Rezdiffra 60 mg film-coated tablets

Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (consistent with fibrosis stages F2 to F3).

Posology

The posology is based on the patient's body weight (see section 5.2):

  • For patients weighing < 100 kg, the recommended dose is 80 mg taken orally once daily.

  • For patients weighing ≥ 100 kg, the recommended dose is 100 mg taken orally once daily.

Missed or delayed doses

If a dose of resmetirom is missed, the patient should take the next dose at the scheduled time. A double dose should not be taken to make up for the missed dose.

CYP2C8 inhibitors

Concomitant use of resmetirom with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. If resmetirom is used concomitantly with a moderate CYP2C8 inhibitor (e.g., clopidogrel, deferasirox, teriflunomide), the dose of resmetirom should be reduced from 100 mg to 80 mg for patients weighing ≥ 100 kg and from 80 mg to 60 mg for patients weighing < 100 kg (see section 4.5).

Special populations

Hepatic impairment

• Mild hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment (Child Pugh A). Safety and efficacy have not been demonstrated in Child-Pugh A cirrhosis (see section 5.2).

• Moderate or severe hepatic impairment

Increased exposure (C_max and AUC) of resmetirom has been observed in patients with moderate or severe hepatic impairment. Resmetirom should not be used in patients with moderate or severe (Child-Pugh B or C) hepatic impairment (see section 5.2).

Renal impairment

• Mild renal impairment (eGFR 60 to 89 mL/min), moderate renal impairment (eGFR 30 to 59 mL/min) and severe renal impairment (eGFR 15 to 29 mL/min)

No dose adjustment of resmetirom is recommended in patients with mild, moderate or severe renal impairment. In moderate or severe renal impairment the increase in exposure is within the expected variability of exposure (see section 5.2).

Elderly

No dose adjustment is required in patients aged ≥ 65 years (see section 5.2).

Paediatric population

The safety and efficacy of resmetirom in children and adolescents less than 18 years old have not yet been established. No data are available.

Method of administration

Oral use.

Resmetirom may be taken with or without food (see section 5.2).

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

Gallbladder events

In clinical studies, cholecystitis was observed more often in resmetirom-treated patients than in placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

Use in other liver diseases

Resmetirom has not been studied in patients with other underlying liver diseases. Resmetirom should be used with caution in MASH patients with other underlying liver diseases such as autoimmune liver diseases or active viral hepatitis. Resmetirom should be used with caution in patients with alcohol-related liver disease.

Liver enzymes

Conduct liver enzyme monitoring periodically during treatment. If hepatotoxicity is suspected, discontinue resmetirom treatment and continue to monitor liver chemistry.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Resmetirom is partially metabolised by CYP2C8.

Effects of other medicinal products on resmetirom

CYP2C8 inhibitors

Clopidogrel, a moderate CYP2C8 inhibitor, increased resmetirom exposure (1.3-fold in C_max and 1.7-fold in AUC) in healthy adult subjects. Dose adjustment of resmetirom is recommended when used concomitantly with moderate CYP2C8 inhibitors. As greater increases are expected with strong inhibitors (e.g. gemfibrozil), their use is not recommended (see section 4.2).

OATP1B1, OATP1B3 and BCRP inhibitors

No clinically significant differences in the pharmacokinetics of resmetirom were observed when used concomitantly with ciclosporin (an OATP1B1/1B3 and BCRP inhibitor).

Effects of resmetirom on other medicinal products

HMG-CoA reductase inhibitors (statins)

The effect of resmetirom on the pharmacokinetics of statins (i.e., simvastatin, rosuvastatin, pravastatin and atorvastatin) was evaluated in studies in healthy subjects:

• Simvastatin: AUC increased by 1.7-fold and C_max by 1.4-fold following a single dose of simvastatin 20 mg with resmetirom (100 mg/day).

• Rosuvastatin: AUC increased by 1.4-fold and C_max by 1.8-fold following a single dose of rosuvastatin 20 mg with resmetirom (100 mg/day).

• Pravastatin: AUC increased by 1.4-fold and C_max by 1.3-fold following a single dose of pravastatin 40 mg with resmetirom (100 mg/day).

• Atorvastatin: AUC increased by 1.4-fold with no change in C_max following a single dose of atorvastatin 20 mg with resmetirom (100 mg/day).

The dose of rosuvastatin and simvastatin should be limited to a daily dose of 20 mg and the dose of pravastatin and atorvastatin should be limited to a daily dose of 40 mg.

CYP2C8 substrates

Resmetirom is a substrate and mild inhibitor of CYP2C8. In a clinical study in healthy subjects, co-administration of a single oral dose of pioglitazone (15 mg), a moderately sensitive CYP2C8 substrate, with resmetirom (100 mg/day) resulted in a 1.5 fold increase in the AUC of pioglitazone, with no change in C_max.

Although no dose adjustment is required, clinical monitoring is recommended when resmetirom is used with certain CYP2C8 substrates for which small increases in exposure may lead to serious or dose-related adverse reactions.

Warfarin

In healthy subjects with stable INR, administration of resmetirom (100 mg/day) for multiple days had minimal effect on the AUC and C_max of R- and S-warfarin. No dose adjustment is required.

Pregnancy

There are no data from the use of resmetirom in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of resmetirom during pregnancy.

Breast-feeding

It is unknown whether resmetirom and/or its metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to abstain from resmetirom therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No fertility data are available in humans. Animal studies do not indicate any direct or indirect effects on fertility (see section 5.3).

Resmetirom has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequently reported adverse reactions are diarrhoea, nausea, and pruritus.

Diarrhoea typically occurred at treatment initiation, was mild to moderate and self-limiting, resolving on average in 2 to 3 weeks. The median time to complete resolution of diarrhoea was 3 to 4 weeks. Nausea occurred at treatment initiation and was mild to moderate, occurring more commonly in female patients.

Other rare events included cholecystitis and urticaria.

The most common reason for discontinuation in all age groups was withdrawal by subject.

Tabulated list of adverse reactions

Unless otherwise stated, the frequencies of adverse reactions in Table 1 are based on all-cause adverse event frequencies identified in patients randomised to the double-blind treatment arms of the Phase 3 clinical studies (MAESTRO-NASH and MAESTRO-NAFLD-1).

Adverse reactions are listed by MedDRA system organ class and 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); very rare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1: List of adverse reactions in MAESTRO-NASH and MAESTRO-NAFLD-1

¹ The term “cholecystitis” includes Preferred Terms of bile duct stone, biliary colic, biliary dilatation, cholecystitis, cholecystitis acute, cholecystitis chronic and cholangitis.

² A higher incidence of cholecystitis and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo. However, the Exposure Adjusted Incidence Rates (EAIRs) for these events were less than 1 per 100 patient years (PY) for all treatment arms.

Description of selected adverse reactions

Liver enzyme elevations

Mild increases in mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in the first 4 weeks after initiating treatment with resmetirom. These elevations were more common in patients on concomitant statin therapy. In both resmetirom dose arms, the mean elevation in ALT and AST values was less than 1.5 times baseline at 4 weeks after treatment initiation. These values returned to baseline around 8 weeks after initiating treatment.

Thyroid function tests

A decrease in levels of prohormone free T4 (FT4) of mean 2%, 13%, and 17% was seen at 12 months in patients treated with placebo, resmetirom 80 mg once daily, and resmetirom 100 mg once daily, respectively, with minimal changes in active hormone T3 or in TSH. There were no clinical findings associated with FT4 decreases.

Other special populations

Elderly

Of the 1794 patients with MASH in clinical studies of resmetirom who received the recommended dose (80 mg or 100 mg), 440 (25%) were 65 years of age or older and 54 (3%) were 75 years of age or older. Discontinuation rates among older patients ≥ 65 years of age in MAESTRO-NASH were higher at 100 mg than 80 mg.

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.

In clinical studies in healthy subjects, the highest dose of resmetirom tested was 200 mg once daily for up to 14 days, without reports of any additional adverse reactions.

If overdose occurs the patient should be monitored for signs or symptoms of adverse reactions (see section 4.8), and supportive care should be provided as needed.

The medicinal product is unlikely to be removed by haemodialysis due to high protein binding (see section 5.2).

Pharmacotherapeutic group: Bile and liver therapy, liver therapy, ATC code: A05BA11.

Mechanism of action

Resmetirom is a liver-directed partial agonist for the thyroid hormone receptor beta (THR-β). Resmetirom produced 83.8% of the maximum response compared to triiodothyronine (T3), with an EC₅₀ of 0.21 μM in an in vitro functional assay for THR-β activation. The same functional assay for thyroid hormone receptor alpha (THR-α) agonism showed 48.6% efficacy for resmetirom relative to T3, with an EC₅₀ of 3.74 μM. THR-β is the predominant form of THR in the liver. Stimulation of THR-β in the liver improves mitochondrial function and lipid metabolism, and increases fatty acid β-oxidation, thereby reducing lipotoxic liver fat, inflammation and liver fibrosis. Resmetirom's liver directed THR-β agonism is particularly relevant in the treatment of MASH and leads to minimal off-target activity on THR-α in tissues such as heart and bone.

