommended for Tafinlar when administered with trametinib for the following adverse reactions of trametinib: retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism.

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.

a       National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

b       See Table 1 for recommended dose reductions of Tafinlar.

The following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Malignancies [see Warnings and Precautions (5.1)]
  
• Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)]
  
• Hemorrhage [see Warnings and Precautions (5.3)]
  
• Cardiomyopathy [see Warnings and Precautions (5.4)] 
  
• Uveitis [see Warnings and Precautions (5.5)]
  
• Serious Febrile Reactions [see Warnings and Precautions (5.6)]
  
• Serious Skin Toxicity [see Warnings and Precautions (5.7)]
  
• Hyperglycemia [see Warnings and Precautions (5.8)]
  
• Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.9)]

      Clinical Trials Experience 

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section reflect exposure to Tafinlar administered as a single agent in 586 patients with various solid tumors and exposure to Tafinlar administered with trametinib in 559 patients with melanoma and 93 patients with NSCLC. The safety of Tafinlar as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received Tafinlar 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. Tafinlar was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of Tafinlar was 300 mg (range: 118 to 300 mg).

Metastatic or Unresectable BRAF V600 Mutation Positive Melanoma

Tafinlar as a Single Agent

Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of the BREAK-3 study [see Clinical Studies (14.1)].This study, a multicenter, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive Tafinlar 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology (≥ Grade 2), corrected QT interval greater than or equal to 480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated with Tafinlar and 2.8 months for dacarbazine-treated patients. The population exposed to Tafinlar was 60% male, 99% White, and had a median age of 53 years.

The most commonly occurring adverse reactions (≥20%) in patients treated with Tafinlar were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).

The incidence of adverse events resulting in permanent discontinuation of study medication in the BREAK-3 study was 3% for patients treated with Tafinlar and 3% for patients treated with dacarbazine. The most frequent (≥2%) adverse reactions leading to dose reduction of Tafinlar were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%).

a       Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity.

b       Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1).

c       Includes skin papilloma and papilloma.

d       cuSCC = cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma.

e       Cases of cuSCC were required to be reported as Grade 3 per protocol.

f       NA = not applicable.

a       Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity.

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

Other clinically important adverse reactions observed in less than 10% of patients (N = 586) treated with Tafinlar were:

Gastrointestinal Disorders: Pancreatitis

Immune System Disorders: Hypersensitivity manifesting as bullous rash

Renal and Urinary Disorders: Interstitial nephritis

Tafinlar Administered with Trametinib

The safety of Tafinlar when administered with trametinib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600E or V600K mutation-positive melanoma who received Tafinlar in two trials, the COMBI-d study (n = 209) a multicenter, double-blind, randomized (1:1), active controlled trial and the COMBI-v study (n = 350) a multicenter, open-label, randomized (1:1), active controlled trial. In the COMBI-d and COMBI-v studies, patients received Tafinlar 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or a known history of G6PD deficiency [see Clinical Studies (14.2)].

Among these 559 patients, 199 (36%) were exposed to Tafinlar for >6 months to 12 months while 185 (33%) were exposed to Tafinlar for ≥1 year. The median age was 55 years (range: 18 to 91), 57% were male, 98% were White, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated LDH at baseline and 0.5% had a history of brain metastases.

The most commonly occurring adverse reactions (≥20%) for Tafinlar in patients receiving Tafinlar plus trametinib in the COMBI-d and COMBI-v studies were: pyrexia, rash, chills, headache, arthralgia, and cough.

Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, observed in the COMBI-d study.

The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies [see Clinical Studies (14.2)]. Patients receiving Tafinlar plus trametinib had a median duration of exposure of 11 months (range: 3 days to 30 months) to Tafinlar. Among the 209 patients receiving Tafinlar plus trametinib, 26% were exposed to Tafinlar for >6 months to 12 months while 46% were exposed to Tafinlar for >1 year.

