Enalapril maleate Tablets USP 2.5mg Taj Pharma

1.NAME OF THE MEDICINAL PRODUCT
a) Enalapril maleate Tablets USP 2.5mg Taj Pharma
b) Enalapril maleate Tablets USP 5mg Taj Pharma
c) Enalapril maleate Tablets USP 10mg Taj Pharma
d) Enalapril maleate Tablets USP 20mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
a) Each tablet contains
Enalapril maleate USP 2.5mg
Excipients q.s.

b) Each tablet contains
Enalapril maleate USP 5mg
Excipients q.s.

c) Each tablet contains
Enalapril maleate USP 10mg
Excipients q.s.

d) Each tablet contains
Enalapril maleate USP 20mg
Excipients q.s.
For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Tablet.
White circular biplanar uncoated tablets

4. CLINICAL PARTICULARS

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)

Enalapril can be used alone or in combination with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1).

4.2 Posology and method of administration
The absorption of Enalapril Tablets is not affected by food.

The dose should be individualised according to patient profile (see 4.4) and blood pressure response.

Hypertension
Enalapril can be used alone or in combination with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1).

The initial dose is 5 to maximally 20 mg, depending on the degree of hypertension and the condition of the patient (see below). Enalapril Tablets are 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. 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 Tablets are used in addition to diuretics and, where appropriate, digitalis or beta-blockers. The initial dose of Enalapril 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 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.

Suggested Dosage Titration of Enalapril 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 4.4 ‘).

Blood pressure and renal function should be monitored closely both before and after starting treatment with Enalapril Tablets (see 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 Tablets. The appearance of hypotension after the initial dose of Enalapril Tablets does not imply that hypotension will recur during chronic therapy with Enalapril 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.

Creatinine Clearance (CrCL) mL/min	Initial Dose mg/day
30<CrCL<80 ml/min.	5 – 10 mg
10<CrCL30 ml/min.	2.5 mg
CrCL10 ml/min.	2.5 mg on dialysis days*

*See 4.4 – Haemodialysis Patients.

Enalaprilat is dialysable. Dosage on nondialysis days should be adjusted depending on the blood pressure response.

Use in Elderly
The dose should be in line with the renal function of the elderly patient (see 4.4, Renal Function Impairment).

Use in paediatrics
There is limited clinical trial experience of the use of Enalapril Tablets in hypertensive paediatric patients (see 4.4, 5.1 and 5.2).

For patients who can swallow tablets, the dose should be individualised according to patient profile and blood pressure response. The recommended initial dose is 2.5 mg in patients 20 to <50 kg and 5 mg in patients 50 kg. Enalapril Tablets are given once daily. The dosage should be adjusted according to the needs of the patient to a maximum of 20 mg daily in patients 20 to <50 kg and 40 mg in patients 50 kg. (See 4.4.)

Enalapril 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.

4.3 Contraindications
• Hypersensitivity to enalapril, to any of the excipients or any other ACE inhibitor

History of angioedema associated with previous ACE-inhibitor therapy
Hereditary or idiopathic angioedema
Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
Enalapril tablets should not be administered with aliskiren containing products in patients with diabetes 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
Pretreatment assessment of renal function:

Evaluation of the patient should include assessment of renal function prior to initiation of therapy, and during treatment where appropriate.

Symptomatic hypotension: Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving Enalapril tablets, hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting (see sections 4.5 and 4.8). In 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 (see “Posology and method of administration” for management of these patients). In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of ‘Enalapril’ 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 a supine position. Volume repletion with oral fluids or intravenous normal saline may be required. Intravenous atropine may be necessary if there is associated bradycardia. A transient hypotensive response is not a contra-indication to further doses, which can usually be given 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 Enalapril tablets. This effect is anticipated, and usually is not a reason to discontinue treatment. If such hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or Enalapril tablets may become necessary.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy
As with all vasodilators, ACE inhibitors should be given with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

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

Renal failure has been reported in association with enalapril tablets and has been occurring 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 tablets is usually reversible.

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

Renovascular hypertension:
There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE 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 a recent kidney transplantation.
Treatment with ‘Enalapril’ is therefore not recommended.

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

Neutropenia/Agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia 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.

Hypersensitivity / Angioneurotic oedema:
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported with angiotensin-converting enzyme inhibitors, including Enalapril tablets. This may occur at any time during treatment. In such cases, Enalapril tablets should be discontinued immediately 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 angioedema 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 non-blacks.

