- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Add-on therapySevikar HCT is indicated in adult patients whose blood pressure is not adequately controlled on the combination of olmesartan medoxomil and amlodipine taken as dual-component formulation.
Substitution therapySevikar HCT is indicated as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide, taken as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component formulation (hydrochlorothiazide or amlodipine).
AdultsThe recommended dose of Sevikar HCT is 1 tablet per day.
Add-on therapySevikar HCT 20 mg/5 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 20 mg and amlodipine 5 mg taken as dual-component combination. Sevikar HCT 40 mg/5 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg and amlodipine 5 mg taken as dual-component combination or in patients whose blood pressure is not adequately controlled on Sevikar HCT 20 mg/5 mg/12.5 mg.Sevikar HCT 40 mg/5 mg/25 mg may be administered in patients whose blood pressure is not adequately controlled on Sevikar HCT 40 mg/5 mg/12.5 mg.Sevikar HCT 40 mg/10 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg and amlodipine 10 mg taken as dual-component combination or by Sevikar HCT 40 mg/5 mg/12.5 mg.Sevikar HCT 40 mg/10 mg/25 mg may be administered in patients whose blood pressure is not adequately controlled on Sevikar HCT 40 mg/10 mg/12.5 mg or by Sevikar HCT 40 mg/5 mg/25 mg.A step-wise titration of the dosage of the individual components is recommended before changing to the triple-component combination. When clinically appropriate, direct change from dual-component combination to the triple-component combination may be considered.
Substitution therapyPatients controlled on stable doses of olmesartan medoxomil, amlodipine and hydrochlorothiazide taken at the same time as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component formulation (hydrochlorothiazide or amlodipine) may be switched to Sevikar HCT containing the same component doses.The maximum recommended dose of Sevikar HCT is 40 mg/10 mg/25 mg per day.
Older people (age 65 years or over)Caution, including more frequent monitoring of blood pressure, is recommended in older people, particularly at the maximum dose of Sevikar HCT 40 mg/10 mg/25 mg per day. An increase of the dosage should take place with care in older people (see sections 4.4 and 5.2).Very limited data are available on the use of Sevikar HCT in patients aged 75 years or older. Extreme caution, including more frequent monitoring of blood pressure, is recommended.
Renal impairmentThe maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 30 60 mL/min) is Sevikar HCT 20 mg/5 mg/12.5 mg, owing to limited experience of the 40 mg olmesartan medoxomil dosage in this patient group. Monitoring of serum concentrations of potassium and creatinine is advised in patients with moderate renal impairment. The use of Sevikar HCT in patients with severe renal impairment (creatinine clearance < 30 mL/min) is contraindicated (see sections 4.3, 4.4 and 5.2).
Hepatic impairmentSevikar HCT should be used with caution in patients with mild hepatic impairment (see sections 4.4 and 5.2). In patients with moderate hepatic impairment the maximum dose should not exceed Sevikar HCT 20 mg/5 mg/12.5 mg once daily. Close monitoring of blood pressure and renal function is advised in patients with 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 HCT should therefore be administered with caution in these patients. The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with impaired liver function.Use of Sevikar HCT is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2), cholestasis or biliary obstruction (see section 4.3).
Paediatric populationSevikar HCT is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.
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. Sevikar HCT can be taken with or without food.
Patients with hypovolaemia or sodium depletion:Symptomatic hypotension may occur in patients who are volume and/or sodium depleted as a result of vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to administration of Sevikar HCT 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 medicinal products that affect this system 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 HCT is used in patients with impaired renal function, periodic monitoring of serum concentrations of potassium and creatinine is recommended. Use of Sevikar HCT is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections 4.2, 4.3 and 5.2). Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy. There is no experience of the administration of Sevikar HCT in patients with a recent kidney transplant or in patients with end-stage renal impairment (i. e. creatinine clearance < 12 mL/min).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS):There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Hepatic impairment:Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section 5.2). Furthermore, minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease. Care should be taken when Sevikar HCT is administered in patients with mild to moderate hepatic impairment.In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section 4.2).In patients with impaired hepatic function, amlodipine should be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose.Use of Sevikar HCT is contraindicated in patients with severe hepatic impairment, cholestasis or biliary obstruction (see section 4.3).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:Due to the amlodipine component of Sevikar HCT, as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Primary aldosteronism:Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Sevikar HCT is not recommended in such patients.
Metabolic and endocrine effects:Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy. Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.
