SPEXOTRAS 0.05mg / ml powder for oral solution medication leaflet

Spexotras 0.05 mg/ml powder for oral solution

One bottle contains trametinib dimethyl sulfoxide equivalent to 4.7 mg of trametinib.

Each ml of the reconstituted solution contains 0.05 mg of trametinib.

Each ml of the reconstituted solution contains 100 mg of sulfobutylbetadex sodium, 0.8 mg of methylparahydroxybenzoate and 1.98 mg of sodium.

For the full list of excipients, see section 6.1.

Powder for oral solution.

White or almost white powder.

Low-grade glioma

Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged1 year and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemictherapy.

High-grade glioma

Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged1 year and older with high-grade glioma (HGG) with a BRAF V600E mutation who have received atleast one prior radiation and/or chemotherapy treatment.

Treatment with Spexotras should be initiated and supervised by a qualified physician experienced inthe 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 alternativevalidated test.

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

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

Table 1 Dosing regimen by body weight

Recommended dose

Body weight*

Volume of oral solution (ml) once daily corresponding to mg trametinib8 kg 6 ml 0.30 mg9 to 10 kg 7 ml 0.35 mg11 kg 8 ml 0.40 mg12 to 13 kg 9 ml 0.45 mg14 to 17 kg 11 ml 0.55 mg18 to 21 kg 14 ml 0.70 mg22 to 25 kg 17 ml 0.85 mg26 to 29 kg 18 ml 0.90 mg30 to 33 kg 20 ml 1 mg34 to 37 kg 23 ml 1.15 mg38 to 41 kg 25 ml 1.25 mg42 to 45 kg 28 ml 1.40 mg46 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.

Treatment with Spexotras should continue until disease progression or until the development ofunacceptable 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 individualpatient 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 nextscheduled dose. If vomiting occurs after taking Spexotras, an additional dose should not beadministered and the next dose should be taken at the next scheduled time.

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

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

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

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

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 byone dose level when resuming therapy.

Refer to Table 3 for dose level guidance.

Grade 4 Discontinue permanently, or interrupt therapy until Grade 0 to1 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 dosereduction level) and to approximately 50% of the recommended dose (second dose reduction level) areshown in Table 3.

Table 3 Recommended dose reduction levels for adverse reactions

Recommended dose Reduced dose

Dose after the first Dose after the

Body weight ml solution (mg trametinib)reduction second reduction(once daily)(once daily) (once daily)8 kg 6 ml (0.30 mg) 5 ml 3 ml9 to 10 kg 7 ml (0.35 mg) 5 ml 4 ml11 kg 8 ml (0.40 mg) 6 ml 4 ml12 to 13 kg 9 ml (0.45 mg) 7 ml 5 ml14 to 17 kg 11 ml (0.55 mg) 8 ml 6 ml18 to 21 kg 14 ml (0.70 mg) 11 ml 7 ml22 to 25 kg 17 ml (0.85 mg) 13 ml 9 ml26 to 29 kg 18 ml (0.90 mg) 14 ml 9 ml30 to 33 kg 20 ml (1 mg) 15 ml 10 ml34 to 37 kg 23 ml (1.15 mg) 17 ml 12 ml38 to 41 kg 25 ml (1.25 mg) 19 ml 13 ml42 to 45 kg 28 ml (1.40 mg) 21 ml 14 ml46 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 followingthe same dosing steps as de-escalation may be considered. The trametinib dose should not exceed therecommended dose indicated in Table 1.

Dose modifications for selected adverse reactions

If a patient’s temperature is ≥38°C, therapy with trametinib and dabrafenib should be interrupted. Incase of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Treatment withanti-pyretics such as ibuprofen or acetaminophen/paracetamol should be initiated. The use of oralcorticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patientsshould be evaluated for signs and symptoms of infection and, if necessary, treated in line with localpractice (see section 4.4). Therapy should be restarted if the patient is symptom-free for at least24 hours either (1) at the same dose level, or (2) reduced by one dose level if pyrexia is recurrentand/or was accompanied by other severe symptoms including dehydration, hypotension or renalfailure.

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

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 combinationwith trametinib. If the LVEF recovers, treatment with trametinib may be restarted, but the dose shouldbe 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 ventriculardysfunction or clinically significant LVEF reduction which does not recover within 4 weeks (seesection 4.4).