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 4.3).

Patients receiving co-administration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

Anaphylactic reactions during hymenoptera desensitisation:
Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom (e.g. Bee or Wasp 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 sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.

Haemodialysis patients:
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.

Hypoglycaemia
Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor, should be told to closely monitor for hypoglycemia, especially during the first month of combined use. (See 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 / Anesthesia:
In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Enalapril 5 mg, tablets block angiotensin-II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Hyperkalaemia
Elevations in serum potassium have been observed in some patients treated with ACE 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 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 section 4.5)

Lithium
The combination of lithium and Enalapril is generally not recommended (see section 4.5).

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.”

Lactose
Enalapril tablets contains lactose and therefore should not be used by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Enalapril Tablets contains less than 200 mg of lactose per tablet.

Paediatric population
There is limited efficacy and safety experience in hypertensive children>6 years old, but no experience in other indications. Limited pharmacokinetic data are available in children above 2 months of age. (Also see section 4.2, section 5.1, and section 5.2) Enalapril tablets is not recommended in children in other indications than hypertension.

‘Enalapril’ is 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.

4.5 Interaction with other medicinal products and other forms of interaction
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).

Potassium sparing diuretics or 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 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 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.

Mammalian Target of Rapamycin (mTOR) Inhibitors
Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see section 4.4).

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 sections 4.4 and 4.8).

Alcohol
Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetyl salicylic 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 foetal 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).

Breastfeeding:
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 in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of Enalapril in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

4.7 Effects on ability to drive and use machines
When driving vehicles or operating machines it should be taken in to 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, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <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 haemolytic).

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 4.4).

Nervous system and psychiatric disorders
Common: headache, depression, syncope, taste alteration
Uncommon: confusion, somnolence, insomnia, nervousness, paresthesia, vertigo
Rare: dream abnormality, sleep disorders
Very common: dizziness

Eye disorders:
Very common: blurred vision.

Ear and Labyrinth disorders:
Uncommon: Tinnitus

Cardiac and vascular disorders:
Common: hypotension (including orthostatic hypotension), syncope, chest pain, rhythm disturbances, angina pectoris, tachycardia

Uncommon: orthostatic hypotension, palpitations, myocardial infarction or cerebrovascular accident^*, possibly secondary to excessive hypotension in high risk patients (see 4.4)

Rare: Raynaud’s phenomenon

* Incidence rates were comparable to those in the placebo and active control groups in the clinical trials.

Respiratory 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 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.

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.

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-aldosterone 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 times and 200 times 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 sulphate). Enalaprilat may be removed from the general circulation by haemodialysis. (See section 4.4, Haemodialysis Patients.) Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors

Enalapril tablets contain 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 catalyses the conversion of angiotensin I into the pressor substance angiotensin II. After absorption, Enalapril tablets are hydrolysed to Enalaprilat which inhibits ACE. Inhibition of ACE results in decreased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion.

ACE is identical to kinase II, the use of ACE inhibitors may therefore block the degradation of bradykinin, a potent vasodepressor peptide. The possible role of this mechanism in the therapeutic effects of enalapril has not yet been elucidated.

Mechanism of action
While the mechanism through which Enalapril 5 mg, tablets lower blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, which plays a major role in the regulation of blood pressure, Enalapril 5 mg, tablets are antihypertensive even in patients with low-renin hypertension.

Pharmacodynamic effects
Administration of Enalapril 5 mg, tablets 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 5 mg, tablets 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 5 mg, tablets 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 pretreatment glomerular filtration rates, the rates were usually increased. In short term clinical studies in diabetic and nondiabetic 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 thiazidetype diuretics, the blood pressure lowering effects of Enalapril 5 mg, tablets are at least additive.

Enalapril 5 mg, tablets 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, 5mg tablets 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 Blockade of the renin angiotensin aldosterone system (RAAS)

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHROND (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACEinhibitor 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 endorgan damage. VA NEPHROND 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 ACEinhibitor 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.