Pharmacodynamic effects

Liver fat content

Resmetirom decreases liver fat content as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) or FibroScan controlled attenuation parameter (CAP). Reductions in liver fat content by MRI-PDFF were observed at 16 (the first assessment) and 52 weeks of treatment. Reductions in liver fat content by CAP were observed at 52 weeks of treatment.

Reductions in lipids

Resmetirom reduces blood low density lipoprotein (LDL) cholesterol, apolipoprotein B, lipoprotein (a) and triglyceride levels. Reductions in all lipid endpoints were observed initially after 4 weeks (the first assessment) and sustained at 24 and through 52 weeks of treatment.

Prohormone FT4

Decreased concentrations of prohormone FT4 were observed at the first assessment at 4 weeks of treatment. Similar decreases in FT4 were observed during treatment.

Sex hormone binding globulin (SHBG)

Resmetirom increased concentrations of sex hormone binding globulin (SHBG) at the first assessment at 4 weeks of treatment and at longer durations of treatment; by week 52, SHBG increased from baseline 145% (95% CI: 128, 160%) for 80 mg, 205% (95% CI: 182, 229%) for 100 mg and -0.4% (95% CI: -4, 2%) for placebo. No known adverse reactions were associated with SHBG elevations..

Cardiac electrophysiology

At a dose of 200 mg given for 7 days, resmetirom did not prolong the QT interval, PR interval, QRS interval, or alter heart rate in a study in healthy subjects.

Clinical efficacy and safety

The efficacy of resmetirom was studied in one multicentre, randomised, double-blind, placebo-controlled, clinical study in patients with MASH with liver fibrosis (MAESTRO-NASH). The 54-month outcomes portion of MAESTRO-NASH remains ongoing. The dual primary endpoints of the 52-week analysis were the effects of resmetirom versus placebo on: 1) the percentage of patients with resolution of NASH (ballooning 0, inflammation 0,1) associated with at least a 2-point reduction in NAFLD Activity Score (NAS) and without worsening of fibrosis by liver biopsy, and 2) the histological improvement from baseline demonstrated by at least a 1-point improvement in fibrosis (NASH Clinical Research Network [CRN] system) by liver biopsy with no worsening of NAS (total of three NAS components: ballooning, inflammation and steatosis).

Patients with metabolic risk factors were included in MAESTRO-NASH who had a baseline or recent historic liver biopsy showing NASH with a NAS of at least 4 and fibrosis stage 2 or 3.

The 52-week assessment included 917 patients with F2 or F3 fibrosis who received resmetirom 80 mg (n=306), resmetirom 100 mg (n=308), or placebo (n=303) once daily, in addition to lifestyle counselling on diet and exercise. Patients were on stable doses of medicinal products for diabetes, dyslipidaemia and hypertension. Patients were stratified by baseline type-2 diabetes status (present/absent) and fibrosis stage.

Demographics and baseline disease characteristics were balanced between treatment arms. The mean (SD) age at baseline was 57 (11) years. 25% of patients were older than 65 years, and 2% of patients were 75 years of age or older. Overall, 56% were female, ethnicity was 21% Hispanic, and races included 89% White, 3% Other, 3% Asian and 2% Black. The mean BMI was 36 (7) and mean body weight was 101 (23) kg. The baseline disease and comorbidity characteristics are shown in Table 2.

Table 2: Baseline disease and comorbidity characteristics in F2 and F3 patients enrolled in MAESTRO-NASH

Note: Patients who were rescored F4 at baseline were considered F3 for the purposes of stratification and analysis and are included in F3 numbers.

The 80 and 100 mg doses of resmetirom achieved both primary endpoints with statistically significant improvement relative to placebo in NASH resolution and fibrosis improvement (by 1 stage) (Table 3). Confidence intervals for other study endpoints were not controlled for multiple determinations. NASH resolution and fibrosis improvement were consistent regardless of age, gender, diabetes status, and baseline fibrosis stage. NASH resolution and fibrosis improvement (combined) and 2-stage reduction in fibrosis also improved with both doses of resmetirom relative to placebo.

Table 3: Effect of resmetirom in F2/F3 patients at week 52 on the primary liver biopsy endpoints of MAESTRO-NASH

Note: Missing data were considered as non-responders. Additionally, 11 patients whose biopsies were delayed outside of the analysis window due to COVID-related issues were excluded.

Decreases from baseline in liver enzymes in resmetirom versus placebo-treated patients were observed at week 12 and continued to decline over 1 year (Table 4).

