Enalapril maleate/Hydrochlorothiazide 20/12.5mg Tablets

Each tablet contains 20mg enalapril maleate and 12.5mg hydrochlorothiazide.

Each tablet contains 122.16 mg lactose monohydrate.

For a full list of excipients see section 6.1.

Round, flat, bevelled edge, one-side scored, white tablets.

Diameter: 8 mm.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

Treatment of essential hypertension.

This fixed dose replaces the combination of 20 mg enalapril maleate and 12.5 mg hydrochlorothiazide in patients who have been stabilised on the individual active substances given in the same proportions as separate medications.

This fixed dose combination is not suitable for initial therapy.

Enalapril maleate/Hydrochlorothiazide 20/12.5mg Tablets can be administered in a single dose/day with or without food.

Individual dose titration with both active substances can be recommended. When clinically appropriate, direct change from ACE inhibitor monotherapy to the fixed combination may be considered.

Prior diuretic therapy

Treatment with diuretics should be discontinued 2 to 3 day before the start of the treatment with Enalapril Maleate/Hydrochlorothiazide 20 mg/12.5 mg.

Dosage in patients with normal renal function

The usual dosage is one tablet, taken once daily.

Dosage in Renal Insufficiency

Creatinine clearance greater than 30 ml/min

The dose of enalapril should be titrated in patients with renal impairment whose creatinine clearance is 30 ml/min before switching to the fixed combination. Loop diuretics are preferred to thiazides in this population.

The dose of enalapril maleate and hydrochlorothiazide should be kept as low as possible (see section 4.4).

Potassium and creatinine should be monitored periodically in these patients, e.g. every 2 months when the treatment has been stabilised (see section 4.4).

Creatinine clearance < 30 ml/min: see section 4.3.

Special population

In salt/volume depleted patients, the starting dose is 5 mg enalapril or lower. Individual dose titration with enalapril and hydrochlorothiazide is recommended.

Use in the elderly

The use in the elderly has been shown to be as good as in younger hypertensive patients. In case of physiological renal impairment, titration with the monocomponent enalapril is recommended prior to using the fixed combination.

Use in children and adolescents(<18 years)

Safety and effectiveness of Enalapril maleate/Hydrochlorothiazide 20/12.5mg Tablets in children and adolescents has not been established.

This medicinal product must not be used in patients with:

• hypersensitivity to enalapril, other ACE-inhibitorsor to any of the excipients

• a history of angioedema (Quincke's oedema) linked to previous treatment with an angiotensin-converting enzyme (ACE) inhibitor and/or in patients with hereditary or idiopathic angioedema

• 2^nd and 3^rd trimester of pregnancy (see section 4.4 and 4.6)

• hypersensitivity to hydrochlorothiazide or other sulphonamide-derived drugs

• severe renal impairment (creatinine clearance <30 ml/min)

• severe hepatic impairment/hepatic encephalopathy

ASSOCIATED WITH ENALAPRIL

Symptomatic hypotension

Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving enalapril, symptomatic hypotension is more likely to occur if the patient is volume-depleted or has electrolyte imbalance which may occur due to diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting (see section 4.5 and 4.8).

In patients with heart failure, with or without renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatremia or renal dysfunction. In these patients, therapy must be started under medical supervision preferably in a hospital and the patients must be followed closely whenever the dose of enalapril and/or diuretic is adjusted.

Similar considerations may apply to patients with ischemic heart disease or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can be given usually at reduced doses or either of the active substances may be used appropriately alone without difficulty once the blood pressure has increased after volume expansion.

In some patients with heart failure who have normal or low blood pressure, additional lowering of systematic blood pressure may occur with enalapril. This effect is anticipated and usually is not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or enalapril may be necessary.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy

As with all vasodilators, ACE inhibitors should be given with caution in patients with left ventricular valvular or aortic outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

Renal function impairment

In cases of renal impairment (creatinine clearance < 80 ml/min), the initial enalapril dosage should be adjusted according to the patient's creatinine clearance (see section 4.2) and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatanine are part of normal medical practice for these patients.