Electrolyte imbalance:As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8). The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5). Conversely, due to antagonism at the angiotensin-II receptors (AT1) through the olmesartan medoxomil component of Sevikar HCT hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Close monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels (e. g. heparin) should be co-administered cautiously with Sevikar HCT (see section 4.5) and with frequent monitoring of potassium levels. There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment. Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia. Dilutional hyponatraemia may occur in oedematous patients in hot weather.
Lithium:As with other angiotensin II receptor antagonists, the coadministration of Sevikar HCT and lithium is not recommended (see section 4.5).
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. Patients with heart failure should be treated with caution. In a long-term, placebo controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the reported incidence of pulmonary oedema was higher in the amlodipine group than in the placebo group (see section 5.1). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
Sprue-like enteropathy:In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan medoxomil in cases where no other etiology is identified. In cases where symptoms disappear and sprue-like enteropathy is confirmed by biopsy, treatment with olmesartan medoxomil should not be restarted.
Pregnancy:Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor 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 receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Paediatric population:Sevikar HCT is not indicated in children and adolescents under the age of 18 years.
Older people:In older people, increase of the dosage should take place with care (see section 5.2).
Photosensitivity:Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with Sevikar HCT, it is recommended to stop the treatment. If re-administration of the diuretic is deemed necessary, it is recommended to protect the areas exposed to the sun or to artificial UVA.
Other:As with any antihypertensive agent, excessive blood pressure reduction in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics. As with all other angiotensin II receptor antagonists, the blood pressure lowering effect of olmesartan is somewhat less in black patients than in non-black patients, however, this effect was not seen in one of the three clinical trials with Sevikar HCT that included black patients (30 %), see also section 5.1.
Potential interactions related to the Sevikar HCT combination:
Concomitant use not 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 receptor antagonists. In addition, renal clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore use of Sevikar HCT 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.
Concomitant use requiring caution
Baclofen:Potentiation of antihypertensive effect may occur.
Non-steroidal anti-inflammatory medicinal products:NSAIDs (i.e. acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics and angiotensin II receptor antagonists. In some patients with compromised renal function (e. g. dehydrated patients or older people with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in older people. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.
Concomitant use to be taken into account
Amifostine:Potentiation of antihypertensive effect may occur.
Other antihypertensive agents:The blood pressure lowering effect of Sevikar HCT can be increased by concomitant use of other antihypertensive medicinal products.
Alcohol, barbiturates, narcotics or antidepressants:Potentiation of orthostatic hypotension may occur.
Potential interactions related to olmesartan medoxomil:
Concomitant use not recommended
ACE-inhibitors, angiotensin II receptor blockers or aliskiren:Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
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 that affect potassium are to be prescribed in combination with Sevikar HCT, monitoring of serum potassium is advised.
Bile acid sequestering agent colesevelam:Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered (see section 5.2).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 amlodipine
Concomitant use requiring caution
Effects of other medicinal products on amlodipineCYP3A4 inhibitors:Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in older people. Clinical monitoring and dose adjustment may thus be required.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.Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Effects of amlodipine on other medicinal productsThe blood pressure-lowering effect 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, warfarin or ciclosporin. Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg dailyPotential interactions related to hydrochlorothiazide:
Concomitant use not recommended
Medicinal products affecting potassium levels:The potassium-depleting effect of hydrochlorothiazide (see section 4.4) may be potentiated by the coadministration of other medicinal products associated with potassium loss and hypokalaemia (e. g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives). Such concomitant use is therefore not recommended.
Concomitant use requiring caution
Calcium salts:Thiazide diuretics may increase serum calcium owing to decreased excretion. If calcium supplements must be prescribed, serum calcium should be monitored and calcium dosage adjusted accordingly.
Cholestyramine and colestipol resins:Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Digitalis glycosides:Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.
Medicinal products affected by serum potassium disturbances:Periodic monitoring of serum potassium and ECG is recommended when Sevikar HCT is administered with medicinal products affected by serum potassium disturbances (e. g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes (ventricular tachycardia): - Class Ia antiarrhythmics (e. g. quinidine, hydroquinidine, disopyramide). - Class III antiarrhythmics (e. g. amiodarone, sotalol, dofetilide, ibutilide). - Some antipsychotics (e. g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol). - Others (e. g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).
Non-depolarizing skeletal muscle relaxants (e. g. tubocurarine):The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.
Anticholinergic agents (e. g. atropine, biperiden):Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Antidiabetic medicinal products (oral agents and insulin):The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4).
