1. Name Of The Medicinal Product
Enalapril 20mg Tablets.
2. Qualitative And Quantitative Composition
Each tablet contains 20mg Enalapril (as maleate).
For excipients, see 6.1.
3. Pharmaceutical Form
Tablet.
White circular biplaner uncoated tablets with 20 embossed on one face and score line on the other.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of hypertension:
All grades of essential hypertension and renovascular hypertension.
Treatment of heart failure:
In heart failure, Enalapril 20mg, tablets should be used as an adjunctive therapy with non-potassium-sparing diuretics and, where appropriate, digitalis. Enalapril 20mg, tablets have been shown to improve symptoms, retard the progression of the disease, and reduce mortality and hospitalisation.
Prevention of symptomatic heart failure:
When used in asymptomatic patients with left ventricular dysfunction, Enalapril 20mg, tablets retard the development of symptomatic heart failure, and reduce hospitalisation for heart failure.
Prevention of coronary ischaemic events in patients with left ventricular dysfunction:
Enalapril 20mg, tablets reduce both the incidence of myocardial infarction and hospitalisation for unstable angina pectoris.
4.2 Posology And Method Of Administration
The maximum daily dose is 40 mg.
The absorption of Enalapril 20mg, tablets is not affected by food intake.
Essential and renovascular hypertension:
Treatment should be initiated with 5 mg once a day. Where concomitant therapy is a diuretic, the recommended initial dose of Enalapril 20mg, tablets is 2.5 mg (see “With concomitant diuretic therapy”). The dose should be titrated to give optimum control of blood pressure. The usual maintenance dose is 10-20 mg given once daily. In severe hypertension, the dosage may be increased incrementally to a maximum of 40 mg once daily.
The dosage of other antihypertensive agents being used together with Enalapril 20 mg, tablets may need to be adjusted. Where Enalapril 20 mg, tablets replace a beta-blocking drug in the therapeutic regime, the beta-blocking agent should not be discontinued abruptly; the dosage should be titrated down after commencing therapy with Enalapril 20 mg, tablets.
With concomitant diuretic therapy:
The recommended initial dose of Enalapril tablets is 2.5 mg. Symptomatic hypotension can occur following the initial dose of Enalapril tablets; this is more likely to occur when Enalapril tablets are added to previous diuretic therapy. Caution is recommended, therefore, since these patients may be volume- or salt-depleted. If possible, the diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with Enalapril 20 mg, tablets.
Enalapril 20 mg, tablets minimise the development of thiazide-induced hypokalaemia and hyperuricaemia.
Use in the elderly (over 65 years):
The starting dose should be 2.5 mg. Enalapril 20 mg, tablets are effective in the treatment of hypertension in the elderly. Some elderly patients may be more responsive to Enalapril 20 mg, tablets than younger patients.
The dose should be titrated according to need for the control of blood pressure.
Heart failure / Asymptomatic left ventricular dysfunction:
The recommended starting dose in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction is 2.5 mg once daily initiated under close medical supervision. For patients with severe heart failure, therapy should be initiated in hospital. Evidence of systolic left ventricular dysfunction should be obtained by relevant techniques (e.g. radionuclide ventriculography or echocardiography or equivalent) prior to initiation of preventive treatment; however, a repeated measurement may not be necessary in patients with one or more myocardial infarctions and documented reduction in cardiac function.
Following initiation of therapy, the dose should be titrated gradually to the usual maintenance dose of 20 mg, given as a single dose or two divided doses, according to the tolerability of the patient. In patients with symptomatic heart failure, this dosage schedule has been shown to improve survival.
The dose titration of Enalapril 20 mg, tablets may be performed over a two- to four-week period or more rapidly if indicated by the presence of residual signs and symptoms of heart failure. Blood pressure and renal function should be monitored closely both before and during treatment with Enalapril 20 mg, tablets. Serum potassium should also be monitored.
Some patients, other than those with severe heart failure, are considered to be at higher risk when started on an ACE inhibitor and are recommended for initiation of therapy in hospital. Research data have shown such patients to be: those on multiple or high-dose diuretics (e.g.> 80 mg frusemide); patients with hypovolaemia; hyponatraemia (serum sodium < 130 mmol/l); pre-existing hypotension (systolic blood pressure < 90 mmHg); patients with unstable cardiac failure; renal impairment (serum creatinine> 150 mmol/l); those on high-dose vasodilator therapy; patients aged 70 years or over (see “Special warnings and special precautions for use”).
In order to decrease the possibility of symptomatic hypotension, patients on previous high-dose diuretics should have the diuretic dose reduced before introducing Enalapril 20 mg, tablets. The appearance of hypotension after the initial dose of Enalapril 20 mg, tablets does not preclude subsequent careful dose titration with the drug, following effective treatment of the hypotension.
Use in impaired renal function: (see “Special warnings and special precautions for use”)
Enalapril 20 mg, tablets are excreted by the kidney. It should be used with caution in patients with renal impairment. The recommended starting dose is 2.5 mg. The dose should be titrated against the response, and should be kept as low as possible to maintain adequate control of blood pressure or heart failure.
