Spexotras 0.05 mg/ml powder for oral solution

Low-grade glioma

Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged 1 year and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.

High-grade glioma

Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged 1 year and older with high-grade glioma (HGG) with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment.

Treatment with Spexotras should be initiated and supervised by a qualified physician experienced in the use of anti-cancer medicinal products.

Before taking Spexotras, patients must have confirmation of BRAF V600E mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If the CE-marked IVD is not available, confirmation of BRAF V600E should be assessed by an alternative validated test.

Spexotras is used in combination with dabrafenib dispersible tablets. See the summary of product characteristics (SmPC) for posology of dabrafenib dispersible tablets.

Posology

The recommended once-daily dose of Spexotras is determined by body weight (Table 1).

Table 1 Dosing regimen by body weight

Duration of treatment

Treatment with Spexotras should continue until disease progression or until the development of unacceptable toxicity. There are limited data in patients older than 18 years of age with glioma, therefore continued treatment into adulthood should be based on benefits and risks to the individual patient as assessed by the physician.

Missed or delayed doses

If a dose of Spexotras is missed, it should only be taken if it is more than 12 hours until the next scheduled dose. If vomiting occurs after taking Spexotras, an additional dose should not be administered and the next dose should be taken at the next scheduled time.

Dose modification

The management of adverse reactions may require dose reduction, treatment interruption or treatment discontinuation (see Tables 2 and 3).

If treatment-related toxicities occur, then both trametinib and dabrafenib should be simultaneously dose reduced, interrupted or discontinued. Exceptions where dose modifications are necessary for only one of the two treatments are detailed below for uveitis, RAS mutation-positive non-cutaneous malignancies (primarily related to dabrafenib), left ventricular ejection fraction (LVEF) reduction, retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED) and interstitial lung disease (ILD)/pneumonitis (primarily related to trametinib).

Dose modifications or interruptions are not recommended for adverse reactions of cutaneous malignancies (see dabrafenib dispersible tablets SmPC for further details).

Table 2 Dose modification schedule based on the grade of any adverse reactions (excluding pyrexia)

The recommended dose reductions to approximately 75% of the recommended dose (first dose reduction level) and to approximately 50% of the recommended dose (second dose reduction level) are shown in Table 3.

Table 3 Recommended dose reduction levels for adverse reactions

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 trametinib dose should not exceed the recommended dose indicated in Table 1.

Dose modifications for selected adverse reactions

Pyrexia

If a patient's temperature is ≥ 38° C, therapy with trametinib and dabrafenib should be interrupted. 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 and, if necessary, treated in line with local practice (see section 4.4). Therapy 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.

Dose modification exceptions (where only one of the two therapies is dose reduced) for selected adverse reactions

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

Trametinib should be interrupted in patients who have an absolute decrease of >10% in LVEF compared to baseline and the ejection fraction is below the institution's lower limit of normal (LLN) (see section 4.4). No dose modification of dabrafenib is required when taken in combination with trametinib. If the LVEF recovers, treatment with trametinib may be restarted, but the dose should be reduced by one dose level with careful monitoring (see section 4.4).

Trametinib should be permanently discontinued in patients with Grade 3 or 4 left ventricular dysfunction or clinically significant LVEF reduction which does not recover within 4 weeks (see section 4.4).

Retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED)

If patients report new visual disturbances such as diminished central vision, blurred vision or loss of vision at any time while on combination therapy with trametinib and dabrafenib, a prompt ophthalmological assessment is recommended. In patients who are diagnosed with RVO, treatment with trametinib should be permanently discontinued. If RPED is diagnosed, follow the dose modification schedule in Table 4 below for trametinib (see section 4.4). No dose modification of dabrafenib is required when taken in combination with trametinib for confirmed cases of RVO or RPED.

Table 4 Recommended dose modifications for trametinib for RPED

Interstitial lung disease (ILD)/Pneumonitis

Trametinib must 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. Trametinib must be permanently discontinued in patients diagnosed with treatment-related ILD or pneumonitis. No dose modification of dabrafenib is required when taken in combination with trametinib for cases of ILD or pneumonitis.

Uveitis

No dose modifications are required for uveitis as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, dabrafenib should be withheld until resolution of ocular inflammation, and then dabrafenib should be restarted reduced by one dose level. No dose modification of trametinib is required when taken in combination with dabrafenib (see section 4.4).

RAS mutation-positive non-cutaneous malignancies

The benefits and risks must be considered before continuing treatment with dabrafenib in patients with a non-cutaneous malignancy that has a RAS mutation. No dose modification of trametinib is required when taken in combination with dabrafenib (see section 4.4).

Special populations

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment. Available data from a clinical pharmacology study indicate a limited impact of moderate to severe hepatic impairment on trametinib exposure (see section 5.2). Trametinib should be used with caution in patients with moderate or severe hepatic impairment.

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. There are no data with trametinib in patients with severe renal impairment; therefore, the potential need for dose adjustment cannot be determined (see section 5.2). Trametinib should be used with caution in patients with severe renal impairment.

