Active Ingredient and Strength	DABRAFENIB MESYLATE 59.25 MG EQUIVALENT TO DABRAFENIB - 50 MG
Dosage Form	CAPSULE
Manufacturer and Country	GLAXO OPERATIONS UK LIMITED (TRADING AS GLAXO WELLCOME OPERATIONS) - UNITED KINGDOM SIEGFRIED BARBERA S.L. - SPAIN NOVARTIS PHARMACEUTICAL MANUFACTURING LLC - SLOVENIA
Registration Number	SIN14830P
Licence Holder	NOVARTIS (SINGAPORE) PTE LTD
Forensic Classification	PRESCRIPTION ONLY MEDICINES
Anatomical Therapeutic Chemical (ATC) code	L01EC02

3 Indications

Unresectable or metastatic melanoma
Dabrafenib as monotherapy or in combination with trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see Section 12 Clinical Studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Adjuvant treatment of melanoma
Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of patients with melanoma with BRAF V600 mutation, and involvement of lymph node(s), following complete resection.

Advanced non-small cell lung cancer
Dabrafenib in combination with trametinib is indicated for the treatment of patients with advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation (see Section 12 Clinical Studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Locally advanced or metastatic anaplastic thyroid cancer
Dabrafenib in combination with trametinib is indicated for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with a BRAF V600 mutation and with no satisfactory locoregional treatment options (see section 12 Clinical studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Low-grade glioma
Dabrafenib in combination with trametinib is indicated for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy (see section 12 Clinical studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

4 Dosage regimen and administration

Treatment with Tafinlar should be initiated by a physician experienced in the use of anticancer therapies.

Tafinlar is available in two dosage forms, hard capsules and dispersible tablets

The efficacy and safety of Tafinlar have not been established in patients with wild-type BRAF solid tumors (see section 12 Clinical Studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Confirmation of BRAF V600 mutation using an approved/validated test is required for selection of patients appropriate for treatment with Tafinlar as monotherapy and in combination with Mekinist (see section 12 Clinical Studies – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

When Tafinlar is used in combination with Mekinist, please also refer to the full Mekinist prescribing information.
Note: dabrafenib capsules and dispersible tablets are not fully bioequivalent/interchangeable; caution is advised when consideration is given to changing formulations due to any difficulty in swallowing solid forms.

Dosage regimen

General target population

Hard Capsules

Adult patients

The recommended dosage for Tafinlar capsules in adult patients (either as monotherapy or in combination with Mekinist) is 150 mg given orally twice daily (corresponding to a total daily dose of 300 mg), independent of body weight.

Recommended dose level reductions for Tafinlar capsules in adult patients are provided in Table 4-1.

Pediatric patients

The recommended dosage for Tafinlar capsules in pediatric patients who weigh at least 26 kg, is based on body weight (Table 4-2). A recommended dose of Tafinlar capsules for patients who weigh less than 26 kg has not been established.

Recommended dose level reductions for Tafinlar capsules in pediatric patients are provided in Table 4-3.

Dispersible Tablets

The recommended dosage and dose level reductions for Tafinlar dispersible tablets are based on body weight (Table 4-4).

Duration of treatment

The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity.

In the adjuvant melanoma setting, the treatment duration is limited to a maximum of 1 year.

The recommended duration of treatment for pediatric patients with LGG is until loss of clinical benefit or until unacceptable toxicity. There are limited data in patients older than 18 years of age with LGG who require first systemic therapy. Therefore, continued treatment into adulthood should be based on benefits and risks to the individual patient as assessed by the physician.

Missed dose

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

Dose adjustments

Tafinlar as monotherapy and in combination with Mekinist

The management of adverse events/adverse drug reactions may require treatment interruption, dose reduction, or treatment discontinuation.

Dose modifications or interruptions are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see section 6 Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

For pyrexia management guidance see section below.

The recommended dose modification schedule is provided in Table 4-5. 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 Tafinlar dose should not exceed 150 mg twice daily.

Pyrexia management: Therapy should be interrupted (Tafinlar when used as monotherapy, and both Tafinlar and Mekinist when used in combination) if a patient’s temperature is ≥38°C (100.4°F). In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia.Treatment with anti-pyretics such as ibuprofen or acetaminophen/paracetamol should be initiated. Patients should be evaluated for signs and symptoms of infection (see section 6 Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Tafinlar, or both Tafinlar and Mekinist when used in combination, should be restarted if patient is symptom free for at least 24 hours either (1) at the same dose level or (2) reduced by one dose level, if pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension, or renal failure. The use of oral corticosteroids should be considered in those instances in which anti- pyretics are insufficient.

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

Exceptions where dose modifications are necessary for Tafinlar only:

Uveitis management: No dose modifications are required as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, withhold Tafinlar until resolution of ocular inflammation and then restart Tafinlar reduced by one dose level. No dose modification of trametinib is required when taken in combination with Tafinlar.

Special Populations

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. Based on the population pharmacokinetic analysis, mild and moderate renal impairment had no significant effect on the oral clearance of Tafinlar or on the concentrations of its metabolites (see section 11 Clinical Pharmacology, Pharmacokinetics – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). There are no clinical data in patients 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 the oral clearance of Tafinlar or on the concentrations of its metabolites (see section 11 Clinical Pharmacology, Pharmacokinetics – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). There are no clinical data in patients 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 Tafinlar 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.

Pediatric patients
The safety and efficacy of Tafinlar in combination with trametinib in pediatric patients with low-grade glioma younger than 1 year old and/or < 8kg have not been established. Tafinlar is not recommended in this age group.

TAFINLAR is not indicated for pediatric patients (<18 years old) with melanoma, NSCLC or anaplastic thyroid cancer.

Geriatric patients (65 years of age or above)

No dosage adjustment is required in patients over 65 years of age (see section 11 Clinical Pharmacology, Pharmacokinetics – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Method of administration

Tafinlar should be taken at similar times every day, leaving an interval of approximately 12 hours between doses.

If a patient vomits after taking Tafinlar, the patient should not retake the dose and should take the next scheduled dose.

When Tafinlar and Mekinist are taken in combination, the once-daily dose of Mekinist should be taken at the same time each day with either the morning dose or the evening dose of Tafinlar.

Hard Capsules

The capsules should be taken without food, at least one hour before or two hours after a meal (see section 11 Clinical pharmacology – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). The capsules should be swallowed whole with a glass of water. The capsules must not be chewed or crushed.

Dispersible Tablets

The suspension should be taken without food, at least one hour before or two hours after a meal (see section 11 Clinical pharmacology – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Breast-feeding and/or baby formula may be given on demand if a patient is unable to tolerate the fasting conditions. Tafinlar dispersible tablets are to be taken as a suspension only and should not be swallowed whole, chewed, or crushed.

The suspension is prepared in a provided dosing cup. The suspension can be administered using three different methods: via drinking the suspension from dosing cup, or swallowing the suspension received from oral syringe filled with the suspension withdrawn from the dosing cup or receiving the suspension via feeding tube.

Care should be taken to ensure the entire dose is administered. It may take 3 minutes (or more) to fully suspend the tablets. Once they are dispersed, the suspension should be cloudy white.

Administer the suspension no later than 30 minutes after the tablets have been dispersed. If more than 30 minutes have passed, dispose of the suspension in line with local regulations and restart from the beginning.

A complete and illustrated set of instructions for the dispersible tablets is in section 14 Pharmaceutical information – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information.

5 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed.