2013年9月3日，葛兰素史克（GSK）黑色素瘤新药Tafinlar（dabrafenib）已获欧盟委员会（EC）批准，作为一种口服靶向药物，用于携带BRAF V600E突变的手术不可切除性黑色素瘤或转移性黑色素瘤成人患者的治疗。
Dabrafenib是一种激酶抑制剂，靶向于BRAF蛋白，这是机体内一个生物信号通路中的关键元件，该信号通路调节细胞的正常生长和死亡，包括皮肤细胞。
今年5月，Tafinlar及另一种黑色素瘤新药Mekinist（trametinib）均获得了FDA的批准。Tafinlar为BRAF抑制剂，作为一种单药口服胶囊，适用于携带BRAF V600E突变的手术不可切除性黑色素瘤或转移性黑色素瘤成人患者的治疗。Mekinist为首个MEK抑制剂，作为一种单药口服片剂，适用于携带BRAF V600E或V600K突变的手术不可切除性黑色素瘤或转移性黑色素瘤成人患者的治疗。
转移性黑色素瘤中，约有一半携带BRAF突变，该异常突变能促使黑色素瘤生长和扩散，其中BRAF V600E突变约占转移性黑色素瘤所有BRAF V600突变的85%，BRAF V600K突变约占转移性黑色素瘤所有BRAF V600突变的10%。
TAFINLAR(达拉非尼[dabrafenib])胶囊，为口服使用
适应证和用途
（1）TAFINLAR是一种激酶抑制剂适用于有不能切除或转移黑色素瘤与用FDA-批准测试检测BRAF V600E 突变患者的治疗。
（2）TAFINLAR与曲美替尼联用是适用为有被FDA批准检验检出BRAF V600E或V600K突变有不可切除的或转移黑色素瘤患者的治疗。联合的使用是根据显示持久反应率。尚未证实对TAFINLAR与曲美替尼联用疾病相关的症状和总体生存的改善。
使用的限制：TAFINLAR不适用为野生型BRAF-抑制剂治疗患者的治疗。
剂量和给药方法
（1）TAFINLAR作为单药开始治疗前确证在肿瘤标本中存在BRAF V600E突变。TAFINLAR与曲美替尼开始联用治疗前确认肿瘤样品中存在BRAF V600E或V600K突变。
（2）TAFINLAR的推荐剂量是150 mg口服每天2次作为单药或与曲美替尼联用2 mg口服每天1次。餐前至少1小时和餐后至少2小时服用TAFINLAR
剂型和规格
胶囊：50mg，75mg.
禁忌证
无。
警告和注意事项
（1）新原发恶性病，皮肤和非皮肤：当TAFINLAR被使用与曲美替尼联用可能发生。TAFINLAR治疗开始前和用治疗，和联合治疗终止后监视患者新恶性病。
（2）在BRAF野生型黑色素瘤促进肿瘤：用BRAF抑制剂可能发生细胞增殖增加。
（3）出血：接受TAFINLAR与曲美替尼联用患者可能发生重大出血事件。监视出血体征和症状。
（4）静脉血栓栓塞：接受TAFINLAR与曲美替尼联用患者可能发生深静脉血栓形成和肺栓塞。
（5）心肌病：TAFINLAR与曲美替尼联用治疗前，治疗后1个月，其后然后每2至3个月评估LVEF。
（6）眼毒性：对任何视力障碍进行眼科评价。
（7）严重发热反应：当TAFINLAR与曲美替尼联用时可能发生。
（8）严重皮肤毒性：监视皮肤毒性和继发感染。对不可耐受的2级，和3和4级皮疹尽管中断TAFINLAR 3周内不改善中断用药。
（9）高血糖：在预先存在糖尿病和高血糖患者监视血清糖水平。
（10）葡萄糖-6-磷酸脱氢酶缺乏：密切监视溶血性贫血。
（11）胚胎胎儿毒性：可能致胎儿危害。忠告有生殖潜能女性对胎儿风险。TAFINLAR可能使激素性避孕药低效和应使用另外避孕方法。
不良反应
（1）对TAFINLAR作为单药最常见不良反应(≥20%)是角化过度，头痛，发热，关节炎，乳头状瘤，脱发，和掌跖红肿疼痛综合征。
（2）TAFINLAR与曲美替尼联用最常见不良反应(≥20%)包括发热，畏寒，疲乏，皮疹，恶心，呕吐，腹泻，腹痛，外周性水肿，咳嗽，头痛，关节痛，夜汗，食欲减低，便秘，和肌痛。
药物相互作用
（1）避免同时给予CYP3A4和CYP2C8的强抑制剂。
（2）避免同时给予CYP3A4和CYP2C8强诱导剂。
（3）同时使用药物是CYP3A4，CYP2C8，CYP2C9，CYP2C19,和CYP2B6敏感底物，导致这些药物丧失疗效。
特殊人群中使用
（1）哺乳母亲：终止药物和哺乳。
（2）有生殖潜能女性和男性：忠告女性患者治疗期间和终止治疗后共2周使用高效避孕。忠告有生殖潜能男性患者精子生成受损潜在风险。

Tafinlar 50 mg & 75 mg hard capsules
1. Name of the medicinal product
Tafinlar® 50 mg hard capsules
Tafinlar® 75 mg hard capsules
2. Qualitative and quantitative composition
Each hard capsule contains dabrafenib mesilate equivalent to 50 mg of dabrafenib.