Paediatric population

The safety and efficacy of combination therapy with trametinib and dabrafenib in children below 1 year of age have not been established. No data are available. Studies in juvenile animals have shown effects of trametinib which were not observed in adult animals (see section 5.3). Longer-term safety data in paediatric patients are currently limited.

Method of administration

Spexotras is for oral use.

Spexotras powder must be reconstituted to the oral solution by the pharmacist prior to being dispensed. It is recommended that a healthcare professional discusses how to administer the prescribed daily dose of the oral solution with the patient or caregiver prior to administration of the first dose.

Spexotras should be taken without food, at least one hour prior to or two hours after a meal (see section 5.2). Breast-feeding and/or baby formula may be given on demand if a patient is unable to tolerate the fasting conditions.

It is recommended that the dose of Spexotras is taken at a similar time every day, using the re-usable oral syringe provided. The once-daily dose of Spexotras should be taken at the same time each day with either the morning dose or the evening dose of dabrafenib.

If the patient is unable to swallow and has a nasogastric tube in situ, the Spexotras oral solution can be administered via the tube.

Instructions for preparation are provided in section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Spexotras is intended for use in combination with dabrafenib dispersible tablets as there are limited efficacy data for trametinib monotherapy and for dabrafenib monotherapy in BRAF V600 mutation-positive glioma. The dabrafenib dispersible tablets SmPC must be consulted prior to initiation of treatment. For additional information on warnings and precautions associated with dabrafenib treatment, please refer to the dabrafenib dispersible tablets SmPC.

BRAF V600E testing

The efficacy and safety of trametinib in combination with dabrafenib have not been evaluated in patients whose glioma tested negative for the BRAF V600E mutation.

New malignancies

New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib.

Cutaneous malignancies

Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma and new primary melanoma have been observed in adult patients treated with trametinib in combination with dabrafenib (see section 4.8). It is recommended that skin examination be performed prior to initiation of therapy with trametinib and monthly throughout treatment and for up to six months after treatment. Monitoring should continue for 6 months following discontinuation of trametinib or until initiation of another anti-neoplastic therapy.

Suspicious skin lesions should be managed with dermatological excision and do not require treatment modifications. Patients should be instructed to inform their physicians immediately if new skin lesions develop.

Non-cutaneous malignancies

Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancies when RAS mutations are present. Please refer to the dabrafenib dispersible tablets SmPC (section 4.4). No dose modification of trametinib is required for RAS mutation-positive malignancies when taken in combination with dabrafenib.

Haemorrhage

Haemorrhagic events have been reported in adult and paediatric patients taking trametinib in combination with dabrafenib (see section 4.8). Major haemorrhagic events and fatal haemorrhages have occurred in adult patients taking trametinib in combination with dabrafenib. The potential for these events in patients with low platelet counts (<75 000/mm³) has not been established as such patients were excluded from clinical studies. 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.

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

Trametinib in combination with dabrafenib has been reported to decrease LVEF in both adult and paediatric patients (see section 4.8). In clinical studies in paediatric patients, the median time to onset for the first occurrence of LVEF decrease was around one month. In clinical studies in adult patients, the median time to onset of the first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 and 5 months.

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 studies; 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 (see section 4.2 regarding dose modification).

In patients receiving trametinib in combination with dabrafenib, 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.

Pyrexia

Fever has been reported in adult and paediatric clinical studies with trametinib (see section 4.8). The incidence and severity of pyrexia are increased with the combination therapy (see dabrafenib dispersible tablets SmPC section 4.4). In patients receiving trametinib in combination with dabrafenib, pyrexia may be accompanied by severe rigors, dehydration and hypotension which in some cases can lead to acute renal insufficiency. In paediatric patients who received trametinib in combination with dabrafenib, the median time to onset for the first occurrence of pyrexia was 1.3 months.

Therapy with trametinib and dabrafenib should be interrupted if the patient's temperature is ≥ 38° C (see section 5.1). 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. Therapy can be restarted once the fever resolves. If fever is associated with other severe signs or symptoms, therapy should be restarted at a reduced dose once fever resolves and as clinically appropriate (see section 4.2).

Blood pressure changes

Both hypertension and hypotension have been reported in patients in clinical studies with trametinib in combination with dabrafenib (see section 4.8). Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate.

Interstitial lung disease (ILD)/Pneumonitis

In a Phase III study in adult patients, 2.4% (5/211) of patients treated with trametinib monotherapy developed ILD or pneumonitis; all five patients required hospitalisation. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). In two studies in adult patients treated with trametinib in combination with dabrafenib, 1% of patients developed pneumonitis or ILD (see section 4.8).

Trametinib must 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. Trametinib should be permanently discontinued in patients diagnosed with treatment-related ILD or pneumonitis (see section 4.2). Therapy with dabrafenib may be continued at the same dose.

