Enalapril Maleate Tablets 5 mg

Tablet Enalapril Maleate Tablets 5 mg are white, round, biconvex tablets, bisected on one side. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4.1 Therapeutic indications • Treatment of hypertension • Treatment of symptomatic heart failure • Prevention of symptomatic heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction ≤35%) (see section 5.1).4.2 Posology and method of administration Posology The absorption of enalapril maleate is not affected by food. The dose should be individualized according to patient profile (see section 4.4) and blood pressure response. Paediatric population There is limited clinical trial experience of the use of enalapril in hypertensive paediatric patients (see sections 4.4, 5.1 and 5.2). **Hypertension** The initial dose is 5 to maximally 20 mg, depending on the degree of hypertension and the condition of the patient (see below). Enalapril Maleate is given once daily. In mild hypertension, the recommended initial dose is 5 to 10 mg. Patients with a strongly activated renin-angiotensin-aldosterone system, (e.g. renovascular hypertension, salt and/or volume depletion, cardiac decompensation, or severe hypertension) may experience an excessive blood pressure fall following the initial dose. A starting dose of 5 mg or lower is recommended in such patients and the initiation of treatment should take place under medical supervision. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril. A starting dose of 5 mg or lower is recommended in such patients. If possible, diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with Enalapril Maleate Tablets. Renal function and serum potassium should be monitored*.* The usual maintenance dose is 20 mg daily. The maximum maintenance dose is 40 mg daily. **Heart Failure/Asymptomatic Left Ventricular Dysfunction** In the management of symptomatic heart failure, Enalapril Maleate is used in addition to diuretics and, where appropriate, digitalis or beta-blockers. The initial dose of Enalapril Maleate Tablets in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction is 2.5 mg, and it should be administered under close medical supervision to determine the initial effect on the blood pressure. In the absence of, or after effective management of, symptomatic hypotension following initiation of therapy with Enalapril Maleate Tablets in heart failure, the dose should be increased gradually to the usual maintenance dose of 20 mg, given in a single dose or two divided doses, as tolerated by the patient. This dose titration is recommended to be performed over a 2 to 4 week period. The maximum dose is 40 mg daily given in two divided doses. Table 1: Suggested Dosage Titration of Enalapril Maleate Tablets in Patients with Heart Failure/Asymptomatic Left Ventricular Dysfunction | | | | --- | --- | | **Week** | **Dose** **mg/day** | | Week 1 | **Days 1 to 3:** 2.5 mg/day\* in a single dose **Days 4 to 7:** 5 mg/day in two divided doses | | Week 2 | 10 mg/day in a single dose or in two divided doses | | Weeks 3 and 4 | 20 mg/day in a single dose or in two divided doses | \Special precautions should be followed in patients with impaired renal function or taking diuretics (See section 4.4). Blood pressure and renal function should be monitored closely both before and after starting treatment with Enalapril Maleate Tablets (see section 4.4) because hypotension and (more rarely) consequent renal failure have been reported. In patients treated with diuretics, the dose should be reduced if possible before beginning treatment with Enalapril Maleate Tablets. The appearance of hypotension after the initial dose of Enalapril Maleate Tablets does not imply that hypotension will recur during chronic therapy with Enalapril Maleate Tablets and does not preclude continued use of the drug. Serum potassium and renal function also should be monitored. **Dosage in Renal Insufficiency** Generally, the intervals between the administration of enalapril should be prolonged and/or the dosage reduced. Table 2: Dosage in Renal Insufficiency | | | | --- | --- | | **Creatinine Clearance (CrCL)** **mL/min** | **Initial Dose** **mg/day** | | 306 years old, but no experience in other indications. Limited pharmacokinetic data are available in children above 2 months of age. (Also see sections 4.2, 5.1, and 5.2) Enalapril Maleate Tablets are not recommended in children in other indications than hypertension. Enalapril Maleate Tablets are not recommended in neonates and in paediatric patients with glomerular filtration rate <30 ml/min/1.73 m2, as no data are available. (See section 4.2) **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 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 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. **Lactose** Enalapril Maleate Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. **Sodium** This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium free'.4.5 Interaction with other medicinal products and other forms of interaction Medicines increasing the risk of angioedema Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see sections 4.3 and 4.4). Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4). **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). **Potassium sparing diuretics, potassium supplements, or other drugs that may increase serum potassium** Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with Enalapril Maleate Tablets. Potassium-sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when Enalapril Maleate Tablets is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of Enalapril Maleate Tablets with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium. Ciclosporin Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended. Heparin Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended. **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 section 4.4). The hypotensive effects 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 antihypertensive agents** Concomitant use of these agents 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 further increase lithium levels and enhance the risk of 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). **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). **Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 (COX-2) Inhibitors** Non-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 or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors. The co-administration 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. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter. **Gold** Nitritoid 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. **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 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. (See sections 4.4 and 4.8). **Alcohol** Alcohol enhances the hypotensive effect of ACE inhibitors. **Acetylsalicylic acid, thrombolytics and β- blockers** Enalapril can be safely administered concomitantly with acetyl salicylic acid (at cardiologic doses), thrombolytics and β- blockers. **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 contraindicated during the second and third trimesters 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 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). Maternal oligohydramnios, presumably representing decreased fetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development. 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). **Breast-feeding** 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 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 Maleate Tablets 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.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 or weariness may occur.4.8 Undesirable effects Undesirable effects reported for enalapril include: 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 the lymphatic system disorders:** | | | *uncommon:* | anaemia (including aplastic and hemolytic) | | *rare*: | neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases | | **Endocrine disorders:** | | | *not known:* | syndrome of inappropriate antidiuretic hormone secretion (SIADH) | | **Metabolism and nutrition disorders:** | | | *uncommon*: | hypoglycaemia (see section 4.4) | | **Psychiatric disorders:** | | | *common:* | depression | | *uncommon:* | confusion, insomnia, nervousness | | *rare*: | dream abnormality, sleep disorders | | **Nervous system disorders:** | | | *very common:* | dizziness | | *common:* | headache, syncope, taste alteration | | *uncommon:* | somnolence, paresthesia, vertigo | | **Eye disorders:** | | | *very common*: | blurred vision | | **Ear and labyrinth disorders:** | | | *Uncommon:* | tinnitus | | **Cardiac disorders:** | | | *common:* | chest pain, rhythm disturbances, angina pectoris, tachycardia | | *uncommon*: | palpitations, myocardial infarction or cerebrovascular accident\, possibly secondary to excessive hypotension in high-risk patients (see Section 4.4) | | **Vascular disorders:** | | | *common:* | hypotension (including orthostatic hypotension) | | *uncommon* | flushing, orthostatic hypotension | | *rare:* | Raynaud's phenomenon | | **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 | | | | | **Gastro-intestinal disorders:** | | | *very common:* | nausea | | *common*: | diarrhoea, abdominal pain | | *uncommon*: | ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer | | *rare*: | stomatitis/aphthous ulcerations, glossitis | | *very rare*: | intestinal angioedema | | | | | **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 | | *not known:* | 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** | | | *Uncommon:* | muscle cramps | | **Renal and urinary disorders:** | | | *uncommon*: | renal dysfunction, renal failure, proteinuria | | *rare*: | oliguria | | **Reproductive system and breast disorders:** | | | *uncommon*: | impotence | | *rare*: | gynecomastia | | **General disorders and administration site conditions:** | | | *very common*: | asthenia | | *common*: | fatigue | | *uncommon*: | malaise, fever | | **Investigations:** | | | *common*: | hyperkalaemia, increases in serum creatinine | | *uncommon*: | increases in blood urea, hyponatraemia | | *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 trials **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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose Limited data are available for overdosage in humans. The most prominent features of overdosage reported to date are marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdosage 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. 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. If ingestion is recent, take measures aimed at eliminating enalapril maleate (e.g. emesis, gastric lavage, administration of absorbents, and sodium sulfate). Enalaprilat may be removed from the general circulation by haemodialysis. (See section 4.4). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Angiotensin-converting enzyme inhibitors, ATC Code: C09A A02 Enalapril (enalapril maleate) is the maleate salt of enalapril, a derivative of two amino acids; L-alanine and L-proline. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion. ACE is identical to kinase II. Thus Enalapril Maleate Tablets may also block the degradation of bradykinin, a potent vasodepressor peptide. However the role that this plays in the therapeutic effects of Enalapril Maleate Tablets remains to be elucidated. **Mechanism of action** While the mechanism through which Enalapril Maleate Tablets lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Enalapril Maleate Tablets are antihypertensive even in patients with low-renin hypertension. **Pharmacodynamic effects** Administration of enalapril maleate 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 maleate 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 maleate 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 maleate are at least additive. Enalapril maleate may reduce or prevent the development of thiazide-induced hypokalaemia. In patients with heart failure on therapy with digitalis and diuretics, treatment with oral