If patients report new visual disturbances such as diminished central vision, blurred vision or loss ofvision at any time while on combination therapy with trametinib and dabrafenib, a promptophthalmological assessment is recommended. In patients who are diagnosed with RVO, treatmentwith trametinib should be permanently discontinued. If RPED is diagnosed, follow the dosemodification schedule in Table 4 below for trametinib (see section 4.4). No dose modification ofdabrafenib 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 untilresolution. If RPED worsens follow instructions below andwithhold 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 Resume trametinib at a lower dose level (see Table 3) or

Grade 0 or 1 within 3 weeks discontinue trametinib in patients on the lowest dose level.

Grade 2 or 3 RPED that does not Permanently discontinue trametinib.

improve to at least Grade 1 within3 weeks

Trametinib must be withheld in patients with suspected ILD or pneumonitis, including patientspresenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea,hypoxia, pleural effusion or infiltrates, pending clinical investigations. Trametinib must bepermanently discontinued in patients diagnosed with treatment-related ILD or pneumonitis. No dosemodification of dabrafenib is required when taken in combination with trametinib for cases of ILD orpneumonitis.

No dose modifications are required for uveitis as long as effective local therapies can control ocularinflammation. If uveitis does not respond to local ocular therapy, dabrafenib should be withheld untilresolution 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 (seesection 4.4).

RAS mutation-positive non-cutaneous malignancies

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

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

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

The safety and efficacy of combination therapy with trametinib and dabrafenib in children below1 year of age have not been established. No data are available. Studies in juvenile animals have showneffects of trametinib which were not observed in adult animals (see section 5.3). Longer-term safetydata in paediatric patients are currently limited.

Spexotras is for oral use.

Spexotras powder must be reconstituted to the oral solution by the pharmacist prior to beingdispensed. It is recommended that a healthcare professional discusses how to administer the prescribeddaily 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 sametime as dabrafenib dispersible tablet, which has reduced exposure with food. Spexotras shouldtherefore 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 thefasting conditions.

It is recommended that the dose of Spexotras is taken at a similar time every day, using the re-usableoral syringe provided. The once-daily dose of Spexotras should be taken at the same time each daywith 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 beadministered 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 limitedefficacy 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 oftreatment. For additional information on warnings and precautions associated with dabrafenibtreatment, 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 inpatients whose glioma tested negative for the BRAF V600E mutation.

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

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

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

Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancieswhen 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 incombination with dabrafenib.

Haemorrhagic events have been reported in adult and paediatric patients taking trametinib incombination with dabrafenib (see section 4.8). Major haemorrhagic events and fatal haemorrhageshave occurred in adult patients taking trametinib in combination with dabrafenib. The potential forthese events in patients with low platelet counts (<75 000/mm3) has not been established as suchpatients were excluded from clinical studies. The risk of haemorrhage may be increased withconcomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patients should betreated as clinically indicated.

Trametinib in combination with dabrafenib has been reported to decrease LVEF in both adult andpaediatric patients (see section 4.8). In clinical studies in paediatric patients, the median time to onsetof 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. Patientswith left ventricular dysfunction, New York Heart Association Class II, III, or IV heart failure, acutecoronary syndrome within the past 6 months, clinically significant uncontrolled arrhythmias, anduncontrolled hypertension were excluded from clinical studies; safety of use in this population istherefore unknown. LVEF should be evaluated in all patients prior to initiation of treatment withtrametinib, one month after initiation of therapy, and then at approximately 3-monthly intervals whileon treatment (see section 4.2 regarding dose modification).

In patients receiving trametinib in combination with dabrafenib, there have been occasional reports ofacute, severe left ventricular dysfunction due to myocarditis. Full recovery was observed whenstopping treatment. Physicians should be alert to the possibility of myocarditis in patients who developnew or worsening cardiac signs or symptoms.

Fever has been reported in adult and paediatric clinical studies with trametinib (see section 4.8). Theincidence and severity of pyrexia are increased with the combination therapy (see dabrafenibdispersible 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 canlead to acute renal insufficiency. In paediatric patients who received trametinib in combination withdabrafenib, 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 ≥38ºC(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. Theuse of oral corticosteroids should be considered in those instances in which anti-pyretics areinsufficient. Patients should be evaluated for signs and symptoms of infection. Therapy can berestarted once the fever resolves. If fever is associated with other severe signs or symptoms, therapyshould be restarted at a reduced dose once fever resolves and as clinically appropriate (seesection 4.2).

