Treatment of essential hypertension

Adults

The recommended starting dose of Olmesartan medoxomil is 10 mg once daily. In patients whose blood pressure is not adequately controlled at this dose, the dose of Olmesartan medoxomil may be increased to 20 mg once daily as the optimal dose. If additional blood pressure reduction is required, Olmesartan medoxomil dose may be increased to a maximum of 40 mg daily or hydrochlorothiazide therapy may be added. The antihypertensive effect of Olmesartan medoxomil is substantially present within 2 weeks of initiating therapy and is maximal by about 8 weeks after initiating therapy. This should be borne in mind when considering changing the dose regimen for any patient.

In order to assist compliance, it is recommended that Olmetec tablets be taken at about the same time each day, with or without food, for example at breakfast time. Elderly

No adjustment of dosage is generally required in elderly patients (see below for dose recommendations in patients with renal impairment). If up-titration to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

Renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 20 – 60 mL/min) is 20 mg Olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group. The use of Olmesartan medoxomil in patients with severe renal impairment (creatinine clearance < 20 mL/min) is not recommended, since there is only limited experience in this patient

group (see sections 4.4, 5.2).

Hepatic impairment

No adjustment of dosage recommendations is required for patients with mild hepatic impairment. In patients with moderate hepatic impairment, an initial dose of10 mg Olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. There is no experience of Olmesartan medoxomil in patients with severe hepatic impairment, therefore use is not recommended in this patient group (see sections 4.4 and 5.2). Olmesartan medoxomil should not be used in patients with biliary obstruction (see 4.3).

Children and adolescents

Olmetec is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

1.1.   Dual Blockade of the Renin-Angiotensin-aldosterone System (RAAS):

Combination of Olmesartan with ACE inhibitors, or aliskiren may cause increased risks of hyperkalemia, worsening of kidney function and hypotension. Therefore, this combination should not be used, especially in patients with kidney problems.

Intravascular volume depletion:

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Olmesartan medoxomil.

Other conditions with stimulation of the renin-angiotensin-aldosterone system:

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists.

Renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin- angiotensin- aldosterone system.

Renal impairment and kidney transplantation:

When Olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections 4.2, 5.2). There is no experience of the administration of Olmesartan medoxomil in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance <12 mL/min).

Hepatic impairment:

There is no experience in patients with severe hepatic impairment and therefore use of Olmesartan medoxomil in this patient group is not recommended (see section 4.2 for dosage recommendations in patients with mild or moderate hepatic impairment). Hyperkalaemia:

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

The risk, that may be fatal, is increased in elderly, in patients with renal insufficiency and in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect the renin- angiotensin-aldosterone system, the benefit risk ratio should be evaluated and other alternatives considered.

The main risk factors for hyperkalaemia to be considered are:

-  Diabetes, renal impairment, age (> 70 years)

-   Combination with one or more other medicinal products that affect the renin- angiotensin-aldosterone system and/or potassium supplements. Some medicinal products or therapeutic class of medicinal products may provoke a hyperkalaemia: salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptors antagonists, non steroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressor as ciclosporin or tacrolimus, trimethoprim

-    Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extended trauma).

Close-monitoring of serum potassium in at risk patients is recommended (see section 4.5).

Lithium:

As with other angiotensin-II receptor antagonists, the combination of lithium and Olmesartan medoxomil is not recommended (see section 4.5).

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy:

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Olmesartan medoxomil is not recommended in such patients.

Ethnic differences:

As with all other angiotensin II antagonists, the blood pressure lowering effect of Olmesartan medoxomil is somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Sprue-like Enteropathy

Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Olmetec in cases where no other etiology is identified.

Pregnancy:

Angiotensin II antagonists should not be initiated during pregnancy. Unless continued angiotensin II antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Other:

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interaction studies have only been performed in adults.

Dual RAAS Blockade:

The   combination   of   Olmesartan   with ACEIs             or         other           ARBs is contraindicated in patients with diabetes mellitus or renal impairment.

Aliskiren fumarate (In patients with diabetes, except for patients with very poor blood pressure control with other antihypertensive treatment)

Dual blockade (e.g by adding ACE inhibitor to Olmesartan ) should not be used, especially in patients with Kidney problems.

Effects of other medicinal products on Olmesartan medoxomil:

Potassium supplements and potassium sparing diuretics:

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium (see section 4.4). Such concomitant use is therefore not recommended.

Other antihypertensive medications:

The blood pressure lowering effect of Olmesartan medoxomil can be increased by concomitant use of other antihypertensive medications.