Enalapril 20 mg, tablets are dialysable. Dialysis patients may be given the usual dose of Enalapril 20 mg, tablets on dialysis days (see “Special warnings and special precautions for use”–“Haemodialysis patients”). On the days patients are not on dialysis, the dosage should be tailored to the bloodpressure response.
Children:
The paediatric use of Enalapril 20 mg, tablets has not been studied.
4.3 Contraindications
Pregnancy: Second and third trimesters of pregnancy (see sections 4.4 and 4.6.)
Hypersensitivity:
Hypersensitivity to the product or any of the components, and in patients with a history of angioneurotic oedema following previous treatment with an ACE inhibitor.
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 20 mg, 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. 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).
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 develops, 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 20 mg, 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 20 mg, tablets may become necessary.
Impaired renal function:
Enalapril 20 mg, tablets should be used with caution in patients with renal insufficiency as they may require reduced or less frequent doses (see “Posology and method of administration”).
Close monitoring of renal function before and during therapy should be performed as deemed appropriate in those with renal insufficiency. In the majority, renal function will not be altered, or may improve.
Renal failure has been reported in association with Enalapril 20 mg, 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 20 mg, tablets is usually reversible.
Some hypertensive patients, with no apparent pre-existing renal disease, have developed increases in blood urea and creatinine when Enalapril 20 mg, tablets have been given concurrently with a diuretic. Dosage reduction of Enalapril 20 mg, tablets and/or discontinuation of the diuretic may be required.
This situation should raise the possibility of an underlying renal artery stenosis (see comment below).
Renovascular hypertension:
Enalapril 20 mg, tablets can be used when surgery is not indicated, or prior to surgery. In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases of blood urea and creatinine, reversible upon discontinuation of therapy, have been seen. This is especially likely to occur in patients treated with diuretics and/or those with renal insufficiency.
Angioneurotic oedema:
Angioneurotic oedema has been reported with angiotensin-converting enzyme inhibitors, including Enalapril 20 mg, tablets. This may occur at any time during treatment. In such cases, Enalapril 20 mg, tablets should be discontinued immediately and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Where swelling is confined to the face, lips and mouth the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be monitored carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airways obstruction, appropriate therapy such as subcutaneous adrenaline (0.5 ml, 1:1000) should be administered promptly.
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 “Contraindications”). In particular, black or Afro-Caribbean patients receiving ACE inhibitors have been reported to have a higher incidence of Angioedema compared to nonblacks.
Other hypersensitivity reactions including urticaria have been reported.
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.
Haemodialysis patients:
A high incidence of anaphylactoid reactions has been reported in patients dialysed with high-flux membranes and treated concomitantly with an ACE inhibitor. This combination should therefore be avoided.
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.
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-inhibitorinduced 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 20 mg, tablets block angiotensin-II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.
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 profilie 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).
General:
Where Enalapril 20 mg, tablets have been used as a single agent in hypertension, Afro-Caribbean patients may show a reduced therapeutic response.
Enalapril 20 mg, tablets should not be used in patients with aortic stenosis or outflow tract obstruction.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Drug interactions:
Combination with other antihypertensive agents such as beta-blockers, methyldopa, calcium antagonists, and diuretics may increase the antihypertensive efficacy.
Adrenergic-blocking drugs should only be combined with Enalapril 20 mg, tablets under careful supervision. Concomitant propranolol may reduce the bioavailability of Enalapril 20 mg, tablets, but this does not appear to be of any clinical significance.
Concomitant therapy with lithium may increase the serum lithium concentration.
Plasma potassium:
Plasma potassium usually remains within normal limits, although cases of hyperkalaemia have been reported. If Enalapril 20 mg, tablets are given with a potassium-losing diuretic, the likelihood of diuretic-induced hypokalaemia may be lessened. Enalapril 20 mg, tablets may elevate plasma potassium levels in patients with renal failure. Potassium supplements, potassium-sparing diuretics and potassiumcontaining salt substitutes are not recommended, particularly in patients with impaired renal function, since they may lead to significant increases in plasma potassium. However, if the concomitant use of these agents is deemed appropriate, they should be used with caution and with frequent monitoring of plasma potassium.
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. Long-term controlled clinical trials with enalapril have not confirmed these findings, and do not preclude the use of enalapril in diabetic patients. It is advised however, that caution should be exercised in this patient population.
Narcotic drugs / Antipsychotics:
Postural hypotension may occur with ACE inhibitors.
Allopurinol, cytostatic or immunosuppressive agents, systematic corticosteroids or procainamide:
Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.
Non-steroidal anti-inflammatory drugs:
The administration of a non-steroidal anti-inflammatory agent may reduce the antihypertensive effect of an ACE inhibitor. However, in a clinical pharmacology study indomethacin or sulindac was administered to hypertensive patients receiving Enalapril 20 mg, tablets and there was no evidence of a blunting of the antihypertensive action of Enalapril 20 mg, tablets. Furthermore, it has been described that NSAIDS and ACE inhibitors exert an additive effect on the increase in serum potassium, whereas renal function may decrease. These effects are in principle reversible, and occur especially in patients with compromised renal function.