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

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

Trametinib must be withheld in patients with suspected ILD or pneumonitis, including patientspresenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea,hypoxia, pleural effusion or infiltrates, pending clinical investigations. Trametinib should bepermanently discontinued in patients diagnosed with treatment-related ILD or pneumonitis (seesection 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, decreasedacuity and other visual phenomena have been reported in adult clinical studies with trametinib. Inclinical studies, uveitis and iridocyclitis have also been reported in adult and paediatric patients treatedwith trametinib in combination with dabrafenib.

Trametinib is not recommended in patients with a history of RVO. The safety of trametinib in patientswith predisposing factors for RVO, including uncontrolled glaucoma or ocular hypertension,uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity orhypercoagulability syndromes, has not been established.

If patients report new visual disturbances, such as diminished central vision, blurred vision or loss ofvision at any time while on trametinib therapy, a prompt ophthalmological assessment isrecommended. 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 bepermanently discontinued.

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

Rash has been observed in 49% of paediatric patients in clinical studies when trametinib is used incombination with dabrafenib (see section 4.8). The majority of these cases were Grade 1 or 2 and didnot require any dose interruptions or dose reductions.

Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drugreaction 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 monitoredclosely for skin reactions. If signs and symptoms suggestive of SCARs appear, treatment should bewithdrawn.

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

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

Renal failure has been identified in ≤1% of adult patients treated with trametinib in combination withdabrafenib. Observed cases in adult patients were generally associated with pyrexia and dehydrationand responded well to dose interruption and general supportive measures. Granulomatous nephritis hasalso been reported in adult patients. Patients should be routinely monitored for serum creatinine whileon 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 adverse reactions have been reported in adult and paediatric patients in clinical studies withtrametinib in combination with dabrafenib (see section 4.8). It is recommended that patients have liverfunction monitored every four weeks for 6 months after treatment initiation. Liver monitoring may becontinued thereafter as clinically indicated.

As metabolism and biliary excretion are the primary routes of elimination of trametinib, administrationof trametinib should be undertaken with caution in patients with moderate to severe hepaticimpairment (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 pulmonaryembolism or deep vein thrombosis such as shortness of breath, chest pain or arm or leg swelling, theyshould immediately seek medical care. Permanently discontinue treatment for life-threateningpulmonary embolism.

Colitis and enterocolitis have been reported in paediatric patients treated with trametinib incombination with dabrafenib (see section 4.8). Colitis and gastrointestinal perforation, including fataloutcome, have been reported in adult patients. Trametinib should be used with caution in patients withrisk factors for gastrointestinal perforation, including history of diverticulitis, metastases to thegastrointestinal tract and concomitant use of medicinal products with a recognised risk ofgastrointestinal perforation.

Cases of sarcoidosis have been reported in adult patients treated with trametinib in combination withdabrafenib, 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 effectivemethods of contraception should be provided. Women of childbearing potential must use effectivemethods of contraception during therapy and for 16 weeks after the last dose of Spexotras. Malepatients taking trametinib in combination with dabrafenib should be informed of the potential risk forimpaired spermatogenesis, which may be irreversible (see section 4.6).

Haemophagocytic lymphohistiocytosis

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

The occurrence of TLS, which may be fatal, has been associated with the use of trametinib incombination 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. Patientswith risk factors for TLS should be closely monitored and prophylactic hydration should beconsidered. TLS should be treated promptly, as clinically indicated.

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 andother medicines. In preclinical studies in animals that were administered CDs intravenously, therewere observations of renal toxicity and ototoxicity. Safety aspects of CDs have been considered duringthe development and safety assessment of the medicinal product. There are limited safety data on theeffects of CDs in children <2 years of age.

Methyl parahydroxybenzoate

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

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 maximumdaily trametinib dose of 2 mg (40 ml).

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.

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

Trametinib is an in vitro substrate of the efflux transporter P-gp. As it cannot be excluded that stronginhibition 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).

Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the pharmacokinetics ofother 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, whichmay 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 hormonalcontraceptives less effective.

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

The trametinib oral solution contains 100 mg/ml of sulfobutylbetadex sodium which may have thepotential to affect the solubility and bioavailability of other oral medicinal products. Caution should betaken when the trametinib oral solution is administered with oral medicinal products that have lowbioavailability 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 and4.5 of the dabrafenib dispersible tablets SmPC.

