INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
HEXAL-LISINOPRIL™ 5 tablets
HEXAL-LISINOPRIL™ 10 tablets
HEXAL-LISINOPRIL™ 20 tablets

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

HEXAL-LISINOPRIL™ 5 tablets
HEXAL-LISINOPRIL™ 10 tablets
HEXAL-LISINOPRIL™ 20 tablets

COMPOSITION
Each HEXAL-LISINOPRIL 5 tablet contains 5 mg lisinopril as the dihydrate.
Each HEXAL-LISNOPRIL 10 tablet contains 10 mg lisinopril as the dihydrate.
Each HEXAL-LISINOPRIL 20 tablet contains 20 mg lisinopril as the dihydrate.

PHARMACOLOGICAL CLASSIFICATION
A.7.1.3 Other hypotensives

PHARMACOLOGICAL ACTION
Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor peptide angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion. The latter decrease may result in an increase in serum potassium concentration.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is also antihypertensive in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodilatory peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated.
The use of lisinopril for the treatment of patients within 24 hours after acute myocardial infarction is based on the outcome of the GISSI-3-trial. The Gruppo Italiano per lo Studio della Soprawivenza nell'Infarcto Miocardico (GISSI-3) study was a multicentre, controlled, randomised, unblinded clinical trial conducted in 19 394 patients with acute myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week) mortality and on longer-term death and markedly impaired cardiac function. Patients presenting within 24 hours of the onset of symptoms who were haemodynamically stable were randomised, in a 2 x 2 factorial design, to six weeks of either 1) lisinopril alone (n = 4841) , 2) nitrates alone (n = 4869), lisinopril plus nitrates (n = 4841) or 4) open control (n = 4843).
All patients received routine therapies, including thrombolytics (72%) , aspirin (84%) and a beta-blocker (31%), as appropriate, normally utilized in acute myocardial infarction patients.
The protocol excluded patients with hypotension (systolic blood pressure < 100 mmHg), severe heart failure, cardiogenic shock and renal dysfunction (serum creatinine >2 mg/dL and/or proteinuria >500 mg/24h). Doses of lisinopril were adjusted according to the protocol (See "DOSAGE AND DIRECTIONS FOR USE")
Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of treatment.
The primary outcomes of the trial were the overall mortality at 6 weeks and a combined end-point at 6 months after the myocardial infarction, consisting of a number of patients who died, had late (day 4) clinical congestive heart failure or had extensive left ventricular damage. Patients receiving lisinopril (n = 9646) alone or with nitrates had an 11% lower relative risk of death (2p [two-tailed] = 0.04) compared to patients receiving no lisinopril (n = 9672) (619 patients [6.4%] vs 693 patients [7.2%] respectively, representing a 0.8% absolute reduction in death) at six weeks. The reduction in mortality at six months was not significant, but this was not a primary outcome measure.
Although patients randomised to receive lisinopril for up to six weeks fared numerically better on the combined end-point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography and substantial excess use of lisinopril between 6 weeks and 6 months in the group randomised to 6 weeks of lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with lisinopril, had a higher (9,0% vs 3,7%) incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) and renal dysfunction (2,4% vs 1,1%) in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline creatinine concentration).
Pharmacokinetics
Peak serum concentrations occurred within 6 to 8 hours, although there was a trend to a small delay in time taken to reach peak plasma concentrations in acute myocardial infarction patients. Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12.6 hours. The extent of absorption of lisinopril was approximately 25%, with interpatient variability (6 - 60%) at all doses tested (5 - 80 mg).
Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose.
Lisinopril is excreted unchanged in the urine.
Impaired renal function decreases elimination of lisinopril, which is excreted via the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Older patients have higher blood levels and higher values for the area under the plasma concentration time curve than younger patients. Lisinopril can be removed by dialysis.