Visual impairment

Disorders associated with visual disturbance, including RPED and RVO, may occur with trametinib, in some cases with a time to onset of several months. Symptoms such as blurred vision, decreased acuity and other visual phenomena have been reported in adult clinical studies with trametinib. In clinical studies, uveitis and iridocyclitis have also been reported in adult and paediatric patients treated with trametinib in combination with dabrafenib.

Trametinib is not recommended in patients with a history of RVO. The safety of trametinib in patients 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.

If patients report new visual disturbances, such as diminished central vision, blurred vision or loss of vision at any time while on trametinib therapy, a prompt ophthalmological assessment is recommended. If RPED is diagnosed, the dose modification schedule in Table 4 should be followed (see section 4.2); if uveitis is diagnosed, please refer to the dabrafenib dispersible tablets SmPC (section 4.4). In patients who are diagnosed with RVO, treatment with trametinib should be permanently discontinued.

No dose modification of dabrafenib is required when taken in combination with trametinib following diagnosis of RVO or RPED. No dose modification of trametinib is required when taken in combination with dabrafenib following diagnosis of uveitis.

Rash

Rash has been observed in about 47% of paediatric patients in clinical studies when trametinib is used in combination with dabrafenib (see section 4.8). The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions.

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 trametinib/dabrafenib combination therapy in adult patients. 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, treatment should be withdrawn.

Rhabdomyolysis

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

Pancreatitis

Pancreatitis has been reported in adult and paediatric patients treated with trametinib in combination with dabrafenib in clinical studies (see section 4.8). Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when restarting treatment after an episode of pancreatitis.

Renal failure

Renal failure has been identified in ≤ 1% of adult patients treated with trametinib in combination with dabrafenib. Observed cases in adult patients were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has also been reported in adult patients. Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, treatment may need to be interrupted as clinically appropriate. Trametinib 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).

Hepatic events

Hepatic adverse reactions have been reported in adult and paediatric patients in clinical studies with trametinib in combination with dabrafenib (see section 4.8). It is recommended that patients have liver function monitored every four weeks for 6 months after treatment initiation. Liver monitoring may be continued thereafter as clinically indicated.

Hepatic impairment

As metabolism and biliary excretion are the primary routes of elimination of trametinib, administration of trametinib should be undertaken with caution in patients with moderate to severe hepatic impairment (see sections 4.2 and 5.2).

Deep vein thrombosis/Pulmonary embolism

Pulmonary embolism or deep vein thrombosis can occur. 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 treatment for life-threatening pulmonary embolism.

Gastrointestinal disorders

Colitis and enterocolitis have been reported in paediatric patients treated with trametinib in combination with dabrafenib (see section 4.8). Colitis and gastrointestinal perforation, including fatal outcome, have been reported in adult patients. Trametinib 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 adult patients treated with trametinib in combination with dabrafenib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases, treatment with trametinib and dabrafenib was maintained. In case of a diagnosis of sarcoidosis, relevant treatment should be considered.

Women of childbearing potential/Fertility in males

Before initiating treatment in women of childbearing potential, appropriate advice on effective methods of contraception should be provided. Women of childbearing potential must use effective methods of contraception during therapy and for 16 weeks after the last dose of Spexotras. Male patients taking trametinib in combination with dabrafenib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible (see section 4.6).

Haemophagocytic lymphohistiocytosis

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

Tumour lysis syndrome (TLS)

The occurrence of TLS, which may be fatal, has been associated with the use of trametinib in combination with dabrafenib (see section 4.8). Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. Patients with risk factors for TLS should be closely monitored and prophylactic hydration should be considered. TLS should be treated promptly, as clinically indicated.

Excipients

Sulfobutylbetadex sodium

Spexotras oral solution contains the cyclodextrin sulfobutylbetadex sodium (100 mg/ml). Cyclodextrins (CDs) are excipients which can influence the properties of the active substance and other medicines. In preclinical studies in animals that were administered CDs intravenously, there were observations of renal toxicity and ototoxicity. Safety aspects of CDs have been considered during the development and safety assessment of the medicinal product. There are limited safety data on the effects of CDs in children <2 years of age.

Methyl parahydroxybenzoate

This medicinal product contains methyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed).

Sodium

This medicinal product contains 1.98 mg sodium per ml of Spexotras oral solution, equivalent to 4% of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult at the maximum daily trametinib dose of 2 mg (40 ml).

Potassium

This medicinal product contains potassium, less than 1 mmol (39 mg) per maximum daily dose, i.e. essentially 'potassium-free'.

Interaction studies have only been performed in adults.

Effect of other medicinal products on trametinib

As trametinib 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 (see section 5.2). Drug-drug interactions via these hydrolytic enzymes cannot be ruled out and could influence the exposure to trametinib.

Trametinib 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 trametinib, caution is advised when co-administering trametinib 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, trametinib is unlikely to significantly affect the pharmacokinetics of other medicinal products via interaction with CYP enzymes or transporters (see section 5.2). Trametinib 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 trametinib.