Non-steroidal anti-inflammatory drugs (NSAIDs):

NSAIDs (including acetylsalicylic acid at doses> 3 g/day and also COX-2 inhibitors) and angiotensin-II receptor antagonists may act synergistically by decreasing glomerular filtration. The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of acute renal failure. Monitoring of renal function at the beginning of treatment should be recommended as well as regular hydration of the patient.

Additionally, concomitant treatment can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their partial loss of efficacy.

Other compounds:

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of Olmesartan was observed. Coadministration of warfarin and digoxin had no effect on the pharmacokinetics of Olmesartan.

Effects of Olmesartan medoxomil on other medicinal products:

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and angiotensin II antagonists. Therefore use of Olmesartan medoxomil and lithium in combination is not recommended (see section 4.4). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Other compounds:

Compounds which have been investigated in specific clinical studies in healthy volunteers include warfarin, digoxin, an antacid (magnesium aluminium hydroxide), hydrochlorothiazide and pravastatin. No clinically relevant interactions were observed and in particular Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Olmesartan had no clinically relevant inhibitory effects on in vitro human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4, and had no or minimal inducing effects on rat cytochrome P450 activities. Therefore in vivo interaction studies with known cytochrome P450 enzyme inhibitors and inducers were not conducted, and no clinically relevant interactions between Olmesartan and drugs metabolised by the above cytochrome P450 enzymes are expected.

Pregnancy:

Epidemiological evidence regarding the risk of teratogenicity following exposure to

ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II antagonists, similar risks may exist

for this class of drugs. Unless continued angiotensin receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Angiotensin II antagonists therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 “Preclinical Safety Data”.)

Should exposure to angiotensin II antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II antagonists should be closely observed for hypotension (see also sections 4.3 and 4.4).

Lactation:

Olmesartan is excreted in the milk of lactating rats but it is not known whether Olmesartan is excreted in human milk. Because no information is available regarding the use of Olmetec during breast-feeding, Olmetec is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

No studies on the effect on the ability to drive and use machines have been performed. With respect to driving vehicles or operating machines, it should be taken into account that occasionally dizziness or fatigue may occur in patients taking antihypertensive therapy.

a.       Tabulated list of Adverse reaction:

Market experience

The following adverse reactions have been reported in post-marketing experience. They are listed by System Organ Class and ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000) including isolated reports.

Clinical trials

In double-blind, placebo-controlled monotherapy studies, the overall incidence of treatment-emergent adverse events was 42.4% on olmesartan medoxomil and 40.9% on placebo.

In placebo-controlled monotherapy studies, the only adverse drug reaction that was unequivocally related to treatment was dizziness (2.5% incidence on olmesartan medoxomil and 0.9% on placebo).

In long-term (2-year) treatment, the incidence of withdrawals due to adverse events on olmesartan medoxomil 10 – 20 mg once daily was 3.7%. The following adverse events have been reported across all clinical trials with olmesartan medoxomil (including trials with active as well as placebo control), irrespective of causality or incidence relative to placebo. They are listed by body system and ranked under headings of frequency using the conventions described :

Additional information on special populations

In elderly patients the frequency of hypotension is slightly increased from rare to uncommon.

b.      Description of selected adverse reaction:

Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers. A causal relationship, however, has not been established.

Cases of autoimmune hepatitis with a latency of few months to years have been reported post-marketing, that were reversible after the withdrawal of Olmesartan.

Post Marketing Experience

Data from one controlled trial and an epidemiologic study have suggested that high- dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo inpatients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, decrease in time-to-onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke,revascularization death) in the olmesartan group compared to the placebo group (15olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).

The epidemiologic study included patients 65 years and older with overall exposure of

>300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for < 6 months.

Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics.

c.       Other special population:

Renal impairment and kidney transplantation:

When Olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections 4.2, 5.2). There is no experience of the administration of Olmesartan medoxomil in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance <12 mL/min).

Hepatic impairment:

There is no experience in patients with severe hepatic impairment and therefore use of Olmesartan medoxomil in this patient group is not recommended (see section 4.2 for dosage recommendations in patients with mild or moderate hepatic impairment). Pregnancy:

The use of angiotensin II antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II antagonists is contraindicated during the second and third trimester of pregnancy

Elderly

No adjustment of dosage is generally required in elderly patients (see below for dose recommendations in patients with renal impairment). If up-titration to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

Pediatric population:

The safety of olmesartan was monitored in 361 children and adolescents, aged 1-17 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:

•  Epistaxis is a common adverse event in children (i.e. ≥ 1/100 to < 1/10) that has not

been reported in adults.

•  During the 3 weeks of double-blind study, the incidence of treatment emergent dizziness and headache nearly doubled in children 6-17 years of age in the high olmesartan dose group.