Metformin:Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
Beta-blockers and diazoxide:The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Pressor amines (e. g. noradrenaline):The effect of pressor amines may be decreased.Medicinal products used in the treatment of gout (e. g. probenecid, sulfinpyrazone and allopurinol):Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.
Amantadine:Thiazides may increase the risk of adverse effects caused by amantadine.
Cytotoxic agents (e. g. cyclophosphamide, methotrexate):Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.
Salicylates:In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.
Methyldopa:There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
Ciclosporin:Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.
Tetracyclines:Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea. This interaction is probably not applicable to doxycycline.
PregnancyThe use of Sevikar HCT is contra-indicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4). Given the effects of the individual components in this combination product on pregnancy, the use of Sevikar HCT is not recommended during the first trimester of pregnancy (see section 4.4).
Olmesartan medoxomilThe use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contra-indicated during the 2nd and 3rd trimester 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 receptor 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 receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.Exposure to angiotensin II receptor antagonists therapy during the 2nd and 3rd trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3). Should exposure to angiotensin II receptor antagonists have occurred from the 2nd trimester of pregnancy, ultrasound check of renal function and skull is recommended.Infants, whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see also sections 4.3 and 4.4).
HydrochlorothiazideThere is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the 2nd and 3rd trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
AmlodipineData 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.
Breast-feedingBecause no information is available regarding the use of Sevikar HCT during breast-feeding, Sevikar HCT is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.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. Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Sevikar HCT during breast feeding is not recommended. If Sevikar HCT is used during breast feeding, doses should be kept as low as possible.
FertilityReversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers.Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3)
|MedDRASystem Organ Class||Adverse reactions||Frequency|
|Infections and infestations||Upper respiratory tract infection||Common|
|Urinary tract infection||Common||Common|
|Blood and lymphatic system disorders||Leucopenia||Very rare||Rare|
|Bone marrow depression||Rare|
|Immune system disorders||Anaphylactic reaction||Uncommon|
|Drug hypersensitivity||Very rare|
|Metabolism and nutrition disorders||Hyperkalaemia||Uncommon||Rare|
|Hypochloraemic alkalosis||Very rare|
|Psychiatric disorders||Confusional state||Rare||Common|
|Mood changes (including anxiety)||Uncommon|
|Sleep disorders (including insomnia)||Uncommon||Rare|
|Nervous system disorders||Dizziness||Common||Common||Common||Common|
|Peripheral neuropathy||Very rare|
|Loss of appetite||Uncommon|
|Eye disorders||Visual disturbance (including diplopia, blurred vision)||Uncommon||Rare|
|Worsening of myopia||Uncommon|
|Ear and labyrinth disorders||Vertigo||Uncommon||Uncommon||Rare|
|Myocardial infarction||Very rare|
|Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)||Very rare||Rare|
|Angina pectoris||Uncommon||Uncommon (incl. aggravation of angina pectoris)|
|Vasculitis (including necrotising angiitis)||Very rare||Rare|
|Respiratory, thoracic and mediastinal disorders||Cough||Uncommon||Common||Very rare|
|Acute interstitial pneumonia||Rare|
|Altered bowel habits (including diarrhoea and constipation)||Uncommon|
|Gingival hyperplasia||Very rare|
|Paralytic ileus||Very rare|
|Sprue-like enteropathy (see section 4.4)||Very rare|
|Hepato-biliary disorders||Hepatitis||Very rare|
|Jaundice (intrahepatic cholestatic icterus)||Very rare||Rare|
|Skin and subcutaneous tissue disorders||Alopecia||Uncommon|
|Erythema multiforme||Very rare|
|Cutaneous lupus erythematodes-like reactions||Rare|
|Exfoliative dermatitis||Very rare|
|Photosensitivity reactions||Very rare||Uncommon|
|Quincke oedema||Very rare|
|Reactivation of cutaneous lupus erythematodes||Rare|
|Toxic epidermal necrolysis||Rare|
|Stevens-Johnson syndrome||Very rare|
|Musculoskeletal and connective tissue disorders||Muscle spasm||Common||Rare||Uncommon|
|Renal and urinary disorders||Pollakiuria||Common|
|Increased urinary frequency||Uncommon|
|Acute renal failure||Rare|
|Reproductive system and breast disorders||Erectile dysfunction||Uncommon||Uncommon||Uncommon|
|General disorders and administration site conditions||Asthenia||Common||Uncommon||Uncommon|
|Investigations||Blood creatinine increased||Common||Rare||Common|
|Blood urea increased||Common||Common||Common|
|Blood uric acid increased||Common|
|Blood potassium decreased||Uncommon|
|Gamma glytamyl transferase increased||Uncommon|
|Alanine aminotransferase increased||Uncommon|
|Aspartate aminotransferase increased||Uncommon|
|Hepatic enzymes increased||Common||Very rare (mostly consistent with cholestatis)|
|Blood creatine phosphokinase increased||Common|
|Table 2: Combination of olmesartan medoxomil and amlodipine|