or injection enalapril maleate was associated with decreases in peripheral resistance and blood pressure. Cardiac output increased, while heart rate (usually elevated in patients with heart failure) decreased. Pulmonary capillary wedge pressure was also reduced. Exercise tolerance and severity of heart failure, as measured by New York Heart Association criteria, improved. These actions continued during chronic therapy. In patients with mild to moderate heart failure, enalapril retarded progressive cardiac dilatation/enlargement and failure, as evidenced by reduced left ventricular end diastolic and systolic volumes and improved ejection fraction. **Dual Blockage of the renin-angiotensin-aldosterone system (RAAS)** Two 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 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. CV 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. **Clinical efficacy and safety** A multicentre, randomised, double-blind, placebo-controlled trial (SOLVD Prevention trial) examined a population with asymptomatic left ventricular dysfunction (LVEF<35%). 4228 patients were randomised to receive either placebo (n=2117) or enalapril (n=2111). In the placebo group, 818 patients had heart failure or died (38.6%) as compared with 630 in the enalapril group (29.8%) (risk reduction: 29%; 95% CI; 21 - 36%; p<0.001). 518 patients in the placebo group (24.5%) and 434 in the enalapril group (20.6%) died or were hospitalized for new or worsening heart failure (risk reduction 20%; 95% CI; 9-30%; p<0.001). A multicentre, randomised, double-blind, placebo-controlled trial (SOLVD treatment trial) examined a population with symptomatic congestive heart failure due to systolic dysfunction (ejection fraction <35%). 2569 patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n=1284) or enalapril (n=1285). There were 510 deaths in the placebo group (39.7%) as compared with 452 in the enalapril group (35.2%) (reduction in risk, 16%; 95% CI, 5 - 26%; p=0.0036). There were 461 cardiovascular deaths in the placebo group as compared with 399 in the enalapril group (risk reduction 18%, 95% CI, 6 - 28%, p<0.002), mainly due to a decrease of deaths due to progressive heart failure (251 in the placebo group vs 209 in the enalapril group, risk reduction 22%, 95% CI, 6 - 35%). Fewer patients died or were hospitalised for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26%; 95% CI, 18 - 34%; p<0.0001). Overall in SOLVD study, in patients with left ventricular dysfunction, enalapril maleate reduced the risk of myocardial infarction by 23% (95% CI, 11 – 34%; p<0.001) and reduced the risk of hospitalisation for unstable angina pectoris by 20% (95% CI, 9 – 29%; p<0.001). **Paediatric population** There is limited experience of the use in hypertensive paediatric patients >6 years. In a clinical study involving 110 hypertensive paediatric patients 6 to 16 years of age with a body weight ≥20 kg and a glomerular filtration rate>30 mL/min/1.73 m2, patients who weighed <50 kg received either 0.625, 2.5 or 20 mg of enalapril daily and patients who weighed ≥50 kg received either 1.25, 5 or 40 mg of enalapril daily. Enalapril administration once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of enalapril was consistent across all subgroups (age, Tanner stage, gender, race). However, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. The maximum dose studied was 0.58 mg/kg (up to 40 mg) once daily. The adverse experience profile for paediatric patients is not different from that seen in adult patients.5.2 Pharmacokinetic properties **Absorption** Oral enalapril 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 tablet is approximately 60%. The absorption of oral enalapril is not influenced by the presence of food in the gastro-intestinal tract. Following absorption, oral enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin-converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur about 4 hours after an oral dose of Enalapril Maleate Tablets. The effective half-life for accumulation of enalaprilat following multiple doses of oral Enalapril Maleate Tablets is 11 hours. In subjects with normal renal function, steady-state serum concentrations of enalaprilat were reached after 4 days of treatment. **Distribution** Over the range of concentrations which are therapeutically relevant, enalaprilat binding to human plasma proteins does not exceed 60%. **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 (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). Enalaprilat may be removed from the general circulation by haemodialysis. The dialysis clearance is 62 ml/min. **Children and adolescents** A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female paediatric patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg enalapril maleate. There were no major differences in the pharmacokinetics of enalaprilat in children compared with historic data in adults. The data indicate an increase in AUC (normalised to dose per body weight) with increased age; however, an increase in AUC is not observed when data are normalised by body surface area. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours. **Lactation** After a single 20 mg oral dose in five 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 women 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 1.44 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 one mother and 10 mg in two mothers; enalapril levels were not determined.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 foetotoxic (causing injury and/or death to the foetus) when given in the second or third trimester.

6.1 List of excipients Lactose monohydrate Sodium bicarbonate Pregelatinized maize starch Maize starch Magnesium stearate6.2 Incompatibilities Not applicable6.3 Shelf life 2 years6.4 Special precautions for storage Do not store above 25°C. Store in the original package6.5 Nature and contents of container Aluminium – Aluminium Blister strips 28 tablets6.6 Special precautions for disposal and other handling No special requirements