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

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

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

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

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

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

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

In clinical studies of paediatric patients treated with trametinib in combination with dabrafenib, themost 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) adversereactions 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 previouslyestablished in adult patients. The following additional adverse reactions have so far only been reportedin adult patients treated with trametinib tablets and dabrafenib capsules: cutaneous squamous cellcarcinoma, 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, leftventricular dysfunction, interstitial lung disease, rhabdomyolysis (uncommon), gastrointestinalperforation, haemophagocytic lymphohistiocytosis (rare), tumour lysis syndrome, myocarditis,

Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (frequency notknown).

The safety of trametinib in combination with dabrafenib has been evaluated in a pooled safety set of171 paediatric patients across two studies in patients with BRAF V600 mutation-positive advancedsolid tumours. Four (2.3%) patients were 1 to <2 years of age, 39 (22.8%) patients were 2 to <6 yearsof age, 54 (31.6%) patients were 6 to <12 years of age and 74 (43.3%) patients were 12 to <18 years ofage at enrolment. The mean treatment duration was 2.3 years.

Adverse reactions (Table 5) are listed below by MedDRA system organ class ranked by frequencyusing 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 beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Table 5 Adverse reactions with trametinib in combination with dabrafenib

Very common Paronychia, nasopharyngitis*1

Common Urinary tract infection, cellulitis

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

Very common Skin papilloma

Very common Neutropenia*2, anaemia, leukopenia*

Common Thrombocytopenia*

Common Hypersensitivity

Common Dehydration, decreased appetite

Very common Headache, dizziness*3

Common Vision blurred, visual impairment, uveitis*4

Uncommon Retinal detachment, periorbital oedema

Common Ejection fraction decreased, bradycardia*

Uncommon Atrioventricular block5

Very common Haemorrhage*6

Common Hypertension, hypotension

Very common Cough*

Common Dyspnoea

Very common Abdominal pain*, constipation, diarrhoea, nausea, vomiting

Common Pancreatitis, stomatitis

Uncommon Colitis*

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

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

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

Very common Arthralgia, pain in extremity

Common Myalgia*, muscle spasms*12

Very common Pyrexia*, fatigue*13, weight increased

Common Mucosal inflammation, face oedema*, chills, oedema peripheral, influenza-likeillness

Very common Transaminases increased*14

Common Hyponatraemia, hypophosphataemia, hyperglycaemia, blood alkaline phosphataseincreased, gamma-glutamyltransferase increased, blood creatine phosphokinaseincreased

*Denotes grouped term of two or more MedDRA preferred terms that were considered clinically similar.1 nasopharyngitis includes pharyngitis2 neutropenia includes neutrophil count decreased and febrile neutropenia3 dizziness includes vertigo4 uveitis includes iridocyclitis5 atrioventricular block includes atrioventricular block first degree6 haemorrhage includes epistaxis, haematuria, contusion, haematoma, international normalised ratioincreased, anal haemorrhage, catheter site haemorrhage, cerebral haemorrhage, ecchymosis, extraduralhaematoma, gastrointestinal haemorrhage, haematochezia, petechiae, post-procedural haemorrhage, rectalhaemorrhage, red blood cell count decreased, upper gastrointestinal haemorrhage, uterine haemorrhage,heavy menstrual bleeding and purpura7 dermatitis acneiform includes acne and acne pustular8 dry skin includes xerosis and xeroderma9 rash includes rash maculo-papular, rash pustular, rash erythematous, rash papular, rash macular10 dermatitis exfoliative generalised includes skin exfoliation and dermatitis exfoliative11 photosensitivity includes photosensitivity reaction and sunburn12 muscle spasms include musculoskeletal stiffness13 fatigue includes malaise and asthenia14 transaminases increased includes aspartate aminotransferase (AST) increased, alanine aminotransferase(ALT) increased and hypertransaminasaemia

Weight increased

Weight increase has only been reported in the paediatric population. It was reported as an adversereaction in 16% of paediatric patients including Grade 3 cases in 5% of patients, with adiscontinuation rate of 0.6% of patients. The median time to onset of the first occurrence of thereported weight increase in paediatric patients receiving trametinib in combination with dabrafenibwas 3.5 months. Weight increase from baseline of ≥2 BMI (body mass index)-for-age percentilecategories was observed in 36% of patients.