|System Organ Class||Frequency||Adverse reactions|
|Immune system disorders||Rare||Drug hypersensitivity|
|Gastrointestinal disorders||Uncommon||Upper abdominal pain|
|Reproductive system and breast disorders||Uncommon||Libido decreased|
|General disorders and administration site conditions||Common||Pitting oedema|
|Musculoskeletal and connective tissue disorders||Uncommon||Pain in extremity|
|Table 3: Combination of olmesartan medoxomil and hydrochlorothiazide|
|System Organ Class||Frequency||Adverse reactions|
|Nervous system disorders||Rare||Disturbances in consciousness (such as loss of consciousness)|
|Skin and subcutaneous tissue disorders||Uncommon||Eczema|
|Musculosceletal and connective tissue disorders||Uncommon||Pain in extremity|
|Investigations||Rare||Minor decreases in mean haemoglobin and haematocrit values|
Reporting of suspected adverse reactionsReporting 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 at: www.mhra.gov.uk/yellowcard
Symptoms:The maximum dose of Sevikar HCT is 40 mg/10 mg/25 mg once daily. There is no information on overdosage with Sevikar HCT in humans. The most likely effect of Sevikar HCT overdosage is hypotension. The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred. Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension, up to and including shock with fatal outcome, has been reported. Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.
Treatment:In the event of overdosage with Sevikar HCT, treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms. If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine. Clinically significant hypotension due to an overdose of Sevikar HCT requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. The dialysability of olmesartan or hydrochlorothiazide is unknown. The degree to which olmesartan and hydrochlorothiazide are removed by haemodialysis has not been established.
Results of Clinical StudiesIn a 12-week, double-blind, randomised, parallel-group study in 2492 patients (67% Caucasian patients), treatment with Sevikar HCT 40 mg/10 mg/25 mg resulted in significantly greater reductions in diastolic and systolic blood pressures than treatment with either of the corresponding dual combinations, olmesartan medoxomil 40 mg plus amlodipine 10 mg, olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg and amlodipine 10 mg plus hydrochlorothiazide 25 mg, respectively. The additional blood pressure lowering effect from Sevikar HCT 40 mg/10 mg/25 mg compared to the analogous dual combinations was between -3.8 and -6.7 mmHg for seated diastolic and between -7.1 and -9.6 mmHg for seated systolic blood pressure and occurred within the first 2 weeks.The proportions of patients reaching blood pressure goal (< 140/90 mmHg for non-diabetic patients and < 130/80 mmHg for diabetic patients) at week 12 ranged from 34.9% to 46.6% for the dual combination treatment groups compared to 64.3% for Sevikar HCT 40 mg/10 mg/25 mg.In a second double-blind, randomised, parallel-group study in 2690 patients (99.9% Caucasian patients), treatment with Sevikar HCT (20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg, 40 mg/10 mg/25 mg) resulted in significantly greater reductions in diastolic and systolic blood pressure compared to the corresponding dual combinations, olmesartan medoxomil 20 mg plus amlodipine 5 mg, olmesartan medoxomil 40 mg plus 5 mg amlodipine and olmesartan medoxomil 40 mg plus 10 mg amlodipine, respectively, after 10 weeks of treatment. The additional blood pressure lowering effect from Sevikar HCT compared to the corresponding dual combinations was between -1.3 and -1.9 mmHg for seated diastolic and between -2.7 and -4.9 mmHg for seated systolic blood pressure.The proportions of patients reaching blood pressure goal (< 140/90 mmHg for non-diabetic patients and < 130/80 mmHg for diabetic patients) at week 10 ranged from 42.7% to 49.6% for the dual combination treatment groups compared to 52.4% to 58.8% for Sevikar HCT.In a randomised, double-blind, add-on study in 808 patients (99.9 % Caucasian patients) not adequately controlled after 8-weeks therapy with olmesartan medoxomil 40 mg plus amlodipine 10 mg dual combination treatment with Sevikar HCT resulted in numerically additional seated blood pressure reduction of -1.8/-1.0 mmHg when treated with Sevikar HCT 40 mg/10 mg/12.5 mg and a statistically significant additional seated blood pressure reduction of -3.6/-2.8 mmHg when treated with Sevikar HCT 40 mg/10 mg/25 mg compared to the olmesartan medoxomil 40 mg plus amlodipine 10 mg dual combination.Treatment with Sevikar HCT 40 mg/10 mg/25 mg triple-combination therapy resulted in a statistically significantly greater percentage of subjects reaching their blood pressure goal compared to olmesartan medoxomil 40 mg plus amlodipine 10 mg dual combination therapy (41.3% vs. 24.2%); while the treatment with Sevikar HCT 40 mg/10 mg/12.5 mg triple-combination therapy resulted in a numerically greater percentage of subjects reaching their blood pressure goal compared to olmesartan medoxomil 40 mg plus amlodipine 10 mg dual-combination therapy (29.5% vs. 24.2%) in subjects not adequately controlled on dual-combination therapy.The antihypertensive effect of Sevikar HCT was similar irrespective of age and gender, and was similar in patients with and without diabetes. Other information:Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
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 co-administered active substances 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).