Each hard capsule contains dabrafenib mesilate equivalent to 75 mg of dabrafenib.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Hard capsule (capsule).
Opaque dark red capsules, approximately 18 mm long, with capsule shell imprinted with 'GS TEW' and '50 mg'.
Opaque dark pink capsules, approximately 19 mm long, with capsule shell imprinted with 'GS LHF' and '75 mg'.
4. Clinical particulars
4.1 Therapeutic indications
Dabrafenib is indicated in monotherapy for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see section 5.1).
4.2 Posology and method of administration
Treatment with dabrafenib should be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products.
Before taking dabrafenib, patients must have confirmation of tumour BRAF V600 mutation using a validated test.
The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma therefore dabrafenib should not be used in patients with BRAF wild-type melanoma (see sections 4.4 and 5.1).
Posology
The recommended dose of dabrafenib is 150 mg (two 75 mg capsules) twice daily (corresponding to a total daily dose of 300 mg). Dabrafenib should be taken at least one hour before, or at least 2 hours after a meal, and leaving an interval of approximately 12 hours between doses. Dabrafenib should be taken at similar times every day to increase patient compliance.
Duration of treatment
Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity (see Table 2).
Missed doses
If a dose is missed, it should not be taken if it is less than 6 hours until the next dose.
Dose modification
Two dabrafenib capsule strengths, 50 mg and 75 mg, are available to effectively manage dose modification requirements.
The management of adverse reactions may require treatment interruption, dose reduction, or treatment discontinuation (see Tables 1 and 2).
Dose modifications or interruptions are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see section 4.4).
Therapy should be interrupted if the patient's temperature is ≥ 38.5°C. Patients should be evaluated for signs and symptoms of infection (see section 4.4).
Recommended dose level reductions and recommendations for dose modifications are provided in Table 1 and Table 2, respectively. Posology adjustments resulting in a dose lower than 50 mg twice daily are not recommended.
Table 1: Recommended dabrafenib dose level reductions

Dose level	Resulting 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

Table 2: Dabrafenib dose modification schedule based on the grade of any Adverse Events (AE)

Grade (CTC-AE)*	Recommended dabrafenib 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.
Non-Caucasian patients
The safety and efficacy of dabrafenib in non-Caucasian patients have not been established. No data are available.
Older people
No adjustment of the initial dose is required in patients > 65 years of age.
Renal impairment
No dose adjustment is required for patients with mild or moderate renal impairment. There are no clinical data in subjects with severe renal impairment and the potential need for dose adjustment cannot be determined (see section 5.2). Dabrafenib should be used with caution in patients with severe renal impairment.
Hepatic impairment
No dose adjustment is required for patients with mild hepatic impairment. There are no clinical data in subjects with moderate to severe hepatic impairment and the potential need for dose adjustment cannot be determined (see section 5.2). Hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites and patients with moderate to severe hepatic impairment may have increased exposure. Dabrafenib should be used with caution in patients with moderate or severe hepatic impairment.
Paediatric population
The safety and efficacy of dabrafenib have not yet been established in children and adolescents (< 18 years). No clinical data are available. Studies in juvenile animals have shown adverse effects of dabrafenib which had not been observed in adult animals (see section 5.3).
Method of administration
The capsules are to be swallowed whole with water. They should not be chewed or crushed and should not be mixed with food or liquids due to chemical instability of dabrafenib.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma therefore dabrafenib should not be used in patients with wild-type BRAF melanoma (see sections 4.2 and 5.1).
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 of pre-renal origin in subjects with normal baseline renal function (see section 4.8). 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 dabrafenib should be interrupted if the patient's temperature is ≥ 38.5°C. Patients should be evaluated for signs and symptoms of infection. Dabrafenib 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, dabrafenib should be restarted at a reduced dose once fever resolves and as clinically appropriate (see section 4.2).