Antacids:
Induce decreased bioavailability of ACE inhibitors.
Sympathomimetics:
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is being obtained.
Alcohol:
Alcohol enhances the hypotensive effect of ACE inhibitors.
Cyclosporin:
Cyclosporin increases the risk of hyperkalaemia with ACE inhibitors.
4.6 Pregnancy And Lactation
Use in pregnancy:
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 fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3.) Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).
Use during lactation:
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 breast-feeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of 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 into account that Enalapril 20mg tablets may cause side effects such as dizziness, light headedness, headache, tiredness, confusion and blurred vision..
4.8 Undesirable Effects
Severe hypotension and renal failure have occurred in association with therapy with Enalapril 20 mg, tablets. These appear to occur in certain specific sub-groups (see “Special warnings and special precautions for use”).
Other adverse reactions:
Dizziness and headaches are the most commonly reported side effects. Less frequently, fatigue, asthenia, hypotension, orthostatic hypotension, syncope, nausea, diarrhoea, muscle cramps, rash, and cough have been reported. Even less frequently, renal dysfunction, renal failure, and oliguria have been reported.
Rarely reported side effects include:
Cardiovascular: myocardial infarction or cerebrovascular accident, possibly secondary to severe hypotension in high-risk patients (see “Special warnings and special precautions for use”), chest pain, palpitations, rhythm disturbances, angina pectoris.
Gastro-intestinal: ileus, pancreatitis, hepatic failure, hepatitis - either hepatocellular or cholestatic, jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis.
Nervous system / Psychiatric: depression, confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo.
Respiratory: pulmonary infiltrates, bronchospasm, asthma, dyspnoea, rhinorrhoea, sore throat, and hoarseness.
Skin: diaphoresis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, pruritus, urticaria, alopecia.
Other: impotence, flushing, taste alteration, tinnitus, glossitis, blurred vision.
A complex of symptoms has been reported which may include fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.
Hypersensitivity / Angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely (see “Special warnings and special precautions for use”).
Laboratory test findings: increases in blood urea and plasma creatinine, reversible on discontinuation of Enalapril 20 mg, tablets, are most likely to occur in the presence of severe heart failure or bilateral renal artery stenosis, especially in patients with renal insufficiency (see “Special warnings and special precautions for use”). However, increases in blood urea and plasma creatinine may occur without evidence of preexisting renal impairment, especially in patients taking diuretics. In this event, undiagnosed renal artery stenosis should be suspected. Dosage reduction of Enalapril 20 mg, tablets and/or discontinuation of the diuretic should be considered.
Hyperkalaemia and hyponatraemia have also been reported in a few cases (for further information see “Interactions with other medicaments and other forms of interaction – Plasma potassium”).
Decreases in haemoglobin and haematocrit as well as elevation of liver enzymes and/or serum bilirubin have been reported in a few patients, and are usually reversible upon discontinuation of Enalapril 20 mg, tablets.
Decreases in platelets and white cell count, and rare cases of neutropenia, thrombocytopenia, bone-marrow depression, and agranulocytosis have been reported, but a causal relationship to Enalapril 20 mg, tablets has not been established.
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. 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 ingestion is recent, induce emesis. Enalapril can be removed from the general circulation by haemodialysis.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Enalapril 20 mg, 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 20 mg, 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. The possible role of this mechanism in the therapeutic effects of enalapril has not yet been elucidated.
While the mechanism through which Enalapril 20 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 20 mg, tablets are antihypertensive even in patients with low-renin hypertension.
5.2 Pharmacokinetic Properties
Enalapril 20 mg, 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 20mg, tablets is approximately 60%.
Following absorption, Enalapril 20 mg, 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 20 mg, 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 20 mg, 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 20 mg, 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.
Lactation: After a single 20mg oral dose in five postpartum women the average peak Enalapril milk level was 1.7μg/L (range 0.54 to 5.9 μg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7μg/L (range 1.2 to 2.3μg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively 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 2μg/L 4 hours after a dose and peak Enalaprilat levels of 0.75μg/L about 9 hours after the dose. The total amount of Enalapril and Enalaprilat measured in milk during the 24 hour period was 1.44μg/L and 0.63μg/L of milk respectively. Enalaprilat milk levels were undetectable
Enalapril levels were not determined.
5.3 Preclinical Safety Data
No relevant information.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Enalapril 20 mg, tablets contain the following inactive ingredients:
- Lactose
- Maize starch
- Glycerol distearate
6.2 Incompatibilities
None.
6.3 Shelf Life
24 months.
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 20 mg tablets are available in aluminium foil blisters containing 28 tablets.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
Pharmadreams Ltd
Old Police Station
Church Street, Swadlincote
Derbyshire, DE11 8LN
UK
8. Marketing Authorisation Number(S)
PL 28395/0003
9. Date Of First Authorisation/Renewal Of The Authorisation
30th July 2007
10. Date Of Revision Of The Text
15th October 2010
LEGAL CATEGORY
POM