Table 4: Mean percent change from baseline to week 48 in liver enzymes in F2-F3 patients – ANCOVA with Placebo-based (-CR) Multiple Imputation (Week 52 Modified Intent-to-Treat Population – F2/F3)

ANCOVA = analysis of covariance; %CFB = percent change from baseline; CI = confidence interval; CR=copy reference

Note: n = number of patients used to compute LSM after imputation (imputation was not done for patients with no baseline data).

Note: Patients that were F3 at eligibility and re-evaluated as F4 at baseline by either pathologist are included in this analysis

% CFB = percent change from baseline

For a number of NASH biomarkers, in patients with increased baseline, greater improvements from baseline to week 52 were observed in resmetirom versus placebo-treated patients, including CK-18, ELF score, PIIINP, TIMP-1, and Hyaluronic Acid (HA).

The results of imaging endpoints overall showed support of the primary evaluation as shown in the following table (Table 5).

Table 5: Mean change from baseline for Imaging Endpoints at Week 52 in F2/F3 patients– ANCOVA with Placebo-based (CR) Multiple Imputation (Week 52 Modified Intent-to-Treat Population – F2/F3)

ANCOVA = analysis of covariance; CFB = change from baseline; CI = confidence interval; CR=Copy Reference

Note: n = number of patients used to compute LSM after imputation (imputation was not done for patients with no baseline data).

Note: Patients that were F3 at eligibility and re-evaluated as F4 at baseline by either pathologist are included in this analysis

Resmetirom reduced lipid and lipoprotein particles to a greater extent than placebo (Table 6). At week 24, resmetirom significantly reduced LDL-C, the key secondary endpoint of MAESTRO-NASH, at both studied doses.

Table 6: Mean percent change from baseline to week 52 in LDL-C in F2/F3 patients

Note: N is based on 917 total patients minus one patient in the Resmetirom 80 mg group who did not have a baseline LDL-C value.

Note: Missing data imputed with Placebo-based (CR) Multiple Imputation

Paediatric population

The Medicines and Healthcare products Regulatory Agency has deferred the obligation to submit the results of studies with resmetirom in one or more subsets of the paediatric population in the treatment of metabolic dysfunction-associated steatohepatitis (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The Medicines and Healthcare products Regulatory Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

Following once daily doses, steady state is typically reached within 3 to 6 days of dosing. Resmetirom steady state exposure increases in a dose proportional manner between doses of 40 mg (0.5 times the lowest approved recommended dose) and 100 mg. Resmetirom exposure increases in a greater than dose-proportional manner between doses of 100 mg and 200 mg (2 times the highest approved recommended dose) by about 5.6-fold. Resmetirom exposure increased 1.5- to 3-fold following once daily dosing; however, the MGL-3623 metabolite does not accumulate. The estimated resmetirom systemic exposure at steady state in MASH patients derived from population pharmacokinetic (PK) modeling is summarised in Table 7 below.

Resmetirom exposure is similar between MASH patients with F2 stage fibrosis and F3 stage fibrosis.

Table 7: Resmetirom estimated systemic exposure at steady state in patients with MASH with fibrosis (F2 and F3)

Absorption

The resmetirom median time to maximum plasma concentration (T_max) is approximately 4 hours following multiple daily doses of resmetirom 80 mg or 100 mg.

Effect of food

Concomitant administration with a high-fat meal (approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively) had no clinically relevant effect on the oral bioavailability of resmetirom.

Concomitant food administration resulted in a 33% decrease in C_max, an 11% decrease in AUC, and a delay in median T_max by about 2 hours compared to under fasted condition.

Distribution

The apparent volume of distribution at steady-state (Vd/F) of resmetirom is highly correlated with body weight. Based on population PK analysis, in MASH patients with fibrosis stage F2/F3 and a median body weight of 99 kg, the median Vd/F at steady state was 62.8 L. Resmetirom is over 99% protein-bound in plasma.

Biotransformation

In vitro studies showed that resmetirom is partially metabolised by CYP2C8 and is a substrate of transporters including OATP1B1, OATP1B3 and BCRP. Resmetirom has two major metabolites: oxalic acid and MGL-3623. MGL-3623 is approximately 30-fold less potent at THR-β than resmetirom. MGL-3623 represented approximately 16% and oxalic acid represented approximately 15% of total plasma AUC in a repeat-dose oral mass balance study using a 100 mg solution dose of resmetirom. MGL-3623 does not accumulate with repeated dosing of resmetirom.

Elimination

Based on a population pharmacokinetic analysis, in MASH patients with fibrosis stage F2/F3, the median terminal plasma half-life (t_½) of resmetirom is 4.5 hours. The mean apparent clearance (CL/F) at steady state is 18.6 L/h (CV%: 64.4).