Cutaneous Squamous Cell Carcinoma (cuSCC)
Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with dabrafenib (see section 4.8). It is recommended that skin examination be performed prior to initiation of therapy with dabrafenib and monthly throughout treatment and for up to six months after treatment for cuSCC. Monitoring should continue for 6 months following discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy.
Cases of cuSCC should be managed by dermatological excision and dabrafenib treatment should be continued without any dose adjustment. Patients should be instructed to immediately inform their physician if new lesions develop.
New primary melanoma
New primary melanomas have been reported in clinical trials. These cases 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 secondary/recurrent malignancy
In vitro experiments have demonstrated paradoxical activation of mitogen activated protein kinase (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 dabrafenib 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 dabrafenib when administered in combination with the MEK inhibitor, trametinib (colorectal cancer, pancreatic cancer).
Prior to initiation of treatment patients should undergo a head and neck examination with minimally visual inspection of oral mucosa and lymph node palpation, as well as chest/abdomen Computerised Tomography (CT) scan. During treatment patients should be monitored as clinically appropriate which may include a head and neck examination every 3 months and a chest/abdomen CT scan every 6 months. Anal examinations and pelvic examinations (for women) are recommended before and at the end of treatment or when considered clinically indicated. Complete blood cell counts should be performed as clinically indicated.
Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices.
Renal failure
Renal failure has been identified in < 1 % of patients treated with dabrafenib. Observed cases were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has been reported (see section 4.8). Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, dabrafenib may need to be interrupted as clinically appropriate. Dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting (see section 5.2).
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) while on therapy.
Pancreatitis
Pancreatitis has been reported in < 1 % of dabrafenib-treated subjects. One of the events occurred on the first day of dosing and recurred following re-challenge at a reduced dose. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting dabrafenib after an episode of pancreatitis.
QT prolongation
Worst-case QTc prolongation of > 60 millisecond (msec) was observed in 3 % of dabrafenib-treated subjects (One > 500 msec in the integrated safety population). Treatment with dabrafenib is not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicinal products known to prolong the QT interval.
Electrocardiogram (ECG) and electrolytes (including magnesium) must be monitored in all patients before treatment with dabrafenib, after one month of treatment and after dose modification. Further monitoring is recommended in particular in patients with moderate to severe hepatic impairment monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with dabrafenib is not recommended in patients with QTc > 500 msec. If during treatment the QTc exceeds 500 msec, dabrafenib treatment should be temporarily interrupted, electrolyte abnormalities (including magnesium) should be corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur once the QTc decreases below 500 msec and at a lower dose as described in Table 2. Permanent discontinuation of dabrafenib treatment is recommended if the QTc increase meets values of both > 500 msec and > 60 msec change from pre-treatment values.
Effects of other substances on dabrafenib
Dabrafenib is a substrate of CYP2C8 and CYP3A4. Potent inducers of these enzymes should be avoided when possible as these agents may decrease the efficacy of dabrafenib (see section 4.5).
Agents that increase gastric pH might decrease the bioavailability of dabrafenib and should be avoided when possible (see section 4.5).
Effects of dabrafenib on other substances
Dabrafenib is an inducer of metabolising enzymes which may lead to loss of efficacy of many commonly used medicinal products (see examples in section 4.5). A drug utilisation review (DUR) is therefore essential when initiating dabrafenib treatment. Concomitant use of dabrafenib with medicinal products that are sensitive substrates of certain metabolising enzymes or transporters (see section 4.5) should generally be avoided if monitoring for efficacy and dose adjustment is not possible.
Concomitant administration of dabrafenib with warfarin may result in decreased warfarin exposure. Caution should be exercised and additional International Normalized Ratio (INR) monitoring is recommended when dabrafenib is used concomitantly with warfarin and at discontinuation of dabrafenib (see section 4.5).
Concomitant administration of dabrafenib with digoxin may result in decreased digoxin exposure. Caution should be exercised and additional monitoring of digoxin is recommended when digoxin (a transporter substrate) is used concomitantly with dabrafenib and at discontinuation of dabrafenib (see section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on dabrafenib
Dabrafenib is a substrate for the metabolising enzymes CYP2C8 and CYP3A4, while the active metabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are therefore 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) are coadministered with dabrafenib. Avoid coadministration of dabrafenib with potent inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St John's wort (Hypericum perforatum)) of CYP2C8 or CYP3A4.
Pharmacokinetic data showed an increase in repeat dose dabrafenib Cmax (26 %) and AUC (57 %) with ketoconazole (a CYP3A4 inhibitor), and increases in hydroxy- and desmethyl-dabrafenib AUC (increases of 48 and 61 %, respectively). A decrease of 33 % in AUC was noted for carboxy-dabrafenib.
