Treatment of essential hypertension.
Add-on therapy
Sevikar 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 therapy
Sevikar 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)
 

Posology
Adults
The recommended dose of Sevikar HCT is 1 tablet per day.
Add-on therapy
Sevikar 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 dualcomponent 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 dualcomponent 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 dualcomponent 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 therapy
Patients 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.
Elderly (age 65 years or over)
Caution, including more frequent monitoring of blood pressure, is recommended in elderly
patients, 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 elderly patients (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 impairment
The 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 impairment
Sevikar 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 population
Sevikar 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.
Dual Blockade of the Renin-Angiotensin-aldosterone System (RAAS):
Combination of Sevikar HCT 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.
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).
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 potassiuim 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.
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.
Elderly patients:
In the elderly, 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
Dual RAAS Blockade:
The combination of Sevikar HCT with Aliskiren, ACEIs or other ARBs is contraindicated in
patients with diabetes mellitus or renal impairment.
Dual blockade (e.g by adding ACE inhibitor to Sevikar ) should not be used, especially in
patients with Kidney problems.
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 elderly patients
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 the elderly. 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
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.
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 amlodipine
Concomitant use requiring caution
Effects of other medicinal products on amlodipine
CYP3A4 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 the elderly. 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 hyperkalemia after administration of verapamil and intravenous
dantrolene. Due to risk of hyperkalemia, 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 products
The 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 daily
Potential 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 tetracyclineinduced increase in urea. This interaction is probably not applicable to doxycycline
 

Pregnancy
The 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 medoxomil
The 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).
Hydrochlorothiazide
There 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 preeclampsia 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.
Amlodipine
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.
Lactation
Because no information is available regarding the use of Sevikar HCT during breastfeeding,
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.
Fertility
Reversible 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
 

No studies on the effects on the ability to drive and use machines have been performed.
However, it should be borne in mind that dizziness, headache, nausea or fatigue may
occasionally occur in patients taking antihypertensive therapy and that these symptoms may
impair the ability to react. Caution is recommended especially at the start of treatment
 

a. Summary of the safety profile:
The safety of Sevikar HCT was investigated in clinical trials in 7826 patients receiving
olmesartan medoxomil in combination with amlodipine and hydrochlorothiazide.
Adverse reactions from clinical trials, post-authorization safety studies and spontaneous
reporting are summarized in table 1 for Sevikar HCT as well as for the individual components
olmesartan medoxomil, amlodipine and hydrochlorothiazide based on the known safety profile
of the single components.
The most commonly reported adverse reactions during treatment with Sevikar HCT are
peripheral oedema, headache and dizziness.
b. Tabulated list of Adverse reaction:
The following terminologies have been used in order to classify the occurrence of undesirable
effects:
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)

Table 1: Overview of adverse reactions with Sevikar HCT and the single components

c. Description of selected adverse reaction:
Single cases of rhabdomyolysis have been reported in temporal association with the intake of
angiotensin II receptor blockers. Single cases of extrapyramidal syndrome have been reported in
patients treated with amlodipine

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.
Further adverse reactions reported in clinical trials or from post marketing experience with a
fixed-dose combination of olmesartan medoxomil and amlodipine and not already reported for
Sevikar HCT, olmesartan medoxomil monotherapy or amlodipine monotherapy or reported in a
higher frequency for the dual combination (Table 2):

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 in patients 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 (15 olmesartan
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.
d. Other special population:
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).
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)

To report any side effect (s)

·         Saudi Arabia

− The National Pharmacovigilance Center (NPC)

-  SFDA Call Center: 19999

-  E-mail: npc.drug@sfda.gov.sa

-  Website: https://ade.sfda.gov.sa

·         Other GCC states /other countries

-Please contact the relevant competent authority.

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.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

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.
 

