Enalapril/Hydrochlorothiazide 20/12.5 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Enalapril /Hydrochlorothiazide 20 mg/12.5 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains enalapril maleate 20 mg and hydrochlorothiazide 12.5 mg.
Excipient with known effect: Each tablet contains 89.60mg lactose (as lactose monohydrate)
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Tablet
White oval, biconvex snap tab tablet, one side scored, other side marked "E H"
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of essential hypertension.
This fixed dose combination is indicated in patients whose blood pressure is not adequately controlled with enalapril alone.
This fixed dose may also replace 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.
4.2 Posology and method of administration
Posology
The dosage of Enalapril / Hydrochlorothiazide should be determined primarily by the experience with the enalapril maleate component. Enalapril /Hydrochlorothiazide 20 mg/12.5 mg 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.
Dosage in patients with normal renal function
The usual dosage is one tablet, taken once daily. If necessary, the dosage may be increased to two tablets, taken once daily.
Dosage in renal insufficiency
- Creatinine clearance > 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). In patients with creatinine clearance of >30 and <80 mL/min, Enalapril / Hydrochlorothiazide should be used only after titration of the individual components.
- 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.
Paediatric use
Safety and effectiveness of Enalapril /Hydrochlorothiazide 20 mg/12.5 mg in children has not been established.
Method of administration Oral use.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Severe renal impairment (creatinine clearance <30 ml/min).
• Anuria.
• History of angioneurotic edema (Quincke’s oedema) associated with previous ACE-inhibitor therapy.
• Hereditary or idiopathic angioedema.
• Hypersensitivity to other ACE-inhibitors/ sulfonamide-derived drugs.
• Second and third trimesters of pregnancy (see section 4.4 and 4.6).
• Severe hepatic impairment/hepatic encephalopathy
• Stenosis of the renal arteries
• The concomitant use of Enalapril / Hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL / min / 1.73 m2) (see sections 4.5 and 5.1).
4.4 Special warnings and precautions for use
ASSOCIATED WITH ENALAPRIL
Aortic 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
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 (see section 4.2 and Special warnings and precautions for use, Enalapril/Hydrochlorothiazide, Renal function impairment; Hydrochlorothiazide, Renal function impairment in section 4.4).
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 inhibitors. 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 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 (see Special warnings and precautions for use, Hydrochlorothiazide, Hepatic disease in section 4.4).
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 oedema 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.
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-blacks. However, in general it appears that Blacks have an increased risk for angioedema.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. (see also 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
The use of enalapril is not indicated in patients requiring dialysis for renal failure. 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 Special warnings and precautions for use, Hydrochlorothiazide, Metabolic and endocrine effects in section 4.4 and 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 (see section 4.5).
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, worsening of renal function, age (>70 years) diabetes mellitus, intercurrent events in particular dehydration, acute cardiac decompensation, metabolic acidosis or those concomitantly using potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients using other medicinal products associated with increases in serum potassium (e.g. heparin). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal, arrhythmias.If concomitant use of the above mentioned agents is deemed necessary, they should be used with caution and with regular monitoring of serum potassium is recommended (see Special warnings and precautions for use, Enalapril/Hydrochlorothiazide, Risk of hyperkalemia; Hydrochlorothiazide, Metabolic and endocrine effects in section 4.4 and section 4.5).
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.
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 of fluid and electrolyte balances may precipitate hepatic encephalopathy in patients with hepatic disease (see section 4.2 and Special warnings and precautions for use, Enalapril/Hydrochlorothiazide, Renal function impairment; Enalapril, Renal function impairment in section 4.4).
Renal function impairment
Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min. or below (i.e., moderate or severe renal insufficiency) (see section 4.2 and Special warnings and precautions for use, Enalapril-Hydrochlorothiazide, Renal function impairment; Enalapril, Renal function impairment in section 4.4).
Enalapril /Hydrochlorothiazide should not be administered to patients with renal insufficiency (creatinine clearance <80 ml/min) until titration of the individual components has shown the need for the doses present in the combination tablet.
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 Special warnings and precautions for use, Enalapril, Diabetic patients in section 4.4). Thiazide may decrease serum sodium, magnesium and potassium levels.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however, at the 12.5 mg dose of hydrochlorothiazide contained in Enalapril-Hydrochlorothiazide, minimal or no effect was reported. In addition, in clinical studies with 6 mg of hydrochlorothiazide no clinically significant effect on glucose, cholesterol, triglycerides, sodium, magnesium or potassium was reported.
Hyperuricaemia
Hyperuricaemia and/or gout may be precipitated in certain patients receiving thiazide therapy. This effect on hyperuricemia appears to be dose-related. In addition enalapril may increase urinary uric acid and thus may attenuate the hyperuricaemic effect of 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 xerostomia, thirst, weakness, lethargy, somnolence, 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).
Hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and usually does not require treatment.
Calcaemia
Thiazide may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. 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.
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.