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, if possible, be avoided during treatment with dabrafenib.
Effect of dabrafenib on other medicinal products
Dabrafenib is an enzyme inducer and increases the synthesis of drug-metabolising enzymes including CYP3A4, CYP2Cs and CYP2B6 and may increase the synthesis of transporters. This results in reduced plasma levels of medicinal products metabolised by these enzymes, and may affect some transported medicinal products. The reduction in plasma concentrations can lead to lost or reduced clinical effect of these medicinal products. There is also a risk of increased formation of active metabolites of these medicinal products. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGTs (glucuronide conjugating enzymes). The transport protein Pgp may also be induced as well as other transporters, e g MRP-2, BCRP and OATP1B1/1B3.
In vitro, dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4. In a clinical drug interaction study, Cmax and AUC of oral midazolam (a CYP3A4 substrate) decreased by 61 % and 74 %, respectively with co-administration of repeat dose dabrafenib using a formulation with lower bioavailability than dabrafenib formulation.
Interactions with many medicinal products eliminated through metabolism or active transport is expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.
The number of affected medicinal products is expected to be large; although the magnitude of the interaction will vary. Groups of medicinal products that can be affected include, but are not limited to:
• Analgesics (e.g. fentanyl, methadone)
• Antibiotics (e.g. clarithromycin, doxycyline)
• Anticancer agents (e.g. cabazitaxel)
• Anticoagulants (e.g. acenocoumarol, warfarin (see section 4.4))
• Antiepileptic (e.g. carbamazepine, phenytoin, primidone, valproic acid)
• Antipsychotics (e.g. haloperidol)
• Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)
• Cardiac glycosides (e.g. digoxin, see section 4.4)
• Corticosteroids (e.g. dexamethasone, methylprednisolone)
• HIV antivirals (e.g. amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir)
• Hormonal contraceptives (see section 4.6)
• Hypnotics (e.g. diazepam, midazolam, zolpidem)
• Immunosuppressants (e.g. cyclosporin, tacrolimus, sirolimus)
• Statins metabolized by CYP3A4 (e.g. atorvastatin, simvastatin)
Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib. Upon discontinuation of dabrafenib offset of induction is gradual, concentrations of sensitive CYP3A4, CYP2B6, CYP2C8, CYP2C9 and CYP2C19, UDP glucuronosyl transferase (UGT) and transporter substrates may increase and patients should be monitored for toxicity and dosage of these agents may need to be adjusted.
In vitro, dabrafenib is a mechanism based inhibitor of CYP3A4. Therefore, transient inhibition of CYP3A4 may be observed during the first few days of treatment.
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 can not 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 humanorganic 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.
Effect of food on dabrafenib
Patients should take dabrafenib at least one hour prior to or two hours after a meal due to the effect of food on dabrafenib absorption (see section 5.2).
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Women of chilbearing potential/Contraception in females
Women of childbearing potential must use effective methods of contraception during therapy and for 4 weeks following discontinuation. Dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception should be used (see section 4.5).
Pregnancy
There are no data from the use of dabrafenib in pregnant women. Animal studies have shown reproductive toxicity and embryofoetal developmental toxicities, including teratogenic effects (see section 5.3). Dabrafenib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus. If the patient becomes pregnant while taking dabrafenib, the patient should be informed of the potential hazard to the foetus.
Breast-feeding
It is not known whether dabrafenib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the breast-feeding child cannot be excluded. A decision should be made whether to discontinue breastfeeding or discontinue dabrafenib, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
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 (see section 5.3). Male patients should be informed of the potential risk for impaired spermatogenesis, which may be irreversible.
4.7 Effects on ability to drive and use machines
Dabrafenib has minor influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of dabrafenib should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills. Patients should be made aware of the potential for fatigue and eye problems to affect these activities.
4.8 Undesirable effects
Summary of the safety profile
The safety profile is based on data from five clinical monotherapy studies and included 578 patients with melanoma. The most frequently occurring adverse drug reactions (ADRs) (≥ 15 %) reported with dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, papilloma, alopecia, rash and vomiting.
