Essential hypertension.

 

The fixed dose combination Concor 5 plus resp. Concor 10 plus is indicated in patients whose blood pressure is not adequately controlled on bisoprolol or hydrochlorothiazide alone.

 

The fixed dose combinations (Concor 5 plus or Concor 10 plus) are indicated in patients whose blood pressure is not adequately controlled on bisoprolol fumarate or hydrochlorothiazide alone.

 

Individual dose titration with the single agents is recommended.

 

When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.

 

Renal impairment

 

In co-existing impairment of kidney function the elimination of the HCTZ component of Concor 5 plus/Concor 10 plus is reduced, so that preference may have to be given to the lower dose form (Concor 5 plus) (see also section 4.4).

Elderly patients

 

Principally, no dose adjustment is required.

 

Pediatric patients

 

There is no pediatric experience with Concor 5 plus or Concor 10 plus therapy. Its use in children is therefore not recommended.

 

method and duration of administration

 

The film-coated tablets are to be swallowed whole with some liquid in the morning before, during or after breakfast.

 

The duration of treatment is not limited. It depends upon the nature and severity of the disease.

 

Bisoprolol therapy should not be stopped abruptly, particularly not in patients with coronary heart disease, as this may lead to acute deterioration of the patient's state of health.

 

Concor 5 plus or Concor 10 plus must not be used in: • acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy • cardiogenic shock • second- or third-degree AV block (without a pacemaker) • sick sinus syndrome • sinoatrial block • symptomatic bradycardia with less than 60 beats per minute at the beginning of therapy • severe bronchial asthma • late stages of peripheral arterial occlusive disease or Raynaud's syndrome • untreated pheochromocytoma (see section 4.4) • metabolic acidosis • severe renal impairment with oliguria or anuria (creatinine clearance less than 30 ml/min and/or serum creatinine more than 1.8 mg/100 ml) • acute glomerulonephritis • coma and hepatic precoma • refractory hypokalaemia • severe hyponatraemia • hypercalcaemia • gout • known hypersensitivity to bisoprolol, hydrochlorothiazide or other thiazides, sulphonamides or any of the other excipients (see section 6.1)

Therapy with Concor plus must not be stopped abruptly, particularly in patients with coronary heart disease, as this may lead to transitory deterioration of the patient's state of health (see section 4.2).

 

Particularly close monitoring by the physician is necessary in:

 

•           heart failure (in patients with concomitant stable chronic heart failure, treatment must be initiated with bisoprolol as single agent using the recommended titration phase)

•           bronchospasm (bronchial asthma, obstructive airways diseases)

•           concomitant treatment with inhalation anaesthetics

•           diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia can be masked

•           strict fasting

•           ongoing desensitisation therapy

•           first degree AV block

•           Prinzmetal’s angina

•           peripheral arterial occlusive disease (aggravation of complaints may occur especially when starting therapy)

•           hypovolaemia

•           impaired liver function

Although cardio selective (beta1) beta-blockers may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers, these should be avoided in patients with obstructive airways diseases, unless there are compelling clinical reasons for their use. Where such reasons exist, Concor plus may be used with caution. In bronchial asthma or other chronic obstructive pulmonary dysfunction that may be associated with symptoms, concomitant bronchodilator therapy is indicated. An increase in airway resistance may occasionally occur in asthma patients, requiring a higher dose of ß₂– sympathomimetics.

 

Metabolic alkalosis may worsen due to the disturbed fluid and electrolyte balance.

 

As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. This applies also to ongoing desensitization therapy. Adrenaline does not always produce the desired therapeutic effect in these cases.

 

In patients with psoriasis or with a history of psoriasis, beta- blockers (e.g. bisoprolol) should only be prescribed if the risk-to-benefit ratio has been carefully weighed.

 

In patients with pheochromocytoma beta-blockers (e.g. bisoprolol) must not be administered until after alpha-receptor blockade.

 

Under treatment with beta-blockers (e.g. bisoprolol) the symptoms of thyrotoxicosis may be masked.

 

Acute cholecystitis has been reported in patients with cholelithiasis.

 

Disturbances of the electrolyte and fluid balance

 

Due to the hydrochlorothiazide component, long-term treatment with Concor 5 plus or Concor 10 plus may lead to disturbances of the electrolyte and fluid balance, in particular hypokalemia and hyponatremia, also hypomagnesaemia, hypochloridemia as well as hypercalcemia.