Clinical efficacy and safety

A multicentre, randomised, doubleblind, placebocontrolled trial (SOLVD Prevention trial) examined a population with asymptomatic left ventricular dysfunction (LVEF<35%). 4,228 patients were randomised to receive either placebo (n=2,117) or enalapril (n=2,111). 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; 2136%; p<0.001). 518 patients in the placebo group (24.5%) and 434 in the enalapril group (20.6%) died or were hospitalised for new or worsening heart failure (risk reduction 20%; 95% CI; 930%; 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%). 2,569 patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n=1,284) or enalapril (n=1,285). 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, 526% ; 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, 628%, 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, 635%). 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, 5mg tablets reduced the risk of myocardial infarction by 23% (95% CI, 1134%; p<0.001) and reduced the risk of hospitalisation for unstable angina pectoris by 20% (95% CI, 929% ; 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
Enalapril tablets are rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from Enalapril tablets is approximately 60%.

Following absorption, Enalapril tablets are rapidly and extensively hydrolysed to enalaprilat. Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of Enalapril tablets. Excretion of Enalapril tablets is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose and intact enalapril. In subjects with normal renal function, steady state serum concentrations of enalaprilat were achieved by the fourth day of administration. The effective half-life for accumulation of enalaprilat following multiple doses of Enalapril tablets is 11 hours. Accumulation may occur, however in patients with severely impaired renal function, and the dosage of enalapril should be adjusted accordingly. The absorption of Enalapril tablets is not influenced by the presence of food in the gastro-intestinal tract. The extent of absorption and hydrolysis of enalapril is similar for the various doses in the recommended therapeutic range.

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

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

Elimination
Excretion of enalapril is primarily renal. The principal components in urine are enalapril, 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 40-60ml/min) steady state AUC of enalapril 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 enalapril 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). Enalapril may be removed from the general circulation by haemodialysis. The dialysis clearance is 62ml/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 enalapril 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 enalapril 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 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 1.44 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 dose 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 foetotoxic (causing injury and/or death to the foetus) when given in the second or third trimester.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Enalapril 5mg tablets contain the following inactive ingredients:
Lactose
Maize Starch
Glycerol distearate

6.2 Incompatibilities
None.

6.3 Shelf life
2 years.

6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package.

6.5 Nature and contents of container
Enalapril 5mg tablets are available in aluminium foil blisters containing 28 tablets.

6.6 Special precautions for disposal and other handling
Not applicable.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Package leaflet: Information for the patient

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
– If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

What is in this leaflet
1. What Enalapril Maleate is and what it is used for
2. Before you are given Enalapril Maleate
3. How you will be given Enalapril Maleate
4. Possible side effects
5. How Enalapril Maleate is stored
6. Further Information

1. What Enalapril Maleate is and what it is used for
Enalapril Maleate Tablets (referred to as ‘Enalapril’ throughout this leaflet) contains the active substance enalapril maleate.

‘Enalapril’ belongs to a group of medicines known as ACE inhibitors (Angiotensin Converting Enzyme Inhibitors). ‘Enalapril’ works by causing your blood vessels to widen. This helps your blood pressure to fall. It also makes it easier for your heart to pump blood around your body.

The medicine usually starts to work within an hour, and the effect lasts for at least 24 hours. Some people will require several weeks of treatment until the best effect on their blood pressure is seen.

‘Enalapril’ is used:

To treat high blood pressure – also called hypertension
To treat heart failure (weakening of heart function). It can lower the need to go to hospital and can help some patients live longer.
To prevent the signs of heart failure. The signs include: shortness of breath, tiredness after light physical activity such as walking, or swelling of the ankles and feet.

2. Before you are given Enalapril Maleate
Do not take ‘Enalapril’ if:

You are allergic to enalapril maleate, any other ACE inhibitors (type of medicines similar to ‘Enalapril’), or any of the other ingredients of this medicine (see Section 6: Further Information).
Any member of your family has had an allergic reaction to these medicines or you have ever had swelling of your face, eyelids, lips, mouth, tongue or throat which caused difficulty in swallowing or breathing (angioedema) when the reason why was not known or it was inherited.
You have diabetes or impaired kidney function and are treated with a blood pressure lowering medicine containing aliskiren.
You are more than 3 months pregnant. (it is also better to avoid ‘ENALAPRIL’ in early pregnancy – see pregnancy section ).
If you are being treated with sacubitril/valsartan, a medicine for heart failure.

Do not take ‘Enalapril’ if any of the above apply to you.

If you are not sure about taking ‘Enalapril’, talk to your doctor.