Tabulated summary of adverse reactions
ADRs which were reported are listed below by MedDRA body system organ class and by frequency. The following convention has been utilised for the classification of frequency:
Very common
 ≥ 1/10
Common
 ≥ 1/100 to < 1/10
Uncommon
 ≥ 1/1,000 to < 1/100
Rare
 ≥ 1/10,000 to < 1/1,000
Not known
(cannot be estimated from the available data)
Table 3: Adverse reactions reported in melanoma trials

System Organ Class	Frequency (all grades)	Adverse Reactions
Neoplasms benign, malignant and unspecified (including cysts and polyps)	Very common	Papilloma
	Common	Cutaneous squamous cell carcinoma
	Common	Seborrhoeic keratosis
	Common	Acrochordon (skin tags)
	Common	Basal cell carcinoma
	Uncommon	New primary melanoma
Immune system disorders	Uncommon	Hypersensitivity
	Uncommon	Panniculitis
Metabolism and nutrition disorders	Very common	Decreased appetite
	Common	Hypophosphataemia
	Common	Hyperglycaemia
Nervous system disorders	Very common	Headache
Eye disorders	Uncommon	Uveitis
Respiratory, thoracic and mediastinal disorders	Very common	Cough
Gastrointestinal disorders	Very common	Nausea
	Very common	Vomiting
	Very common	Diarrhoea
	Common	Constipation
	Uncommon	Pancreatitis
Skin and subcutaneous tissue disorders	Very common	Hyperkeratosis
	Very common	Alopecia
	Very common	Rash
	Very common	Palmar –plantar erythrodysaesthesia syndrome
	Common	Dry skin
	Common	Pruritus
	Common	Actinic keratosis
	Common	Skin lesion
	Common	Erythema
Musculoskeletal and connective tissue disorders	Very common	Arthralgia
	Very common	Myalgia
	Very common	Pain in extremity
Renal and urinary disorders	Uncommon	Renal failure, acute renal failure
	Uncommon	Nephritis
General disorders and administration site conditions	Very common	Pyrexia
	Very common	Fatigue
	Very common	Chills
	Very common	Asthenia
	Common	Influenza-like illness
Investigations	Common	LVEF decrease
	Uncommon	QT prolongation

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
Ireland
IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie
United Kingdom
the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
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 as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency or pre-renal origin in subjects with normal baseline renal function. 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 sections 4.2 and 4.4).
Cutaneous squamous cell carcinoma
Cutaneous squamous cell carcinomas (including those classified as keratoacanthoma or mixed keratoacanthoma subtype) occurred in 9 % of patients treated with dabrafenib. 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 dabrafenib. Cases were managed with excision and did not require treatment modification (see section 4.4).
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 section 4.4). Cases of RAS-driven malignancies have been seen with dabrafenib. Patients should be monitored as clinically appropriate.
QT prolongation
One subject in the integrated safety population experienced a QTcB > 500 ms and only 3 % experienced worst-case QTc prolongation of > 60 msec.
LVEF decrease
Decreased LVEF has been reported in 1 % of patients with most cases being asymptomatic and reversible. Patients with LVEF lower than the institutional lower limit of normal were not included in clinical trials with dabrafenib.
Arthralgia
Arthralgia was reported very commonly in clinical trials with dabrafenib (25 %) although these were mainly grade 1 and 2 in severity with Grade 3 occurring uncommonly (< 1 %) and no Grade 4 occurrences being reported.
Hypophosphataemia
Hypophosphataemia has been reported commonly in clinical trials with dabrafenib (7 %). It should be noted that approximately half of these occurrences (4 %) were Grade 3 in severity.
Pancreatitis
Pancreatitis has been reported in dabrafenib-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 dabrafenib after an episode of pancreatitis (see section 4.4).
Renal failure
Renal failure due to pyrexia-associated pre-renal azotaemia or granulomatous nephritis was uncommon; however dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN). Caution should be used in this setting (see section 4.4).
Special populations
Elderly
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 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.
4.9 Overdose
There is no specific treatment for an overdose of dabrafenib. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE23
Mechanism of action
Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 50 % of melanoma. The most commonly observed BRAF mutation is V600E which accounts for approximately 90 % of the BRAF mutations that are seen in melanoma.
Preclinical data generated in biochemical assays demonstrated that dabrafenib inhibits BRAF kinases with activating codon 600 mutations (Table 4).
Table 4: Kinase inhibitory activity of dabrafenib against RAF kinases

Kinase	Inhibitory concentration 50 (nM)
BRAF V600E	0.65
BRAF V600K	0.50
BRAF V600D	1.8
BRAF WT	3.2
CRAF WT	5.0

Dabrafenib demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated ERK) and inhibited cell growth of BRAF V600 mutant melanoma cell lines, in vitro and in animal models.
In subjects with BRAF V600 mutation positive melanoma, administration of dabrafenib resulted in inhibition of tumour phosphorylated ERK relative to baseline.
Determination of BRAF mutation status
Before taking dabrafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. 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). The 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 BRAF V600E or V600K mutation positive tumors were eligible for study participation.