Hypersensitivity
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 with the use of thiazides.
ASSOCIATED WITH ENALAPRIL AND HYDROCHLOROTHIAZIDE
Symptomatic hypotension and electrolyte fluid imbalance
Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving Enalapril/Hydrochlorothiazide, 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). Regular determination of serum electrolytes should be performed at appropriate intervals in such patients.
Special attention should be paid 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.
In hypertensive 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 functional renal impairment. 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/ Hydrochlorothiazide and/or diuretic is adjusted. Similar consideration may apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in 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/
Hydrochlorothiazide. 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 / Hydrochlorothiazide may be necessary.
Renal functional impairment
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 recognized promptly and treated appropriately, renal failure when associated with therapy with enalapril is usually reversible.
In cases of renal impairment (creatinine clearance < 80 ml/min and >30 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.
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 (see Special warnings and precautions for use, Enalapril, Renal function impairment; Hydrochlorothiazide, Renal function impairment in section 4.4). If this occurs, therapy with Enalapril/Hydrochlorothiazide should be discontinued. This situation should raise the possibility of underlying renal artery stenosis (see Special warnings and precautions for use. Enalapril, Renovascular hypertension in section 4.4).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Risk of hyperkalaemia
The combination of enalapril and a low-dose diuretic does not preclude the development of hyperkalaemia. (see Special warnings and precautions for use, Enalapril, Hyperkalaemia in section 4.4).
Lithium
The combination of lithium with enalapril and diuretic agents is generally not recommended (see section 4.5).
Lactose
Enalapril/Hydrochlorothiazide contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Paediatric use
The safety and efficacy of this product have not been established in children.
4.5 Interaction with other medicinal products and other forms of interaction
ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Other Antihypertensive Agents
Concomitant use of these agents may increase the hypotensive effects of enalapril and hydrochlorothiazide. 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 further increase lithium levels and enhance the risk of lithium toxicity with ACE inhibitors.
Use of Enalapril-Hydrochlorthiazide with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4.)
Non-Steroidal Anti-Inflammatory Drugs including acetylsalicylic acid = 3g/day
Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor or may decrease the diuretic, natriuretic and antihypertensive effects of diuretics.
NSAIDs (including COX-2 inhibitors) 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 patients who are volume-depleted, including those on diuretic therapy). Therefore, the combination should be administered with caution in patients with compromised renal function.
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 (thiazides 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 sections 4.2 and 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.
Tricyclic antidepressants / Antipsychotics /Anaesthetics / Narcotics
Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see section 4.4).
Gold
Nitritoid reactions (symptoms of vasodilatation including facial flushing, nausea, vomiting, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported rarely in patients receiving ACE inhibitor therapy including enalapril.
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors. Antidiabetics
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment (see section 4.8).
Alcohol
Alcohol enhanced the hypotensive effect of ACE inhibitors Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates
Enalapril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, betablockers and/or nitrates.
RELATED TO HYDROCHLOROTHIAZIDE
Alcohol, barbiturates, narcotics 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 ( see section 4.8).
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 hydrochlorothiazide 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, noradrenaline)
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.
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 (increased ventricular irritability).
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, procainamide). 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 Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.
Kaliuretic Diuretics (e.g., Furosemide), Carbenoxolone, or Laxative Abuse Hydrochlorothiazide may increase the loss of potassium and/or magnesium. Paediatric Population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
ACE-inhibitors
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4).The use of ACE inhibitors is contra-indicated during the 2nd and 3rd trimester of pregnancy (see section 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. 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.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also 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 also section 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.
Rare cases of hypoglycaemia have been reported following exposure near term.
Lactation
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 /Hydrochlorothiazide in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience.
In case of an older infant the use of Enalapril /Hydrochlorothiazide in breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.
Hydrochlorothiazide
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Enalapril /Hydrochlorothiazide during breast feeding is not recommended. If Enalapril /Hydrochlorothiazide is used during breast feeding, doses should be kept as low as possible
Hypersensitivity to sulphonamide-derived drugs, hypokalaemia and nuclear icterus might occur Because of the potential for serious adverse reactions in nursing infants from both drugs, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of this therapy for the mother.
4.7 Effects on ability to drive and use machines
When driving vehicles or operating machines it should be taken into account that occasionally dizziness, vertigo or fatigue may occur (see section 4.8).