Renal failure has been reported in association with enalapril, and has been mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognised promptly and treated appropriately, renal failure when associated with therapy with enalapril is usually reversible

Some hypertensive patients, with no apparent pre-existing renal disease have developed increases in blood urea and creatinine when enalapril has been given concurrently with a diuretic. Dosage reduction of enalapril and /or discontinuation of the diuretic may be required. This situation should raise the possibility of underlying renal artery stenosis (see section 4.4. – renovascular hypertension).

Renovascular hypertension

There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitor. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function.

Kidney transplantation

There is no experience regarding the administration of enalapril in patients with a recent kidney transplantation. Treatment with enalapril is therefore not recommended.

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow up.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia rarely occurs . Enalapril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy. If enalapril is used in such patients, periodical monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

Hypersensitivity/angioneurotic oedema

Angioneurotic edema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril. This may occur at any time during treatment. In such cases, enalapril should be discontinued promptly, and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips, the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.

Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

Angioneurotic edema associated with laryngeal edema may be fatal.

Very rarely, fatalities have been reported due to angiooedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery.

Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly.

Black patients taking ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. (see section 4.3)

Anaphylactoid reactions during hymenoptera desensitization

Rarely, patients receiving ACE inhibitors during desensitization with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each desensitization.

Anaphylactoid reactions during LDL apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulphate develop life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.

Haemodialysis patients

Anaphylactoid reactions have been described in patients dialysed with high-flux membranes (e.g., AN 69^®) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Diabetic patients

In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should closely be monitored during the first month of treatment with an ACE inhibitor. (see section 4.5)

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Surgery/anaesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril blocks angiotensin II formation secondary to compensatory renin secretion. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitor, including enalapril. Patients at risk for the development of hyperkalemia include those with renal insufficiency, diabetes mellitus, or those concomitantly using potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or those patients using other medicinal products associated with increases in serum potassium (e.g. heparin). If concomitant use of the above mentioned agents is deemed necessary, regular monitoring of serum potassium is recommended.

Ethnic differences

As with other angiotensin converting enzyme inhibitors, enalapril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Interactions

This medicinal product IS GENERALLY NOT RECOMMENDED in combination with potassium-sparing diuretics, potassium salts and estramustine (see section 4.5).

Pregnancy

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor 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 ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

ASSOCIATED WITH HYDROCHLOROTHIAZIDE

Hepatic impairment

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations in fluid and electrolyte balances may precipitate hepatic encephalopathy in patients with hepatic disease. In this case, treatment with the diuretic must be stopped immediately.

Enalapril maleate/Hydrochlorothiazide 20/12.5mg Tablets is generally not recommended in combination with sultopride (see section 4.5).

ASSOCIATED WITH ENALAPRIL AND HYDROCHLOROTHIAZIDE

Interaction

This medicinal product is generally not recommended in combination with lithium due to the potential of lithium toxicity (see section 4.5).

Precautions for use

ASSOCIATED WITH HYDROCHLOROTHIAZIDE

Fluid/electrolyte balance

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 (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with enalapril may reduce diuretic-induced hypokalaemia. 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).

Dilutional hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and usually does not require treatment.

Natraemia

Sodium levels must be assessed before the initiation of treatment, and at regular intervals thereafter. All diuretic treatment can cause hyponatraemia, with potentially serious consequences. Since a decrease in natraemia may initially be asymptomatic, regular monitoring is essential and must be even more frequent in at-risk populations such as the elderly, malnourished and cirrhotic (see section 4.8 and section 4.9).

Kalaemia

Potassium depletion and hypokalaemia are the major risks associated with thiazide and related diuretics. Hypokalaemia (< 3.5 mmol/l) must be prevented in certain at-risk populations, such as elderly and/or malnourished patients, especially when receiving combination therapy, cirrhotic patients with oedema and ascites, coronary patients, patients with heart failure. In these cases, hypokalaemia increases the cardiotoxicity of digitalis glycosides and the risk of arrhythmia.

In patients with a long QT interval, whether congenital or substance-induced, hypokalaemia increases the risk of severe arrhythmia, in particular potentially fatal torsade de pointes, especially in patients with bradycardia.

Potassium levels must be regularly monitored, starting in the first week of treatment.

Calcaemia

Thiazide may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium.

Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Magnesium plasma levels

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. The salt and volume depletion caused by thiazides reduces the urinary elimination of uric acid. Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Renal impairment

Thiazide diuretics are fully efficacious only in patients with normal renal function or mild renal impairment (evaluated, for example, according to creatinine clearance). In the elderly, the value for creatinine clearance must be adjusted for age, weight and sex.

Hypovolaemia, secondary to diuretic-induced fluid and sodium loss at the beginning of treatment, leads to reduced glomerular filtration. This can cause an increase in blood urea and creatinine.

This transient functional renal impairment is without consequence in patients with normal renal function, but can aggravate pre-existing renal impairment.

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotaemia. Cumulative effects of the drug may develop in patients with impaired renal function. If progressive renal impairment becomes evident, as indicated by a rising non-protein nitrogen, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.

Athletes/anti-doping test

The attention of athletes is drawn to the fact that this medicinal product contains an active substance which may induce a positive reaction in anti-doping tests.

Other

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

ASSOCIATED WITH ENALAPRIL AND HYDROCHLOROTHIAZIDE

Functional renal impairment

Some hypertensive patients with no apparent pre-existing renal disease have developed signs of functional renal impairment. If this occurs, treatment must be discontinued. Reinstitution of therapy at reduced dosage may be possible, or either of the components may be used appropriately alone.

Hypotension and fluid/electrolyte imbalance

Patients must be systematically monitored for clinical signs of fluid/electrolyte imbalance, which may occur during intercurrent diarrhoea or vomiting. Regular monitoring of plasma electrolytes must be undertaken in such patients.

Significant hypotension may require the initiation of intravenous isotonic saline.

Transient hypotension is not a contra-indication to continued treatment. After volume repletion and establishment of satisfactory blood pressure, treatment can be reinstituted, either at a lower dosage or either of the components may be used appropriately alone.

Risk of hypokalaemia

The combination of an ACE inhibitor and non-potassium-sparing diuretic does not preclude the development of hypokalaemia, in particular in diabetic or renally impaired patients. Plasma potassium must be regularly monitored.

Paediatric use

The safety and efficacy of this product have not been demonstrated in controlled studies in children.

ASSOCIATED WITH THE EXCIPIENTS

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

RELATED TO ENALAPRIL

Potassium-sparing diuretics and potassium supplements

ACE inhibitors attenuate diuretic induced potassium loss. Potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes may lead to a significant increase in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring serum potassium (see section 4.4).

Diuretics (thiazide or loop diuretics)

Prior treatment with high-dosed diuretics may result in volume depletion and thus in a risk of hypotension when initiating therapy with enalapril (see section 4.4). The hypotensive effect can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of enalapril.

Other antihypertensives

Concomitant use of these agents (e.g. beta-adrenergic blocking agents, methyldopa, calcium channel blockers) may increase the hypotensive effects of enalapril. Concomitant use with nitroglycerine and other nitrates or other vasodilators, may further reduce blood pressure.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased lithium toxicity with ACE inhibitors. Use of enalapril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

Tricyclicantidepressants/antipsychotics/anaesthetic/narcotics

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of the blood pressure (see section 4.4).

Non steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid > 300 mg/day

Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor.

NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as the elderly or dehydrated.

Gold

Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Antidiabetics

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, ß-blockers, nitrates

Enalapril may be used concomitantly with acetylsalicylic acid (at cardiological doses), thrombolytics,ß-blockers and/or nitrates.

RELATED TO HYDROCHLOROTHIAZIDE

When given concurrently, the following drugs may interact with thiazide diuretics:

Alcohol, barbiturates, narcotic or antidepressants:

Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin):

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic drug may be required. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Other antihypertensive drugs

Additive effect.

Cholestyramine and colestipol resins

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

Single doses of either cholestyramine or colestipol resins bind the hydrochlorthiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent respectively.

Corticosteroids, ACTH

Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g. adrenaline)

Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine)

Possible increased responsiveness to the muscle relaxant.

Lithium

Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity; concomitant use is not recommended.

Medicinal products used in the treatment of gout (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.

Anticholinergic agents (e.g. atropine, biperiden)

Increase of the bioavailability to thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Cytotoxic agents (eg 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.

Cyclosporine

Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-type complications.

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 Enalapril/hydrochlorothiazide 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 antiarrythmics (eg quinidine, hydroquinidine, disopyramide).

