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| ENAHEXAL 5mg are white round convex tablets, scored, marked | GK2 GEA. |
| ENAHEXAL 10mg are white round convex tablets, scored, marked |  |
| ENAHEXAL 20mg are white round convex tablets, scored, marked |  |
ENAHEXAL lowers blood pressure in patients with hypertension and improves the signs and symptoms associated with chronic heart failure.
Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotension I to the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release), and decreased aldosterone secretion.
ACE is identical to kininase II. Thus ENAHEXAL may also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of ENAHEXAL remains to be elucidated.
While the mechanism through which ENAHEXAL lowers 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, ENAHEXAL is antihypertensive even in patients with low-renin hypertension.
The onset of action of oral ENAHEXAL is gradual and smooth; it begins within one hour and its effects usually continue for 24 hours. Consequently, ENAHEXAL may be administered on a once-daily basis, with the advantages this brings in convenience and compliance.
The Studies of (patients with) Left Ventricular Dysfunction (SOLVD) was a multicentre, placebo controlled, double blind study of 6797 patients assessed as having Left Ventricular Dysfunction. All patients had a Left Ventricular Ejection Fraction of ≤ 35% and were classified as New York Heart Association Class I-IV (NYHA).
The 2569 symptomatic patients (primarily NYHA Class II and III) were randomised into a Treatment arm, whilst the 4228 asymptomatic patients (NYHA Class I) were randomised into the Prevention arm. The combined results demonstrated an overall reduced risk for the development of major ischemic events. ENAHEXAL decreased the incidence of myocardial infarction and reduced the number of hospitalisations for unstable angina pectoris in patients with left ventricular dysfunction.
In the Prevention arm, ENAHEXAL significantly prevented the development of symptomatic heart failure and reduced the number of hospitalisations for ear failure. ENAHEXAL in the Treatment arm, as an adjunct to conventional therapy, significantly reduced overall mortality and hospitalisation for heart failure and improved NYHA functional class. In CONSENSUS, a similar study involving 253 patients with severe heart failure (NYHA Class IV), ENAHEXAL was shown to improve symptoms and reduce mortality significantly.
The cardioprotective properties of ENAHEXAL were demonstrated in these studies by the beneficial effects on survival and retardation of the progression of heart failure in patients with symptomatic heart failure; retardation of the development of symptomatic heart failure in asymptomatic patients with left ventricular dysfunction; and prevention of coronary ischemic events in patients with left ventricular dysfunction, specifically reduction in the incidence of myocardial infarction and reduction in hospitalisation for unstable angina pectoris.
Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral ENAHEXAL is approximately 60%.
Following absorption, oral enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of ENAHEXAL. Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril. Except for conversion to enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. In subjects with normal renal function, steady-state serum concentrations of enalaprilat were achieved by the fourth day of administration of ENAHEXAL. The effective half-life for accumulation of enalaprilat following multiple doses of oral ENAHEXAL is 11 hours. The absorption of oral ENAHEXAL is not influenced by the presence of food in the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril are similar for the various doses in the recommended therapeutic range.
Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of oral enalapril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C enalapril maleate. Radioactivity was found to cross the placenta following administration of 14C enalapril maleate to pregnant hamsters.
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 ENAHEXAL 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.
Chronic administration of ENAHEXAL to patients with essential hypertension and renal insufficiency may be associated with improvements in renal function, evidenced by increased glomerular filtration rate.
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.
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.
Clinical data have shown that enalapril reduced the frequency of ventricular arrhythmias in patients with heart failure, although the underlying mechanisms and clinical significance are not known.
There is no significant change in the plasma half-life of ENAHEXAL in elderly patients.
No pharmacokinetic data is available on the effect of ENAHEXAL in patients with hepatic dysfunction.
Treatment of:
All grades of essential hypertension
Renovascular hypertension
All degrees of heart failure
In patients with symptomatic heart failure, ENAHEXAL is also indicated to:
Prevention of symptomatic heart failure
In asymptomatic patients with left ventricular dysfunction, ENAHEXAL is indicated to:
Prevention of coronary ischemic events in patients with Left Ventricular Dysfunction
ENAHEXAL is indicated to:
Since absorption of ENAHEXAL tablets is not affected by food, the tablets may be administered before, during, or after meals.
