Safety profile of TAFINLAR® (dabrafenib) +  MEKINIST® (trametinib)

Adverse reactions reported in the integrated safety population of TAFINLAR + MEKINIST in the studies MEK115306, MEK116513, BRF113928, and BRF115532 (n=1076)^1,2

The corresponding frequency for each adverse drug reaction is based on the following: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000).^1,2

Table adapted from TAFINLAR and MEKINIST SmPCs.^1,2

The most common adverse reactions (incidence ≥20%) for TAFINLAR + MEKINIST were: pyrexia, fatigue, nausea, chills, headache, diarrhoea, vomiting, arthralgia and rash.

Contraindications

TAFINLAR contraindications: Hypersensitivity to the active substance or to the following excipients: microcrystalline cellulose, magnesium stearate, colloidal silicone dioxide, red iron oxide (E172), titanium dioxide (E171), hypromellose (E464), black iron oxide (E172), shellac, propylene glycol.¹

MEKINIST contraindications: Hypersensitivity to the active substance or to the following excipients: mannitol (E421), microcrystalline cellulose (E460), hypromellose (E464), croscarmellose sodium (E468), magnesium stearate (E470b), sodium laurilsulfate, colloidal silicon dioxide (E551), titanium dioxide (E171), polyethylene glycol, iron oxide yellow (E172), polysorbate 80 (E433) and iron oxide red (E172).²

Special populations¹

Elderly
Patients ≥65 years were more likely to experience adverse reactions leading to permanent discontinuation of the medicinal product, dose reduction, and dose interruption than those <65 years. Please refer to the SmPCs for further information about the safety profile in elderly populations.

TAFINLAR + MEKINIST in patients with brain metastases
The safety and efficacy of the combination of TAFLINLAR + MEKINIST have been evaluated in a multi-cohort, open-label, Phase II study in patients with BRAF V600 mutant melanoma with brain metastases. The safety profile observed in these patients appears to be consistent with the integrated safety profile of the combination.

Special warnings and precautions for use^1,2

When TAFINLAR is given in combination with MEKINIST, the SmPC of TAFINLAR and MEKINIST must be consulted prior to initiation of combination treatment. For additional information on warnings and precautions associated with treatment, please refer to the respective SmPC.

BRAF V600 testing

The efficacy and safety of TAFINLAR + MEKINIST has not been evaluated in patients whose melanoma tested negative for the BRAF V600 mutation. TAFINLAR should not be used in patients with wild-type BRAF melanoma and NSCLC.

TAFINLAR + MEKINIST in patients with melanoma who have progressed on a BRAF inhibitor
There are limited data in patients taking the combination of TAFINLAR + MEKINIST who have progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be lower in these patients. Therefore, other treatment options should be considered before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of treatments following progression on a BRAF inhibitor therapy has not been established.

New malignancies
New malignancies, cutaneous and non-cutaneous, can occur with TAFINLAR + MEKINIST.

Cutaneous malignancies

Cutaneous squamous cell carcinoma (cuSCC)

Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with TAFINLAR + MEKINIST. In the integrated safety population of patients with melanoma and advanced NSCLC, cuSCC occurred in 2% (19/1076) of patients receiving TAFINLAR + MEKINIST. The median time to diagnosis of the first occurrence of cuSCC in study MEK115306 was 223 days (range 56 to 510 days) in the combination therapy arm and 60 days (range 9 to 653 days) in the TAFINLAR monotherapy arm. In the Phase III study BRF115532 (COMBI-AD) in the adjuvant treatment of melanoma, 1% (6/435) of patients receiving TAFINLAR + MEKINIST as compared to 1% (5/432) of patients receiving placebo developed cuSCC. The median time to onset of the first occurrence of cuSCC in the combination arm of the adjuvant treatment study was approximately 18 weeks and was 33 weeks in the placebo arm.

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 or until initiation of another anti-neoplastic therapy.

Cases of cuSCC should be managed by dermatological excision and TAFINLAR treatment or, if taken in combination, TAFINLAR + MEKINIST 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 melanoma was reported in patients receiving TAFINLAR + MEKINIST. Cases of new primary melanoma can be managed with excision and do not require treatment modification. Monitoring for skin lesions should occur as described for cuSCC.

Non-cutaneous malignancies

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. RAS-associated malignancies have been reported in clinical trials with 
TAFINLAR + MEKINIST (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 are recommended before and at the end of treatment or when considered clinically indicated. Complete blood cell counts and blood chemistry should be performed as clinically indicated.

The benefits and risks should be considered before administering TAFINLAR in patients with a prior or concurrent cancer associated with RAS mutations. No dose modification of trametinib is required with TAFINLAR + MEKINIST.

Following discontinuation of TAFINLAR, 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.

Haemorrhage

Haemorrhagic events, including major haemorrhagic and fatal haemorrhages, have occurred in patients taking TAFINLAR + MEKINIST. The potential for these events in patients with low platelet counts (<75,000) has not been established, as such patients were excluded from clinical trials. The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patients should be treated as clinically indicated.

