DILVAS 5 (Tablets) DILVAS 10 (Tablets)

COMPOSITION: DILVAS 5 Each tablet contains Enalapril maleate 5 mg. DILVAS 10 Each tablet contains Enalapril maleate 10 mg. PHARMACOLOGICAL CLASSIFICATION: A 7.1.3 Vascular medicines - Other hypotensives. PHARMACOLOGICAL ACTION: Enalapril maleate is an angiotensin converting enzyme (ACE) inhibitor and is hydrolysed by esterases in the liver to produce the parent dicarboxylic acid, enalaprilat, a specific, long acting, nonsulphydryl angiotensin converting enzyme inhibitor. The essential effect of enalaprilat on the renin-angiotensin system is to inhibit the conversion of the inactive angiotensin I to the active angiotensin II. The principal pharmacological and clinical effects of ACE inhibitors arise from the fact that the synthesis of angiotensin II is suppressed. Pharmacokinetics: Enalapril is absorbed from the gastro-intestinal tract, and has an oral bio-availability of approximately 60%. Peak plasma of enalapril occur within an hour and it has a plasma half-life of approximately 1.3 hours, while the active form, enalaprilat, only peaks after 3-4 hours and has a plasma half-life of up to 11 hours. Enalaprilat is 50-60% bound to plasma proteins. Elimination is mainly via the kidneys (60%) as intact enalapril, as well as the active enalaprilat. The remainder is eliminated in the faeces. INDICATIONS: DILVAS is indicated for the treatment of: 1. Essential hypertension. 2. Renovascular hypertension. 3. Congestive heart failure. DILVAS, usually in combination with diuretics and digitalis, is indicated for the treatment of symptomatic congestive heart failure. In these patients enalapril has been shown to improve symptoms, increase survival, and to decrease the frequency of hospitalisation (see "Pharmacological Action"). 4. Asymptomatic left ventricular dysfunction. In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction <35% ), enalapril reduces the rate of development of overt heart failure and reduces the incidence of hospitalisation for heart failure (see "Pharmacological Action" for details). CONTRA-INDICATIONS: Hypersensitivity to enalapril or any other angiotensin converting enzyme inhibitor. Pregnancy and lactation. DILVAS should not be prescribed to patients with aortic stenosis or outflow tract obstruction. porphyria. WARNINGS: Should a woman become pregnant while receiving an ACE-inhibitor, treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy, the doctor should consider alternative medication. ACE-inhibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios, which may eventually lead to craniofacial deformities, limb contractures and hypoplastic lung development, as well as hypotension, hyperkalemia, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective scull ossification have been observed. Prematurity and low birth weight can occur.

Infants whose mothers have taken DILVAS should be carefully observed for hypotension, oliguria and hyperkalaemia. DOSAGE AND DIRECTIONS FOR USE: The absorption of enalapril maleate is not affected by food. Preferably the starting dose of DILVAS should be given at bedtime, since some patients may experience a precipitous fall in blood pressure. 1. Essential hypertension, Adults: Initial dose: 5 mg once daily. Maintenance dose: 10 to 20 mg once daily. The dosage should be adjusted according to the needs of the patient. The dosage may be given in 2 divided doses if control is inadequate with a single dose. Elderly patients: Initial dose: 2.5 mg once daily Renal impairment: Renal status Creatinine clearance Initial dosage (mL/min) (mg/day) Mild impairment Moderate impairment Severe impairment (patients normally on dialysis) <80 >30 <30 >10 <10 5 mg 2.5 mg 2.5 mg on dialysis days*

* Enalapril is dialysable. Dosage on non-dialysis days should be adjusted according to the blood pressure response of the patient.

Concomitant diuretic treatment: Initial dose: 2.5 mg once daily. The dosage should be adjusted according to the needs of the patient. Caution: Patients on diuretics may be volume or salt depleted. It is advised that the diuretic the withdrawn, if possible, for 2 or 3 days before therapy with DILVAS is started, and resumed later if necessary. 2. Renovascular Hypertension: Initial dose: 2.5 mg once daily. Maintenance dose: 20 mg daily in a single dose or 2 divided doses. The dosage should be adjusted according to the needs of the patient. Caution: Patients on diuretics maybe volume or salt depleted. It is advised that the diuretic be withdrawn, if possible, for 2 or 3 days before therapy with DILVAS is started, and resumed later if necessary. 3. Congestive heart failure: Initial dose: 2.5 mg once daily. Maintenance dose: 20 mg daily in a single dose or 2 divided doses. Caution: Severe first-dose hypotension may occur in patients on loop diuretics. Temporary withdrawal of the diuretic may cause rebound pulmonary oedema. If possible the other diuretic should be reduced before treatment with DILVAS is started. Treatment should be initiated under medical supervision to determine the initial effect on the blood pressure. After the effective management of the initial hypotension, or in the absence of hypotension, the dose should be increased gradually (over 2-4 weeks) to the usual maintenance dose of 10-20 mg daily, in a single or divided dose, according to the patient's response. Serum potassium should be monitored. (see Drug Interactions"). 4. Asymptomatic left ventricular dysfunction: Initial dose: 2.5 mg once daily.

