- enalapril maleate
POM: Prescription only medicine
This information is intended for use by health professionals
Excipient(s) with known effect:For the full list of excipients, see section 6.1.
PosologyThe dosage of Innozide should be determined primarily by the experience with the enalapril maleate component. Adults
Essential hypertensionThe usual dosage is one tablet, taken once daily. If necessary, the dosage may be increased to two tablets, taken once daily. Prior diuretic therapy: symptomatic hypotension may occur following the initial dose of Innozide; this is more likely in patients who are volume and/or salt depleted as a result of prior diuretic therapy. The diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with Innozide.
Dosage in renal insufficiencyThiazides 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).In patients with creatinine clearance of >30 and <80 ml/min, Innozide should be used only after titration of the individual components.
Use in the elderlyIn clinical studies the efficacy and tolerability of enalapril maleate and hydrochlorothiazide, administered concomitantly, were similar in both elderly and younger hypertensive patients.
Paediatric populationSafety and effectiveness in children have not been established.
Method of administrationOral use.
Hypotension and Electrolyte Fluid ImbalanceSymptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving Innozide, symptomatic hypotension is more likely to occur if the patient has been volume - depleted, e.g., by diuretic therapy, dietary salt restriction, diarrhoea or vomiting (see sections 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 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 associated 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, hyponatraemia or functional renal impairment. In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of Innozide and/or diuretic is adjusted. Similar considerations may apply to patients with ischaemic heart 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 contra-indication to further doses, which can be given usually 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 systemic blood pressure may occur with Innozide. 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 Innozide may be necessary.
Renal Function ImpairmentRenal 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. Innozide should not be administered to patients with renal insufficiency (creatinine clearance <80 ml/min. and >30 ml/min.) until titration of enalapril has shown the need for the dose present in this formulation (see section 4.2). 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 Maleate, Renal Function Impairment; Hydrochlorothiazide, Renal Function Impairment in section 4.4). If this occurs, therapy with Innozide should be discontinued. This situation should raise the possibility of underlying renal artery stenosis (see Special warnings and precautions for use, Enalapril Maleate, 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, hyperkalaemia, and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
HyperkalaemiaThe combination of enalapril and a low-dose diuretic cannot exclude the possibility of a hyperkalaemia to occur (see Special warnings and precautions for use, Enalapril Maleate, Hyperkalaemia in section 4.4).
LithiumThe combination of lithium with enalapril and diuretic agents is generally not recommended (see section 4.5).
LactoseInnozide contains less than 200 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Paediatric populationSafety and efficacy in children has not been established. Enalapril Maleate AorticStenosis/Hypertrophic Cardiomyopathy As with all vasodilators, ACE inhibitors should be given with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.
Renal Function ImpairmentRenal 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 (see section 4.2 and Special warnings and precautions for use, Enalapril Maleate-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.
Haemodialysis PatientsThe use of enalapril is not indicated in patients requiring dialysis for renal failure. Anaphylactoid reactions have been reported 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.
Kidney TransplantationThere is no experience regarding the administration of enalapril in patients with a recent kidney transplantation. Treatment with enalapril is therefore not recommended.
Hepatic failureRarely, 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/AgranulocytosisNeutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. 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, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.
HyperkalaemiaElevations in serum potassium have been observed in some patients treated with ACE inhibitors, including enalapril. Risk factors for the development of hyperkalaemia include those with renal insufficiency, worsening of renal function, age (>70 years), diabetes mellitus, inter-current events in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs 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. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see Special warnings and precautions for use, Enalapril Maleate-Hydrochlorothiazide, Hyperkalemia; Hydrochlorothiazide, Metabolic and Endocrine Effects in section 4.4 and section 4.5).
HypoglycaemiaDiabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycaemia, especially during the first month of combined use (see Special warnings and precautions for use, Hydrochlorothiazide, Metabolic and Endocrine Effects in section 4.4 and section 4.5).
Hypersensitivity/Angioneurotic OedemaAngioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril maleate. This may occur at any time during treatment. In such cases, Innozide should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. 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 receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to Whites. 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). Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema. Anaphylactoid Reactions during Hymenoptera Desensitisation Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation. Anaphylactoid Reactions during LDL-Apheresis Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactic reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.