Pharmaco-therapeutic group: Angiotensin II antagonists, calcium channel blockers and diuretics.
ATC code: C09DX03.
Sevikar HCT is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, a
calcium channel blocker, amlodipine besilate and a thiazide diuretic, hydrochlorothiazide. The
combination of these ingredients has an additive antihypertensive effect, reducing blood pressure
to a greater degree than each component alone.
Olmesartan medoxomil is an orally active, selective angiotensin II receptor (type AT1)
antagonist. Angiotensin II is the primary vasoactive hormone of the renin-angiotensinaldosterone system and plays a significant role in the pathophysiology of hypertension. The
effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of
aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the
vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the
AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of
olmesartan is independent of the source or route of synthesis of angiotensin II. The selective
antagonism of the angiotensin II (AT1) receptors by olmesartan results in increases in plasma
renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone
concentrations.
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 abrupt 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.
The effect of olmesartan medoxomil on mortality and morbidity is not yet known.
The amlodipine component of Sevikar HCT is a calcium channel blocker that inhibits the
transmembrane influx of calcium ions through the potential-dependent L-type channels into the
heart and smooth muscle. Experimental data indicate that amlodipine binds to both
dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective,
with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The
antihypertensive effect of amlodipine derives from a direct relaxant effect on arterial smooth
muscle, which leads to a lowering of peripheral resistance and hence of blood pressure.
In hypertensive patients, amlodipine 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 abrupt cessation of therapy.
Following administration of therapeutic doses to patients with hypertension, amlodipine
produces an effective reduction in blood pressure in the supine, sitting and standing positions.
Chronic use of amlodipine is not associated with significant changes in heart rate or plasma
catecholamine levels. In hypertensive patients with normal renal function, therapeutic doses of
amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective
renal plasma flow, without changing filtration fraction or proteinuria.
In haemodynamic studies in patients with heart failure and in clinical studies based on exercise
tests in patients with NYHA class II-IV heart failure, amlodipine was found not to cause any
clinical deterioration, as measured by exercise tolerance, left ventricular ejection fraction and
clinical signs and symptoms.
A placebo-controlled study (PRAISE) designed to evaluate patients with NYHA class III-IV
heart failure receiving digitalis, diuretics and ACE inhibitors, has shown that amlodipine did not
lead to an increase in the risk of mortality and morbidity in patients with heart failure.
In a follow-up, long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with
NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of
underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics,
amlodipine had no effect on total or cardiovascular mortality. In this same population amlodipine
was associated with increased reports of pulmonary oedema despite no significant difference in
the incidence of worsening heart failure as compared to placebo.
A randomized double-blind morbidity-mortality study called the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer
drug therapies: amlodipine 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40 mg/d
(ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25
mg/d in mild to moderate hypertension.”
A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a
mean of 4.9 years. The patients had at least one additional CHD risk factor, including: previous
myocardial infarction or stroke (> 6 months prior to enrollment) or documentation of other
atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C < 35 mg/dL (11.6%), left
ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current
cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There
was no significant difference in the primary endpoint between amlodipine-based therapy and
chlorthalidone-based therapy: RR 0.98 95% CI (0.90-1.07) p=0.65. Among secondary endpoints,
the incidence of heart failure (component of a composite combined cardiovascular endpoint) was
significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% vs.
7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was no significant difference in
all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy. RR
0.96 95% CI [0.89-1.02] p=0.20.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of
thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte
reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent
amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma
renin activity and increases aldosterone secretion, with consequent increases in urinary
potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is
mediated by angiotensin II and therefore coadministration of an angiotensin II receptor
antagonist tends to reverse the potassium loss associated with thiazide diuretics. With
hydrochlorothiazide, onset of diuresis occurs at about 2 hours and peak effect occurs at about 4
hours post-dose, whilst the action persists for approximately 6-12 hours.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide
monotherapy reduces the risk of cardiovascular mortality and morbidity.
Results of Clinical Studies
In 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 triplecombination 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 dualcombination therapy.
The antihypertensive effect of Sevikar HCT was similar irrespective of age and gender, and was
similar in patients with and without diabetes
 