Subsequently, all patient samples were re-tested using the bioMerieux (bMx) THxID BRAF validated assay, which has CE marking. The bMx THxID BRAF assay is an allele-specific PCR performed on DNA extracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and V600K mutations with high sensitivity (down to 5 % V600E and V600K sequence in a background of wild-type sequence using DNA extracted from FFPE tissue). Non-clinical and clinical studies with retrospective bi-directional Sanger sequencing analyses have shown that the test also detects the less common BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of the specimens from the non-clinical and clinical studies (n = 876) that were mutation positive by the THxID BRAF assay and subsequently were sequenced using the reference method, the specificity of the assay was 94 %.
Clinical efficacy and safety
The efficacy of dabrafenib in the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma has been evaluated in 3 studies (BRF113683 [BREAK-3], BRF113929 [BREAK-MB], and BRF113710 [BREAK-2]) including patients with BRAF V600E and/or V600K mutations.
Included in these studies were in total 402 subjects with BRAF V600E and 49 subjects with BRAF V600K mutation. Patients with melanoma driven by BRAF mutations other than V600E were excluded from the confirmatory trial and with respect to patients with the V600K mutation in single arm studies the activity appears lower than in V600E tumours.
No data is available in patients with melanoma harbouring BRAF V600 mutations others than V600E and V600K. Efficacy of dabrafenib in subjects previously treated with a protein kinase inhibitor has not been investigated.
Previously untreated patients (Results from the Phase III study [BREAK-3])
The efficacy and safety of dabrafenib were evaluated in a Phase III randomized, open-label study [BREAK 3] comparing dabrafenib to dacarbazine (DTIC) in previously untreated patients with BRAF V600E mutation positive advanced (unresectable Stage III) or metastatic (Stage IV) melanoma. Patients with melanoma driven by BRAF mutations other than V600E were excluded.
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. Patients on the DTIC arm were allowed to cross over to 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 % Cl 0.18, 0.51; p < 0.0001) was achieved. Efficacy results from the primary analysis and a post-hoc analysis with 6-months additional follow up are summarized in Table 5. Overall survival data from a further post-hoc analysis based on a 18 December 2012 data cut are shown in Figure 1.
Table 5: Efficacy in previously untreated patients (BREAK-3 Study, 25 June 2012)

Data as of December 19, 2011		Data as of June 25, 2012
	Dabrafenib N=187	DTIC N=63	Dabrafenib N=187	DTIC N=63
Progression-free survival
Median, months (95 % CI)	5.1 (4.9, 6.9)	2.7 (1.5, 3.2)	6.9 (5.2,9.0)	2.7 (1.5,3.2)
HR (95 % CI)	0.30 (0.18, 0.51) P < 0.0001		0.37 (0.24, 0.58) P < 0.0001
Overall responsea
% (95 % CI)	53 (45.5, 60.3)	19 (10.2, 30.9)	59 (51.4, 66.0)	24 (14, 36.2)
Duration of response
Median, months (95 % CI)	N=99 5.6 (4.8, NR)	N=12 NR (5.0, NR)	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 confirmed complete +partial response.
As of 25 June 2012 cut-off, thirty five subjects (55.6 %) of the 63 randomized to DTIC had crossed over to dabrafenib and 63 % of subjects randomised to dabrafenib and 79 % of subjects randomised to DTIC had progressed or died. Median PFS after cross-over was 4.4 months.
Table 6: Survival data from the primary analysis and post-hoc analyses

Cut-off date	Treatment	Number of deaths (%)	Hazard Ratio (95% CI)
December 19, 2011	DTIC	9 (14%)	0.61 (0.25, 1.48) (a)
	dabrafenib	21 (11%)
June 25, 2012	DTIC	21 (33%)	0.75 (0.44, 1.29) (a)
	dabrafenib	55 (29%)
December 18, 2012	DTIC	28 (44%)	0.76 (0.48, 1.21) (a)
	dabrafenib	78 (42%)

a) Patients were not censored at the time of cross-over
Overall survival data from a further post-hoc analysis based on the 18 December 2012 data cut demonstrated a 12 month OS rate of 63 % and 70 % for DTIC and dabrafenib treatments respectively.
Figure 1: 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) in the V600E patient population, as assessed by investigators. The confirmed OIRR and other efficacy results per investigator assessment are presented in Table 7.
Table 7: Efficacy data in patients with brain metastases (BREAK-MB Study)

All Treated Subjects Population
	BRAF V600E (Primary)		BRAF V600K
	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 < 0.001b	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)
Median, months	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 BRAF V600E mutation positive subjects.