Maintenance dose: 20 mg daily in a single dose or 2 divided doses. Caution: Treatment should be initiated under close medical supervision to determine the initial effect on the blood pressure. The dose should be increased gradually (over 2-4 weeks) to the usual maintenance dose of 10-20 mg daily, in a single or divided dose, according to the patient's response. Paediatric use: Studies in children have not been done. SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Side-effects: More commonly reported side-effects include headache, dizziness and hypotension. Other side-effects include the following: Hypersensitivity reactions: Angioneurotic oedema of the face (which may be fatal), extremities, lips, tongue, glottis and/or larynx have been reported (See "Special Precautions"). Cardiovascular: Cerebrovascular accident or myocardial infarction, possibly secondary to excessive hypotension, may occur in high risk patients (see "Special Precautions"). Chest pain, palpitations, syncope, orthostatic hypotension, rhythm disturbances and angina pectoris. Gastro-intestinal Nausea, diarrhoea, ileus, hepatocellular or cholestatic hepatitis, pancreatitis, jaundice, vomiting, abdominal pain, constipation, dyspepsia, anorexia and stomatitis. Special senses: Taste disturbances, tinnitus, glossitis and blurred vision. Dermatological: Skin rashes, diaphoresis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, pruritus, urticaria and alopecia. Respiratory: Persistent dry cough, bronchospasm/asthma, rhinorrhoea, sore throat and hoarseness, dyspnoea and pulmonary infiltrates. Nervous system/psychiatric: Confusion, depression, somnolence, insomnia, paraesthesia, vertigo and nervousness. Other: Fatigue, renal impairment, hyperkalemia, weakness, muscle cramps, impotence and flushing. A symptom complex has been reported which may include the following: fever, vasculitis, serositis, myalgia, arthralgia/arthritis. elevated erythrocyte sedimentation rate, a positive antinuclear antibody test, eosinophilia and leukocytosis. Photosensitivity, rash and other dermatological manifestations may also occur. Special precautions: Hypersensitivity reactions/angioedema: The onset of angioedema usually is within hours, or at most a week, after starting therapy with an ACE inhibitor, but may also occur after prolonged therapy. Angioedema involving the tongue, glottis or larynx may lead to airway obstruction. It is advised that treatment with DILVAS be discontinued and appropriate treatment (e.g. adrenaline, antihistamines etc.) be given immediately. Impaired renal function: Great caution and specialist supervision is advised when DILVAS is prescribed to patients with impaired renal function, particularly if renovascular disease is present or suspected. Patients with peripheral vascular disease or generalized atherosclerosis may have clinically silent renovascular disease. It is advised that renal function should be assessed in all patients, before therapy is initiated.