Haemorrhagic events were observed in 34% of paediatric patients, with Grade 3 events occurring in1.2% of patients. The most frequent haemorrhagic event (epistaxis) was reported in 18% of paediatricpatients. The median time to onset of the first occurrence of haemorrhagic events in paediatric patientswas 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 anticoagulanttherapy. If haemorrhage occurs, patents should be treated as clinically indicated (see section 4.4).

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 onemonth. In clinical studies in adult patients, the median time to onset of the first occurrence of leftventricular 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 clinicalstudies with trametinib. Trametinib in combination with dabrafenib should be used with caution inpatients with conditions that could impair left ventricular function (see sections 4.2 and 4.4).

Pyrexia has been reported in clinical studies with trametinib as monotherapy and in combination withdabrafenib; 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 in11% of patients. Please refer to the dabrafenib dispersible tablets SmPC.

Hepatic adverse reactions have been reported in adult and paediatric clinical studies with trametinib incombination with dabrafenib. In the paediatric safety population, increased ALT and AST were verycommon, reported in 13% and 16% of patients, respectively (see section 4.4). The hepatic adversereactions of increased ALT and AST were the most common events in adult patients, the majority ofthese events were either Grade 1 or 2. For trametinib monotherapy, more than 90% of these liverevents occurred within the first 6 months of treatment. Liver events were detected in clinical studieswith monitoring every four weeks. It is recommended that patients receiving treatment with trametinibhave liver function monitored every four weeks for 6 months. Liver monitoring may be continuedthereafter as clinically indicated (see section 4.4).

Hypertension was reported in 2.3% of paediatric patients, with Grade 3 events occurring in 1.2% ofpatients. The median time to onset of the first occurrence of hypertension in paediatric patients was5.4 months.

Hypotension was reported in 4.1% of paediatric patients, with Grade ≥3 events occurring in 2.3% ofpatients. The median time to onset of the first occurrence of hypotension in paediatric patients was2.2 months.

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

Patients treated with trametinib may develop ILD or pneumonitis. Trametinib should be withheld inpatients with suspected ILD or pneumonitis, including patients presenting with new or progressivepulmonary 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, ophthalmologicalreactions, including uveitis 3.5% and iridocyclitis 1.8%, have been reported. Grade 3 uveitis occuredin 1.8% of paediatric patients. Retinal pigment epithelial detachment (RPED) occurred in <1% ofpaediatric patients. Disorders associated with visual disturbances, including RPED and RVO, havealso been observed with trametinib in adult patients. Symptoms such as blurred vision, decreasedacuity and other visual disturbances have been reported in adult clinical studies with trametinib (seesections 4.2 and 4.4).

Rash has been observed in 49% of paediatric patients in trametinib and dabrafenib combination studiesin the integrated safety population. The majority of these cases were Grade 1 or 2 and did not requireany dose interruptions or dose reductions (see sections 4.2 and 4.4).

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

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 serumamylase and lipase. Patients should be closely monitored when restarting treatment after an episode ofpancreatitis (see section 4.4).

Renal failure has been reported with trametinib in combination with dabrafenib. Renal failure due topyrexia-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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No acute overdose symptoms have been reported in paediatric patients who received trametinib incombination with dabrafenib in clinical studies. Persistent overdosing of trametinib could result inincreased 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 asnecessary.

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

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

MEK by BRAF and inhibits MEK kinase activity.

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

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

The clinical efficacy and safety of dabrafenib plus trametinib combination therapy in paediatricpatients 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 todabrafenib plus trametinib or carboplatin plus vincristine, and patients with relapsed or refractoryhigh-grade glioma (WHO 2016 Grades 3 and 4) were enrolled into a single-arm dabrafenib plustrametinib cohort.

BRAF mutation status was identified prospectively in tumour tissue via a local test, or by a centrallaboratory using the bioMérieux 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 confirmthe BRAF V600E mutation.

Dabrafenib and trametinib dosing in the clinical study was age- and weight-dependent, withdabrafenib dosed orally at 2.625 mg/kg twice daily for ages <12 years and at 2.25 mg/kg twice dailyfor ages 12 years and older; trametinib was dosed orally at 0.032 mg/kg once daily for ages <6 yearsand at 0.025 mg/kg once daily for ages 6 years and older. Dabrafenib doses were capped at 150 mgtwice daily and trametinib doses at 2 mg once daily. Carboplatin and vincristine were dosed based onage 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 confirmedcomplete/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 performedwhen all patients in both cohorts had completed at least 32 weeks of therapy. The final analysis wasperformed 2 years after completion of enrolment in both cohorts.