• Class III antiarrythmics (eg amiodarone, sotalol, dofetilide, ibutilide).

• Some antipsychotics (eg thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

• Others (eg bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin,pentamidine, terfenadine, vincamine IV).

Calcium salts and vitamin D

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage should be adjusted accordingly.

Laboratory Test Interactions

Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function (see section 4.4).

Carbamazepine

Risk of symptomatic hyponatremia. Clinical and biological monitoring is required.

Iodine Contrast Media

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product.

Patients should be rehydrated before the administration.

Amphotericin B (parenteral), corticosteroids, ACTH or stimulant laxatives

Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.

Pregnancy

ENALAPRIL

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. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3.) Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see 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 second and third 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.

Lactation

HCTZ in combination with ENALAPRIL

Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of Enalapril Maleate/Hydrochlorothiazide 20/12.5 mg tablets in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience.

In the case of an older infant, the use of Enalapril in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

The evaluation of adverse reactions is based on the following information on frequencies:

RELATED TO ENALAPRIL

Blood and lymphatic system disorders:

uncommon: anaemia (including aplastic and haemolytic)

rare: neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, myelosuppression, pancytopenia, lymphadenopathy, autoimmune diseases.

Metabolic and nutrition disorders:

uncommon: hypoglycemia (see section 4.4 'diabetic patients').

Nervous system disorders:

common: headache, depression

uncommon: confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo

rare: dream abnormality, sleep disorders.

Eye disorders:

very common: blurred vision.

Cardiac and vascular disorders:

very common: dizziness

common: hypotension (including orthostatic hypotension), syncope, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in risk patients (see section 4.4), chest pain, rhythm disorders, angina pectoris, tachycardia

uncommon: orthostatic hypotension, palpitations

rare: Raynaud's syndrome.

Respiratory, thoracic and mediastinal disorders:

very common: cough

common: dyspnoea

uncommon: rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma

rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders:

very common: nausea

common: diarrhoea, abdominal pain, taste alteration

uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer

rare: stomatitis/aphthous ulcerations, glossitis.

very rare: intestinal angiooedema

Hepatobiliary disorders:

rare: hepatic failure, hepatitis - either hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice).

Skin and subcutaneous tissue disorders:

common: rash, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see section 4.4).

uncommon: diaphoresis, pruritus, urticaria, alopecia

rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma

A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive ANA, elevated ESR, eosinophilia and leukocytosis. Exanthema, photosensitivity or other dermatologic symptoms may occur.

Renal and urinary disorders:

uncommon: renal dysfunction, renal failure, proteinuria

rare: oliguria.

Reproductive system and breast disorders:

uncommon: impotence

rare: gynaecomastia.

General disorders and administration site conditions:

very common: asthenia

common: fatigue

uncommon:muscle cramps flushing, tinnitus, malaise, fever.

Investigations:

common: hyperkalaemia, increases in serum creatinine

uncommon: increases in blood urea content, hyponatraemia

rare: elevations of liver enzymes, elevations of serum bilirubin.

RELATED TO HYDROCHLOROTHIAZIDE

Infections and infestations:

sialadenitis

Blood and lymphatic system disorders:

leucopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression

Metabolism and nutrition disorders:

anorexia, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalemia), increases in cholesterol and triglycerides

Psychatric disorders:

restlessness, depression, sleep disturbances

Nervous system disorders:

loss of appetite, paraesthesia, light-headedness

Eye disorders:

xanthopsia, transient blurred vision

Ear and labyrinth disorders:

vertigo

Cardiac disorders:

postural hypotension, cardiac arrhythmias

Vascular disorders:

necrotising angiitis (vasculitis, cutaneous vasculitis)

Respiratory, thoracic and mediastinal disorders:

respiratory distress (including pneumonitis and pulmonary oedema)

Gastrointestinal disorders:

gastric irritation, diarrhoea, constipation, pancreatitis

Hepatobillary disorders:

jaundice (intrahepatic cholestatic jaundice)

Skin and subcutaneous tissue disorders:

photosensitivity reactions, rash, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis

Musculoskeletal, connective tissue and bone disorders:

muscle spasm

Renal and urinary disorders:

renal dysfunction, interstitial nephritis

General disorders and administration site conditions:

fever, weakness

No specific information is available with respect to the treatment of an overdose Enalapril maleate/Hydrochlorothiazide 20 mg/6 mg.