Special populations

Hepatic impairment

The use of resmetirom should be avoided in patients with decompensated cirrhosis. Moderate or severe hepatic impairment (Child-Pugh B or C) increases resmetirom C_max and AUC, which may increase the risk of adverse reactions.

The disposition of resmetirom and its metabolite were compared in non-MASH patients with hepatic impairment (mild [N=10], moderate [N=10], and severe [N=3] as indicated by the Child-Pugh method) and subjects with normal hepatic function (n=8) following repeated 80 mg dosing of resmetirom for 6 days.

Compared to subjects with normal hepatic function, following repeated 80 mg dosing for 6 days, the percent ratio of geometric mean of AUC for resmetirom, were 115%, 303%, and 2,350% in patients with mild, moderate, and severe hepatic impairment, respectively. The percent ratio of geometric means for C_max were 133%, 196%, and 919%, respectively (see section 4.2).

The disposition of resmetirom and its metabolite were compared in MASH patients, with MASH cirrhosis categorised with mild hepatic impairment (Child-Pugh Class A) and non-cirrhotic MASH following repeated 100 mg dosing of resmetirom for 6 days. The PK disposition of resmetirom was not altered in MASH cirrhosis patients with mild hepatic impairment (Child-Pugh Class A) compared with non-cirrhotic MASH patients. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A cirrhosis).

The safety and effectiveness of resmetirom have not been established in patients with MASH cirrhosis.

Renal impairment

The pharmacokinetics of resmetirom and its metabolite MGL-3623 were evaluated in subjects with mild, moderate and severe renal impairment. Renal excretion is a minor elimination pathway. In subjects with mild and moderate renal impairment, exposure to resmetirom was comparable to that in subjects with normal renal function and was not clinically relevant. In subjects with severe renal impairment (eGFR < 30 mL/min/ 1.73 m²), repeated dosing resulted in an approximately 1.5-fold increase in AUC and a 1.3-fold increase in C_max for resmetirom compared to matched healthy controls.

Exposure to the metabolite MGL-3623 was increased to a lesser extent. These increases remained within the variability observed in the general population at the recommended dose. Importantly, the observed changes in exposure were not associated with clinically meaningful alterations in pharmacodynamic markers (including thyroid hormones, lipids, and SHBG) or safety signals. Therefore, no dose adjustment is considered necessary in patients with renal impairment (see section 4.2).

Other special populations

The PK of resmetirom were not affected by age (< 65 years and ≥ 65 years), gender or race. Effects of ethnicity were not evaluated.

The results from the population PK model suggest a faster clearance of resmetirom in patients with higher body weight (see section 4.2). No parameter was identified other than body weight in the exposure-response model of resmetirom that impacted efficacy parameters.

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

Carcinogenesis

In a 2-year study in CD-1 mice, resmetirom produced leiomyoma or leiomyosarcoma in the uterus at a dose of 100 mg/kg/day (51 times the maximum recommended dose based on AUC). No tumorigenic effects were observed in female mice at doses of up to 30 mg/kg/day (14 times the maximum recommended dose based on AUC) or in male mice at doses of up to 100 mg/kg/day (35 times the maximum recommended dose based on AUC). In a 2-year study in Sprague-Dawley rats, resmetirom produced benign fibroadenoma in the mammary gland of males at a dose of 30 mg/kg/day (6.5 times the maximum recommended dose based on AUC). No tumorigenic effects were observed in male rats at doses of up to 6 mg/kg/day (3.7 times the maximum recommended dose based on AUC) or in female rats at doses of up to 30 mg/kg/day (3.4 times the maximum recommended dose based on AUC).

Fertility, reproductive and developmental toxicity

In a fertility and early embryonic development study in male and female rats, there were no adverse effects of resmetirom on male or female fertility, reproductive organs, reproductive function or early embryonic development at oral doses up to 30 mg/kg/day (6.9 and 2.6 times the maximum recommended dose based on AUC, for males and females respectively).

No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 100 mg/kg/day (21 times the maximum recommended dose based on AUC) or in pregnant rabbits treated orally with up to 30 mg/kg/day (2.8 times the maximum recommended dose based on AUC) during the period of organogenesis.

Tablet core

Microcrystalline cellulose

Mannitol

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Tablet coating

Poly(vinyl alcohol)

Titanium dioxide (E171)

Macrogol

Talc

Not applicable.

3 years.

Store below 30 °C

Rezdiffra film-coated tablets are supplied in PVC/PCTFE blisters with aluminium foil lidding.

Pack size of 28 film-coated tablets.

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