Mekinist film-coated tablets
Novartis Pharmaceuticals UK Ltd
Mekinist® 0.5 mg film-coated tablets
Mekinist® 2.0 mg film-coated tablets
Mekinist 0.5 mg film-coated tablets
Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib
Mekinist 2 mg film-coated tablets
Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib.
For the full list of excipients, see section 6.1.
Film-coated tablet
Mekinist 0.5 mg film-coated tablets
Yellow, modified oval, biconvex, film-coated tablets, approximately 4.8 x 8.9 mm, with 'GS' debossed on one face and 'TFC' on the opposing face.
Mekinist 2 mg film-coated tablets
Pink, round, biconvex, film-coated tablets, approximately 7.5 mm, with 'GS' debossed on one face and 'HMJ' on the opposing face.
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 (see sections 4.4 and 5.1).
Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy (see section 5.1).
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.
Posology
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 (see Tables 1 and 2).
Dose modifications are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see dabrafenib SmPC for further details).
Table 1 Recommended dose level reductions
|
Dose level
|
Trametinib dose
Used as monotherapy or in combination with dabrafenib
|
Dabrafenib dose*
Only when used in combination with trametinib
|
|
Starting dose
|
2 mg once daily
|
150 mg twice daily
|
|
1st dose reduction
|
1.5 mg once daily
|
100 mg twice daily
|
|
2nd dose reduction
|
1 mg once daily
|
75 mg twice daily
|
|
3rd dose reduction (combination only)
|
1 mg once daily
|
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.
Table 2 Dose modification schedule based on the grade of any Adverse Events (AE)
|
Grade (CTC-AE)*
|
Recommended trametinib dose modifications
Used as monotherapy or in combination with dabrafenib
|
|
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.
|
* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE)
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 ≥ 38.5°C please refer to the dabrafenib SmPC (section 4.2) 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 (see section 4.4).
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 (section 4.2) 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) (see section 4.4). 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 (see section 4.4).
With Grade 3 or 4 left ventricular cardiac dysfunction or if LVEF does not recover trametinib should be permanently discontinued (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 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 (see section 4.4).
Table 3 Recommended dose modifications for trametinib for RPED
|
Grade 1 RPED
|
Continue treatment with retinal eva luation 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 (see section 5.2). 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 (see section 5.2). 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 (see Tables 1 and 2 above) may be required in patients >65 years of age (see section 4.8).
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 (see section 5.3).
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.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 eva luated 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 (see section 5.1). 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 eva luated 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 (section 4.4).
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 (section 4.4).
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 (section 4.4). 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 (see section 4.8). 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 (see section 4.8). 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 eva luated 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 clinical trials with trametinib as monotherapy and in combination with dabrafenib (see section 4.8). The incidence and severity of pyrexia are increased with the combination therapy (see dabrafenib 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.
When trametinib is used in combination with dabrafenib and the patient's temperature is ≥ 38.5°C please refer to the dabrafenib SmPC (section 4.2) 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 (see section 4.8). 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 (see section 4.8).
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 (see section 4.2). 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 (see section 4.8). 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 Table 3 (see section 4.2); if uveitis is diagnosed, please refer to dabrafenib SmPC section 4.4. In patients who are diagnosed with RVO, treatment with trametinib should be permanently discontinued. No dose modification of dabrafenib is required when taken in combination with trametinib following diagnosis of RVO or RPED. No dose modification of trametinib is required when taken in combination with dabrafenib following diagnosis of uveitis.
Rash
Rash has been observed in about 60% of patients in trametinib monotherapy studies and in about 25% of patients in trametinib and dabrafenib combination studies MEK115306 and MEK116513 (see section 4.8). 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 (see section 4.8). 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 eva luation 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 (section 4.4).
Pancreatitis
Pancreatitis has been reported in patients treated with trametinib in combination with dabrafenib in clinical studies. Please refer to the dabrafenib SmPC (section 4.4).
QT prolongation
If during treatment the QTc exceeds 500 msec, please refer to the dabrafenib SmPC section 4.4.
Hepatic events
Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib (see section 4.8). 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 (see sections 4.2 and 5.2).
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 (see section 4.8). 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.
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 trametininb 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.
Combination with dabrafenib
When trametinib is used in combination with dabrafenib see sections 4.4 and 4.5 of the dabrafenib SmPC for interactions.
Effect of food on trametinib
Patients should take trametinib as monotherapy or in combination with dabrafenib at least one hour prior to or two hours after a meal due to the effect of food on trametinib absorption (see section 4.2 and 5.2).
Women of childbearing potential/Contraception in females
Advise female patients of reproductive potential to use highly effective contraception during treatment with trametinib and for 4 months after treatment.