In the COMBI-d study, adverse reactions resulting in discontinuation of Tafinlar occurred in 11% of patients receiving Tafinlar plus trametinib; the most common was pyrexia (1.9%). Adverse reactions leading to dose reductions of Tafinlar occurred in 26% of patients receiving Tafinlar plus trametinib; the most common were pyrexia (14%), neutropenia (1.9%), rash (1.9%), and chills (1.9%). Adverse reactions leading to dose interruptions of Tafinlar occurred in 56% of patients receiving Tafinlar plus trametinib; the most common were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%). 

a       NCI CTCAE version 4.0.

b       Grade 4 adverse reactions limited to headache (n = 1).

c       Includes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash folliculitis.

Other clinically important adverse reactions for Tafinlar across the COMBI-d and COMBI-v studies (N = 559) observed in less than 10% of patients receiving Tafinlar in combination with trametinib were:

Gastrointestinal Disorders: Pancreatitis

Subcutaneous Tissue Disorders: Panniculitis

a       For these laboratory tests the denominator is 556.

b       For these laboratory tests the denominator is 208 for the combination arm, 208-209 for the Tafinlar arm.

c       Grade 4 adverse reactions limited to hyperglycemia (n = 4), hyponatremia and hypophosphatemia (each n = 1), in the pooled combination arm; hyperglycemia (n = 1) in the COMBI-d study combination arm; hypophosphatemia (n = 1) in the Tafinlar arm.

Metastatic, BRAF V600E-Mutation Positive, Non-Small Cell Lung Cancer (NSCLC)

The safety of Tafinlar when administered with trametinib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n = 57) metastatic BRAF V600E mutation-positive NSCLC in a multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received Tafinlar 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of interstitial lung disease or pneumonitis, or history or current retinal vein occlusion [see Clinical Studies (14.3)].

Among these 93 patients, 53 (57%) were exposed to Tafinlar and trametinib for >6 months and 27 (29%) were exposed to Tafinlar and trametinib for ≥1 year. The median age was 65 years (range: 41 to 91); 46% were male; 85% were White; 32% had baseline ECOG performance status 0 and 61% had ECOG performance status 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked.

The most commonly occurring adverse reactions (≥20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

Adverse reactions resulting in discontinuation of Tafinlar occurred in 18% of patients; the most common were pyrexia (2.2%), ejection fraction decreased (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of Tafinlar occurred in 35% of patients; the most common were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vomiting (4.3%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of Tafinlar occurred in 62% of patients; the most common were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%).

Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, of Tafinlar in Study BRF113928.

a       NCI CTCAE version 4.0.

b        Includes fatigue, malaise, and asthenia

c       Includes peripheral edema, edema, and generalized edema.

d       Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular.

e       Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.

Other clinically important adverse reactions for Tafinlar observed in less than 10% of patients with NSCLC receiving Tafinlar in combination with trametinib were:

Gastrointestinal Disorders: Pancreatitis

Renal and Urinary Disorders: Tubulointerstitial nephritis

a       For these laboratory tests the denominator is 91.

b       For these laboratory tests the denominator is 90.

50 mg capsules: Dark red capsule imprinted with ‘GS TEW’ and ‘50 mg’ available in bottles of 120 (NDC 0078-0682-66). Each bottle contains a silica gel desiccant.

75 mg capsules: Dark pink capsule imprinted with ‘GS LHF’ and ‘75 mg’ available in bottles of 120 (NDC 0078-0681-66). Each bottle contains a silica gel desiccant.

Store at 25°C (77°F); excursions permitted to 15ºC to 30°C (59ºF to 86°F) [see USP Controlled Room Temperature].

Tafinlar is usually taken twice daily. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Your doctor will perform blood tests to make sure you have the correct tumor type to be treated with Tafinlar.

Take this medicine on an empty stomach, at least 1 hour before or 2 hours after a meal.

Do not crush, chew, break, or open a Tafinlar capsule. Swallow the capsule whole.

If you need surgery, dental work, or a medical procedure, tell the doctor ahead of time that you are using Tafinlar.

Your doctor will need to check your skin every 2 months while you are using dabrafenib, and for up to 6 months after your treatment ends.

Store at room temperature away from moisture and heat.