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) orcarboplatin plus vincristine (n=37). Median age was 9.5 years, with 34 patients (30.9%) aged12 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 LGGnot otherwise specified (NOS) (18.2%). Metastatic sites were present in 9 patients (8.2%). Priorsurgery was reported in 91 patients (82.7%), among those patients the procedure at last surgery wasresection in 28 patients (25.5%). Systemic corticosteroid use was reported in 44 patients (41.5%).

At the time of the primary analysis, the ORR in the dabrafenib plus trametinib arm showed astatistically significant improvement over carboplatin plus vincristine. The subsequent hierarchicaltesting 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 oftreatment or had discontinued earlier, the overall survival (OS) data were still immature (one deathwas reported in the carboplatin plus vincristine (C+V) arm).

Table 6 Response and progression-free survival based on independent review in the pivotalstudy G2201 (LGG cohort, primary analysis)

Dabrafenib + Trametinib Carboplatin + Vincristine(D+T) (C+V)

N=73 N=37

Best overall response

Complete response (CR), n (%) 2 (2.7) 1 (2.7)

Partial response (PR), n (%) 32 (43.8) 3 (8.1)

Stable disease (SD), n (%) 30 (41.1) 15 (40.5)

Progressive disease (PD), n (%) 8 (11.0) 12 (32.4)

Unknown, n (%) 1 (1.4) 6 (16.2)1

Overall response rate

ORR (CR+PR), (95% CI) 46.6% (34.8 - 58.6%) 10.8% (3.0 - 25.4%)

Odds ratio2, p-value 7.19 (2.3 - 22.4), p<0.001

Risk difference 35.8% (20.6 - 51.0)

Progression-free survival (PFS)

Median (months), (95% CI) 20.1 (12.8 - NE) 7.4 (3.6 - 11.8)

Hazard ratio (95% CI), p-value 0.31 (0.17 - 0.55), p<0.001

NE=not estimable1 4 patients randomised to C+V discontinued prior to receiving treatment.2 Odds ratio (D+T vs C+V) and 95% CI are from a logistic regression with treatment as the only covariate, i.e. itis the odds of observing a response in the D+T arm compared to the odds of observing a response in the C+Varm. Odds ratio >1 favours D+T.

At the time of the final analysis (median duration of follow-up: 39.0 months), the ORR based onindependent review was 54.8% in the D+T arm and 16.2% in the C+V arm with an odds ratio of 6.26.

The analysis also confirmed improved PFS over chemotherapy based on independent review with anestimated 64% risk reduction in progression/death (hazard ratio 0.36). The median PFS was24.9 months in the D+T arm and 7.2 months in the C+V arm. No additional deaths were reported ineither arm at the time of the final analysis.

Figure 1 Kaplan-Meier curves for progression-free survival based on independent review inthe pivotal study G2201 (LGG cohort, final analysis)100%80%60%40%20%

DD++TT ( (nn//N= =4 444/7/733) )

CC+V+V ( (nn//N= =2 266/3/377) )0%0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Time (months)

D+TD +T 73 66 62 57 48 44 39 38 34 27 20 14 10 5 5 3 3 0

C+V

C+V 37 21 16 12 8 6 6 6 5 4 2 0 0 0 0 0 0 0

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 enrolledand treated with dabrafenib plus trametinib. Median age was 13.0 years, with 5 patients (12.2%) aged12 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 pleomorphicxanthoastrocytoma (9.8%). Prior surgery was reported in 40 patients (97.6%), among those patientsthe procedure at last surgery was resection in 24 patients (58.5%). Prior antineoplastic chemotherapywas 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 24 patients (58.5%).

At the time of the final analysis (median duration of follow-up: 45.2 months), the ORR based onindependent review was 56.1% (23/41), (95% CI: 39.7, 71.5): CR in 14 patients (34.1%) and PR in9 patients (22.0%). The median duration of response (DoR) was 27.4 months (95% CI: 9.2, NE).