Based on clinical data, no loss of efficacy of hormonal contraceptives is expected when co-administered with trametinib (see section 5.2). However, use with dabrafenib may render hormonal contraceptives less effective.

Effect of the excipient sulfobutylbetadex sodium on other oral medicinal products with low bioavailability and narrow therapeutic index

The trametinib oral solution contains 100 mg/ml of sulfobutylbetadex sodium which may have the potential to affect the solubility and bioavailability of other oral medicinal products. Caution should be taken when the trametinib oral solution is administered with oral medicinal products that have low bioavailability and a narrow therapeutic index (e.g. imipramine, desipramine).

Also refer to the guidance for medicinal product interactions for dabrafenib found in sections 4.4 and 4.5 of the dabrafenib dispersible tablets SmPC.

Women of childbearing potential/Contraception in females

Women of childbearing potential must use effective methods of contraception during treatment with trametinib and for 16 weeks after stopping treatment.

Use with dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives and an effective alternative method of contraception, such as a barrier method, should be used during trametinib/dabrafenib combination therapy. Please refer to the dabrafenib dispersible tablets SmPC for further information.

Pregnancy

There are no data from the use of trametinib in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Trametinib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus. If trametinib is used during pregnancy, or if the patient becomes pregnant while taking trametinib, the patient should be informed of the potential hazard to the foetus.

Breast-feeding

It is not known whether trametinib is excreted in human milk. A risk to the breast-feeding child cannot be excluded. Trametinib should not be administered to breast-feeding mothers. A decision should be made whether to discontinue breast-feeding or discontinue trametinib, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data in humans for trametinib. In animals, no fertility studies have been performed, but effects were seen on female reproductive organs (see section 5.3). Trametinib may impair fertility in humans.

Men taking trametinib in combination with dabrafenib

Effects on spermatogenesis have been observed in animals given dabrafenib. Male patients taking trametinib in combination with dabrafenib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Please refer to the dabrafenib dispersible tablets SmPC for further information.

Trametinib has minor influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of trametinib should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor and cognitive skills. Patients should be made aware of the potential for fatigue, dizziness or eye problems to affect these activities.

Summary of the safety profile

In clinical studies of paediatric patients treated with trametinib in combination with dabrafenib, the most common adverse reactions (reported at a frequency ≥ 20%) were: pyrexia (65%), rash (47%), headache (40%), vomiting (38%), fatigue (35%), dry skin (34%), diarrhoea (31%), haemorrhage (30%), nausea (26%), dermatitis acneiform (26%), neutropenia (25%), abdominal pain (23%) and cough (22%). The most frequently reported severe (Grade 3/4) adverse reactions were: neutropenia (15%), pyrexia (9%), transaminases increased (6%) and weight increased (5%). Long-term data on growth and skeletal maturation in paediatric patients are currently limited (see section 5.3).

The safety profile in paediatric patients was largely consistent with the safety profile previously established in adult patients. The following additional adverse reactions have so far only been reported in adult patients treated with trametinib tablets and dabrafenib capsules: cutaneous squamous cell carcinoma, seborrhoeic keratosis, peripheral neuropathy (including sensory and motor neuropathy), lymphoedema, dry mouth, actinic keratosis, photosensitivity, renal failure (common), melanoma, acrochordon, sarcoidosis, chorioretinopathy, pneumonitis, acute renal failure, nephritis, cardiac failure, left ventricular dysfunction, interstitial lung disease, rhabdomyolysis (uncommon), gastrointestinal perforation, haemophagocytic lymphohistiocytosis (rare), tumour lysis syndrome, myocarditis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (frequency not known).

Tabulated list of adverse reactions

The safety of trametinib in combination with dabrafenib has been evaluated in a pooled safety set of 171 paediatric patients across two studies in patients with BRAF V600 mutation-positive advanced solid tumours. Four (2.3%) patients were 1 to <2 years of age, 39 (22.8%) patients were 2 to <6 years of age, 54 (31.6%) patients were 6 to <12 years of age and 74 (43.3%) patients were 12 to <18 years of age at enrolment. The mean treatment duration was 80 weeks.

Adverse reactions in the integrated paediatric safety population (Table 5) are listed below by MedDRA system organ class ranked by frequency using the following convention: 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), very rare (<1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5 Adverse reactions reported in the integrated paediatric safety population of trametinib in combination with dabrafenib (n=171)

Description of selected adverse reactions

Weight increased

Weight increase has only been reported in the paediatric population. It was reported as an adverse reaction in 16% of paediatric patients including Grade 3 cases in 4.7% of patients, with a discontinuation rate of 0.6% of patients. The median time to onset of the first occurrence of the reported weight increase in paediatric patients receiving trametinib in combination with dabrafenib was 3.1 months. Weight increase from baseline of ≥ 2 BMI (body mass index)-for-age percentile categories was observed in 29.8% of patients.