4.8 Undesirable effects
Side effects reported with Enalapril /Hydrochlorothiazide, enalapril alone or hydrochlorothiazide alone either during clinical studies or after the drug was marketed include as follows:
The evaluation of adverse reactions is based on the following information on frequencies:
Very common (> 1/10)
Common: (> 1/100 up to < 1/10)
Uncommon: (> 1/1.000 up to < 1/100)
Rare: (> 1/10.000 up to < 1/1.000)
Very rare: (< 1/10.000)
Not known (Frequency on the basis of available data not assessable)
Blood and the Lymphatic System Disorders:
uncommon: anemia (including aplastic and hemolytic) rare: neutropenia, decreases in hemoglobin, decreases in hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases
Endocrine disorders:
not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Metabolism and Nutrition Disorders:
common: hypokalemia, increase of cholesterol, increase of triglycerides, hyperuricemia
uncommon: hypoglycemia (see section 4.4), hypomagnesemia, gout**
rare: increase in blood glucose
very rare: hypercalcemia (see section 4.4)
Nervous System and Psychiatric Disorders:
common: headache, depression, syncope, taste alteration
uncommon: confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo, decreased libido**
rare: dream abnormality, sleep disorders, paresis (due to hypokalemia)
Other ADRs (frequency is unknown): restlessness, loss of appetite, light headedness
Eye Disorders:
very common: blurred vision
Other ADRs (frequency is unknown): xanthopsia
Ear and Labyrinth Disorders:
uncommon: tinnitus
Cardiac and Vascular Disorders:
very common: dizziness
common: hypotension, orthostatic hypotension, rhythm disturbances, angina pectoris, tachycardia
uncommon: flushing, palpitations, myocardial infarction or cerebrovascular accident*, possibly secondary to excessive hypotension in high risk patients (see section 4.4)
rare: Raynaud’s phenomenon
Other ADRs (frequency is unknown): Cardiac arrhythmias, necritising anginitis (vasculitis, cutaneous vasculitis)
Respiratory, Thoracic and Mediastinal Disorders:
very common: cough common: dyspnea
uncommon: rhinorrhea, sore throat and hoarseness, bronchospasm/asthma rare: pulmonary infiltrates, respiratory distress (including pneumonitis and pulmonary edema), rhinitis, allergic alveolitis/eosinophilic pneumonia
Gastrointestinal Disorders:
very common: nausea common: diarrhea, abdominal pain
uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer, flatulence** rare: stomatitis/aphthous ulcerations, glossitis very rare: intestinal angioedema
Hepatobiliary Disorders:
rare: hepatic failure, hepatic necrosis (may be fatal), hepatitis - either hepatocellular or cholestatic, jaundice, cholecystitis (in particular in patients with pre-existing cholelithiasis)
Skin and Subcutaneous Tissue Disorders:
common: rash (exanthema), hypersensitivity/angioneurotic edema: angioneurotic edema 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, purpura, cutaneous lupus erythematosus, erythroderma, pemphigus
A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.
Musculoskeletal, Connective Tissue and Bone Disorders:
common: muscle cramps uncommon: arthralgia**
Renal and Urinary Disorders:
uncommon: renal dysfunction, renal failure, proteinuria rare: oliguria, interstitial nephritis
Reproductive System and Breast Disorders:
uncommon: impotence rare: gynaecomastia
General Disorders and Administration Site Conditions:
very common: asthenia common: chest pain, fatigue uncommon: malaise, fever
Investigations:
common: hyperkalemia, increases in serum creatinine
uncommon: increases in blood urea, hyponatremia
rare: elevations of liver enzymes, elevations of serum bilirubin
*Incidence rates were comparable to those in the placebo and active control groups in the clinical trial.
**Only seen with doses of hydrochlorothiazide 12.5 mg and 25 mg.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Yellow Card Scheme :Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
No specific information is available with respect to the treatment of an overdose of Enalapril /Hydrochlorothiazide 20 mg/12.5 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 marked 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, hypocloremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
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 /Hydrochlorothiazide 20 mg/12.5 mg should be discontinued and the patient should be carefully monitored.
The recommended treatment of overdosage is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Recommended measures include induction of vomiting, administration of activated charcoal (absorbents) and administration of a laxative like sodium sulphate 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. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
5 PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group: ACE inhibitors, combinations ATC-Code: C09B A02
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.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
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 antihypertensive 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.
5.2 Pharmacokinetic properties
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 reco very, 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 angiotensin converting enzyme 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%
Lactation:
After a single 20 mg oral dose in 5 postpartum women the average peak enalapril milk level was 1.7 pg/L (range 0.54 to 5.9 pg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7 pg/L (range 1.2 to 2.3 pg/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 pg/L 4 hours after a dose and peak enalaprilat levels of 0.75 pg/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 pg/L and 0.63 pg/L of milk respectively.
Enalaprilat milk levels were undetectable (<0.2 pg/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 to moderate renal insufficiency (creatanince 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 ciculation 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.
5.3 Preclinical safety data
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
calcium hydrogen phosphate, dihydrate lactose monohydrate magnesium stearate maize starch
sodium hydrogen carbonate talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C. Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
The tablets are packed in Al/PA/Al/PVC blisters which are inserted into a carton folder.
pack sizes:10, 14, 20, 28, 30, 49, 50, 50x1, 60, 98, 100 tablets.
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd
3 Howard Road Eaton Socon St. Neots
Cambridgeshire PE19 8ET UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0490
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 15/11/2010
10 DATE OF REVISION OF THE TEXT
11/02/2015