Concomitant administration of olmesartan medoxomil, amlodipine and hydrochlorothiazide had
no clinically-relevant effects on the pharmacokinetics of either component in healthy subjects.
Following oral administration of Sevikar HCT in normal healthy adults, peak plasma
concentrations of olmesartan, amlodipine and hydrochlorothiazide are reached in about 1.5 to 3
hours, 6 to 8 hours, and 1.5 to 2 hours, respectively. The rate and extent of absorption of
olmesartan medoxomil, amlodipine and hydrochlorothiazide from Sevikar HCT are the same as
when administered as a dual-fixed combination of olmesartan medoxomil and amlodipine
together with a hydrochlorothiazide single-component tablet or when administered as a dualfixed combination of olmesartan medoxomil and hydrochlorothiazide together with an
amlodipine single-component tablet with the same dosages. Food does not affect the
bioavailability of Sevikar HCT.
Olmesartan medoxomil:
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 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).
Metabolism 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 hepatobiliary 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.
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.
Metabolism 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.
Hydrochlorothiazide:
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.
Metabolism 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.
Elderly:
In hypertensive patients, the olmesartan 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 (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 elderly patients 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 elderly and younger
subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and
elimination half life in elderly patients. 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 elderly patients 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
 

Olmesartan medoxomil/ Amlodipine /Hydrochlorothiazide combination
Repeated dose toxicity study in rats demonstrated that the combined administration of
olmesartan medoxomil, amlodipine and hydrochlorothiazide neither augmented any of the
previously reported and existing toxicities of the individual agents, nor induced any new toxicity,
and no toxicologically synergistic effects were observed.
No additional mutagenicity, carcinogenicity, and reproductive toxicity studies for Sevikar HCT
have been conducted based on the well-understood safety profile of the individual active
ingredients.
Olmesartan medoxomil
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;
reduction in heart weight; 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.
Like other AT1 receptor antagonists olmesartan medoxomil was found to increase the incidence
of chromosome breaks in cell cultures in vitro, but not in vivo. The overall data of a
comprehensive genotoxicity testing programme suggest that olmesartan is very unlikely to exert
genotoxic effects under conditions of clinical use.
Olmesartan medoxomil was not carcinogenic in rats or transgenic mice.
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 and pelvic dilatation of the kidney was seen after exposure of the dams in
late pregnancy and lactation. In rabbits there was no indication of a fetotoxic effect.
Amlodipine
Reproductive toxicology
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration
of labour and decreased pup survival at dosages approximately 50 times greater than the
maximum recommended dosage for humans based on mg/kg.
Impairment of fertility
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and
females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum
recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats
were treated with amlodipine besilate for 30 days at a dose comparable with the human dose
based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as
well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.
Carcinogenesis, mutagenesis
Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to
provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of
carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum
recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated
dose for mice but not for rats.
Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
*Based on patient weight of 50 kg
Hydrochlorothiazide
Studies with hydrochlorothiazide have shown equivocal evidence for a genotoxic or carcinogenic
effect in some experimental models. However, the extensive human experience with
hydrochlorothiazide has failed to show an association between its use and an increase in
neoplasma
 

Tablet core
• Starch, pregelatinised maize
• Silicified microcrystalline cellulose (microcrystalline cellulose and silica colloidal anhydrous)
• Croscarmellose sodium
• Magnesium stearate
Film coat
• Opadry® II Pink 85F24118 for Sevikar HCT 20 mg/5mg /12.5mg tablet
• Opadry® II Yellow 85F32331 for Sevikar HCT 40mg/5mg/12.5mg & 40mg/5mg/25mg tablet
• Opadry® II Pink 85F25437 for Sevikar HCT 40mg/10mg/12.5mg & 40mg/10mg/25mg tablet
 

Not applicable
 

This medicinal product does not require any special storage conditions.
Store below 30 °C
 

Aluminum/Aluminum Blister Packs of 28 film-coated tablets
 

No special requirements