1. Name Of The Medicinal Product
Sevikar 20 mg/5 mg film-coated tablets
Sevikar 40 mg/5 mg film-coated tablets
Sevikar 40 mg/10 mg film-coated tablets
2. Qualitative And Quantitative Composition
Sevikar 20 mg/5 mg film-coated tablets:
Each film-coated tablet of Sevikar contains 20 mg of olmesartan medoxomil and 5 mg of amlodipine (as amlodipine besilate).
Sevikar 40 mg/5 mg film-coated tablets:
Each film-coated tablet of Sevikar contains 40 mg of olmesartan medoxomil and 5 mg of amlodipine (as amlodipine besilate).
Sevikar 40 mg/10 mg film-coated tablets:
Each film-coated tablet of Sevikar contains 40 mg of olmesartan medoxomil and 10 mg of amlodipine (as amlodipine besilate).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet
Sevikar 20 mg/5 mg film-coated tablets:
White, round, film-coated tablet with C73 debossed on one side.
Sevikar 40 mg/5 mg film-coated tablets:
Cream, round, film-coated tablet with C75 debossed on one side.
Sevikar 40 mg/10 mg film-coated tablets:
Brownish-red, round, film-coated tablet with C77 debossed on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of essential hypertension.
Sevikar is indicated in adult patients whose blood pressure is not adequately controlled on olmesartan medoxomil or amlodipine monotherapy (see section 4.2 and section 5.1).
4.2 Posology And Method Of Administration
Adults
The recommended dosage of Sevikar is 1 tablet per day.
Sevikar 20 mg/5 mg may be administered in patients whose blood pressure is not adequately controlled by 20 mg olmesartan medoxomil or 5 mg amlodipine alone.
Sevikar 40 mg/5 mg may be administered in patients whose blood pressure is not adequately controlled by Sevikar 20 mg/5 mg.
Sevikar 40 mg/10 mg may be administered in patients whose blood pressure is not adequately controlled by Sevikar 40 mg/5 mg.
A step-wise titration of the dosage of the individual components is recommended before changing to the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.
For convenience, patients receiving olmesartan medoxomil and amlodipine from separate tablets may be switched to Sevikar tablets containing the same component doses.
Sevikar can be taken with or without food.
Elderly (age 65 years or over)
No adjustment of the recommended dose is generally required for elderly patients (see section 5.2).
If up-titration to the maximum dose of 40 mg olmesartan medoxomil daily is required, blood pressure should be closely monitored.
Renal impairment
The maximum dose of olmesartan medoxomil 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 Sevikar in patients with severe renal impairment (creatinine clearance < 20 mL/min) is not recommended (see 4.4, 5.2).
Monitoring of potassium levels and creatinine is advised in patients with moderate renal impairment.
Hepatic impairment
Sevikar should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.4, 5.2).
In patients with moderate hepatic impairment, an initial dose of 10 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.
As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. Sevikar should therefore be administered with caution in these patients.
Paediatric population
The safety and efficacy of Sevikar in children and adolescents below 18 years has not been established. No data are available.
Method of administration:
The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.
4.3 Contraindications
Hypersensitivity to the active substances, to dihydropyridine derivatives or to any of the excipients (see section 6.1).
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Severe hepatic insufficiency and biliary obstruction (see section 5.2).
Due to the component amlodipine Sevikar is also contraindicated in patients with:
- severe hypotension.
- shock (including cardiogenic shock).
- obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis).
- haemodynamically unstable heart failure after acute myocardial infarction
4.4 Special Warnings And Precautions For Use
Patients with hypovolaemia or sodium depletion:
Symptomatic hypotension may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to administration of Sevikar or close medical supervision at the start of the treatment is recommended.
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 medicinal products that affect this system, such as angiotensin II receptor antagonists, has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.
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 Sevikar is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Sevikar 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 Sevikar in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance < 12 mL/min).
Hepatic impairment:
Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section 5.2). Care should be taken when Sevikar is administered in patients with mild to moderate hepatic impairment. In moderately impaired patients, the dose of olmesartan medoxomil should not exceed 20 mg (see section 4.2). Use of Sevikar in patients with severe hepatic impairment is contraindicated (see section 4.3).
