4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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

Body weight*

Recommended dose

Volume of oral solution (ml) once daily

corresponding to mg trametinib

8 kg

6 ml

0.30 mg

9 to 10 kg

7 ml

0.35 mg

11 kg

8 ml

0.40 mg

12 to 13 kg

9 ml

0.45 mg

14 to 17 kg

11 ml

0.55 mg

18 to 21 kg

14 ml

0.70 mg

22 to 25 kg

17 ml

0.85 mg

26 to 29 kg

18 ml

0.90 mg

30 to 33 kg

20 ml

1 mg

34 to 37 kg

23 ml

1.15 mg

38 to 41 kg

25 ml

1.25 mg

42 to 45 kg

28 ml

1.40 mg

46 to 50 kg

32 ml

1.60 mg

≥51 kg

40 ml

2 mg

*Round body weight to the nearest kg, if necessary.

The recommended dose for patients with a body weight less than 8 kg has not been established.

Please refer to the dabrafenib dispersible tablets SmPC, “Posology” and “Method of administration”, for dosing instructions for treatment with dabrafenib when used in combination with Spexotras.

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)

Grade (CTCAE)*

Recommended trametinib 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 to 1 and reduce by one dose level when resuming therapy.

Refer to Table 3 for dose level guidance.

Grade 4

Discontinue permanently, or interrupt therapy until Grade 0 to 1 and reduce by one dose level when resuming therapy.

Refer to Table 3 for dose level guidance.

* The intensity of clinical adverse reactions graded by the Common Terminology Criteria for Adverse Events (CTCAE)

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

Body weight

Recommended dose

Reduced dose

ml solution (mg trametinib)

(once daily)

Dose after the first reduction

(once daily)

Dose after the second reduction

(once daily)

8 kg

6 ml (0.30 mg)

5 ml

3 ml

9 to 10 kg

7 ml (0.35 mg)

5 ml

4 ml

11 kg

8 ml (0.40 mg)

6 ml

4 ml

12 to 13 kg

9 ml (0.45 mg)

7 ml

5 ml

14 to 17 kg

11 ml (0.55 mg)

8 ml

6 ml

18 to 21 kg

14 ml (0.70 mg)

11 ml

7 ml

22 to 25 kg

17 ml (0.85 mg)

13 ml

9 ml

26 to 29 kg

18 ml (0.90 mg)

14 ml

9 ml

30 to 33 kg

20 ml (1 mg)

15 ml

10 ml

34 to 37 kg

23 ml (1.15 mg)

17 ml

12 ml

38 to 41 kg

25 ml (1.25 mg)

19 ml

13 ml

42 to 45 kg

28 ml (1.40 mg)

21 ml

14 ml

46 to 50 kg

32 ml (1.60 mg)

24 ml

16 ml

≥51 kg

40 ml (2 mg)

30 ml

20 ml

Dose adjustment for Spexotras below 50% of the recommended dose is not recommended.

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 asymptomatic, 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

Grade 1 RPED

Continue treatment with retinal evaluation monthly until resolution. If RPED worsens follow instructions below and withhold trametinib for up to 3 weeks.

Grade 2 or 3 RPED

Withhold trametinib for up to 3 weeks.

Grade 2 or 3 RPED that improves to Grade 0 or 1 within 3 weeks

Resume trametinib at a lower dose level (see Table 3) or discontinue trametinib in patients on the lowest dose level.

Grade 2 or 3 RPED that does not improve to at least Grade 1 within 3 weeks

Permanently discontinue trametinib.

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 exposure is not affected by food (see section 5.2). Spexotras should be taken at the same time as dabrafenib dispersible tablet, which has reduced exposure with food. Spexotras should therefore 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.

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

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 of 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 of the first occurrence of pyrexia was 1.5 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 onset of the 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 49% 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'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy, and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 (70%), rash (49%), headache (47%), vomiting (40%), fatigue (36%), dry skin (35%), diarrhoea (34%), haemorrhage (34%), nausea (29%), dermatitis acneiform (29%), abdominal pain (28%), neutropenia (26%), cough (24%) and transaminases increased (22%). The most frequently reported severe (Grade 3/4) adverse reactions were: neutropenia (15%), pyrexia (11%), 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, 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, tattoo-associated skin reactions (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 2.3 years.