 

Hypokalemia facilitates the development of severe arrhythmia, in some cases torsade de pointes, which may be fatal.

 

Patients with hyperuricemia have a higher risk of gout.

 

Hydrochlorothiazide can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible.

 

During long-term therapy with Concor 5 plus or Concor 10 plus, the serum electrolytes (especially potassium, sodium, calcium), creatinine and urea, blood lipids (cholesterol and triglycerides), uric acid and blood glucose should be monitored regularly.

Hydrochlorothiazide can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible.

 

Note:

 

During treatment with Concor 5 plus or Concor 10 plus patients should ensure an adequate supply of fluid and food rich in potassium (e.g. bananas, vegetables, nuts) to compensate for the increased loss of potassium. The potassium losses may be reduced or prevented by concomitant therapy with potassium-sparing diuretics.

 

General anesthesia

 

In patients undergoing general anesthesia, beta-blockers reduce the incidence of arrythmia and myocardial ischemia during induction, intubation, and postoperatively. It is currently recommended that ongoing beta-blocker therapy should not be interrupted in case of surgery. The anesthetist must be informed that the patient is being treated with beta-blockers as this may lead to potential interactions with other pharmaceuticals, bradyarrhythmia, attenuation of reflex tachycardia and compensation of blood loss due to reduced reflex reactions. If discontinuation of beta-blocker therapy prior to surgery is necessary, treatment should be tapered gradually and be discontinued altogether about 48 hours prior to anesthesia.

 

Photosensitivity reactions may occur in connection with thiazide diuretics. Should photosensitivity reaction occur, exposed body areas are best protected against sun or UVA rays. In severe cases it may become necessary to discontinue therapy with Concor plus.

 

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

 

Use of Concor plus may give positive results in doping tests.

General information:

 

It should be considered that due to serum potassium disturbances certain medicinal products may be affected.

 

Concomitant administration with the following is not recommended:

 

Calcium antagonists of the verapamil type and to a lesser extent those of the diltiazem type: Negative influence on contractility and atrio-ventricular conduction. In patients under beta-blocker therapy, intravenous administration of calcium antagonists of the verapamil type may lead to pronounced hypotension and AV blockade.

 

Centrally acting antihypertensive agents such as clonidine and others (e.g. methyldopa, moxonodine, reserpine): Combination therapy with centrally acting antihypertensives may lead to deterioration of heart failure due to reduction of the central sympathetic tone (reduction of pulse rate and ejection fraction, vasodilatation). Abrupt discontinuation, particularly prior to termination of beta-blockade may increase the risk of rebound hypertension.

 

Lithium: Concor 5 plus or Concor 10 plus may potentiate the cardiotoxic and neurotoxic effect of lithium through reduced lithium excretion.

 

Concomitant administration with the following, only with caution:

 

Calcium antagonists of the dihydropyridine type (e.g. nifedipine, amlodipine): In concomitant administration, the risk of hypotension and impairment of ventricular pumping function in heart failure patients cannot be excluded.

 

Tricyclic antidepressants, barbiturates, phenothiazines as well as other antihypertensives: Increased hypotensive effect.

 

ACE inhibitors (e.g. captopril, enalapril), angiotensin II antagonists: In patients with preexisting sodium depletion and especially in patients with renal arterial stenosis, significant fall in blood pressure and/or acute renal impairment is possible upon initiation of therapy with ACE inhibitors. In sodium depletion resulting from diuretic therapy, the diuretic agent should either be discontinued three days before starting therapy with an ACE inhibitor or initiate ACE inhibitor therapy at a low dose with a gradual increase of dosage.

 

Class I antiarrhythmics (e.g. disopyramide, quinidine, lidocaine, phenytoin, flecainide, propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

 

Class III antiarrhythmics (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.

Antiarrhythmic drugs may produce torsade de pointes: class IA agents (e.g. quinidine, disopyramide) and class III (e.g. amiodarone and sotalol). Hypokalaemia may facilitate the occurrence of torsade de pointes. Hypokalaemia has to be avoided and, if necessary, corrected. Monitor the QT interval. In case of torsade de pointes no antiarrhythmics should be administered (pace maker therapy).

 

Non anti-arrhythmic agents that may induce torsade de pointes: Astemizole, i.v. erythromycin, halofantrine, pentamidine, sparfloxazin, terfenadine and vincamine. Hypokalaemia may facilitate the occurrence of torsade de pointes. In case of hypokalaemia medicinal products that do not induce torsade, de pointes are to be used.