Hyperkalaemia:
As with other angiotensin II antagonists and ACE inhibitors, hyperkalaemia may occur during treatment, especially in the presence of renal impairment and/or heart failure (see section 4.5). Close monitoring of serum potassium levels in at-risk patients is recommended.
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels.
Lithium:
As with other angiotensin II receptor antagonists, the concomitant use of Sevikar and lithium is not recommended (see section 4.5).
Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy:
Due to the amlodipine component of Sevikar as with all 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 medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Sevikar is not recommended in such patients.
Heart failure:
As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.
In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of nonischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo (see section 5.1).
Ethnic differences:
As with all other angiotensin II antagonists, the blood pressure lowering effect of Sevikar can be 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.
Elderly patients
In the elderly, increase of the dosage should take place with care (see section 5.2).
Pregnancy:
Angiotensin II antagonists should not be initiated during pregnancy. Unless continued angiotensin II antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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).
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Potential interactions related to the Sevikar combination:
To be taken into account with concomitant use
Other antihypertensive agents:
The blood pressure lowering effect of Sevikar can be increased by concomitant use of other antihypertensive medicinal products (e.g. alpha blockers, diuretics).
Potential interactions related to the olmesartan medoxomil component of Sevikar
Concomitant use not recommended
Medicinal products affecting potassium levels:
Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products which affect potassium levels are to be prescribed in combination with Sevikar, monitoring of serum potassium levels is recommended.
Lithium:
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II antagonists. Therefore concomitant use of Sevikar and lithium is not recommended (see section 4.4). If concomitant use of Sevikar and lithium proves necessary, careful monitoring of serum lithium levels is recommended.
Concomitant use requiring caution
Non-steroidal anti-inflammatory medicinal products (NSAIDs) including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs:
When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening of renal function and may lead to an increase in serum potassium. Therefore monitoring of renal function at the beginning of such concomitant therapy is recommended, as well as adequate hydration of the patient.
Additional information
After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.
Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin. Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.
Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.
Potential interactions related to the amlodipine component of Sevikar:
Effects of other medicinal products on amlodipine
CYP3A4 inhibitors:
With concomitant use of CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients respectively the plasma concentration of amlodipine increased by 22% and 50 % respectively. However, the clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors. However, no adverse events attributable to such interaction have been reported.
CYP3A4 inducers:
There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (i.e. rifampicin, hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
In clinical interaction studies, grapefruit juice, cimetidine, aluminium/ magnesium (antacid) and sildenafil did not affect the pharmacokinetics of amlodipine.
Effects of amlodipine on other medicinal products
The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other antihypertensive agents.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (alcohol), warfarin or cyclosporin.
There is no effect of amlodipine on laboratory parameters.
4.6 Pregnancy And Lactation
Pregnancy (see section 4.3)
There are no data about the use of Sevikar in pregnant patients. Animal reproductive toxicity studies with Sevikar have not been performed.
Olmesartan medoxomil (active ingredient of Sevikar)
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 2nd and 3rd trimesters of pregnancy (see sections 4.3 and 4.4). |
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 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.
Exposure to angiotensin II antagonists therapy 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 section 5.3).
Should exposure to angiotensin II antagonists have occurred from the second trimester on, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).
Amlodipine (active ingredient of Sevikar)
Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery.
As a consequence, Sevikar is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
Lactation
Olmesartan is excreted into the milk of lactating rats. However, it is not known whether olmesartan passes into human milk. It is not known whether amlodipine is excreted in breast milk. Similar calcium channel blockers of the dihydropyridine type are excreted in breast milk.
Because no information is available regarding the use of olmesartan and amlodipine during breast-feeding, Sevikar is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects On Ability To Drive And Use Machines
Sevikar can have minor or moderate influence on the ability to drive and use machines.
Dizziness, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react.
4.8 Undesirable Effects
Sevikar:
The most commonly reported adverse reactions during treatment with Sevikar are peripheral oedema (11.3%), headache (5.3%) and dizziness (4.5%).
Adverse reactions from Sevikar in clinical trials, post-authorisation safety studies and spontaneous reporting are summarised in the below table as well as adverse reactions from the individual components olmesartan medoxomil and amlodipine based on the known safety profile of these substances.
The following terminologies have been used in order to classify the occurrence of adverse reactions:
Very common (
Common (
Uncommon (
Rare (
Very rare (<1/10,000), not known (cannot be estimated from the available data)
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