INDICATIONS
Lisinopril is indicated in the treatment of mild to moderate hypertension. It may be used alone or concomitantly with other classes of antihypertensive agents.
Lisinopril is indicated in the management of congestive heart failure as an adjunctive treatment with diuretics and, where appropriate, digitalis.
Lisinopril is indicated for the treatment of haemodynamically stable patients, within 24 hours after acute myocardial infarction, to prevent the subsequent development of left ventricular dysfunction or heart failure and to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blocker.
Administration is by the oral route.

CONTRA-INDICATIONS
Breast-feeding mothers :
The safety of lisinopril has not been established in breast-feeding mothers. Lisinopril is contraindicated in patients who are hypersensitive to any components of the product and in patients with a history of angioneurotic oedema relating to previous treatment with angiotensin-converting enzyme inhibitor and in patients with hereditary or idiopathic angiodema (See SPECIAL PRECAUTIONS).
Lisinopril should not be given to patients with aortic stenosis or hypertrophic cardiomyopathy.

WARNINGS

Should a woman become pregnant while receiving an ACE-inhibitor, the treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy, the doctor should institute alternative medication.

ACE-inhibitors can cause foetal and neonatal morbidity when administered to pregnant women during the 2nd and 3rd trimesters.
ACE-inhibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms.
Oligohydramnios, which may result in limb contractures, cranofacial deformities and hypoplastic lung development, as well as hypotension, renal failure, hyperkalaemia, oliguria and anuria in new-borns have been reported after administration of ACE-inhibitors in the second and third trimesters. Cases of defective skull ossification have been observed.
Prematurity and low birth mass can occur.
The adverse effects to the embryo and foetus do not appear to have resulted from intra-uterine ACE-inhibitor exposure limited to the first trimester.
Infants whose mothers have taken lisinopril should be closely observed for hypotension, oliguria and hyperkalaemia.
Lisinopril crosses the human placenta. Limited experience indicates that peritoneal dialysis may be of some benefit in the clearance of lisinopril from the neonatal circulation. Lisinopril can theoretically be removed from the neonatal circulation by exchange transfusion.

DOSAGE AND DIRECTIONS FOR USE
Absorptionof lisinopril tablets is not affected by food, and tablets may be administered before, during or after meals. Lisinopril should be administered in a single daily dose. Lisinopril should be taken at approximately the same time each day.
Mild to Moderate Hypertension
The recommended starting dose is 10 mg. The usual effective maintenance dosage is 20 mg administered in a single daily dose. Dosage should be adjusted according to blood pressure response.
A maximum dose of 40 mg a day in hypertension is recommended.
If the desired therapeutic effect cannot be achieved in a period of 2 to 4 weeks on a certain dose level, the dose can further be increased.
Diuretic-Treated Patients
Symptomatic hypotension may occur following initiation of therapy with lisinopril; this is more likely in patients who are being treated currently with diuretics. Caution is recommended in all patients who may be volume- and/or salt-depleted. The diuretic should be discontinued 2 to 3 days before beginning therapy with lisinopril. (See SPECIAL PRECAUTIONS). In hypertensive patients in whom the diuretic cannot be discontinued, therapy with lisinopril should be initiated with a 5 mg dose. The subsequent dosage of lisinopril should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.
Dosage Adjustment in Renal Impairment
A lower dose is required in the presence of renal impairment, in patients in whom diuretic therapy cannot be discontinued and in patients who are volume- and/or salt-depleted for any reason.
Dosage in patients with renal impairment should be based on creatinine clearance as outlined