Warnings and precautions
Talk to your doctor before taking ‘Enalapril’ if:

You have low blood pressure (you may notice this as faintness or dizziness, especially when standing).
You have a condition involving the blood vessels in the brain.
You have a heart problem.
You have kidney disease, including narrowed blood vessels in your kidneys (renal artery stenosis) or recently had a kidney transplant. These may lead to higher levels of potassium in your blood which can be serious. Your doctor may need to adjust your dose of ‘Enalapril’ or monitor your blood level of potassium.
You have a liver problem.
You have a blood problem such as low or lack of white blood cells (neutropenia/agranulocytosis), low blood platelet count (thrombocytopenia) or a decreased number of red blood cells (anaemia).
You have ever had an allergic reaction, ‘angioneurotic oedema’ or ‘angioedema’. The signs include itching, red marks on the hands, feet and throat, swelling of the face, around the eyes, lips, tongue or throat with difficulty in swallowing or breathing. You should be aware that black patients are at increased risk of these type of reactions to ACE inhibitors.
You are a dialysis patient, are taking diuretics (water tablets), are on a salt restriction diet, or have suffered from excessive vomiting or diarrhoea recently.
You have diabetes. You should monitor your blood for low blood glucose levels, especially during the first month of treatment. The level of potassium in your blood can also be higher.
You take extra potassium in your diet or a salt substitute that contains potassium.
You are over 70 years of age.
You have collagen vascular disease (e.g. lupus erthematosus, rheumatoid arthritis or scleroderma), are on therapy that suppresses your immune system, are taking the drugs allopurinol or procainamide, or any combinations of these.
If you are taking an mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus: medicines used to treat certain types of cancer or to prevent the body’s immune system from rejecting a transplanted organ) or a medicine containing a neprilysin inhibitor such as sacubitril (available as fixed-dose combination with valsartan), used in patients with heart failure, and racecadotril, used in patients with acute diarrhea. You may be at increased risk for an allergic reaction called angioedema (rapid swelling under the skin in area such as the throat).
You are taking any of the following medicines used to treat high blood pressure:
- an angiotensin II receptor blocker (ARBs) (also known as sartans – for example valsartan, telmisartan, irbesartan, etc.), in particular if you have diabetes-related kidney problems.
- aliskiren

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.

See also information under the heading “Do not take Enalapril if”

You must tell your doctor if you think you are (or might become) pregnant. This medicine is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see Pregnancy section).

You should be aware that ‘Enalapril’ lowers the blood pressure in black patients less effectively than in non-black patients.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking ‘ENALAPRIL’.

If you are about to have a procedure
If you are about to have any of the following, tell your doctor that you are taking ‘Enalapril’:

Any surgery or receive anaesthetics (even at the dentist).
A Treatment to remove cholesterol from your blood called ‘LDL apheresis’.
A desensitization treatment, to lower the effect of an allergy to bee or wasp stings.

If any of the above apply to you, talk to your doctor or dentist before the procedure.

Other medicines and ‘Enalapril’
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. This includes herbal medicines. This is because ‘ENALAPRIL’ can affect the way some medicines work. Also some other medicines can affect the way ‘ENALAPRIL’ works.

Your doctor may need to change your dose and/or to take other precautions.

In particular tell your doctor or pharmacist if you are taking any of the following medicines:

