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MEKINIST F.C TABS 7 x 0.5 mg.

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MEKINIST

Neoplastic Disorders

ACTIVE INGREDIENTS


Trametinib (as dimethyl sulfoxide).

Trametinib

PRESENTATION AND DOSSAGE

F.C TABS: 7 x 0.5 mg.

F.C TABS: 7 x 2 mg.

F.C TABS: 30 x 0.5 mg.

F.C TABS: 30 x 2 mg.

RELATED INFORMATION



LACTOSE FREE


NO INTERACTION WITH FOOD

INDICATIONS

Trametinib as monotherapy or in combination with dabrafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy.


DRUG INTERACTION

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

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


CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the excipients.


SPECIAL PRECAUTIONS

When trametinib is given in combination with dabrafenib, the SmPC of dabrafenib must be consulted prior to intiation of treatment. For additional information on warnings and precautions associated with dabrafenib treatment, please refer to the dabrafenib SmPC.

BRAF V600 testing: The safety and efficacy of trametinib have not been evaluated in patients whose melanoma tested negative for the BRAF V600 mutation.

Trametinib monotherapy compared to BRAF inhibitors: Trametinib monotherapy has not been compared with a BRAF inhibitor in a clinical study in patients with BRAF V600 mutation positive unresectable or metastatic melanoma. Based on cross-study comparisons, overall survival and progression-free survival data appear to show similar effectiveness between trametinib and BRAF inhibitors; however, overall response rates were lower in patients treated with trametinib than those reported in patients treated with BRAF inhibitors.

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

Trametinib in combination with dabrafenib in patients with brain metastases: The safety and efficacy of the combination of trametinib and dabrafenib have not been evaluated in patients with a BRAF V600 mutation-positive melanoma which has metastasised to the brain.

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

Cutaneous squamous cell carcinoma (cuSCC): Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with trametinib in combination with dabrafenib. Cases of cuSCC can be managed with excision and do not require treatment modification. Please refer to the dabrafenib SmPC.

New primary melanoma: New primary melanoma was reported in patients receiving trametinib in combination with dabrafenib. Cases of new primary melanoma can be managed with excision and do not require treatment modification. Please refer to the dabrafenib SmPC.

Non-cutaneous malignancy: Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancies when RAS mutations are present. When trametinib is used in combination with dabrafenib please refer to the dabrafenib SmPC. No dose modification of trametinib is required for RAS mutation positive malignancies when taken in combination with dabrafenib.

Haemorrhage: Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, have occurred in patients taking trametinib as monotherapy and in combination with dabrafenib. The majority of bleeding events were mild. Fatal intracranial haemorrhages have occurred for trametinib in combination with dabrafenib in 1% (3/209) of patients in study MEK115306 and in <1% (3/350) of patients in study MEK116513. In these clinical studies, the median time to onset of the first occurrence of haemorrhagic events was 94 days in both studies for the combination of trametinib and dabrafenib. The potential for these events in patients with unstable and/or symptomatic brain metastases or low platelets (<75,000) is not established as patients with these conditions were excluded from clinical trials. The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patients should be treated as clinically indicated.

LVEF reduction/Left ventricular dysfunction: Trametinib has been reported to decrease LVEF, when used as monotherapy or in combination with dabrafenib. In clinical trials, 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 trials; safety of use in this population is therefore unknown. LVEF should be evaluated in all patients prior to initiation of treatment with trametinib, one month after initiation of therapy, and then at approximately 3-monthly intervals while on treatment.

Pyrexia: Fever has been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib. The incidence and severity of pyrexia are increased with the combination therapy. In patients receiving trametinib in combination withdabrafenib, pyrexia may be accompanied by severe rigors, dehydration, and hypotension which in some cases can lead to acute renal insufficiency. When trametinib is used in combination with dabrafenib and the patient’s temperature is ≥38.5oC please refer to the dabrafenib SmPC for dose modifications for dabrafenib. No dose modification of trametinib is required when taken in combination with dabrafenib.

Hypertension: Elevations in blood pressure have been reported in association with trametinib as monotherapy and in combination with dabrafenib, in patients with or without pre-existing hypertension. Blood pressure should be measured at baseline and monitored during treatment with trametinib, with control of hypertension by standard therapy as appropriate.

Interstitial lung disease (ILD)/Pneumonitis: In a Phase III trial, 2.4% (5/211) of patients treated with trametinib monotherapy developed ILD or pneumonitis; all five patients required hospitalisation. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). In studies MEK115306 and MEK116513 <1% (2/209) and 1 % (4/350), respectively, of patients treated with trametinib in combination with dabrafenib developed pneumonitis or ILD.