Haemorrhage

Haemorrhagic events were observed in 30% of paediatric patients, with Grade 3 events occurring in 1.2% of patients. The most frequent haemorrhagic event (epistaxis) was reported in 18% of paediatric patients. The median time to onset of the first occurrence of haemorrhagic events in paediatric patients was 2.4 months. Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, occurred in adult patients taking trametinib in combination with dabrafenib.

The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patents should be treated as clinically indicated (see section 4.4).

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

Decreased LVEF has been reported in 5.3% of paediatric patients, with Grade 3 events occurring in <1% of patients. The median time to onset for the first occurrence of LVEF decrease was around one month. In clinical studies in adult patients, the median time to first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 to 5 months.

Patients with LVEF lower than the institutional lower limit of normal were not included in clinical studies with trametinib. Trametinib in combination with dabrafenib should be used with caution in patients with conditions that could impair left ventricular function (see sections 4.2 and 4.4).

Pyrexia

Pyrexia has been reported in clinical studies with trametinib as monotherapy and in combination with dabrafenib; however, the incidence and severity of pyrexia are increased with the combination therapy (see section 4.4). Pyrexia was reported in 65% of paediatric patients, with Grade 3 events occurring in 8.8% of patients. Please refer to the dabrafenib dispersible tablets SmPC.

Hepatic events

Hepatic adverse reactions have been reported in adult and paediatric clinical studies with trametinib in combination with dabrafenib. In the paediatric safety population, increased ALT and AST were very common, reported in 12.3% and 15.2% of patients, respectively (see section 4.4). The hepatic adverse reactions of increased ALT and AST were the most common events in adult patients, the majority of these events were either Grade 1 or 2. For trametinib monotherapy, more than 90% of these liver events occurred within the first 6 months of treatment. Liver events were detected in clinical studies with monitoring every four weeks. It is recommended that patients receiving treatment with trametinib have liver function monitored every four weeks for 6 months. Liver monitoring may be continued thereafter as clinically indicated (see section 4.4).

Blood pressure changes

Hypertension was reported in 2.3% of paediatric patients, with Grade 3 events occurring in 1.2% of patients. The median time to onset of the first occurrence of hypertension in paediatric patients was 5.4 months.

Hypotension was reported in 3.5% of paediatric patients, with Grade ≥ 3 events occurring in 2.3% of patients. The median time to onset of the first occurrence of hypotension in paediatric patients was 1.5 months.

Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate (see section 4.4).

Interstitial lung disease (ILD)/Pneumonitis

Patients treated with trametinib may develop ILD or pneumonitis. Trametinib 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. For patients diagnosed with treatment-related ILD or pneumonitis, trametinib should be permanently discontinued (see sections 4.2 and 4.4).

Visual impairment

In paediatric patients treated with trametinib in combination with dabrafenib, ophthalmological reactions, including uveitis 1.8% and iridocyclitis 1.2%, have been reported. Grade 3 uveitis occured in <1% of paediatric patients. Retinal pigment epithelial detachment (RPED) occurred in <1% of paediatric patients. Disorders associated with visual disturbances, including RPED and RVO, have also been observed with trametinib in adult patients. Symptoms such as blurred vision, decreased acuity and other visual disturbances have been reported in adult clinical studies with trametinib (see sections 4.2 and 4.4).

Rash

Rash has been observed in about 47% of paediatric patients in trametinib and dabrafenib combination studies in the integrated safety population. The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions (see sections 4.2 and 4.4).

Rhabdomyolysis

Rhabdomyolysis has been reported in adult patients taking trametinib. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated (see section 4.4).

Pancreatitis

Pancreatitis was reported in 1.2% of paediatric patients, with <1% of patients with Grade 3 severity. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when restarting treatment after an episode of pancreatitis (see section 4.4).

Renal failure

Renal failure has been reported with trametinib in combination with dabrafenib. Renal failure due to pyrexia-associated pre-renal azotaemia or granulomatous nephritis was uncommon in adult patients; however, trametinib 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).

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

No acute overdose symptoms have been reported in paediatric patients who received trametinib in combination with dabrafenib in clinical studies. Persistent overdosing of trametinib could result in increased rash, decreased LVEF, or retinal abnormalities. There is no specific treatment for overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, mitogen-activated protein kinase (MEK) inhibitors, ATC code: L01EE01

Mechanism of action

Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are components of the extracellular signal-related kinase (ERK) pathway. In human cancers, this pathway is often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity.

Combination with dabrafenib

Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway.

Thus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the combination provides concomitant inhibition of the pathway. The combination of trametinib with dabrafenib has shown anti-tumour activity in BRAF V600 mutation-positive cancer cell lines in vitro and delays the emergence of resistance in vivo in BRAF V600 mutation-positive xenografts.

Clinical efficacy and safety

Paediatric population

The clinical efficacy and safety of dabrafenib plus trametinib combination therapy in paediatric patients aged 1 to <18 years with BRAF V600 mutation-positive glioma was evaluated in a multi-centre, open-label, Phase II clinical study (EudraCT 2015-004015-20). Patients with low-grade glioma (WHO 2016 Grades 1 and 2) who required first systemic therapy were randomised in a 2:1 ratio to dabrafenib plus trametinib or carboplatin plus vincristine, and patients with relapsed or refractory high-grade glioma (WHO 2016 Grades 3 and 4) were enrolled into a single-arm dabrafenib plus trametinib cohort.