Medicines containing potassium (including dietary salt substitutes), other drugs which can increase potassium in your body (such as heparin and co-trimoxazole also known as trimethoprim/sulfamethoxazole).
Water tablets (potassium sparing diuretics) such as spironolactone,eplerenone, triamterene or amiloride. Taking ‘Enalapril’ at the same time may increase the levels of potassium in your blood.
Other medicines to lower blood pressure, such as beta-blockers, angiotensin-receptor-blockers, water tablets (diuretics) such as thiazides, furosemide, bumetanide, a medicine called aliskiren or medicines for chest pain (angina) such as nitroglycerine. Taking ‘Enalapril’ at the same time may cause low blood pressure.
If you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the headings “Do not take Enalapril if” and “Warnings and precautions”
Lithium (for some types of mental illness)
Medicines for depression called ‘Tricyclic antidepressants,’medicines for serious mental illness called ‘anti psychotics’; anaesthetics or narcotics such as morphine (for severe pain). Taking these medicines at the same time as ‘Enalapril’ may cause low blood pressure.
Medicines used for stiffness and inflammation associated with painful conditions, particularly those affecting your muscles, bones and joints:
- non-steroidal anti-inflammatory drugs, including COX-2- inhibitors (medicines that reduce inflammation, and can be used to help relieve pain)
- gold therapy can lead to flushing of your face, feeling sick (nausea), vomiting and low blood pressure, when taken with ‘Enalapril’.
An mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus; medicines used to treat certain types of cancer or to prevent the body’s immune system from rejecting a transplanted organ). See also information under the heading “Warnings and precautions”
A medicine containing a neprilysin inhibitor such as sacubitril (available as fixed-dose combination with valsartan) and racecadotril. The risk of angioedema (swelling of the face, lips, tongue or throat with difficulty in swallowing or breathing) may be increased. See also information under the headings “Do not take Enalapril” and “Warnings and precautions”.
Aspirin (acetylsalicylic acid).
Medicines used to dissolve blood clots (thrombolytics).
Certain cough and cold medicines and weight reducing medicines which contain something called a ‘sympathomimetic agent’ .
Medicines for diabetes, (including oral antidiabetic medicines and insulin). ‘Enalapril’ may cause your blood sugar levels to drop even further when taken with these medicines. This is more likely to occur during the first weeks of taking ‘Enalapril’ and in patients with kidney problems. You should check your blood sugar level closely during the first month of taking ‘Enalapril’
Alcohol

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking ‘Enalapril’.

If you are going to have an anaesthetic (for an operation), tell your doctor or dentist that you are taking ‘Enalapril’.

‘Enalapril’ with food, drink and alcohol

You can take ‘Enalapril’ with or without food.
If you drink alcohol while taking ‘Enalapril’ it may cause your blood pressure to drop too much and you may feel dizzy, light-headed or faint. Take care with the amount of alcohol you drink.

Pregnancy and Breast-feeding

Pregnancy
You must tell your doctor if you think you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby. Your doctor will normally advise you to stop taking ‘Enalapril’ before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of ‘Enalapril’. ‘Enalapril’ is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast-feeding
Tell your doctor if you are breast-feeding or about to start breastfeeding. Breast-feeding newborn babies (first few weeks after birth), and especially premature babies, is not recommended whilst taking ‘Enalapril’.

In the case of an older baby your doctor should advise you on the benefits and risks of taking ‘Enalapril’ whilst breast-feeding, compared to other treatments.

Driving and using machines
‘Enalapril’ may make you feel tired or dizzy. If this happens do not drive or use any tools or machines.

‘Enalapril’ contains lactose
Lactose is a type of sugar. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3. How you will be given Enalapril Maleate
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. The dose of ‘Enalapril’ will depend on the condition being treated and any other medicines you are taking.

Taking ‘Enalapril’ tablets

Swallow the tablets with water. You can take them with or without food.
Take your tablet at about the same time each day. Take the ‘Enalapril’ tablet marked for the correct day on the blister pack. This will help you remember whether you have taken it.

The first ‘Enalapril’ tablets you take may make your blood pressure fall by more than doses you take after that. The first tablets may make you feel dizzy or light-headed. It may help to lie down until you feel better. This effect becomes less likely with future doses. If you are concerned, talk to your doctor or pharmacist.

The doctor will check how you respond to taking ‘Enalapril by taking your blood pressure and doing some blood tests.

Adults with high blood pressure (hypertension)

The initial dose is 5 mg per day up to 20 mg taken once a day depending on your blood pressure.
Some patients may need a lower starting dose.
The usual long term dose is 20 mg taken once a day.
The maximum daily dose is 40 mg taken once a day.

The actual dose, decided by your doctor, will depend on your blood pressure and other medical conditions.

If you are taking a high dose of water tablets (diuretics), your doctor may ask you to stop taking them for 2 to 3 days before you start taking ‘Enalapril’.

Adults with heart failure

The starting dose is usually 2.5mg taken once a day.
Your doctor will raise this amount step by step until the dose that is right for you has been achieved.
The usual long term dose is 20mg each day, taken in one or two doses.
The maximum daily dose is 40mg, split into two doses of 20mg.

People with kidney problems

If you have kidney problems, the doctor will alter the amount of ‘Enalapril’ you take depending on how well your kidneys are working.
If you are on kidney dialysis your dosage may vary day by day. Your doctor will let you know what your dose should be.