Visual impairment

In clinical trials ophthalmologic reactions, including uveitis, iridocyclitis and iritis, have been reported in patients treated with TAFINLAR + MEKINIST. Patients should be routinely monitored for visual signs and symptoms (such as change in vision, photophobia and eye pain) while on therapy. MEKINIST is not recommended in patients with a history of retinal vein occlusion (RVO). The safety of MEKINIST in subjects with predisposing factors for RVO, including uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes, has not been established. In patients who are diagnosed with RVO, treatment with MEKINIST should be permanently discontinued.

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

Retinal pigment epithelial dystrophy (RPED) and RVO may occur with TAFINLAR + MEKINIST. No dose modification of TAFINLAR is required when taken in combination with MEKINIST following diagnosis of RVO or RPED.

Pyrexia

Fever has been reported in clinical trials with TAFINLAR + MEKINIST.

The incidence and severity of pyrexia are increased with combination therapy. In the combination therapy arm of study MEK115306 in patients with unresectable or metastatic melanoma, pyrexia was reported in 57% (119/209) of patients with 7% Grade 3, as compared to the TAFINLAR monotherapy arm with 33% (69/211) of patients reporting pyrexia, 2% Grade 3. In the Phase II study BRF113928 in patients with advanced NSCLC, the incidence and severity of pyrexia were increased slightly when TAFINLAR was used in combination with MEKINIST (48%, 3% Grade 3) as compared to dabrafenib monotherapy (39%, 2% Grade 3). In the Phase III study BRF115532 in the adjuvant treatment of melanoma, the incidence and severity of pyrexia were higher in the TAFINLAR + MEKINIST arm (67%; 6% Grade 3/4) as compared to the placebo arm (15%; <1% Grade 3).

For patients with unresectable or metastatic melanoma who received TAFINLAR + MEKINIST and developed pyrexia, approximately half of the first occurrences of pyrexia happened within the first month of therapy and approximately one-third of the patients had 3 or more events.

Therapy should be interrupted if the patient's temperature is ≥38°C. 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. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patients should be evaluated for signs and symptoms of infection. When used as monotherapy, or both TAFINLAR and MEKINIST when used in combination, should be restarted if the 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. Please see individual SmPCs for further information.

Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction

TAFINLAR + MEKINIST has been reported to decrease LVEF. No dose modification of TAFINLAR is required when taken in combination with MEKINIST. In patients receiving TAFINLAR in combination with MEKINIST, there have been occasional reports of acute, severe left ventricular dysfunction due to myocarditis. Full recovery was observed when stopping treatment. Physicians should be alert to the possibility of myocarditis in patients who develop new or worsening cardiac signs or symptoms. Trametinib should be used with caution in patients with impaired left ventricular function. Patients with left ventricular dysfunction, New York Heart Association Class II, III, or IV heart failure, acute coronary syndrome within the past 6 months, clinically significant uncontrolled arrhythmias, and uncontrolled hypertension were excluded from clinical trials; safety of use in this population is therefore unknown. LVEF should be evaluated in all patients prior to initiation of treatment with trametinib, one month after initiation of therapy, and then at approximately 3-monthly intervals while on treatment.

Renal failure

Renal failure has been identified in ≤1% of patients treated with TAFINLAR + MEKINIST. Observed cases were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has been reported. Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, TAFINLAR may need to be interrupted as clinically appropriate. TAFINLAR has not been studied in patients with renal insufficiency (defined as creatinine >1.5 x upper limit of normal), therefore caution should be used in this setting.

Hepatic events

Hepatic adverse events have been reported in clinical trials with TAFINLAR + MEKINIST. It is recommended that patients receiving treatment with TAFINLAR + MEKINIST have liver function monitored every 4 weeks for 6 months after treatment initiation with trametinib. Liver monitoring may be continued thereafter as clinically indicated. 

Hypertension

Elevations in blood pressure have been reported in association with TAFINLAR + MEKINIST, in patients with or without pre-existing hypertension. Blood pressure should be measured at baseline and monitored during treatment with MEKINIST, with control of hypertension by standard therapy as appropriate.

Interstitial lung disease (ILD)/Pneumonitis

Cases of pneumonitis or ILD have been reported in clinical trials with TAFINLAR + MEKINIST. MEKINIST should be withheld in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. MEKINIST should be permanently discontinued for patients diagnosed with treatment-related ILD or pneumonitis. If TAFINLAR is being used in combination with MEKINIST then therapy with TAFINLAR may be continued at the same dose.

Rash

Rash has been observed in about 60% of patients in TAFINLAR monotherapy studies and about 24% of patients in clinical trials with TAFINLAR + MEKINIST. The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions.

Rhabdomyolysis

Rhabdomyolysis has been reported in patients taking TAFINLAR + MEKINIST. In some cases, patients were able to continue MEKINIST. In more severe cases, hospitalisation, interruption or permanent discontinuation of MEKINIST or TAFINLAR + MEKINIST was required. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated.