Adverse reactions (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 with trametinib in combination with dabrafenib

Infections and infestations

Very common

Paronychia, nasopharyngitis*1

Common

Urinary tract infection, cellulitis

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Very common

Skin papilloma

Blood and lymphatic system disorders

Very common

Neutropenia*2, anaemia, leukopenia*

Common

Thrombocytopenia*

Immune system disorders

Common

Hypersensitivity

Metabolism and nutrition disorders

Common

Dehydration, decreased appetite

Nervous system disorders

Very common

Headache, dizziness*3

Eye disorders

Common

Vision blurred, visual impairment, uveitis*4

Uncommon

Retinal detachment, periorbital oedema

Cardiac disorders

Common

Ejection fraction decreased, bradycardia*

Uncommon

Atrioventricular block5

Vascular disorders

Very common

Haemorrhage*6

Common

Hypertension, hypotension

Respiratory, thoracic and mediastinal disorders

Very common

Cough*

Common

Dyspnoea

Gastrointestinal disorders

Very common

Abdominal pain*, constipation, diarrhoea, nausea, vomiting

Common

Pancreatitis, stomatitis

Uncommon

Colitis*

Skin and subcutaneous tissue disorders

Very common

Dermatitis acneiform*7, dry skin*8, pruritus, rash*9, erythema

Common

Dermatitis exfoliative generalised*10, alopecia, palmar-plantar erythrodysaesthesia syndrome, folliculitis, skin lesion, panniculitis, hyperkeratosis, photosensitivity*11

Uncommon

Acute febrile neutrophilic dermatosis, skin fissures, night sweats, hyperhidrosis

Musculoskeletal and connective tissue disorders

Very common

Arthralgia, pain in extremity

Common

Myalgia*, muscle spasms*12

General disorders and administration site conditions

Very common

Pyrexia*, fatigue*13, weight increased

Common

Mucosal inflammation, face oedema*, chills, oedema peripheral, influenza-like illness

Investigations

Very common

Transaminases increased*14

Common

Hyponatraemia, hypophosphataemia, hyperglycaemia, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatine phosphokinase increased

*Denotes grouped term of two or more MedDRA preferred terms that were considered clinically similar.

1 nasopharyngitis includes pharyngitis

2 neutropenia includes neutrophil count decreased and febrile neutropenia

3 dizziness includes vertigo

4 uveitis includes iridocyclitis

5 atrioventricular block includes atrioventricular block first degree

6 haemorrhage includes epistaxis, haematuria, contusion, haematoma, international normalised ratio increased, anal haemorrhage, catheter site haemorrhage, cerebral haemorrhage, ecchymosis, extradural haematoma, gastrointestinal haemorrhage, haematochezia, petechiae, post-procedural haemorrhage, rectal haemorrhage, red blood cell count decreased, upper gastrointestinal haemorrhage, uterine haemorrhage, heavy menstrual bleeding and purpura

7 dermatitis acneiform includes acne and acne pustular

8 dry skin includes xerosis and xeroderma

9 rash includes rash maculo-papular, rash pustular, rash erythematous, rash papular, rash macular

10 dermatitis exfoliative generalised includes skin exfoliation and dermatitis exfoliative

11 photosensitivity includes photosensitivity reaction and sunburn

12 muscle spasms include musculoskeletal stiffness

13 fatigue includes malaise and asthenia

14 transaminases increased includes aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased and hypertransaminasaemia

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 5% 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 3.5 months. Weight increase from baseline of ≥2 BMI (body mass index)-for-age percentile categories was observed in 36% of patients.

Haemorrhage

Haemorrhagic events were observed in 34% 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 2.6 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 of 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 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 70% of paediatric patients, with Grade 3 events occurring in 11% 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 13% and 16% 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 4.1% 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 2.2 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 3.5% and iridocyclitis 1.8%, have been reported. Grade 3 uveitis occured in 1.8% 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 49% 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.

4.9. Overdose

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.