Creatinine clearance (mL/min)	Starting dose         (mg/day)
<70 >30	5-10

Safety has not been established in patients with creatinine clearance below 30 mL/min. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 20 mg daily.
Renovascular Hypertension
Special care to be exercised in some patients with renovascular hypertension because of the possibility of exaggerated response.
The dosage should be lowered to 2,5 mg or 5 mg and the patient should be monitored.
Congestive Heart Failure
In patients not adequately controlled by digitalis and/or diuretics, lisinopril may be added in a starting dose of 2,5 mg once a day. This may be increased at 4 week intervals in patients requiring an additional therapeutic effect. Dose adjustment should be based on the clinical response of the individual patients. The usual effective dosage range is 5 to 20 mg per day administered in a single dose.
Patients at high risk of symptomatic hypotension, e.g. patients with salt-depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy, should have these conditions corrected, prior to therapy with lisinopril. The effect of the starting dosage of lisinopril on blood pressure should be monitored carefully.
Acute Myocardial Infarction
Treatment with lisinopril may be started within 24 hours of the onset of symptoms. The first dose of lisinopril is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily thereafter. Patients with a low systolic blood pressure (120 mmHg or less) should be given a lower dose - 2,5 mg orally (see Special precautions). If hypotension occurs (systolic blood pressure less than or equal to 100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2,5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour), lisinopril should be withdrawn.
Dosing should continue for 6 weeks. The benefit appears to be greatest in patients with large myocardial infarctions and evidence of impaired left ventricular function. Patients who develop symptoms of heart failure should continue with lisinopril (see " Dosage and Directions for Use" for Congestive Heart Failure).
Lisinopril is compatible with intravenous or transdermal glycerol trinitrate.
Pediatric use
Safety and effectiveness of lisinopril in children has not been established.
Use in the elderly
There are no age-related changes in the efficacy or safety profile of the agent. When advanced age is associated with a decrease in renal function, however, the guidelines set out in the dose adjustment table (see renal impairment above) should be used to determine the starting dose of lisinopril.
Thereafter, the dosage should be adjusted according to the blood pressure response.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-Effects
The following side-effects may occur more frequently:
Dizziness, headache, diarrhoea, fatigue, nausea and cough.
Other side-effects include:
Orthostatic effects (including hypotension), rash, fatigue
Hypersensitivity/Angioneurotic Oedema
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx, which may be fatal, have been reported (see SPECIAL PRECAUTIONS).
Cardiovascular
Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients (see SPECIAL PRECAUTIONS), palpitation, tachycardia.
Digestive
Abdominal pain and indigestion, dry mouth, hepatitis - either hepatocellular or cholestatic, jaundice, pancreatitis, vomiting
Nervous system
Mood alterations, mental confusion, paraesthesia, vertigo, taste disturbance and sleep disturbances have been reported.
Respiratory
Bronchospasm, rhinitis, sinusitus
Skin
Urticaria, diaphoresis, alopecia, pruritis
Psoriasis and severe skin disorders have been reported, including pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme.
Urogenital
Uraemia, oliguria/anuria, renal dysfunction, acute renal failure, impotence
A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibody (ANA), elevated erythrocyte sedimentation rate, eosinophilia and leucocytosis. Rash, photosensitivity, or other dermatological manifestations may occur.
Laboratory Test Findings
Increases in blood urea and serum creatinine, liver enzymes and serum bilirubin, usually reversible upon discontinuation of lisinopril, have been seen.
Decreases in white blood cell count, haemoglobin and haematocrit may occur.
Hyperkalaemia has occurred. Hyponatraemia has occurred.
Bone marrow depression, manifest as anaemia, and/or leucopenia and/or thrombocytopenia have also been reported. Agranulocytosis has been reported.
Special Precautions
Symptomatic Hypotension
Symptomatic hypotension may occur in uncomplicated hypertensive patients. In hypertensive patients receiving lisinopril, 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 congestive 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.
In these patients, initiation of therapy and dose adjustment should be monitored under close medical supervision.
In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of lisinopril and/or a diuretic is adjusted.
Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom 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 contra-indication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion. In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with lisinopril.
This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of lisinopril may be necessary.
Hypotension in Acute Myocardial Infarction
Treatment with lisinopril must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator.
These are patients with systolic blood pressure of 100 mmHg or lower or cardiogenic shock.
During the first 3 days following the infarction; the dose should be reduced if the systolic blood pressure is 120 mmHg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2,5 mg if systolic blood pressure is 100 mmHg or lower. If hypotension persists (systolic blood pressure less than 90 mmHg for more than 1 hour) then lisinopril should be withdrawn.
Impaired Renal Function
In patients with congestive heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, has been reported in this situation.
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with angiotensin converting enzyme inhibitors, 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 hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, especially when lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of lisinopril and/or discontinuation of the diuretic and/or lisinopril may be required.
In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/L and/or proteinurea exceeding 500 mg/24 hour. If renal dysfunction develops during treatment with lisinopril (serum creatinine concentration exceeding 265 micromol/L or a doubling from the pre-treatment value) then the physician should consider withdrawl of lisinopril.
Haemodialysis Patients
Anaphylactoid reactions have been reported in patients undergoing certain haemodialysis procedures (e.g. with the high flux membrane 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 different class of antihypertensive agent.
Hypersensitivity/Angioneurotic Oedema
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors (including lisinopril). In such cases, lisinopril 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 resolves without treatment, although antihistamines have been useful in relieving symptoms.
Angioneurotic oedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway.
The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred. These patients should never receive any ACE inhibitor again. Lisinopril causes a higher rate of angiodema in black patients than in non-black patients. Patients with a history of angiodema unrelated to ACE- inhibitor therapy may be at increased risk of angiodema while receiving an ACE-inhibitor (See CONTRA-INDICATIONS).
Desensitization
Less frequently, patients receiving ACE-inhibitors during desensitization with hymenoptera venom have experienced life-threatening anaphylactic reactions. These reactions were avoided by temporarily with-holding ACE inhibitor therapy prior to each desensitization.
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/Anaesthesia
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, lisinopril may 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.
Serum Potassium - See INTERACTIONS