The initial dose is 5mg and is given once daily. The usual maintenance dose is 20mg taken daily. The dosage should be adjusted according to the needs of the patient to a maximum of 40mg daily.
Since blood pressure and renal function in such patients may be particularly sensitive to ACE inhibition, therapy should be initiated with a lower starting dose (2.5-5mg). The dosage should then be adjusted according to the needs of the patient. Most patients may be expected to respond to one 20mg tablet taken once daily. For patients with hypertension who have been treated recently with diuretics, caution is recommended (see next paragraph).
Symptomatic hypotension may occur following the initial dose of ENAHEXAL; this is more likely in patients who are being treated currently with diuretics. Caution is recommended, therefore, since these patients may be volume or salt-depleted. The diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with ENAHEXAL. If this is not possible, the initial dose of ENAHEXAL should be low (2.5mg) to determine the initial effect on the blood pressure. Dosage should then be adjusted according to the needs of the patient.
Generally, the intervals between the administration of enalapril should be prolonged and/or the dosage reduced.
Table 1
| Renal status | Creatinine clearance (ml/min) |
Initial dose (mg/day) |
|---|---|---|
| Mild impairment | < 80 - >30 ml/min | 5 mg |
| Moderate impairment | ≤ 30 - >10 ml/mn | 2.5 mg |
| Severe impairment (Normally, these patients will be on dialysis*) |
≤10 ml/min | 2.5 mg on dialysis days** |
* See Warnings and Precautions: Haemodialysis patients.
** Enalaprilat is dialysable. Dosage on non-dialysis days should be adjusted depending on blood pressure response.
The initial dose of ENAHEXAL in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction is 2.5mg, 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 ENAHEXAL in heart failure, the dose should be increased gradually to the usual maintenance dose of 20mg, given in a single dose or two divided doses, as tolerated by the patient. This dose titration may be performed over a 2- to 4-week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure. In patients with symptomatic heart failure this dosage regimen was effective in reducing mortality.
Blood pressure and renal function should be monitored closely both before and after starting treatment with ENAHEXAL (see Warnings and Precautions) 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 ENAHEXAL. The appearance of hypotension after the initial dose of ENAHEXAL does not imply that hypotension will recur during chronic therapy with ENAHEXAL and does not preclude continued use of the medicine. Serum potassium also should be monitored (see Interactions).
ENAHEXAL is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioneurotic edema relating to previous treatment with an angiotensin-converting enzyme inhibitor. All angiotensin-converting enzyme inhibitors, including ENAHEXAL, are contraindicated in pregnancy because of the potential risk of fetotoxicity.
Symptomatic hypotension was seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving ENAHEXAL, hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting (see Adverse Effects and Interactions). 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, hyponatremia or functional renal impairment. In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of ENAHEXAL and/or diuretic is adjusted. Similar considerations may apply to patients with ischemic heart or cebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
In some patients with heart failure, who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with ENAHEXAL. This effect is anticipated, and usually is not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or ENAHEXAL may be necessary.
In some patients with heart failure, hypotension following the initiation of therapy with ENAHEXAL may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.
Patients with renal insufficiency may require reduced and/or less frequent doses of ENAHEXAL (see Dosage). In some patients, with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases of blood urea and serum creatinine, reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency.
Some patients, with no apparent pre-existing renal disease, have developed minor and usually transient increases in blood urea and serum creatinine when ENAHEAXL has been given concomitantly with a diuretic. Dosage reduction and/or discontinuation of the diuretic and/or ENAHEXAL may be required.
Angioneurotic edema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin-converting enzyme inhibitors, including ENAHEXAL. This may occur at any time during treatment. In such cases, ENAHEXAL should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioneurotic edema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy such as subcutaneous epinephrine solution 1:1000 (0.3ml to 0.5ml) 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 (also see Contraindications).
Rarely, patients receiving ACE inhibitors during densitization with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitization.
Anaphylactoid reactions have been reported in patients dialyzed with high flux membranes (e.g. AN69) 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.
Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextrin sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
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 part of the differential diagnosis of cough.
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril blocks 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.
Coadministration of ACE inhibitors and potassium sparing diuretics can cause severe hyperkalemia. (See Interactions).