The overall safety profile for olmesartan in pediatric patients does not differ significantly from the safety profile in adults.

-To report any side effect (s)

·         Saudi Arabia :

·        

Other GCC states /other countries

Only limited information is available regarding over dosage in humans. The most likely effect of over dosage is hypotension. In the event of over dosage, the patient should be carefully monitored and treatment should be symptomatic and supportive.

No information is available regarding the dialysability of Olmesartan.

Pharmaco-therapeutic group:

Angiotensin II antagonists, ATC code: C09CA08.

Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin II mediated by the AT1

receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors results in increases inplasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin- aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (AT1) receptor.

In hypertension, Olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after cessation of therapy.

Once daily dosing with Olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24 hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.

With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment. Whenused together with hydrochlorothiazide, the reduction in blood pressure is additive and coadministration is well tolerated.

The effect of Olmesartan on mortality and morbidity is not yet known.

Absorption and distribution

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, Olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract.

No intact Olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of Olmesartan from a tablet formulation was 25.6%.

The mean peak plasma concentration (Cmax) of Olmesartan is reached within about 2 hours after oral dosing with Olmesartan medoxomil, and Olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.

Food had minimal effect on the bioavailability of Olmesartan and therefore Olmesartan medoxomil may be administered with or without food.

No clinically relevant gender-related differences in the pharmacokinetics of Olmesartan have been observed.

Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between Olmesartan and other highly bound coadministered drugs is low (as confirmed by the lack of a clinically significant interaction between Olmesartan medoxomil and warfarin). The binding of Olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 – 29 L).

Metabolism and elimination

Total plasma clearance was typically 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). Following a single oral dose of ¹⁴C labelled Olmesartan medoxomil, 10 - 16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed Olmesartan is

cleared by both renal excretion (ca 40%) and hepato-biliary excretion (ca 60%). All recovered radioactivity was identified as Olmesartan. No other significant metabolite was detected. Enterohepatic recycling of Olmesartan is minimal. Since a large proportion of Olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated (see section 4.3).

The terminal elimination half life of Olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 – 0.7 L/h and was independent of dose.

Pharmacokinetics in special populations

Elderly:

In hypertensive patients, the AUC at steady state was increased by ca 35% in elderly patients (65 – 75 years old) and by ca 44% in very elderly patients (75 years old) compared with the younger age group. This may be at least in part related to a mean decrease in renal function in this group of patients.

Renal impairment:

In renally impaired patients, the AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls (see sections 4.2, 4.4).

Hepatic impairment:

After single oral administration, Olmesartan AUC values were 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of Olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment was 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, Olmesartan mean AUC was again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values were similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see sections 4.2, 4.4).

In chronic toxicity studies in rats and dogs, Olmesartan medoxomil showed similar effects to other AT1 receptor antagonists and ACE inhibitors: raised blood urea (BUN) and creatinine (through functional changes to the kidneys caused by blocking AT1 receptors); reduction in heart weight; a reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basal membrane, dilatation of the tubules). These adverse effects caused by the pharmacological action of Olmesartan medoxomil have also occurred in preclinical trials on other AT1 receptor antagonists and ACE inhibitors and can be reduced by simultaneous oral administration of sodium chloride.

In both species, increased plasma renin activity and hypertrophy/hyperplasia of the juxtaglomerular cells of the kidney were observed. These changes, which are a typical effect of the class of ACE inhibitors and other AT1 receptor antagonists, wouldappear to have no clinical relevance.

Like other AT1 receptor antagonists Olmesartan medoxomil was found to increase the

incidence of chromosome breaks in cell cultures in vitro. No relevant effects were observed in several in vivo studies using Olmesartan medoxomil at very high oral doses of up to 2000 mg/kg. The overall data of a comprehensive genotoxicity testing suggest that Olmesartan is very unlikely to exert genotoxic effects under conditions of clinical use.

Olmesartan medoxomil was not carcinogenic, neither in rats in a 2 year study nor in mice when tested in two 6 month carcinogenicity studies using transgenic models.

In reproductive studies in rats, Olmesartan medoxomil did not affect fertility and there was no evidence of a teratogenic effect. In common with other angiotensin II antagonists, survival of offspring was reduced following exposure to Olmesartan medoxomil and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, Olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats, however, there was no indication of a fetotoxic effect.

Microcrystalline cellulose, Lactose monohydrate, Low substitute Hydroxy

propylcellulose, Hydroxy propylcellulose, magnesium stearate, and Opadry white

Not applicable.

No special requirements.

Forming Aluminium / aluminium blister pack.

Packs of 28 film-coated tablets.

No special requirements.