BRAF mutation status was identified prospectively in tumour tissue via a local test, or by a central laboratory using the bioMé rieux THxID-BRAF kit when a local test was not available. In addition, retrospective testing of available tumour samples by the central laboratory was performed to confirm the BRAF V600E mutation.

Dabrafenib and trametinib dosing in the clinical study was age- and weight-dependent, with dabrafenib dosed orally at 2.625 mg/kg twice daily for ages <12 years and at 2.25 mg/kg twice daily for ages 12 years and older; trametinib was dosed orally at 0.032 mg/kg once daily for ages <6 years and at 0.025 mg/kg once daily for ages 6 years and older. Dabrafenib doses were capped at 150 mg twice daily and trametinib doses at 2 mg once daily. Carboplatin and vincristine were dosed based on age and body surface area at doses of 175 mg/m² and 1.5 mg/m², respectively, as weekly infusions. Carboplatin and vincristine were administered in one 10-week induction course followed by eight 6-week cycles of maintenance therapy.

The primary efficacy endpoint in both cohorts was overall response rate (ORR, sum of confirmed complete/CR and partial responses/PR) by independent review based on RANO (2017) criteria for the LGG cohort, and RANO (2010) criteria for the HGG cohort. The primary analysis was performed when all patients in both cohorts had completed at least 32 weeks of therapy.

BRAF mutation-positive paediatric low-grade glioma (WHO Grades 1 and 2)

In the low-grade glioma cohort, 110 patients were randomised to dabrafenib plus trametinib (n=73) or carboplatin plus vincristine (n=37). Median age was 9.5 years, with 34 patients (30.9%) aged 12 months to <6 years, 36 patients (32.7%) aged 6 to <12 years and 40 patients (36.4%) aged 12 to <18 years; 60% were female. The majority of patients (80%) had Grade 1 glioma at initial diagnosis. The most common pathologies were pilocytic astrocytoma (30.9%), ganglioglioma (27.3%) and LGG not otherwise specified (NOS) (18.2%). Metastatic sites were present in 9 patients (8.2%). Prior surgery was reported in 91 patients (82.7%), among those patients the procedure at last surgery was resection in 28 patients (25.5%). Systemic corticosteroid use was reported in 36 patients (32.7%).

The ORR in the dabrafenib plus trametinib arm showed a statistically significant improvement over carboplatin plus vincristine. The subsequent hierarchical testing also demonstrated a statistically significant improvement in progression-free survival (PFS) over chemotherapy (Table 6).

At the time of the primary analysis, conducted after all patients had completed at least 32 weeks of treatment or had discontinued earlier, the overall survival (OS) data were still immature (one death was reported in the carboplatin plus vincristine (C+V) arm).

Table 6 Response and progression-free survival in the pivotal study G2201 (LGG cohort, primary analysis)

Figure 1 Kaplan-Meier curves for progression-free survival in the pivotal study G2201 (LGG cohort, primary analysis)

BRAF mutation-positive paediatric high-grade glioma (WHO Grades 3 and 4)

In the single-arm high-grade glioma cohort, 41 patients with relapsed or refractory HGG were enrolled and treated with dabrafenib plus trametinib for a median duration of 72.7 weeks. Median age was 13.0 years, with 5 patients (12.2%) aged 12 months to <6 years, 10 patients (24.4%) aged 6 to <12 years and 26 patients (63.4%) aged 12 to <18 years; 56% were female. The histological grade at initial diagnosis was Grade 4 in 20 patients (48.8%), Grade 3 in 13 patients (31.7%), Grade 2 in 4 patients (9.8%), Grade 1 in 3 patients (7.3%) and missing in 1 patient (2.4%). The most common pathologies were glioblastoma multiforme (31.7%), anaplastic pleomorphic xanthoastrocytoma (14.6%), HGG NOS (9.8%) and pleomorphic xanthoastrocytoma (9.8%). Prior surgery was reported in 40 patients (97.6%), among those patients the procedure at last surgery was resection in 24 patients (58.5%). Prior antineoplastic chemotherapy was reported for 33 patients (80.5%). Prior radiotherapy was reported for 37 patients (90.2%). Systemic corticosteroid use while on study treatment was reported in 21 patients (51.2%).

The ORR in this cohort was 56.1% (23/41), 95% CI (39.7%, 71.5%): CR in 12 patients (29.3%) and PR in 11 patients (26.8%). The median duration of response (DOR) was 22.2 months (95% CI: 7.6 – NE), with 15 patients (65.2%) censored at the time of the primary analysis.