Elderly patients

Your dose will be decided by your doctor. It will depend on how well your kidneys are working.

Use in children

Experience in the use of ‘Enalapril’ in children with high blood pressure is limited.
If the child can swallow tablets the dose will depend on the child’s weight and how their blood pressure changes after taking ‘Enalapril’. The doctor will decide on the dose
Children with kidney problems are not recommended to take Enalapril
Very young babies (first few weeks after birth) are not recommended to take Enalapril

If you take more Enalapril than you should

Contact your doctor or go to the nearest hospital casualty department straight away. Remember to take with you any remaining tablets and the pack, so the doctor knows what you have taken.

The most common signs and symptoms of overdose are fall in blood pressure and stupor (a state of almost complete lack of consciousness). Other symptoms may include dizziness or lightheadedness due to a fall in blood pressure, forceful and rapid heartbeat, rapid pulse, anxiety, cough, kidney failure, and rapid breathing.

If you forget to take Enalapril
If you miss a dose do not worry. Take your normal dose when it is next due. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Enalapril
If you stop taking your medication, your blood pressure may increase. If your blood pressure becomes too high it may affect the function of your heart and kidneys. Do not stop taking your medicine, unless your doctor has advised you to do so.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects
Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may happen with this medicine:

Stop taking Enalapril and see a doctor or go to a hospital straight away if:

You begin to itch, develop a raised red skin rash (hives), get short of breath or wheezy and develop swelling of the hands, feet or ankles, face, eyes, mouth, lips, tongue or throat, which may cause difficulty in breathing or swallowing. This may mean you are having an allergic reaction to ‘ENALAPRIL’.You should be aware that black patients are at increased risk of these types of reactions.
You get rash which looks like targets, blisters, skin peeling off in sheets, which may appear also on the lips, eyes, mouth, nose and/or genitals. You may also have a high temperature or joint pain (erythema multiforme).
You get severe skin reaction of which symptoms may be reddening of the skin, skin scaling, blistering or raw sores, detachment of the top layer of the skin from bottom layers (‘Steven-Johnson Syndrome’, ‘toxic epidermal necrolysis’).
A bloating feeling and cramping pain in the abdomen (may be caused by an obstruction of the gut)
Heart attack or stroke possibly due to excessive low blood pressure in high-risk patients (patients with blood flow disturbances to the heart or brain)
Severe abdominal pain (may be caused by inflammation of the pancreas)
Blood disorders which affect the cells or elements in the blood and are usually diagnosed by blood tests (symptoms may be tiredness, weakness, shortness of breath, inability to exercise, feeling run down, having constant or re-occurring colds, fever, chills, prolonged bleeding, bruising where cause is unknown, red or purple spots)
Fluid on the lung which causes symptoms such as cough, difficulty breathing
High temperature, tiredness, loss of appetite, stomach pain, feeling sick, jaundice (yellowing of the skin or eyes) and liver failure. These are symptoms of Hepatitis (inflammation of the liver) or bile duct obstruction (stoppage of bile flow from the bile duct in the liver).

When you start taking Enalapril you may feel faint or dizzy. If this happens, it will help to lie down. This is caused by your blood pressure lowering. It should improve as you continue to take the medicine. If you are worried, please talk to your doctor.

Talk to your doctor straight away if you notice any of the following serious side-effects.

A complex side effect has also been reported which may include some or all of the following signs:

Fever, inflammation of your blood vessels, pain and inflammation of muscles or joints
Blood disorders affecting the components of your blood (usually detected by a blood test)
Rash, hypersensitivity to sunlight and other effects on your skin.

Below is a list of side effects that have occurred in patients taking Enalapril.

Very common (may affect more than 1 in 10 people):

blurred vision
dizziness
cough
feeling sick (nausea)
weakness

Common (may affect up to 1 in 10 people):

headache
depression
low blood pressure which may cause light-headedness
Fainting (syncope)
heart rhythm changes
fast heart beat
chest pain or angina pectoris
difficulty breathing
diarrhoea
pain around your stomach area (abdominal pain)
change in sense of taste
rash
tiredness (fatigue)
allergic reaction with swelling of the face, lips, tongue or throat with difficulty in swallowing or breathing
Increased blood potassium level, increased levels of creatinine in your blood (both are usually detected by a test).