 

Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction time and increase the risk of bradycardia.

 

Topical application of beta-blockers (e.g. as in eyedrops for glaucoma treatment) may enhance the systemic effect of bisoprolol.

 

Insulin and oral antidiabetic agents: Increase of blood sugar lowering effect. Blockade of beta-adrenoreceptors may mask symptoms of hypoglycaemia.

 

Anaesthetic agents: Attenuation of reflex tachycardia and increased risk of hypotension (see also section 4.4).

 

Digitalis glycosides: Increase of atrio-ventricular conduction time, reduction in heart rate. . If hypokalaemia and/or hypomagnesaemia develop during treatment with Concor 5 plus or Concor 10 plus the myocardium may show increased sensitivity to cardiac glycosides, leading to an enhanced effect and adverse effects of the glycosides.

 

Non-steroidal antiphlogistic (NSAIDs): Decreased hypotensive effect.

In patients developing hypovolemia the concomitant administration of nonsteroidal anti-inflammatory drugs can trigger acute renal failure.

 

Beta-sympathomimetic drugs: Combination with bisoprolol may reduce the effect of both agents. Higher doses of adrenaline may be required for treatment of allergic reactions.

 

Sympathomimetic drugs that activate alpha- and beta-receptors (e.g. adrenaline, noradrenaline): Potential increase in blood pressure and exacerbated intermittent claudication. Such interactions are more likely in non-selective beta-blockers.

 

The effect of uric acid lowering agents may be attenuated in concomitant use of Concor 5 plus or Concor 10 plus.

 

Potassium losses may be increased by concomitant use of Concor 5 plus or Concor 10 plus and glucocorticoids, ACTH, carbenoxolone, amphotericin B, furosemide or laxatives.

 

Cholestyramine, colestipol: Reduced absorption of the hydrochlorothiazide component of Concor 5 plus or Concor 10 plus.

 

Methyldopa: Hemolysis due to the formation of antibodies to hydrochlorothiazide has been described in isolated cases.

 

Notes to be taken into account in concomitant administration with the following:

 

Corticosteroids: Reduced antihypertensive effect.

 

Mefloquine: Increased risk of bradycardia.

Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blocker but also risk of hypertensive crisis.

 

In high-dose salicylate administration the toxic effect of salicylates on the central nervous system may be intensified

Pregnancy

 

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/new-born. In general, beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and new-born infant. If treatment with beta-adrenoceptor blocker is necessary, beta₁-selective adrenoceptor blockers are preferable.

 

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 second and third trimester may compromise foeto-placental perfusion and may cause fetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational edema, 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.

 

The administration of Concor 5 plus or Concor 10 plus is not recommended during pregnancy as a thiazide diuretic is contained.

 

Lactation

 

Bisoprolol fumarate may be secreted into human breast milk. Hydrochlorothiazide is secreted in a limited amount into human breast milk. Thiazide diuretics, used in high doses for intensive diuresis, can inhibit the milk production. The administration of Concor 5 plus or Concor 10 plus is not recommended during lactation.

 

Fertility

 

No human data on fertility are known for the combination product. Bisoprolol or hydrochlorothiazide had no influence on fertility or on general reproduction performance in animal studies.

Concor 5 plus or Concor 10 plus has no or negligible influence on the ability to drive and to use machines. Due to individually varying reactions to the medicinal product the ability to drive a vehicle or to use machines may be impaired.

 

This should be considered particularly at the start of therapy and upon change of medication, as well as in conjunction with alcohol.

The assessment of adverse reactions is based on the following frequency grouping:

 

Common:         ≥1/100 to <1/10

Uncommon:     ≥1/1,000 to <1/100

Rare:                ≥1/10,000 to <1/1,000

Very rare:         <1/10,000,

not known (cannot be estimated from the available data)

 

Neoplasms benign, malignant and unspecified (incl cysts and polyps):

Not known: Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma).