The use of ENAHEXAL during pregnancy is contraindicated. When pregnancy is detected, ENAHEXAL should be discontinued as soon as possible.
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters. Use of ACE inhibitors during this period has been associated with fetal and neonatal injury including hypotension, renal failure, hyperkalemia, and/or skull hypoplasia in the newborn. Maternal oligohydramnios, presumably representing decreased fetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development.
These adverse effects to the embryo and fetus do not appear to have resulted from intrauterine ACE-inhibitor exposure limited to the first trimester.
Infants whose mothers have taken ENAHEXAL should be closely observed for hypotension, oliguria and hyperkalemia. Enalapril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion.
Enalapril and enalaprilat are secreted in human milk in trace amounts. Caution should be exercised if ENAHEXAL is given to a nursing mother.
ENAHEXAL has not been studied in children.
Pancreatitis may occur with angiotensin-converting enzyme inhibitors and patients with abdominal pain on ACE inhibitators should be tested accordingly.
Studies were performed to assess the teratogenic potential of enalapril in rats and rabbits and its effect on production and postnatal development in rats.
Enalapril given to pregnant rats at doses up to 1200mg/kg/day (2000 times the maximum human dose) from Day 6 through Day 17 of gestation did not reveal any evidence of embryolethality or teratogenicity. Decreased average fetal weight occurred at 1200mg/kg/day. But did not occur at this dosage level if the pregnant animals were given physiological saline for drinking instead of tap water during the dosing period. Average fetal weights were not affected in unsupplemented rats given up to 120mg/kg/day.
Decreased maternal weight gain during the dosing period occurred at doses as low as 12mg/kg/day, but did not occur in saline-supplemented rats given 1200mg/kg/day. Saline supplementation in rats given 100mg/kg/day also prevented increases in serum urea nitrogen which occurred at doses as low as 100mg/kg/day in unsupplemented rats (lowest dose level examined in pregnant rats), but only partially inhibited increases in serum potassium. In supplemented rats serum potassium was elevated in rats given 200mg/kg/day, but not 100mg/kg/day.
Enalapril was not teratogenic to saline-supplemented rabbits given doses up to 30mg/kg/day (50 times the maximum human dose) from Day 6 through Day 18 of gestation. At 30mg/kg/day (50 times the maximum human dose), enalapril produced maternal and fetal toxicity. Doses of 3 and 10mg/kg/day were without maternotoxic or fetotoxic effects in saline-supplemented rabbits.
There were no adverse effects on reproductive performance in male and female rats treated with 10 to 90mg/kg/day of enalapril.
An in vitro Coombs' test of enalapril and its active metabolite (enalaprilat) did not show a positive Coombs' reaction within the range of concentrations tested (which did not induce direct haemolysis).
Neither enalapril nor enalaprilat was mutagenic in the Ames microbial mutagen test with or without metabolic activation.
Rec-Assay, reverse mutation assay with E.coli, sister chromatid exchange with cultured mammalian cells, and the micro-nucleus test with mice, as well as an in vivo cytogenic study using mouse bone marrow.
There was no evidence of a carcinogenic effect when enalapril was administered for 106 weeks to rats at a dose up to 90mg/kg/day (150 times the maximum daily human dose). Enalapril has also been administered for 94 weeks to male and female mice at doses up to 90 and 180mg/kg/day, respectively (150 and 300 times the maximum daily dose for humans( and showed no evidence of carcinogenicity.
ENAHEXAL has been demonstrated to be generally well tolerated. For the most part, adverse experiences have been mild and transient in nature, and have not required discontinuation of therapy.
Dizziness and headache were the more commonly reported side effects. Fatigue and asthenia were reported in 2-3% of patients. Other side effects occurred in less than 2% of patients and included hypotension, orthostatic hypotension, syncope, nausea, diarrhea, muscle cramps, and cough. Skin rash was reported in 1.2% of patients and taste disturbances in 0.5% of patients.
Less frequently renal dysfunction, renal failure and oliguria have been reported.
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely (see Warnings and Precautions).