The pharmacokinetic properties of trametinib have mostly been determined in adult patients using the solid (tablet) formulation. The pharmacokinetics of trametinib following single or repeat weight-adjusted dosing were also evaluated in 244 paediatric patients. Pharmacokinetic characteristics (drug absorption rate and drug clearance) of trametinib in paediatric patients were comparable to those of adults. Weight was found to influence trametinib oral clearance, while age did not. The pharmacokinetic exposures of trametinib at the recommended weight-adjusted dose in paediatric patients were within range of those observed in adults.

Absorption

The trametinib oral solution was rapidly absorbed with a median time to achieve peak plasma concentration (T_max) of 1 hour post-dose. The mean absolute oral bioavailability of the trametinib tablets was 72%. In a relative bioavailability study comparing the oral solution formulation and the tablet formulation after single-dose administration in the fasted state in adults, administration of the oral solution formulation resulted in a 12%, 10% and 71% higher AUC_(0-inf), AUC_(0-last) and C_max respectively as compared to the tablet formulation.

Trametinib exposure increased in a dose-proportional manner between 0.125 mg and 4 mg following repeat once-daily dosing.

In the pivotal paediatric study, steady-state geometric mean (%CV) C_max and AUC_tau were 22.7 ng/ml (41.1%) and 339 ng*hr/ml (22.2%) in the LGG cohort and 21.3 ng/ml (36.3%) and 307 ng*hr/ml (22.8%) in the HGG cohort.

Trametinib accumulates with repeat daily dosing. A mean accumulation ratio of 6.0 was observed for the tablet formulation at 2 mg once-daily dose. Steady state was achieved by Day 15.

Food effect

The impact of food on the pharmacokinetics of the reconstituted oral solution has not been investigated. Administration of a single dose of trametinib (tablet formulation) with a high-fat, high-calorie meal resulted in a 70% and 10% decrease in C_max and AUC, respectively, compared to fasted conditions.

Distribution

Binding of trametinib to human plasma proteins is 97.4%. Trametinib has a volume of distribution of approximately 1200 L determined following administration of a 5 μ g intravenous microdose.

Biotransformation

In vitro and in vivo studies demonstrated that trametinib is metabolised predominantly via deacetylation alone or in combination with mono-oxygenation. The deacetylated metabolite was further metabolised by glucuronidation. CYP3A4 oxidation is considered a minor pathway of metabolism. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, with possible contributions by other hydrolytic enzymes.

Following single and repeated doses of trametinib, trametinib as parent is the main circulating component in plasma.

Elimination

Mean terminal half-life of trametinib is 127 hours (5.3 days) after single-dose administration. The apparent clearance of trametinib in paediatric patients (median body weight: 32.85 kg) was 3.44 L/h (CV of 20%).

Total dose recovery was low after a 10-day collection period (<50%) following administration of a single oral dose of radiolabelled trametinib as a solution, due to the long elimination half-life. Trametinib-related material was excreted predominantly in the faeces (>80% of recovered radioactivity) and to a minor extent in urine (≤ 19%). Less than 0.1% of the excreted dose was recovered as parent in urine.

Medicinal product interactions

Effects of trametinib on drug-metabolising enzymes and transporters

In vitro and in vivo data suggest that trametinib is unlikely to affect the pharmacokinetics of other medicinal products. Based on in vitro studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. Based on in vitro studies, trametinib is an inhibitor of CYP2C8, CYP2C9 and CYP2C19, an inducer of CYP3A4 and an inhibitor of the transporters OAT1, OAT3, OCT2, MATE1, OATP1B1, OATP1B3, P-gp and BCRP. However, based on the low dose and low clinical systemic exposure relative to the in vitro potency of inhibition or induction values, trametinib is not considered to be an in vivo inhibitor or inducer of these enzymes or transporters, although transient inhibition of BCRP substrates in the gut may occur (see section 4.5).

Effects of other medicinal products on trametinib

In vivo and in vitro data suggest that the pharmacokinetics of trametinib are unlikely to be affected by other medicinal products. Trametinib is not a substrate of CYP enzymes or of the transporters BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2 and MATE1. Trametinib is an in vitro substrate of BSEP and the efflux transporter P-gp. Although trametinib exposure is unlikely to be affected by inhibition of BSEP, increased levels of trametinib upon strong inhibition of hepatic P-gp cannot be excluded (see section 4.5).

Effects of trametinib on other medicinal products

The effect of repeat-dose trametinib 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 trametinib. Based on these results, no loss of efficacy of hormonal contraceptives is expected when co-administered with trametinib.

Special patient populations

Hepatic impairment

Population pharmacokinetic analyses and data from a clinical pharmacology study in adult patients with normal hepatic function or with mild, moderate or severe bilirubin and/or AST elevations (based on National Cancer Institute [NCI] classification) indicate that hepatic function does not significantly affect trametinib oral clearance.

Renal impairment

Renal impairment is unlikely to have a clinically relevant effect on trametinib pharmacokinetics given the low renal excretion of trametinib. The pharmacokinetics of trametinib were characterised in 223 adult patients enrolled in clinical studies with trametinib who had mild renal impairment and 35 adult patients with moderate renal impairment using a population pharmacokinetic analysis. Mild and moderate renal impairment had no effect on trametinib exposure (<6% for either group). No data are available in patients with severe renal impairment (see section 4.2).