CoughCough 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/AnaesthesiaEnalapril blocks angiotensin II formation and therefore impairs the ability of patients undergoing major surgery or anaesthesia with agents that produce hypotension to compensate via the renin-angiotensin system. Hypotension which occurs due to this mechanism can be corrected by volume expansion (see section 4.5).
PregnancyACE inhibitors should not be initiated during pregnancy. 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 (see sections 4.3 and 4.6).
Ethnic DifferencesAs 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.
Renal Function ImpairmentThiazides 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 Maleate-Hydrochlorothiazide, Renal Function Impairment; Enalapril Maleate, Renal Function Impairment in section 4.4). Innozide 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.
Hepatic DiseaseThiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma (see Special warnings and precautions for use, Enalapril Maleate, Hepatic Failure in section 4.4).
Metabolic and Endocrine EffectsThiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required (see Special warnings and precautions for use, Enalapril Maleate, Diabetic Patients in section 4.4). Thaizides may decrease serum sodium, magnesium and potassium levels. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, at the 12.5 mg dose of hydrochlorothiazide contained in Innozide, 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. Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of latent hyperparathyroidism. Thiazides should be discontinued before testing parathyroid function. Thiazide therapy may precipitate hyperuricaemia and/or gout in certain patients. 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. 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 gastro-intestinal disturbances such as nausea and vomiting. Although hypokalaemia may develop during 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 with 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 does not usually require treatment. Thiazides may have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesemia.
Anti-doping testHydrochlorothiazide contained in this product can produce a positive analytic result in an anti-doping test.
HypersensitivityIn patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy and bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)Clinical trial data have 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 AgentsConcomitant 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.
LithiumReversible 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 Innozide 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 (NSAIDs) including selective cyclooxygenase-2 (COX-2) inhibitorsNon-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors or diuretics may be attenuated by NSAIDs including selective COX-2 inhibitors.The coadministration of NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or 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. Enalapril Maleate
Potassium-sparing Diuretics or Potassium SupplementsACE 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 significant increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium (see section 4.4)
Diuretics (thiazide or loop diuretics)Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril (see sections 4.2 and 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic or by increasing volume or salt intake.
Tricyclic Antidepressants/Antipsychotics/AnaestheticsConcomitant 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).
GoldNitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril.
Mammalian Target of Rapamycin (mTOR) inhibitorsPatients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see section 4.4).
SympathomimeticsSympathomimetics may reduce the antihypertensive effects of ACE inhibitors (see section 4.5).
AlcoholAlcohol enhances the hypotensive effect of ACE inhibitors.
AntidiabeticsEpidemiological 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 sections 4.4 and 4.8).
Acetyl Salicylic Acid, Thrombolytics and β-blockersEnalapril can be safely administered concomitantly with acetyl salicylic acid (at cardiologic doses), thrombolytics and β-blockers.
Non-depolarising Muscle RelaxantsThiazides may increase the responsiveness to tubocurarine.
Alcohol, Barbiturates, or Opioid AnalgesicsPotentiation of orthostatic hypotension may occur . Antidiabetic Drugs (Oral Agents and Insulin) Dosage adjustment of the antidiabetic drug may be required (see sections 4.4 and 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 gastro-intestinal tract by up to 85 and 43 percent, respectively.
Increasing the QT Interval (e.g., quinidine, procainamide, amiodarone, sotalol)Increased risk of torsades de pointes.
Digitalis GlycosidesHypokalaemia can sensitise or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).
Corticosteroids, ACTHIntensified electrolyte depletion, particularly hypokalaemia. Kaliuretic Diuretics (e.g., Furosemide), Carbenoxolone, or Laxative Abuse Hydrochlorothiazide may increase the loss of potassium and/or magnesium.Pressor Amines (e.g. Noradrenaline)The effect of pressor amines may be decreased (see section 4.5).Cytostatics (e.g., Cyclophosphamide, Methotrexate)Thiazides may reduce the renal excretion of cytotoxic drugs and potentiate their myelosuppressive effects.
Paediatric populationInteraction studies have only been performed in adults.
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 second and third trimester of pregnancy (see sections 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. 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 foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Maternal oligohydramnios, presumably representing decreased foetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development. Should exposure to ACE inhibitors 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.
Breast feedingEnalapril: 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 Innozide in breast-feeding 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 Innozide 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. 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 Innozide during breast-feeding is not recommended. If Innozide is used during breast-feeding, doses should be kept as low as possible.