Blood and lymphatic system disorders:

 

Rare                 Leucopenia, thrombocytopenia

Very rare          Agranulocytosis

 

Psychiatric disorders:

 

Uncommon      Sleep disorders, depression

Rare                 Nightmares, hallucinations

 

Metabolism and nutrition disorders:

 

Common         Hyperglycaemia, hyperuricaemia, disturbances of the fluid and electrolyte balance (in particular hypokalaemia and hyponatraemia, also hypomagnesaemia and hypochloridaemia as well as hypercalcaemia)

Uncommon      Loss of appetite

Very rare          Metabolic alkalosis

 

Nervous system disorders:

 

Common          Dizziness*, headache*

 

Eye disorders:

 

Rare                 Reduced tear flow (to be taken into consideration in patients wearing contact lenses), visual disturbances

Very rare          Conjunctivitis

Not known:      Choroidal effusion, angle-closure glaucoma

 

Ear and labyrinth disorders:

 

Rare                 Hearing disorders

 

Cardiac disorders:

 

Uncommon      Bradycardia, AV-conduction disturbances, deterioration of existing heart failure

 

Vascular disorders:

 

Common          Sensation of cold or numb extremities

Uncommon      Orthostatic dysregulation

Rare:                Syncope

 

Respiratory, thoracic and mediastinal disorders:

 

Uncommon      Bronchospasm in patients with a history of bronchial asthma or obstructive airways disease

Rare                 Allergic rhinitis

Not known:      Interstitial lung disease

 

Gastrointestinal disorders:

 

Common          Nausea, vomiting, diarrhoea, constipation

Uncommon      Abdominal ailments, pancreatitis

 

Hepatobilary disorders:

 

Rare                 Hepatitis, jaundice

 

Skin and subcutaneous tissue disorders:

 

Rare     Hypersensitivity reactions (pruritus, flush, rash, photodermatitis, purpura, urticaria and

angioedema)

Very rare          Beta-blockers can trigger psoriasis, aggravate the condition or lead to psoriasiform rash, hair loss or cutaneous lupus erythematosus

 

Musculoskeletal and connective tissue disorders:

 

Uncommon      Muscle weakness and cramps

 

Reproductive system and breast disorders:

 

Rare                 erectile dysfunction

 

General disorders and administration site conditions:

 

Common          Fatigue*

Uncommon      Asthenia

Very rare          Chest pain

 

Investigations:

 

Common          Increased triglyceride and cholesterin levels, glucosuria

Uncommon      Increase in amylase, reversible increase in serum creatinine and urea

Rare                 Increase in liver enzymes (ASAT, ALAT)

 

*These symptoms occur especially at the start of treatment. They are generally mild and mostly disappear within 1-2 weeks.

 

Description of selected adverse reactions

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

The signs of overdosage are bradycardia, hypotension, bronchospasm, acute heart failure, hypoglycemia and conduction disturbances in ECG recording. There is a wide inter-individual variation in sensitivity to one single high dose of bisoprolol, and patients with heart failure are probably very sensitive.

Bradycardia caused by overdose is treated with atropine (1 – 2 mg i.v.), isoprenaline or with a temporary pacemaker. The decrease in blood pressure is treated with intravenous volume replacement and, if necessary, with vasoconstrictive acting catecholamines.

Bronchospasm can be treated with theophylline, theophylline-derivates or ß-sympathomimetics. If only a short time (0-2 h) has passed since overdose, active charcoal is given to the patient and gastric lavage is to be considered. Heart rate, blood pressure, electrolyte balance and blood glucose must be monitored. The elimination of bisoprolol cannot be significantly increased by hemodialysis.

 

The clinical picture in acute or chronic overdose of hydrochlorothiazide is characterized by the extent of fluid and electrolyte loss. Most common signs are dizziness, nausea, somnolence, hypovolemia, hypotension, hypokalemia.

 

No sufficient data is available on the efficacy of hemodialytic elimination of hydrochlorothiazide

Pharmacotherapeutic group: Selective beta-blocker and thiazide diuretic

ATC code: C07BB07

 

Bisoprolol

 

Bisoprolol is a beta-blocker that holds an intermediate position with regard to lipophilia and hydrophilia. Bisoprolol is a highly selective cardioactive beta₁-blocker without any intrinsic sympathomimetic activity nor clinically relevant membrane-stabilizing effect. Bisoprolol depresses the response to sympathoadrenergic activity through blockade of cardiac beta-receptors. This causes a decrease in heart rate and in contractility and thus a reduction of myocardial oxygen consumption.

 

Hydrochlorothiazide

 

Hydrochlorothiazide is a benzothiadiazine derivative which primarily increases electrolyte excretion and secondarily enhances urinary flow by osmotically bound water.