Patients who were previously untreated or failed at least one prior systemic therapy (Results from the Phase II [BREAK-2])
BRF113710 (BREAK-2) was a multi-centre, single-arm, study that enrolled 92 subjects with metastatic melanoma (Stage IV) with confirmed BRAF V600E or V600K mutation-positive melanoma.
The investigator assessed confirmed response rate in patients with BRAF V600E metastatic melanoma (n=76) was 59 % (95 % CI: 48.2, 70.3) and the median duration of response was 5.2 months (95 % CI: 3.9, not calculable) based on a median follow-up time of 6.5 months. In patients with BRAF V600K mutation positive metastatic melanoma (n=16) the response rate was 13 % (95 % CI: 0.0, 28.7) with a median duration of response of 5.3 months (95 % CI: 3.7, 6.8). Although limited by the low number of patients, median OS appeared consistent with data in patients with BRAF V600E positive tumours.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with dabrafenib in one or more subsets of the paediatric population in melanoma (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Dabrafenib is absorbed orally with median time to achieve peak plasma concentration of 2 hours post-dose. Mean absolute bioavailability of oral dabrafenib is 95 % (90 % CI: 81, 110 %). Dabrafenib exposure (Cmax and AUC) increased in a dose proportional manner between 12 and 300 mg following single-dose administration, but the increase was less than dose-proportional after repeat twice daily dosing. A decrease in exposure was observed with repeat dosing, likely due to induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. Following administration of 150 mg twice daily, geometric mean Cmax, AUC(0-) and predose concentration (C) 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.
Dabrafenib is a substrate of human P-glycoprotein (Pgp) and murine BCRP in vitro. However, these transporters have minimal impact on dabrafenib oral bioavailability and elimination and the risk for clinically relevant drug-drug interactions with inhibitors of Pgp or BCRP is low.
Neither dabrafenib nor its 3 main metabolites were demonstrated to be inhibitors of Pgp in vitro.
Biotransformation
The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib, which is further oxidized via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenib can be decarboxylated via a non-enzymatic process to form desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut and reabsorbed. Desmethyl-dabrafenib is metabolized by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hrs while the carboxy- and desmethyl-metabolites exhibited longer half-lives (21-22 hours). Mean metabolite to parent AUC ratios following repeat-dose administration were 0.9, 11 and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib; while the activity of carboxy-dabrafenib is not likely to be significant.
Elimination
Terminal half-life following an intravenous single microdose is 2.6 hours. Dabrafenib terminal half-life after a single dose is 8 hours due to absorption-limited elimination after oral administration (flip-flop pharmacokinetics). IV plasma clearance is 12 L/hr.
After an oral dose, the major route of elimination of dabrafenib is metabolism, mediated via CYP3A4 and CYP2C8. Dabrafenib related material is excreted primarily in faeces, with 71 % of an oral dose recovered in faeces and 23 % in urine as metabolites only.
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 section 4.2).
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 section 4.2).
Elderly
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.
Paediatric population
No studies have been conducted to investigate the pharmacokinetics of dabrafenib in paediatric patients.
5.3 Preclinical safety data
Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay.
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 indices. Developmental toxicity including embryo-lethality and ventricular septal defects were seen 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).
Male fertility studies with dabrafenib have not been conducted. However, in repeat dose studies, testicular degeneration/depletion was seen in rats and dogs (≥ 0.2 times the human clinical exposure based on AUC). Testicular changes in rat and dog were still present following a 4-week recovery period (see section 4.6).
Cardiovascular effects, including coronary arterial degeneration/necrosis and/or haemorrhage, cardiac atrioventricular valve hypertrophy/haemorrhage and atrial fibrovascular proliferation were seen in dogs (≥ 2 times clinical exposure based on AUC). Focal arterial/perivascular inflammation in various tissues was observed in mice and an increased incidence of hepatic arterial degeneration and spontaneous cardiomyocyte degeneration with inflammation (spontaneous cardiomyopathy) was observed in rats (≥ 0.5 and 0.6 times clinical exposure for rats and mice respectively). Hepatic effects, including hepatocellular necrosis and inflammation, were observed in mice (≥ 0.6 times clinical exposure). Bronchoalveolar inflammation of the lungs was observed in several dogs at ≥ 20 mg/kg/day (≥ 9 times human clinical exposure based on AUC) and was associated with shallow and/or laboured breathing.
Reversible haematological effects have been observed in dogs and rats given dabrafenib. In studies of up to 13 weeks, decreases in reticulocyte counts and/or red cell mass were observed in dogs and rats (≥ 10 and 1.4 times clinical exposure, respectively).
In juvenile toxicity studies in rats, effects on growth (shorter long bone length), renal toxicity (tubular deposits, increased incidence of cortical cysts and tubular basophilia and reversible increases in urea and/or creatinine concentrations), 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.