Table 1. Undesirable effects of Innozide
|System organ class||Very common (≥1/10)||Common (≥1/100 to <1/10)||Uncommon (≥1/1,000 to <1/100)||Rare (≥1/10,000 to <1/1,000)||Very rare (<1/10,000)||Not known (cannot be estimated from the available data)|
|Blood and lymphatic system disorders||Anaemia (including aplastic and haemolytic)||Neutropenia, decreases in haemoglobin, deacreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases|
|Endocrine disorders||Syndrome of inappropriate antidiuretic hormone secretion (SIADH)|
|Metabolism and nutrition disorders||Hypokalaemia, increase of cholesterol, increase of triglycerides, hyperuricaemia||Hypoglycaemia (see section 4.4) ), hypomagnesaemia, gout**||Increase in blood glucose||Hypercalcaemia (see section 4.4)|
|Nervous system and psychiatric disorders||Headache, depression, syncope, taste alteration||Confusion, somnolence, insomnia, nervousness, paresthesia, vertigo, decreased libido**||Dream abnormality, sleep disorders, paresis (due to hypokalaemia)|
|Eye disorders||Blurred vision|
|Ear and labyrinth disorders||Tinnitus|
|Cardiac and vascular disorders||Dizziness||Hypotension, orthostatic hypotension, rhythm disturbances, angina pectoris, tachycardia||Flushing, palpitations, myocardial infarction or cerebrovascular accident*, possibly secondary to excessive hypotension in high risk patients (see section 4.4)||Raynaud's phenomenon|
|Respiratory, thoracic, and mediastinal disorders||Cough||Dyspnoea||Rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma||Pulmonary infiltrates, respiratory distress (including pneumonitis and pulmonary oedema), rhinitis, allergic alveolitis/eosinophilic pneumonia|
|Gastrointestinal disorders||Nausea||Diarrhoea, abdominal pain||Ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer, flatulence**||Stomatitis/aphthous ulcerations, glossitis||Intestinal angiooedema|
|Hepatobiliary disorders||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||Rash (exanthema) hypersensitivity/ angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see section 4.4)||Diaphoresis, pruritus, urticaria, alopecia||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 leucocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.|
|Musculoskeletal, connective tissue, and bone disorders||Muscle cramps||Arthralgia**|
|Renal and urinary disorders||Renal dysfunction, renal failure, proteinuria||Oliguria, interstitial nephritis|
|Reproductive system and breast disorders||Impotence||Gynecomastia|
|General disorders and administration site conditions||Asthenia||Chest pain, fatigue||Malaise, fever|
|Investigations||Hyperkalaemia, increases in serum creatinine||Increases in blood urea, hyponatremia||Elevations of liver enzymes, elevations of serum bilirubin|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
HydrochlorothiazideThe most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias.
Dual BlockadeTwo large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
AbsorptionOral enalapril maleate is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril maleate is approximately 60%. 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 principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril. Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. In subjects with normal renal function, steady state serum concentrations of enalaprilat were achieved by the fourth day of administration of enalapril maleate. The absorption of oral enalapril maleate is not influenced by the presence of food in the gastro-intestinal tract. The extent of absorption and hydrolysis of enalapril are similar for the various doses in the recommended therapeutic range.
DistributionStudies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Enalapril crosses the placental barrier. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
BiotransformationExcept for conversion to enalaprilat, there is no evidence for significant metabolism of enalapril. Hydrochlorothiazide is not metabolised but is eliminated rapidly by the kidney.
EliminationExcretion of enalapril is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril. The effective half-life for accumulation of enalaprilat following multiple doses of oral enalapril maleate is 11 hours. When plasma levels of hydrochlorothiazide have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. Hydrochlorothiazide is not metabolised but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.Renal impairmentEnalaprilat may be removed from the general circulation by haemodialysis.
LactationAfter a single 20 mg oral dose in five postpartum women, the average peak enalapril milk level was 1.7μg/L (range 0.54 to 5.9 μg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7μg/L (range 1.2 to 2.3μg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breast-fed 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 hour period was 1.44μg/L and 0.63 μg/L of milk respectively. Enalaprilat milk levels were undetectable (<0.2μg/L) 4 hours after a single dose of enalapril 5 mg in one mother and 10mg in two mothers; enalapril levels were not determined.
|First authorised:||8 May 1991|
|Last renewed:||10 November 2004|