Uncommon (may affect up to 1 person in 100):

tiredness and low haemoglobin or red blood cell count (anaemia).
low blood sugar levels that may cause anxiety, a sense of heightened awareness or a shaky feeling.
low level of sodium, high level of blood urea (all measured in a blood test)
sudden fall in blood pressure
confusion
sleepy or unable to sleep
nervousness
tingling or pins and needles like sensation in the skin, feeling your skin prickling or being numb
vertigo (spinning sensation)
rapid forceful or uneven heart beats (palpitations)
runny nose
sore throat and hoarseness
coughing and/or wheezing and/or breathing difficulties (asthma)
slow movement of food through your intestine, inflammation of the pancreas, which causes symptoms such as severe pain in the abdomen and back.
being sick (vomiting), indigestion, constipation, loss of appetite
stomach irritation, dry mouth, peptic ulcer (symptoms may be burning, aching pain with an empty feeling and hunger, particularly when the stomach is empty).
excessive sweating
itching
nettle-rash or hives
hair loss
reduced kidney function or kidney failure (symptoms may be lower back pain and reduction in the volume of urine passed)
high level of proteins in the urine, which is usually detected by a blood test.
difficulty getting an erection (impotence)
muscle cramps
flushing
ringing in the ears (tinnitus)
fever
generally feeling unwell
low blood pressure (which may make you feel dizzy when you stand up)
heart attack (possibly due to very low blood pressure in certain high-risk patients, including those with blood flow problems of the heart or brain).
stroke (possibly due to very low blood pressure in high-risk patients)

Rare (may affect up to 1 in 1,000 people):

abnormal dreams, sleep disorders.
small arteries, usually in the fingers and toes, go into spasm causing the skin to become pale or patchy red to blue colour and very cold-(‘Raynaud’s phenomenon’)
changes in blood values such as a lower number of white and red blood cells, lower haemoglobin, lower number of blood platelets.
pulmonary infiltrates (accumulation of fluid or other substances in the lungs, as seen on X-rays), pneumonia (signs may be cough, high temperature and difficulty breathing).
inflammation of your nose
pain, inflammation and/or ulceration of the gums, cheeks, tongue, lips, throat.
liver or gallbladder problems such as lower liver function, inflammation of the liver which may cause yellowing of the skin or eyes (jaundice), higher levels of liver enzymes or bilirubin (measured in a blood test).
reduction in the amount of urine produced per day
enlargement of breasts in men
Bone marrow depression
Autoimmune diseases
Exfoliative dermatitis/erythroderma (severe skin rash with flaking or peeling of the skin), pemphigus (small fluid-filled bumps on the skin)
Swollen glands in neck, armpit or groin.

Very rare (may affect up to 1 in 10,000 people)

swelling in your intestine (intestinal ‘angioedema’). Signs may include stomach pain, feeling sick, vomiting.

Not known:

Overproduction of antidiuretic hormone, which causes fluid retention, resulting in weakness, tiredness or confusion
A symptom complex has been reported which may include some or all of the following: fever, inflammation of the blood vessels (serositis/vasculitis), muscle pain (myalgia/myositis), joint pain (arthralgia/arthritis). Rash, photosensitivity or other skin manifestations may occur.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

Blood tests
Taking Enalapril may affect the results of some blood tests. These include tests on: the blood cells or other parts of it, potassium levels, creatinine or urea, sodium, liver enzymes or bilirubin.

If you are going to have a blood test, it is important to tell your doctor that you are taking Enalapril.

5. How Enalapril Maleate is stored
keep this medicine out of the sight and reach of children.
store in the original package
do not store above 25°C
do not use this medicine after the expiry date shown on the pack.
do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Further information

What Enalapril Maleate contains
The active substance is enalapril maleate
a) Each tablet contains: Enalapril maleate USP 2.5mg
b) Each tablet contains: Enalapril maleate USP 5mg
c) Each tablet contains: Enalapril maleate USP 10mg
d) Each tablet contains: Enalapril maleate USP 20mg
The other ingredients are lactose monohydrate, maize starch, sodium bicarbonate, pregelatinised maize starch, and magnesium stearate. The 10 mg and 20 mg tablets also contain iron oxide (E172).

What Enalapril Maleate looks like and contents of the pack
Enalapril Maleate Tablets is white, round, biconvex tablets, bisected on one side.
All strengths of tablets are available in packs of 28 tablets in foil blister strips.