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

Probability (%)

The trametinib oral solution was rapidly absorbed with a median time to achieve peak plasmaconcentration (Tmax) of 1 hour post-dose. The mean absolute oral bioavailability of the trametinibtablets was 72%. In a relative bioavailability study comparing the oral solution formulation and thetablet formulation after single-dose administration in the fasted state in adults, administration of theoral solution formulation resulted in a 12%, 10% and 71% higher AUC(0-inf), AUC(0-last) and Cmaxrespectively as compared to the tablet formulation.

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

In the pivotal paediatric study, steady-state geometric mean (%CV) Cmax and AUCtau 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 forthe tablet formulation at 2 mg once-daily dose. Steady state was achieved by Day 15.

Administration of a single 2 mg dose of the trametinib oral solution with a low-fat, low-calorie mealresulted in a 12% decrease in Cmax compared to fasted conditions, which is not considered to beclinically significant. The AUClast remained unchanged.

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

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

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

Mean terminal half-life of trametinib is 127 hours (5.3 days) after single-dose administration. Theapparent 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 asingle 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 recoveredradioactivity) and to a minor extent in urine (≤19%). Less than 0.1% of the excreted dose wasrecovered as parent in urine.

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 othermedicinal 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 lowclinical systemic exposure relative to the in vitro potency of inhibition or induction values, trametinibis not considered to be an in vivo inhibitor or inducer of these enzymes or transporters, althoughtransient 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 byother 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 byinhibition of BSEP, increased levels of trametinib upon strong inhibition of hepatic P-gp cannot beexcluded (see section 4.5).

Effects of trametinib on other medicinal products

The effect of repeat-dose trametinib on the steady-state pharmacokinetics of combination oralcontraceptives, norethindrone and ethinyl estradiol, was assessed in a clinical study that consisted of19 female patients with solid tumours. Norethindrone exposure increased by 20% and ethinyl estradiolexposure was similar when co-administered with trametinib. Based on these results, no loss of efficacyof hormonal contraceptives is expected when co-administered with trametinib.

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

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

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

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

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

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

Additionally, in juvenile rats given trametinib, decreased ovarian weights, slight delays in hallmarks offemale sexual maturation (vaginal opening and increased incidence of prominent terminal end budswithin the mammary gland) and slight hypertrophy of the surface epithelium of the uterus wereobserved. All of these effects were reversible following an off-treatment period and attributable topharmacology. However, in rat and dog toxicity studies up to 13 weeks in duration, there were notreatment effects observed in male reproductive tissues.

In embryo-foetal developmental toxicity studies in rats and rabbits, trametinib induced maternal anddevelopmental toxicity. In rats, decreased foetal weights and increased post-implantation loss wereseen 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-clinicalexposures 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 afterdrug-free recovery. In rats, hepatocellular necrosis and transaminase elevations were seen after8 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 cardiachistopathology after 3 weeks at ≥0.25 mg/kg/day trametinib (approximately 3 times human clinicalexposure based on AUC) for up to 3 weeks. In adult rats, mineralisation of multiple organs wasassociated with increased serum phosphorus and was closely associated with necrosis in heart, liverand kidney and haemorrhage in the lung at exposures comparable to the human clinical exposure. Inrats, hypertrophy of the physis and increased bone turnover were observed. In rats and dogs giventrametinib at or below human clinical exposures, bone marrow necrosis, lymphoid atrophy in thymusand GALT and lymphoid necrosis in lymph nodes, spleen and thymus were observed, which have thepotential to impair immune function. In juvenile rats, increased heart weight with no histopathologywas 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 atsignificantly higher concentrations than clinical exposures (IC50 at 2.92 µg/ml, ≥130 times the humanclinical exposure based on Cmax), indicating that there is low risk for phototoxicity to patients takingtrametinib.

In a study in dogs in which trametinib and dabrafenib were given in combination for 4 weeks, signs ofgastrointestinal toxicity and decreased lymphoid cellularity of the thymus were observed at lowerexposures than in dogs given trametinib alone. Otherwise, similar toxicities were observed as incomparable 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 solution3 years.

Reconstituted oral solution

Store below 25ºC.

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 dosingsyringe with 0.5 ml graduation marks.

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

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. Youmay also gently shake.

6. Separate the bottle adapter from the oral syringe. Remove the bottle cap and insert the bottleadapter into the bottle neck. Push hard until the bottle adapter is fully inserted. The bottleadapter 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 localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/23/1781/001

05 January 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.