It is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.
Use with dabrafenib may render hormonal contraceptives less effective and therefore an alternative method of contraception, such as a barrier method, should be used when trametinib is used in combination with dabrafenib. Refer to the dabrafenib SmPC for further information.
Pregnancy
There are no adequate and well-controlled studies of trametinib in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). 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.
Breast-feeding
It is not known whether trametinib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the breast-feeding infant cannot be excluded. 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 as monotherapy or in combination with dabrafenib. In animals, no fertility studies have been performed, but adverse 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. Refer to the dabrafenib SmPC for further information.
Trametinib has minor influence on the ability to drive or use machines. The clinical status of the patient and the adverse reaction profile 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 potential for fatigue, dizziness or eye problems that might affect these activities.
Summary of the safety profile
The safety of trametinib monotherapy has been eva luated in the integrated safety population of 329 patients with metastatic melanoma treated with trametinib 2 mg once daily. Of these patients, 211 patients were treated with trametinib for BRAF V600 mutant melanoma in a randomised open label phase III study (see section 5.1). The most common adverse reactions (≥ 20%) for trametinib include rash, diarrhoea, fatigue, oedema peripheral, nausea, and dermatitis acneiform.
The safety of trametinib in combination with dabrafenib has been eva luated in 2 Phase III studies, MEK115306 and MEK116513, where an analysis of the safety of trametinib in combination with dabrafenib has been conducted in 209 and 350 patients, respectively, with BRAF V600 mutation positive unresectable or metastatic melanoma receiving trametinib (2 mg once daily) and dabrafenib (150 mg twice daily) combination therapy (see section 5.1 combination therapy). The most common adverse reactions (≥ 20%) for trametinib and dabrafenib combination therapy include pyrexia, fatigue, nausea, headache, chills, diarrhoea, rash, arthralgia, hypertension, vomiting and cough.
Tabulated summary of adverse reactions
Adverse reactions are listed below by MedDRA body system organ class.
The following convention has been utilised for the classification of frequency:
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
Not known
(cannot be estimated from the available data)
Categories have been assigned based on absolute frequencies in the clinical trial data. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Trametinib monotherapy
Table 4 Adverse reactions occurring in patients treated with trametinib in the integrated safety population (n=329)
|
System Organ Class
|
Frequency (all grades)
|
Adverse Reactions
|
|
Blood and lymphatic system disorders
|
Common
|
Anaemia
|
|
Immune system disorders
|
Common
|
Hypersensitivitya
|
|
Metabolism and nutrition disorders
|
Common
|
Dehydration
|
|
Eye disorders
|
Common
|
Vision blurred
|
|
Periorbital oedema
|
|
Visual impairment
|
|
Uncommon
|
Chorioretinopathy
|
|
Papilloedema
|
|
Retinal detachment
|
|
Retinal vein occlusion
|
|
Cardiac disorders
|
Common
|
Left ventricular dysfunction
|
|
Ejection fraction decreased
|
|
Bradycardia
|
|
Uncommon
|
Cardiac failure
|
|
Vascular disorders
|
Very common
|
Hypertension
|
|
Haemorrhageb
|
|
Common
|
Lymphoedema
|
|
Respiratory, thoracic and mediastinal disorders
|
Very common
|
Cough
|
|
Dyspnoea
|
|
Common
|
Pneumonitis
|
|
Uncommon
|
Interstitial lung disease
|
|
Gastrointestinal disorders
|
Very common
|
Diarrhoea
|
|
Nausea
|
|
Vomiting
|
|
Constipation
|
|
Abdominal pain
|
|
Dry mouth
|
|
Common
|
Stomatitis
|
|
Uncommon
|
Gastrointestinal perforation
|
|
Colitis
|
|
Skin and subcutaneous disorders
|
Very common
|
Rash
|
|
Dermatitis acneiform
|
|
Dry skin
|
|
Pruritus
|
|
Alopecia
|
|
Common
|
Erythema
|
|
Palmar-plantar erythrodysaesthesia syndrome
|
|
Skin fissures
|
|
Skin chapped
|
|
Musculoskeletal and connective tissue disorders
|
Uncommon
|
Rhabdomyolysis
|
|
General disorders and administration site conditions
|
Very common
|
Fatigue
|
|
Oedema peripheral
|
|
Pyrexia
|
|
Common
|
Face oedema
|
|
Mucosal inflammation
|
|
Asthenia
|
|
Infections and infestation
|
Common
|
Folliculitis
|
|
Paronychia
|
|
Cellulitis
|
|
Rash pustular
|
|
Investigations
|
Very common
|
Aspartate aminotransferase increased
|
|
Common
|
Alanine aminotransferase i |