Dabrafenib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay.
6. Pharmaceutical particulars
6.1 List of excipients
Capsules content
Microcrystalline cellulose
Magnesium stearate
Colloidal silicone dioxide
Capsule shell
Red iron oxide (E172)
Titanium dioxide (E171)
Hypromellose (E464)
Printing ink:
Black iron oxide (E172)
Shellac
Propylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Opaque white high density polyethylene (HDPE) bottle with polypropylene screw cap and a silica gel desiccant.
Each bottle contains either 28 or 120 hard capsules
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
GlaxoSmithKline Trading Services Limited
Currabinny
Carrigaline
County Cork
Ireland
8. Marketing authorisation number(s)
EU/1/13/865/001 – Tafinlar 50 mg – 28 hard capsules
EU/1/13/865/002 – Tafinlar 50 mg – 120 hard capsules
EU/1/13/865/003 – Tafinlar 75 mg – 28 hard capsules
EU/1/13/865/004 – Tafinlar 75 mg – 120 hard capsules
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 26 August 2013
10. Date of revision of the text
9 May 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
2014年1月10日美国食品药品监督管理局(FDA)批准Mekinist (曲美替尼[trametinib])与Tafinlar (达拉非尼[dabrafenib])联用治疗有不可切除的(不能用外科去除)和转移(晚期)晚期黑色素瘤患者。
2013年5月， FDA批准两药作为单药治疗不可切除的或转移黑色素瘤患者。黑色素瘤是最具侵略性类型皮肤癌和是来自皮肤疾病主要死亡病因。美国国家癌症研究所估计2013年76,690 美国人将被诊断有黑色素瘤和9,480人将死于此病。
Trametinib和Tafinlar被用于阻断相同分子通路的不同部位的信号促进癌细胞生长。它们特别适用作为联合治疗肿瘤表达基因突变被称为BRAF V600E和V600K黑色素瘤患者。BRAF蛋白质涉及在正常细胞生长中调节，但在约半数来自皮肤黑色素瘤突变。
FDA的药物评价和研究中心血液学和肿瘤室主任Richard Pazdur，医学博士说：“曲美替尼和Tafinlar是被批注联合治疗黑色素瘤的第一个药物。”“它们为联合使用的发展是根据疾病的生物学通路强有力了解。这个批准说明继续研究药物为临床发展联合的价值。”
在162例有BRAF V600E和V600K突变有不可切除的或转移黑色素瘤参加者的临床试验中证实曲美替尼与Tafinlar联用的安全性和有效性，参加者大多数没有接受既往治疗。参加者接受或曲美替尼与Tafinlar联用和Tafinlar作为单药直至他们的黑色素瘤进展和副作用变成不能耐受。
结果显示用曲美替尼与Tafinlar联用治疗的参加者76%有其癌皱缩和消失(客观反应)平均持续10.5个月。相反，54 percent of 参加者用Tafinlar作为单药治疗经历客观反应平均持续5.6个月。正在进行临床试验确定曲美替尼与Tafinlar联用是否改进生存。
接受曲美替尼与Tafinlar联用参加者报道的最常见副作用包括发热，畏寒，疲倦，皮疹，恶心，呕吐，腹泻，腹痛，外周性水肿(手和足肿胀)，咳嗽，头痛，关节痛，夜汗，食欲减低，便秘和肌肉痛。临床试验期间，当曲美替尼与Tafinlar联合使用发热的发生率和严重程度增加。
严重副作用包括出血，凝块形成，心衰，皮肤问题和眼问题。Tafinlar的严重副作用之一—皮肤新鳞状细胞癌的发展—当药物与曲美替尼联合使用时减少；这与这些两个药物在靶向分子通路的作用一致。在本试验联用时疲乏鳞状细胞癌发生率为7%与之比较用单药时19%。其他临床意义副作用包括肾受损。
应忠告生育能力妇女曲美替尼和Tafinlar在发育胎儿中至出生缺陷。还应忠告男性和妇女曲美替尼和Tafinlar治疗可能致不孕不育。
FDA在监管局加快批准程序下批准曲美替尼和Tafinlar的联用，此程序根据临床数据显示该药物有某个对某个替代性终点有理由预测患者临床获益时允许FDA批准某药治疗某种严重疾病。这个程序提供患者较早得到有前途新药而公司进行验证性临床试验。FDA还在监管局的优先审评下审评这个药物联用，因为它们显示潜能在治疗一种显著严重情况中改进安全性和有效性。
美国FDA批准曲美替尼[Trametinib]与Tafinlar联用为晚期黑色素瘤