Regular testing for proteinuria should be done in patients with existing renal disease or in patients on high doses DILVAS. Significant diminishing of the renal clearance of DILVAS may be caused by impaired renal function, and it is advised that the dosage be reduced and/or given less frequently in such patients. Increased blood urea and serum creatinine may be present in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, especially in patients who also have renal insufficiency. This effect is reversible upon discontinuation of enalapril therapy. When DILVAS is given concomitantly with a diuretic, some patients with no apparent pre-existing renal disease, may develop transient minor increases in blood urea and serum creatinine. A dose reduction of DILVAS and /or the discontinuation of the diuretic may be indicated. Clinical laboratory tests: Increased blood urea and serum creatinine (see "Impaired renal function"). Transient increases in the blood urea and serum creatinine levels may occur in patients without evidence of preexisting renal impairment, especially in patients taking diuretics. Slight increases in haemoglobin, haematocrit and white blood cell counts, as well as elevation of liver enzymes, have been reported. Hyperkalaemia and hyponatremia have occurred. Haemodialysis: Anaphylactoid reactions may occur during haemodialysis, using high-flux polyacrylonitrile membranes, during LDL-apheresis with dextran sulphate columns. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Cough: A non-productive, persistent cough, that resolves after the discontinuation of therapy, has been reported with the use of ACE-inhibitors. ACE-inhibitor cough should be considered as part of the differential diagnosis of cough. Symptomatic hypotension: The initial dose of DILVAS should be reduced in patients with high plasma levels of renin e.g. patients suffering from heart failure or salt or water depleted patients (caused by previous diuretic treatment, dietary salt restriction, diarrhoea, vomiting or dialysis), since these patients are more likely to develop symptomatic hypotension. In patients suffering from heart failure, symptomatic hypotension is more likely to occur in those with more severe degrees of heart failure, as indicated by the use of high dose loop diuretics and by the presence of hyponatraemia or functional renal impairment. Should hypotension develop, the patient should be placed in a supine position and the volume depletion corrected by oral fluids or intravenous normal saline solution. After restoration of blood pressure and volume, treatment may be continued. The risk of hypotension developing may be minimised by giving the first reduced dose of DILVAS at bedtime. An additional lowering of the systemic blood pressure may occur in patients suffering from congestive heart failure, who have normal or low blood pressure. Should the hypotension become symptomatic, a reduction in the dose, or discontinuation of enalapril therapy, may be necessary. In patients with heart failure, therapy should be started under medical supervision and the patients should be closely monitored whenever the dose of DILVAS and/or diuretic is adjusted. Patients with ischaemic heart disease or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident, should likewise be closely monitored. Collagen vascular disorders: Regular white blood cell counts may be needed in patients suffering from vascular disorders, such as systemic lupus erythematosus and scleroderma, and in patients receiving immunosuppressive therapy, especially if they also have impaired renal function. Surgery and anaesthesia: If hypotension occurs during major surgery, or during anaesthesia with hypotension producing agents, and the hypotension is considered to be due to the blocking, by enalapril, of angiotensin II formation secondary to

compensatory renin release, the hypotension can be corrected by volume expansion. Interactions: The anti-hypertensive effect of DILVAS may be increased by the concurrent use of other anti-hypertensive medication, especially if it is combined with diuretics. Raised serum potassium concentrations may develop with concurrent use of potassium-sparing diuretics, such as spironolactone, triamterene or amiloride. The concurrent use of these medications are not recommended, especially in patients with impaired renal function or diabetes mellitus. Potassium supplements, potassium-containing salt substitutes or other medicines that can cause hyperkalaemia, such as cyclosporin and indomethacin, have the same effect. Acute renal failure may develop. If concurrent use of these medications are deemed necessary, they should be used with caution and the serum potassium levels monitored frequently. Concurrent use of DILVAS and salt substitutes are not recommended in patients with congestive heart failure because most of the salt substitutes contain substantial amounts of potassium. DILVAS therapy does not obviate the possible need for potassium supplementation in patients receiving potassium wasting diuretics. The patients should be carefully monitored. Anti-inflammatory agents may reduce the anti-hypertensive effect of DILVAS. Estrogen-induced fluid retention may increase the blood pressure. Patients should be carefully monitored to ensure that the desired anti-hypertensive effect is obtained. The serum lithium concentration may be increased and should be monitored frequently when lithium is administered together with DILVAS. The anti-hypertensive effect of DILVAS is enhanced by the concurrent use of beta-adrenergic blocking agents and methyldopa. Patients should be carefully monitored when DILVAS, ganglion blocking agents or adrenergic blocking agents are prescribed together. Due to insufficient experience with this combination, concurrent treatment with DILVAS and calcium antagonists are not recommended. Patients on ACE inhibitor therapy may experience anaphylactoid reactions during desensitisation with Hymenoptera venom. Sympathomimetics may reduce the antihypertensive effects of DILVAS. Concomitant use of narcotic drugs and antipsychotics with DILVAS may cause postural hypotension. The risk for leucopenia may be increased when DILVAS is given concomitantly with allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide. Alcohol enhances the hypotensive effect of DILVAS. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: Hypotension is the most likely symptom of overdosage and treatment consists of volume expansion by intravenous infusion of normal saline solution. Enalaprilat is removable by haemodialysis. IDENTIFICATION: DILVAS 5: White circular, flat bevelled tablets plain on one side and having a central breakline on the other. DILVAS 10: White circular, flat bevelled tablets plain on one side and having a central breakline on the other. STORAGE INSTRUCTIONS: Store in a dry place, below 25C. KEEP OUT OF REACH OF CHILDREN. NAME AND ADDRESS OF THE MANUFACTURE: CIPLA LTD., Mumbai Central, Mumbai 400 008