Side effects which occurred very rarely, either during controlled clinical trials or after the medicine was marketed, include:
Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Warnings and Precautions)
Chest pain
Palpitations
Rhythm disturbances
Angina pectoris
Ileus
Pancreatitis (see Warnings and Precautions)
Hepatic failure
Hepatitis - either hepatocellular or cholestatic
Jaundice
Abdominal pain
Vomiting
Dyspepsia
Constipation
Anorexia
Stomatitis
Depression
Confusion
Somnolence
Insomnia
Nervousness
Paresthesia
Vertigo
Pulmonary infiltrates
Bronchospasm/asthma
Dyspnea
Rhinorrhea
Sore throat and horseness
Diaphoresis
Erythema multiforme
Exfoliative dermatitis
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Pemphigus
Pruritius
Urticaria
Alopecia
Impotence
Flushing
Taste alteration
Tinnitus
Glossitis
Blurred vision.
A symptom complex has been reported which may include fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.
Clinically important changes in standard laboratory parameters were rarely associated with administration of ENAHEXAL. Increases in blood urea and serum creatinine, and elevations of liver enzymes and/or serum bilirubin have been seen. These are usually reversible upon discontinuation of ENAHEXAL. Hyperkalemia and hyonatremia have occurred.
Decreases in haemoglobin and haematocrit have been reported.
Since the medicine was marketed a small number of cases of neutropenia, thrombocytopenia, bone marrow depression, and agranulocytosis have been reported in which a casual relationship to therapy with ENAHEXAL could not be excluded.
The following additional side effects have been reported; however, a casual relationship to therapy with ENAHEXAL has not been established: pneumonia, urinary tract infection, upper respiratory infection, bronchitis, cardiac arrest, atrial fibrillation, herpes zoster, melena, ataxia, pulmonary embolism and infarction, haemolytic anaemia, including cases of haemolysis in patients with G-6-PD deficiency.
The combination of ENAHEXAL with other antihypertensive medicines may increase the antihypertensive effect, especially in combination with diuretics.
The combination of ENAHEXAL with beta-adrenergic blocking agents, methyldopa, or calcium entry blockers has been shown to improve the efficacy of lowering the blood pressure.
Ganglionic blocking agents or adrenergic blocking agents, combined with ENAHEXAL, should only be administered under careful observation of the patient.
A possible drop in serum-potassium due to thiazide-containing diuretics may be reduced by simultaneous administration of ENAHEXAL.
There are no clinically significant pharmacokinetic medicine interactions between enalapril maleate and the following compounds: hydrochlorothiazide, furosemide, digoxin, timolol, methyldopa, warfarin, indomethacin and sulindac. Propranolol coadministered with enalapril maleate reduces serum enalaprilat concentrations, but this dos not appear to be of any clinical significance. Since cimetidine does not interact with enalapril maleate in animals, it is not anticipated that a medicine interaction will occur in humans.
In clinical trials, serum potassium usually remained within normal limits. In hypertensive patients treated with ENAHEXAL alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2mEq/L were observed. In patients treated with ENAHEXAL plus a thiazide diuretic, the potassium-losing effect of the diuretic was attenuated usually by the effect of enalapril.
If ENAHEXAL is given with a potassium-losing diuretic, duretic-induced hypokalemia may be ameliorated.
Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride) potassium supplements, or potassium-containing sale substitutes.
The use of potassium supplements, potassium-sparing diuretics or potassium containing sale substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium.
If concomitant use of the above mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
As with other medicines which eliminate sodium, lithium clearance may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.
Limited data are available for overdosage in humans. The most prominent feature of overdosage reported to date is marked hypotension, beginning some six hours after ingestion f tablets, concomitant with blockade of the renin-angiotensin system, and stupor. Serum enalaprilat levels 100 times and 200 times higher than usually seen after therapeutic doses have been reported after ingestion of 300mg of 400mg of enalapril, respectively.
The recommended treatment of overdosage is intravenous infusion of normal saline solution. If ingestion is recent, induce emesis. Enalaprilat may be removed from the general circulation by haemodialysis.
Store in a dry place below 25°C.
Prescription Medicine.
ENAHEXAL (enalapril maleate) 5mg, 10mg and 20mg is available in blister platforms of 30 tablets and 500 tablets and also in HDPE bottles of 30 tablets, 100 tablets and 500 tablets.
N/A.
Hexal New Zealand Pty Limited
PO Box 100044 NSMC
Glenfield, Auckland
New Zealand
19 July 2002