Symptoms of overdose are severe hypotension, shock, stupor, bradycadia, electrolyte disturbances and renal failure.

ASSOCIATED WITH ENALAPRIL

Limited data are available on overdose in humans.

Symptoms

The most prominent features of overdose reported to date are markant hypotension beginning some six hours after ingestion of the tablets, concomitant with blockade of the renin-angiotensin system, and stupor.

Symptoms associated with overdose of ACE inhibitors –may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

- Serum enalaprilat levels 100- and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril respectively

ASSOCIATED WITH HYDROCHLOROTHIAZIDE

The signs of acute intoxication are primarily related to fluid/electrolyte imbalance (hyponatramia, hypokalaemia).

In addition to the expected diuresis, overdose of thiazides may produce varying degrees of lethargy, which may progress to coma within a few hours, with minimal depression of respiration and cardiovascular function, and without evidence of serum electrolyte changes or dehydration. The mechanism of thiazide-induced CNS depression is unknown.

Gastrointestinal irritation as well as an increase of blood urea nitrogen (BUN) were reported, and especially in patients with impaired renal function it can come changes of the serum electrolytes. Clinically, nausea, vomiting, hypotension, cramps, dizziness, somnolence, confusional states, polyuria or oliguria to the point of anuria (through hypovolaemia) may occur.

COMBINATION

Treatment is symptomatic and supportive. Treatment with Enalapril maleate/Hydrochlorothiazide 20 mg/6 mg should be discontinued and the patient should be carefully monitored. Recommended measures include induction of vomiting, administration of activated charcoal and administration of a laxative and/or gastric lavage if the tablets were taken recently. Any dehydration, disturbances in the electrolyte balance and hypotension should be treated in an appropriate manner. Enalaprilat can be eliminated form blood circulation via haemodialysis (see section 4.4). The extent to which hydrochlorothiazide is removed is not established.

Pharmacotherapeutic group: ACE inhibitors and diuretics

ATC code: C 09 BA 02

Pharmacological mechanism of action

ASSOCIATED WITH ENALAPRIL

Enalapril maleate is the maleate salt of enalapril, a derivative of two amno-acids , L-alanine and L-proline. Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance angiotensin II.

After absorbtion, enalapril is hydrolysed to enalaprilat, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma rennin activity (due to removal of negative feedback of rennin release), and decreased aldosterone secretion.

ACE is identical to kininase II. Thus enalapril may also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of enalapril remains to be elucidated.

ASSOCIATED WITHN HYDROCHLOROTHIAZIDE

Hydrochlorothiazide is a thiazide diuretic which acts as by inhibiting fluid-expelling and blood pressure-lowering agent which increase the tubular re-absorption of sodium in the cortical diluting segment.

It increases the urinary excretion of sodium and chloride and, to a lesser degree, the excretion of potassium and magnesium, thus increasing diuresis and exerting an anti-hypertensive effect.

Characteristics of the antihypertensive therapy

While the mechanism through which enalparil lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension.

Administration of enalapril to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate.

Symptomatic postural hypotension is infrequent. In some patients the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of enalapril has not been associated with rapid increase in blood pressure.

Effective inhibition of ACE activity usually occurs 2 to 4 hours after oral administration of an individual dose of enalapril. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by 4 to 6 hours after administration. The duration of effect is dose-related.

However, at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours.

In haemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril there was an increase in renal blood flow; glomerular filtration rate was unchanged. There was no evidence of sodium or water retention. However, in patients with low pre-treatment glomerular filtration rates, the rates were usually increased.

In short-term clinical studies in diabetic and non-diabetic patients with renal disease, decreases in albuminuria and urinary excretion of IgG and total urinary protein were seen after the administration of enalapril.

When given together with thiazide-type diuretics, the blood pressure-lowering effects of enalapril are at least additive. Enalapril may reduce or prevent the development of thiazide-induced hypokalaemia.

ASSOCIATED WITH HYDROCHLROTHIAZIDE

The time to onset of diuretic activity is approximately 2 hours. Diuretic activity reaches a peak after 4 hours and is maintained for 6 to 12 hours.