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. Trametinib should be permanently discontinued for patients diagnosed with treatment-related ILD or pneumonitis. If trametinib is being used in combination with dabrafenib then 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 as monotherapy and in combination with dabrafenib. Symptoms such as blurred vision, decreased acuity, and other visual phenomena have been reported in the clinical trials with trametinib. In clincial trials uveitis and iridocyclitis have also been reported in patients treated with trametinib in combination with dabrafenib. Trametinib is not recommended in patients with a history of RVO. The safety of trametinib in subjects with predisposing factors for RVO, including uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes, has not been established. 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, follow the dose modification schedule in the prescribing information; if uveitis is diagnosed, please refer to dabrafenib SmPC. In patients who are diagnosed with RVO, treatment with trametinib should be permanently discontinued. No dose modification of dabrafenib is required when taken in combination with trametinib following diagnosis of RVO or RPED. No dose modification of trametinib is required when taken in combination with dabrafenib following diagnosis of uveitis.

Rash: Rash has been observed in about 60% of patients in trametinib monotherapy studies and in about 25% of patients in trametinib and dabrafenib combination studies MEK115306 and MEK116513. The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions.

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

Renal failure: Renal failure has been identified in patients treated with trametinib in combination with dabrafenib in clinical studies. Please refer to the dabrafenib SmPC.

Pancreatitis: Pancreatitis has been reported in patients treated with trametinib in combination with dabrafenib in clinical studies. Please refer to the dabrafenib SmPC.

QT prolongation: If during treatment the QTc exceeds 500 msec, please refer to the dabrafenib SmPC.

Hepatic events: Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib. It is recommended that patients receiving treatment with trametinib monotherapy or in combination with dabrafenib have liver function monitored every four weeks for 6 months after treatment initiation with trametinib. 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.

Deep vein thrombosis (DVT)/pulmonary embolism (PE): Pulmonary embolism or deep vein thrombosis can occur when trametinib is used as monotherapy or in combination with dabrafenib. 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 trametinib and dabrafenib for life-threatening pulmonary embolism.

Gastrointestinal disorders: Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking trametinib as monotherapy and in combination with dabrafenib. Treatment with trametinib monotherapy or in combination with dabrafenib 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 medications with a recognised risk of gastrointestinal perforation.

See prescribing information for full details.


SIDE EFFECTS

Anaemia ,hypersensitivity, vision blurred, dehydration, left ventricular dysfunction, periorbital oedema, visual impairment, bradycardia, ejection fraction decreased, hypertension, haemorrhage, lymphoedema, cough, dyspnoea, pneumonitis, diarrhoea, nausea, vomiting, constipation, abdominal pain, dry mouth, stomatitis, rash, dermatitis acneiform, dry skin, pruritus, alopecia, erythema, palmar-plantar erythrodysaesthesia syndrome, skin fissures, skin chapped, fatigue, oedema peripheral, pyrexia, face oedema, mucosal inflammation, asthenia, folliculitis, paronychia, cellulitis, rash pustular, aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased, blood creatine phosphokinase increased, heart rate decreased.

See prescribing information for full details.


DOSAGE

Treatment with trametinib should only be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products. Before taking trametinib, patients must have confirmation of BRAF V600 mutation using a validated test. The recommended dose of trametinib, either used as monotherapy or in combination with dabrafenib, is 2 mg once daily. The recommended dose of dabrafenib, when used in combination with trametinib, is 150 mg twice daily.

Missed doses: If a dose of trametinib is missed, only take the dose if it is more than 12 hours until the next scheduled dose. If a dose of dabrafenib is missed, when trametinib is given in combination with dabrafenib, only take the dose of dabrafenib if it is more than 6 hours until the next scheduled dose.

Duration of treatment: It is recommended that patients continue treatment with trametinib until patients no longer derive benefit or the development of unacceptable toxicity.

Treatment adjustments: The management of adverse reactions may require dose reduction, treatment interruption or treatment discontinuation. Dose modifications are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma.

Recommended dose level reductions: Starting dose: Trametinib dose (Used as monotherapy or in combination with dabrafenib) – 2 mg once daily. Dabrafenib dose* (Only when used in combination with trametinib) –  150 mg twice daily.

1st dose reduction: Trametinib dose- 1.5 mg once daily. Dabrafenib dose-  100 mg twice daily.

2nd dose reduction: Trametinib dose– 1 mg once daily. Dabrafenib dose-  75 mg twice daily.

3rd dose reduction (combination only): Trametinib dose– 1 mg once daily. Dabrafenib dose –50 mg twice daily

Dose adjustment for trametinib below 1 mg once daily is not recommended, whether used as monotherapy or in combination with dabrafenib. Dose adjustment for dabrafenib below 50 mg twice daily is not recommended when used in combination with trametinib. *Please refer to the dabrafenib SmPC, Posology and method of administration, for dosing instructions for treatment with dabrafenib monotherapy.

Dose modification schedule based on the grade of any Adverse Events (AE)

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.

Grade 4: Discontinue permanently, or interrupt therapy until Grade 0 to 1 and reduce by one dose level when resuming therapy.

