LEVETIRACETAM GLENMARK 1000 MG FILM-COATED TABLETS - summary of medicine characteristics

Levetiracetam Glenmark 1000 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 1000 mg levetiracetam

Excipients(s) with known effect:

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially □sodium-free □.

For the full list of excipients, see section 6.1.

Film-coated tablet.

White coloured, oblong shaped, scored on one side, film-coated tablets debossed with ‚H‘ on one side and ‚91‘ on other side.

The tablet can be divided into equal doses.

4.1 Therapeutic indications

Levetiracetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy.

Levetiracetam is indicated as adjunctive therapy

in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy.

in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.

in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

4.2 Posology and method of administration

Posology

Monotherapy for adults and adolescents from 16 years of age

The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Add-on therapy for adults (>18 years) and adolescents (12 to 17 years) weighing 50 kg or more

The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.

Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.

Discontinuation

If levetiracetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in infants older than 6 months, children and adolescents weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months): dose decrease should not exceed 7 mg/kg twice daily every two weeks).

Special populations

Elderly (65 years and older)

Adjustment of the dose is recommended in elderly patients with compromised renal function (see “Renal impairment” below).

Renal impairment

The daily dose must be individualised according to renal function.

For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's cre­atinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighing 50 kg or more, the following formula:

[140-age (yean)] x weight (kg)

------------------------------- (x 0.85 for women) 72 x serum, creatinine (mg/dl)

Then CLcr is adjusted for body surface area (BSA) as follows:

CLcr (ml/min)

BSA subject (m3)

Dosing adjustment for adult and adolescent patients weighing more than 50 kg with impaired renal function:

(1) A 750 mg loading dose is recommended on the first day of treatment with levetiracetam.

(2) Following dialysis, a 250 to 500 mg supplemental dose is recommended.

For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.

The CLcr in ml/min/1.73 m2 may be estimated from serum creatinine (mg/dl) determination, for young adolescents, children and infants, using the following formula (Schwartz formula):

Height (cm) x ks

CLcr (ml/min/1.73 m3) = ----------------------------------------

ks= 0.45 in Term infants to 1 year old; ks= 0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in adolescent male

Dosing adjustment for infants, children and adolescent patients weighing less than 50 kg with impaired renal function:

(1) A Levetiracetam oral solution should be used for doses under 250 mg, for doses not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets.

(2) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.

(3) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.

(4) Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is recommended.

(5) Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is recommended.

Hepatic impairment

No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min/1.73m2.

Paediatric population

The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.

The tablet formulation is not adapted for use in infants and children under the age of 6 years. A Levetiracetam oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases a Levetiracetam oral solution should be used.

Monotherapy

The safety and efficacy of Levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established.

There are no data available.

Add-on therapy for infants aged from 6 to 23 months, children (2 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg

A Levetiracetam oral solution is the preferred formulation for use in infants and children under the age of 6 years.

For children 6 years and above, a Levetiracetam oral solution should be used for doses under 250 mg, for doses not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets.

The lowest effective dose should be used. The starting dose for a child or adolescent of 25kg should be 250mg twice daily with a maximum dose of 750mg twice daily.

Dose in children 50 kg or greater is the same as in adults.

Add-on therapy for infants aged from 1 month to less than 6 months

The oral solution is the formulation to use in infants.

Method of administration

The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. After oral administration the bitter taste of Levetiracetam may be experienced. The daily dose is administered in two equally divided doses.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Renal impairment

The administration of Levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see section 4.2).

Acute Kidney injury

The use of levetiracetam has been very rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months.

Blood cell counts

Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders (section 4.8).

Suicide

Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known.

Therefore, patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Abnormal and aggressive behaviours

Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment adaptation or gradual discontinuation should be considered. If discontinuation is considered, please refer to section 4.2.

Worsening of seizures

As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or severity. This paradoxical effect was mostly reported within the first month after levetiracetam initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. Patients should be advised to consult their physician immediately in case of aggravation of epilepsy.

Paediatric population

The tablet formulation is not adapted for use in infants and children under the age of 6 years.

Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

4 CLINICAL PARTICULARS

4.5 Interaction with other medicinal products and other forms of interaction

Antiepileptic medicinal products

Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.

A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20% higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required.

Probenecid

Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite, but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. It is expected that other medicinal products excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and methotrexate, is unknown.

Oral contraceptives and other pharmacokinetics interactions

Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.

Antacids

No data on the influence of antacids on the absorption of levetiracetam are available.

Laxatives

There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.

Food and alcohol

The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.

No data on the interaction of levetiracetam with alcohol are available.

4.6 Fertility, pregnancy and lactation

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The adverse reaction profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications.

Tabulated list of adverse reactions

Adverse reactions reported in clinical studies (adults, adolescents, children and infants >1 month) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. Adverse reactions are presented in the order of decreasing seriousness and their frequency is defined as follows: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) and very rare (<1/10,000).

Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.

Description of selected adverse reactions

The risk of anorexia is higher when levetiracetam is coadministered with topiramate.

In several cases of alopecia, recovery was observed when levetiracetam was discontinued.

Bone marrow suppression was identified in some of the cases of pancytopenia.

Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation.

Paediatric population

In patients aged 1 month to less than 4 years, a total of 190 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. Sixty of these patients were treated with levetiracetam in placebo-controlled studies. In patients aged 4–16 years, a total of 645 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both these paediatric age ranges, these data are supplemented with the post-marketing experience of the use of levetiracetam.

In addition, 101 infants aged less than 12 months have been exposed in a post authorization safety study. No new safety concerns for levetiracetam were identified for infants less than 12 months of age with epilepsy.