Above a certain dose, thiazide diuretics reach a plateau in terms of therapeutic effect whereas adverse reactions continue to multiply. When treatment is ineffective, increasing the dose beyond recommended doses serves no useful purpose and often gives rise to adverse reactions.

ASSOCIATED WITH THE COMBINATION

In clinical studies, the concomitant administration of enalapril and hydrochlorothiazide reduced blood pressure more significantly than either substance alone.

The administration of enalapril inhibits the renin-angiotensin-aldosterone system and tends to reduce the hydrochlorothiazide-induced potassium.

Combination of an ACE inhibitor with a thiazide diuretic produces a synergistic effect and also lessens the risk of hypokalaemia provoked by the diuretic alone.

Co-administration of enalapril and hydrochlorothiazide in various doses has little or no effect on the bioavailability of these two substances.

ASSOCIATED WITH ENALAPRIL

Absorption

Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within 1 hour.Based on urinary recovery, the extent of absorption of enalapril from oral enalapril maleate is approximately 60%.

The absorption of oral enalapril is not influenced by the presence of food in the gastrointestinal tract.

Distribution

Following absorption, oral enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril maleate. The effective half-life for accumulation of enalapril following concentrations of enalaprilat were reached after four days of treatment.

Over the range of concentrations which are therapeutically relevant, enalapril binding to human plasma proteins does not exceed 60%.

After a single 20 mg oral dose in 5 postpartum women the average peak enalapril milk level was 1.7 µg/L (range 0.54 to 5.9 µg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7 µg/L (range 1.2 to 2.3 µg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dosage.

A woman who had been taking oral enalapril 10 mg daily for 11 months had peak enalapril milk levels of 2 µg/L 4 hours after a dose and peak enalaprilat levels of 0.75 µg/L about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hours period was 1.44 µg/L and 0.63 µg/L of milk respectively.

Enalaprilat milk levels were undetectable (<0.2 µg/L) 4 hours after a single dose of enalapril 5 mg in 1 mother and 10mg in 2 mothers; enalapril levels were not determined.

Biotransformation

Except for conversion to enalaprilat, there is no evidence for significant metabolism of enalapril.

Elimination

Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril (about 20%).

Renal impairment

The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild or moderate renal insufficiency (creatinine clearance 40-60 ml/min) steady state AUC of enalaprilat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance 30 ml/min), AUC was increased approximately 8-fold.The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency and time to steady state is delayed (see section 4.2 'Dosage in renal insufficiency').

Enalaprilat may be removed from the general circulation by hemodialysis. The dialysis clearance is 62 ml/min.

ASSOCIATED WITH HYDROCHLOROTHIAZIDE

Absorption

Oral absorption of hydrochlorothiazide is relatively rapid.

The bioavailability of hydrochlorothiazide varies between 60 and 80%. The time to peak plasma concentration (Tmax) varies between 1.5 and 5 hours, with a mean of about 4 hours.

Distribution

Protein binding is approximately 40%.

The mean plasma half-life in fasted individuals has been reported to be 5 to 15 hours.

Elimination

Hydrochlorothiazide is eliminated rapidly by the kidney and excreted unchanged (> 95%) in the urine. At least 61% of the oral dose is eliminated unchanged within 24 hours.

In renal and cardiac impairment, as in the elderly, the renal clearance of hydrochlorothiazide is reduced, and the elimination half-life increased. Elderly subjects also show increased peak plasma concentrations.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that enalapril has no effects on fertility and reproductive performance in rats, and is not teratogenic. In a study in which female rats were dosed prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The compound has been shown to cross the placenta and is secreted in milk. Angiotensin converting enzyme inhibitors, as a class, have been shown to be fetotoxic (causing injury and/or death to the fetus) when given in the second or third trimester. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

sodium hydrogen carbonate

lactose monohydrate

maize starch

pregelatinised starch

talc

magnesium stearate

Not applicable.

3 years

Store in the original package in order to protect from light and moisture.

10, 28, 30, 50, 56, 98, 100 tablets and 100 (100 x 1) unit dose in Alu / Oriented Polyamide/Alu/PVC blister package.

Not all pack sizes may be marketed.

No special requirements.

Sandoz Limited

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

PL 04416/0460

20/12/2002 / 03/01/2007

11/2010