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 2 mg once daily.

If treatment-related toxicities occur when trametinib is used in combination with dabrafenib, then both treatments 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 pyrexia, uveitis, RAS mutation positive non-cutaneous malignancies and QT prolongation (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 modification exceptions (where only one of the two therapies is dose reduced) for selected adverse reactions

Pyrexia: When trametinib is used in combination with dabrafenib and the patient’s temperature is ≥38.5oC please refer to the dabrafenib SmPC for dose modifications for dabrafenib. No dose modification of trametinib is required when taken in combination with dabrafenib.

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.

RAS-mutation-positive non-cutaneous malignancies: Consider the benefits and risks 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.

QT prolongation: If during treatment the QTc exceeds 500 msec, please refer to the dabrafenib SmPC  for dose modifications for dabrafenib. No dose modification of trametinib is required when taken in combination with dabrafenib.

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). No dose modification of dabrafenib is required when trametinib is taken in combination with dabrafenib. If the LVEF recovers, treatment with trametinib may be restarted, but the dose should be reduced by one dose level with careful monitoring. With Grade 3 or 4 left ventricular cardiac dysfunction or if LVEF does not recover trametinib should be permanently discontinued.

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 trametinib therapy, a prompt ophthalmological assessment is recommended. In patients who are diagnosed with RVO, treatment with trametinib, whether given as monotherapy or in combination with dabrafenib, should be permanently discontinued. No dose modification of dabrafenib is required when trametinib is taken in combination with dabrafenib. If RPED is diagnosed follow the dose modification schedule in Table 3 below for trametinib.

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 2-3 RPED: Withhold trametinib for up to 3 weeks.

Grade 2-3 RPED: that improves to Grade 0-1 within 3 weeks: Resume trametinib at a lower dose (reduced by 0.5 mg) or discontinue trametinib in patients taking trametinib 1 mg daily.

Grade 2-3 RPED: that does not improve to at least Grade 1 within 3 weeks: Permanently discontinue trametinib.

Interstitial lung disease (ILD)/Pneumonitis: Withhold trametinib 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. Permanently discontinue trametinib for patients diagnosed with treatment-related ILD or pneumonitis. No dose modification of dabrafenib is required when trametinib is taken in combination with dabrafenib for cases of ILD or pneumonitis.

Renal impairment: No dosage 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 starting dose adjustment cannot be determined. Trametinib should be used with caution in patients with severe renal impairment when administered as monotherapy or in combination with dabrafenib.

Hepatic impairment: No dosage adjustment is required in patients with mild hepatic impairment. There are no clinical data in patients with moderate or severe hepatic impairment; therefore, the potential need for starting dose adjustment cannot be determined. Trametinib should be used with caution in patients with moderate or severe hepatic impairment when administered as monotherapy or in combination with dabrafenib.

Non-Caucasian patients: The safety and efficacy of trametinib in non-Caucasian patients have not been established. No data are available.

Elderly: No initial dose adjustment is required in patients >65 years of age. More frequent dose adjustments may be required in patients >65 years of age.

Paediatric population: The safety and efficacy of trametinib has not been established in children and adolescents (<18 years). No data are available. Studies in juvenile animals have shown adverse effects of trametinib which had not been observed in adult animals.

Method of administration: Trametinib should be taken orally with a full glass of water. Trametinib tablets should not be chewed or crushed. Trametinib should be taken without food, at least 1 hour before or 2 hours after a meal.

It is recommended that the dose of trametinib is taken at a similar time every day. When trametinib and dabrafenib are taken in combination, the once-daily dose of trametinib should be taken at the same time each day with either the morning dose or the evening dose of dabrafenib. If a patient vomits after taking trametinib, the patient should not retake the dose and should take the next scheduled dose.

Please refer to dabrafenib SmPC for information on method of administration when given in combination with trametinib.


OVERDOSE

In clinical trials with trametinib monotherapy one case of accidental overdose was reported; a single dose of 4 mg. No AEs were reported following this event of trametinib overdose. In clinical trials with the combination of trametinib and dabrafenib 11 patients reported trametinib overdose (4 mg); no SAEs were reported. There is no specific treatment for overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.


PREGNANCY & LACTATION

Pregnancy: There are no adequate and well-controlled studies of trametinib in pregnant women.  Trametinib should not be administered to pregnant women or nursing mothers. 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.

Lactation: It is not known whether trametinib is excreted in human milk. See prescribing information for full details.


IMPORTANT NOTES

Special precautions for storage: Store in a refrigerator (2°C to 8°C). Do not freeze. Store in the original package in order to protect from light and moisture. Keep the bottle tightly closed.

Once opened, the bottle may be stored for 30 days at not more than 30°C.   


MANUFACTURER & DISTRIBUTER:

Manufacturer: GLAXO WELLCOME SA, SPAIN

License Holder: GlaxoSmithKline Israel Ltd.


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