 

Hydrochlorothiazide inhibits predominantly sodium absorption in the distal tubule, so that maximally about 15% of the sodium undergoing glomerular filtration can be excreted. The extent of chloride excretion roughly corresponds to that of sodium excretion.

 

Hydrochlorothiazide also causes an increase in potassium excretion which is essentially determined by the potassium secretion in the distal tubule and in the collecting tube (increased exchange between sodium and potassium ions). The saliuretic or diuretic effect of hydrochlorothiazide is not influenced to any appreciable extent by acidosis or alkalosis.

 

The glomerular filtration rate is initially diminished to a slight extent. During long-term therapy with hydrochlorothiazide, the calcium excretion via the kidneys is reduced so that hypercalcemia may result.

 

Hydrochlorothiazide relaxes smooth vascular muscles and thus reduces peripheral resistance.

 

In patients with chronic renal impairment (creatinine clearance less than 30 ml/min and/or serum creatinine above 1.8 mg/100 ml) hydrochlorothiazide is practically ineffective. In patients with renal and ADH-sensitive diabetes insipidus, hydrochlorothiazide has an antidiuretic effect.

 

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).

Bisoprolol

 

About 90% of bisoprolol is bioavailable from film-coated tablets. After intake bisoprolol is absorbed almost completely (> 90%) from the gastrointestinal tract. Along with the very low first-pass effect in

the liver (< 10%) this results in an absolute bioavailability of 88%. Bisoprolol may be taken on an empty stomach as well as with breakfast without any change in absorption or bioavailability. Bisoprolol has a plasma protein binding of about 30%. Pathophysiological changes in plasma proteins, e.g. alpha₁-glycoproteins, do not affect the pharmacokinetics of bisoprolol. Peak plasma concentrations are usually measured 1-3 hours after administration. With its only moderate lipophilia and low plasma protein binding, the distribution volume of bisoprolol is 226 ± 11 l (x ± SEM).

 

Bisoprolol is removed from the body by two equally effective clearance routes with 50% being metabolized by the liver to inactive metabolites which are then renal excreted. The remaining 50% are excreted unmetabolized via the kidneys. Bisoprolol is eliminated from the plasma with a half-life of 10-12 hours. Related to Cmax and AUC of bisoprolol in steady state there is bioequivalence between the fixed combination with hydrochlorothiazide and the single agent.

Hydrochlorothiazide

 

After oral administration about 80% of hydrochlorothiazide is absorbed from the gastrointestinal tract. The systemic availability is 71 ± 15%.

The plasma protein binding of hydrochlorothiazide is 64%; the relative volume of distribution is 0.5-1.1 l/kg.

 

In healthy humans more than 95% of hydrochlorothiazide is excreted via the kidneys as unchanged substance.

With normal kidney function the elimination half-life is 2.5 hours. Peak plasma concentrations are usually measured after 2-5 hours. This period increases in the presence of impaired kidney function and is about 20 hours in patients with terminal renal impairment.

 

The diuretic effect sets in within 1-2 hours and lasts for 10-12 hours depending on the dose; the antihypertensive effect lasts for up to 24 hours

Conventional preclinical toxicity studies (chronic toxicity, mutagenicity, genotoxicity or carcinogenicity) did not reveal any harmful effects on humans caused by bisoprolol and hydrochlorothiazide. Like other beta-blockers, high doses of bisoprolol caused maternal (decreased food intake and weight loss) and embryonal/fetal toxicity (increased incidence of resorptions, reduced birth weight of the newborn, retarded physical development up to the end of the nursing period). Bisoprolol and hydrochlorothiazide were, however, not teratogenic. There was no increase in toxicity when both components were given in combination.

Tablet core:

 

Silica colloidal anhydrous 0.50 mg

Magnesium stearate 2.00 mg

Cellulose microcrystalline 10.00 mg

Maize starch 10.00 mg

Calcium hydrogen phosphate anhydrous 130 mg

Iron oxide red 0.00438 mg

Iron oxide black 0.00600 mg

Dimeticone (100) 0.02450 mg

Macrogol (400) 0.53 mg

Titanium dioxide 1.21 mg

Hypromellose (2910)  2.20 mg

Not applicable.

3 YEARS

Do not store above 30°C.

Blister pack made of a PVC base film and an aluminum cover foil.

 

Package sizes:  30, 50, 100 film-coated tablets, hospital pack

No special requirements.