Interactions
Diuretics
When a diuretic is added to the therapy of a patient receiving lisinopril, the antihypertensive effect is additive.
Patients already on diuretics and especially those, in whom diuretic therapy was recently instituted, may experience an excessive reduction of blood pressure when lisinopril is added.
The possibility of symptomatic hypotension with lisinopril can be minimized by discontinuing the diuretic prior to initiation of treatment with lisinopril.
Other Agents
Indomethacin may diminish the antihypertensive efficacy of concomitantly-administered lisinopril. In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs (NSAIDS), the co-administration of lisinopril may result in further deterioration in renal function.
Lisinopril has been used concomitantly with nitrates without evidence of clinically significant adverse interactions.
Lithium elimination may be reduced. Therefore the lithium levels of serum should be carefully compared if lithium salts are to be administered.
Serum Potassium
Serum potassium tends to rise but usually remains within normal limits, however hyperkalaemia may occur.
Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus and concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride) potassium supplements, or potassium-containing salt substitutes.
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.
If concomitant use of lisinopril and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Serum Lithium
The lithium elimination may be reduced. Therefore the lithium levels of serum should be carefully compared if lithium salts are to be administered.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
The symptoms of over-dosage may include severe hypotension, electrolyte disturbances and renal failure. Treatment is symptomatic and supportive.

IDENTIFICATION

HEXAL-LISINOPRIL 5	Round, convex and a score notch on one side. The tablets are uniformly slightly red coloured.
HEXAL-LISINOPRIL 10	Round, convex and a score notch on one side. The tablets are uniformly slightly red coloured.
HEXAL-LISINOPRIL 20	Round, convex and a score notch on one side. The tablets are uniformly slightly red coloured.

PRESENTATION
White, opaque PVC/aluminium blister strips.
3 (10) blister strips to be packed into a carton i.e. 30 tablets per carton.

STORAGE INSTRUCTIONS
Store in a well-closed container, in a dry place, below 25°C. Protect from light.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBERS

HEXAL-LISINOPRIL 5:	35/7.1.3/0225
HEXAL-LISINOPRIL 10:	35/7.1.3/0226
HEXAL-LISINOPRIL 20:	35/7.1.3/0227

NAME AND BUSINESS ADDRESS OF THE APPLICANT
HEXAL Pharma (SA) (Pty) Ltd
46 Mahogany Road
Mahogany Ridge
Westmead
3608

DATE OF PUBLICATION OF THIS PACKAGE INSERT
09/2002
LISDP2

New addition to this site: April 2005
Source: Community Pharmacy
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