Biotransformation and elimination:Total plasma clearance of olmesartan 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 2-5 days of dosing 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.
Drug interactions:Bile acid sequestering agent colesevelam:Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half life of olmesartan was reduced by 50 52% irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride (see section 4.5).Amlodipine:
Absorption and distribution:After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.The absorption of amlodipine is unaffected by the concomitant intake of food.
Biotransformation and elimination:The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
Absorption and distribution:Following oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the median time to peak concentrations of hydrochlorothiazide was 1.5 to 2 hours after dosing. Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83 1.14 L/kg.
Biotransformation and elimination:Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged active substance in urine. About 60% of the oral dose is eliminated as unchanged active substance within 48 hours. Renal clearance is about 250 300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10 15 hours.
Pharmacokinetics in special populations
Paediatric Population:The European Medicines Agency has waived the obligation to submit the results of studies with Sevikar HCT in all subsets of the paediatric population in essential hypertension.Older people (age 65 years or over):In hypertensive patients, the olmesartan AUC at steady state was increased by ca 35% in older people (65 75 years old) and by ca 44% in very old people (≥ 75 years old) compared with the younger age group (see section 4.2). This may be at least in part related to a mean decrease in renal function in this group of patients. The recommended dosage regimen for older people is, however, the same, although caution should be exercised when increasing the dosage. The time to reach peak plasma concentrations of amlodipine is similar in older and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half life in older people. Increases in AUC and elimination half life in patients with congestive heart failure were as expected for the patient age group in this study (see section 4.4). Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive older people compared to young healthy volunteers.
Renal impairment:In renally impaired patients, the olmesartan 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 and 4.4). The pharmacokinetics of olmesartan medoxomil in patients undergoing haemodialysis has not been studied. Amlodipine is extensively metabolised to inactive metabolites. Ten percent of the substance is excreted unchanged in the urine. Changes in amlodipine plasma concentration are not correlated with the degree of renal impairment. In these patients, amlodipine may be administered at the normal dosage. Amlodipine is not dialysable. The half-life of hydrochlorothiazide is prolonged in patients with impaired renal function.
Hepatic impairment:After single oral administration, olmesartan AUC values are 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 is 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC is again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values are similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see sections 4.2 and 4.4). Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. The clearance of amlodipine is decreased and the half-life is prolonged in patients with impaired hepatic function, resulting in an increase in AUC of about 40% 60% (see sections 4.2 and 4.4). Hepatic impairment does not significantly influence the pharmacokinetics of hydrochlorothiazide.
Tablet core• Starch, pregelatinised maize• Silicified microcrystalline cellulose (microcrystalline cellulose and silica colloidal anhydrous)• Croscarmellose sodium • Magnesium stearate
Film coat• Polyvinyl alcohol• Macrogol 3350• Talc• Titanium dioxide (E 171)• Iron (III) oxide yellow (E 172)• Iron (III) oxide red (E 172) (20/5/12.5, 40/10/12.5, 40/10/25 film-coated tablets only)• Iron (II, III) oxide black (E 172) (20/5/12.5 film-coated tablets only)
|Sevikar HCT 20mg/5mg/12.5mg||PL 08265/0031|
|Sevikar HCT 40mg/5mg/12.5mg||PL 08265/0032|
|Sevikar HCT 40mg/10mg/12.5mg||PL 08265/0033|
|Sevikar HCT 40mg/5mg/25mg||PL 08265/0034|
|Sevikar HCT 40mg/10mg/25mg||PL 08265/0035|
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