Pancreatitis

Pancreatitis has been reported in <1% of patients treated with TAFINLAR + MEKINIST in unresectable or metastatic melanoma clinical trials and about 4% of patients treated with TAFINLAR + MEKINIST in the NSCLC clinical trial. In the adjuvant treatment of melanoma trial, pancreatitis was reported in <1% (1/435) of patients receiving TAFINLAR + MEKINIST, and no patients receiving placebo. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting TAFINLAR after an episode of pancreatitis.

Deep vein thrombosis/Pulmonary embolism

Pulmonary embolism or deep vein thrombosis can occur with TAFINLAR + MEKINIST. If patients develop symptoms of pulmonary embolism or deep vein thrombosis such as shortness of breath, chest pain, or arm or leg swelling, they should immediately seek medical care. Permanently discontinue TAFINLAR + MEKINIST for life-threatening pulmonary embolism.

Severe cutaneous adverse reactions

Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with TAFINLAR + MEKINIST. Before initiating treatment, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs appear, TAFINLAR + MEKINIST should be withdrawn.

Gastrointestinal disorders

Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking TAFINLAR + MEKINIST. Treatment with MEKINIST monotherapy or TAFINLAR + MEKINIST should be used with caution in patients with risk factors for gastrointestinal perforation, including history of diverticulitis, metastases to the gastrointestinal tract and concomitant use of medicinal products with a recognised risk of gastrointestinal perforation.

Sarcoidosis

Cases of sarcoidosis have been reported in patients treated with TAFINLAR + MEKINIST, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases, treatment with TAFINLAR + MEKINIST was maintained. In case of a diagnosis of sarcoidosis, relevant treatment should be considered. It is important not to misinterpret sarcoidosis as disease progression.

Haemophagocytic lymphohistiocytosis

In post-marketing experience, haemophagocytic lymphohistiocytosis (HLH) has been observed in patients treated with TAFINLAR + MEKINIST. Caution should be taken when MEKINIST is administered in combination with TAFINLAR. If HLH is confirmed, administration of TAFINLAR + MEKINIST should be discontinued and treatment for HLH initiated.

Sodium

MEKINIST contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Effects of other medicinal products on dabrafenib
TAFINLAR 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 TAFINLAR.

In vivo and in vitro data suggest that the pharmacokinetics of MEKINIST are unlikely to be affected by other medicinal products. MEKINIST is not a substrate of CYP enzymes or of the transporters BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2, and MATE1. MEKINIST is an 
in vitro substrate of BSEP and the efflux transporter P-gp. Although MEKINIST exposure is unlikely to be affected by inhibition of BSEP, increased levels of MEKINIST upon strong inhibition of hepatic P-gp cannot be excluded.

Effects of dabrafenib on other medicinal products
TAFINLAR is an inducer of metabolising enzymes, which may lead to loss of efficacy of many commonly used medicinal products. A drug utilisation review (DUR) is therefore essential when initiating TAFINLAR treatment. Concomitant use of TAFINLAR with medicinal products that are sensitive substrates of certain metabolising enzymes or transporters should generally be avoided if monitoring for efficacy and dose adjustment is not possible.

Concomitant administration of TAFINLAR with warfarin results in decreased warfarin exposure. Caution should be exercised and additional International Normalised Ratio (INR) monitoring is recommended when TAFINLAR is used concomitantly with warfarin and at discontinuation of TAFINLAR.

Concomitant administration of TAFINLAR 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 TAFINLAR and at discontinuation of TAFINLAR.

The effect of repeat-dose MEKINIST on the steady state pharmacokinetics of combination oral contraceptives norethindrone and ethinyl estradiol was assessed in a clinical study that consisted of 19 female patients with solid tumours. Norethindrone exposure increased by 20% and ethinyl estradiol exposure was similar when co-administered with MEKINIST. Based on these results, no loss of efficacy of hormonal contraceptives is expected when co-administered with MEKINIST monotherapy.

Effect of other medicinal products on trametinib
As MEKINIST is metabolised predominantly via deacetylation mediated by hydrolytic enzymes (e.g. carboxyl-esterases), its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions. Drug-drug interactions via these hydrolytic enzymes cannot be ruled out and could influence the exposure to MEKINIST.

MEKINIST is an in vitro substrate of the efflux transporter P-gp. As it cannot be excluded that strong inhibition of hepatic P-gp may result in increased levels of MEKINIST, caution is advised when co-administering MEKINIST with medicinal products that are strong inhibitors of P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole).

Effect of trametinib on other medicinal products
Based on in vitro and in vivo data, MEKINIST is unlikely to significantly affect the pharmacokinetics of other medicinal products via interaction with CYP enzymes or transporters. MEKINIST may result in transient inhibition of BCRP substrates (e.g. pitavastatin) in the gut, which may be minimised with staggered dosing (2 hours apart) of these agents and MEKINIST.

Based on clinical data, no loss of efficacy of hormonal contraceptives is expected when co-administered with MEKINIST monotherapy.