Race

There are insufficient data to evaluate the potential effect of race on trametinib pharmacokinetics as clinical experience is limited to Caucasians.

Gender

Based on population pharmacokinetic analyses in adult and paedatric patients, gender was found to influence trametinib oral clearance. Although female patients are predicted to have higher exposure than male patients, these differences are unlikely to be clinically relevant and no dose adjustment is warranted.

Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells and micronuclei in the bone marrow of rats.

Trametinib may impair female fertility in humans, as in repeat-dose studies, increases in cystic follicles and decreases in corpora lutea were observed in female rats at exposures below the human clinical exposure based on AUC.

Additionally, in juvenile rats given trametinib, decreased ovarian weights, slight delays in hallmarks of female sexual maturation (vaginal opening and increased incidence of prominent terminal end buds within the mammary gland) and slight hypertrophy of the surface epithelium of the uterus were observed. All of these effects were reversible following an off-treatment period and attributable to pharmacology. However, in rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed in male reproductive tissues.

In embryo-foetal developmental toxicity studies in rats and rabbits, trametinib induced maternal and developmental toxicity. In rats, decreased foetal weights and increased post-implantation loss were seen at exposures below or slightly above the human clinical exposure based on AUC. In an embryo-foetal developmental toxicity study with rabbits, decreased foetal body weight, increased abortions, increased incidence of incomplete ossification and skeletal malformations were seen at sub-clinical exposures based on AUC.

In repeat-dose studies the effects seen after trametinib exposure are found mainly in the skin, gastrointestinal tract, haematological system, bone and liver. Most of the findings are reversible after drug-free recovery. In rats, hepatocellular necrosis and transaminase elevations were seen after 8 weeks at ≥ 0.062 mg/kg/day (approximately 0.8 times human clinical exposure based on AUC).

In mice, lower heart rate, heart weight and left ventricular function were observed without cardiac histopathology after 3 weeks at ≥ 0.25 mg/kg/day trametinib (approximately 3 times human clinical exposure based on AUC) for up to 3 weeks. In adult rats, mineralisation of multiple organs was associated with increased serum phosphorus and was closely associated with necrosis in heart, liver and kidney and haemorrhage in the lung at exposures comparable to the human clinical exposure. In rats, hypertrophy of the physis and increased bone turnover were observed. In rats and dogs given trametinib at or below human clinical exposures, bone marrow necrosis, lymphoid atrophy in thymus and GALT and lymphoid necrosis in lymph nodes, spleen and thymus were observed, which have the potential to impair immune function. In juvenile rats, increased heart weight with no histopathology was observed at 0.35 mg/kg/day (approximately 2 times the human clinical exposure based on AUC).

Trametinib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay at significantly higher concentrations than clinical exposures (IC₅₀ at 2.92 µ g/ml, ≥ 130 times the human clinical exposure based on C_max), indicating that there is low risk for phototoxicity to patients taking trametinib.

Combination with dabrafenib

In a study in dogs in which trametinib and dabrafenib were given in combination for 4 weeks, signs of gastrointestinal toxicity and decreased lymphoid cellularity of the thymus were observed at lower exposures than in dogs given trametinib alone. Otherwise, similar toxicities were observed as in comparable monotherapy studies.

Sulfobutylbetadex sodium

Sucralose (E 955)

Citric acid monohydrate (E 330)

Disodium phosphate (E 339)

Potassium sorbate (E 202)

Methyl parahydroxybenzoate (E 218)

Strawberry flavour

Not applicable.

Powder for oral solution

3 years.

Reconstituted oral solution

Store below 25° C.

Do not freeze.

Discard any unused solution 35 days after reconstitution.

Store in a refrigerator (2° C – 8° C).

Store in the original package in order to protect from light and moisture.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Amber glass bottle of 180 ml with a child-resistant screw cap closure, containing 12 g of powder.

Each carton contains one bottle, one press-in bottle adapter and one 20 ml re-usable oral dosing syringe with 0.5 ml graduation marks.

Spexotras powder must be reconstituted to the oral solution by the pharmacist prior to being dispensed.

Reconstitution instructions (for the pharmacist only):

1. Wash and dry your hands.

2. Check the powder expiry date on the bottle.

3. Tap the bottle to loosen the powder.

4. Remove the cap and add 90 ml distilled or purified water to the powder in the bottle.

5. Attach the cap and invert the bottle repeatedly for up to 5 minutes, until fully dissolved. You may also gently shake.

6. Separate the bottle adapter from the oral syringe. Remove the bottle cap and insert the bottle adapter into the bottle neck. Push hard until the bottle adapter is fully inserted. The bottle adapter should be fully flush with the bottle neck.

7. Write the date of preparation on the carton. The solution expires 35 days after preparation.

8. Inform the recipient of the dose and the date the solution was prepared on.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.