The adverse reaction profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile.

A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of levetiracetam in children 4 to 16 years of age with partial onset seizures. It was concluded that levetiracetam was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioural and emotional functioning indicated a worsening in levetiracetam treated patients on aggressive behaviour as measured in a standardised and systematic way using a validated instrument (CBCL – Achenbach Child Behavior Checklist).

However subjects, who took levetiracetam in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behavior were not worse than baseline.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration. There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.

Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg bodyweight. Therefore there is no need for plasma level monitoring of levetiracetam.

A significant correlation between saliva and plasma concentrations has been shown in adults and children (ratio of saliva/plasma concentrations ranged from 1 to 1.7 for oral tablet formulation and after 4 hours post-dose for oral solution formulation).

Adults and adolescents

Absorption

Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100 %.

Peak plasma concentrations (Cmax) are achieved at 1.3 hours after dosing. Steady-state is achieved after two days of a twice daily administration schedule.

Peak concentrations (Cmax) are typically 31 and 43 pg/ml following a single 1,000 mg dose and repeated 1,000 mg twice daily dose, respectively.

The extent of absorption is dose-independent and is not altered by food.

Distribution

No tissue distribution data are available in humans.

Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %).

The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume.

Biotransformation

Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P450 isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive.

Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6 % of the dose) and the other one by opening of the pyrrolidone ring (0.9 % of the dose).

Other unidentified components accounted only for 0.6 % of the dose.

No enantiomeric interconversion was evidenced in vivo for either levetiracetam or its primary metabolite.

In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected in vivo. Therefore, the interaction of levetiracetam with other substances, or vice versa, is unlikely.

Elimination

The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 ml/min/kg.

The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately 93 % of the dose was excreted within 48 hours). Excretion via faeces accounted for only 0.3 % of the dose.

The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66 % and 24 % of the dose, respectively during the first 48 hours.

The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine clearance.

Elderly

In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease in renal function in this population (see section 4.2).

Renal impairment

The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of levetiracetam, based on creatinine clearance in patients with moderate and severe renal impairment (see section 4.2).

In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods, respectively.

The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis session.

Hepatic impairment

In subjects with mild and moderate hepatic impairment, there was no relevant modification of the clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50 % due to a concomitant renal impairment (see section 4.2).

Paediatric population

Children (4 to 12 years)

Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years), the half-life of levetiracetam was 6.0 hours. The apparent body weight adjusted clearance was approximately 30 % higher than in epileptic adults.

Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours. The apparent body clearance was 1.1 ml/min/kg.

Infants and children (1 month to 4 years)

Following single dose administration (20 mg/kg) of a 100 mg/ml oral solution to epileptic children (1 month to 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 ml/min/kg) than for adults (0.96 ml/min/kg).

In the population pharmacokinetic analysis conducted in patients from 1 month to 16 years of age, body weight was significantly correlated to apparent clearance (clearance increased with an increase in body weight) and apparent volume of distribution. Age also had an influence on both parameters. This effect was pronounced for the younger infants, and subsided as age increased, to become negligible around 4 years of age.

In both population pharmacokinetic analyses, there was about a 20% increase of apparent clearance of levetiracetam when it was co-administered with an enzymeinducing antiepileptic medicinal product.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.

Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent in the mouse at exposure levels similar to human exposure levels and with possible relevance for clinical use were liver changes, indicating an adaptive response such as increased weight and centrilobular hypertrophy, fatty infiltration and increased liver enzymes in plasma.

No adverse reactions on male or female fertility or reproduction performance were observed in rats at doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1 generation.

Two embryo-foetal development (EFD) studies were performed in rats at 400, 1200 and 3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in foetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no effect on embryomortality and no increased incidence of malformations. The NOAEL (No Observed Adverse Effect Level) was 3600 mg/kg/day for pregnant female rats (x 12 the MRHD on a mg/m2 basis) and 1200 mg/kg/day for fetuses.

Four embryo-foetal development studies were performed in rabbits covering doses of 200, 600, 800, 1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and a decrease in foetal weight associated with increased incidence of fetuses with cardiovascular/ske­letal anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the fetuses (equal to the MRHD on a mg/m2 basis).

A peri- and post-natal development study was performed in rats with levetiracetam doses of 70, 350 and 1800 mg/kg/day. The NOAEL was >1800 mg/kg/day for the F0 females, and for the survival, growth and development of the F1 offspring up to weaning (x 6 the MRHD on a mg/m2 basis).

Neonatal and juvenile animal studies in rats and dogs demonstrated that there were no adverse effects seen in any of the standard developmental or maturation endpoints at doses up to 1800 mg/kg/day (x 6 – 17 the MRHD on a mg/m2 basis).

Environmental Risk Assessment (ERA)

The use of Levetiracetam in accordance with the product information is not likely to result in an unacceptable environmental impact (see section 6.6).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Maize starch

Croscarmellose sodium

Povidone (K 30)

Silica colloidal anhydrous

Talc

Magnesium stearate

Tablet coat:

Polyvinyl alcohol, Titanium dioxide (E171), Macrogol 3350 and Talc.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

No special precautions for storage.

6.5 Nature and contents of container

PVC-Aluminium and PVC/PVDC-Aluminium blisters containing 10, 20, 30, 50, 60, 80, 100, 120 or 200 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Glenmark Pharmaceuticals Europe Limited

Laxmi House, 2B Draycott Avenue

Kenton, Middlesex, HA3 0BU

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 25258/0192

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/09/2018