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Logo SINOPREN 5 Tablets
SINOPREN 10 Tablets
SINOPREN 20 Tablets

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

SINOPREN 5 Tablets
SINOPREN 10 Tablets
SINOPREN 20 Tablets

COMPOSITION
Sinopren 5 Tablets
Each tablet contains lisinopril dihydrate
equivalent to anhydrous
lisinopril 5 mg
Sinopren 10 Tablets
Each tablet contains lisinopril dihydrate
equivalent to anhydrous lisinopril 10 mg
Sinopren 20 Tablets
Each tablet contains lisinopril dihydrate
equivalent to anhydrous lisinopril 20 mg

PHARMACOLOGICAL CLASSIFICATION
A7.1.3 Other hypotensives.

PHARMACOLOGICAL ACTION
Mechanism of 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.
Pharmacokinetics
Following oral administration, peak serum concentrations occur within 6 to 8 hours, although there is 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 is approximately 25%, with interpatient variability (6-60%) at all doses tested (5-80 mg). 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 gromerular 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.
Clinical Study
Gruppo italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) Trial:
The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-3) was a clinical trial to assess the efficacy of lisinopril, transdermal glyceryl trinitrate, and their combination in improving survival and ventricular function after acute myocardial infarction. Between June 1991 and July 1993, 19 394 patients were randomized from 200 coronary care units in Italy. Eligible patients presented within 24 h of symptom onset and had no clear indications for or against the study treatments. In a factorial design, patients were assigned 6 weeks of oral lisinopril (2,5 or 5 mg initial dose and then 10 mg daily) or open contol with nitrates (intravenous for the first 24 hr followed by transdermal glyceryl trinitrate 10 mg daily) or open control. Complete clinical data and 6-week follow up were available for 18 895 (97,4%) of the patients who were randomized. Overall 6 week mortality was 6,7%. Lisinopril, started within 24 hr of acute muocardial infarction, produced significant reductions in overall mortality (OR 0,88; 95% CI 0,79 to 0,99) and in the combined outcome measure of mortality and severe ventricular dysfunction (OR 0,90; 95% CI 0,84 to 0,98). The systematic administration of transdermal glyceryl trinitrate did not show any independent effect on the same outcome measures (OR 0,94; 95% CI 0,84 to 1,05 and OR 0,94; 95% CI 0,87 to 1,02). Systematic combined administration of lisinopril and glyceryl trinitrate also produced significant reductions in overall mortality (OR 0,83; 95% CI 0.70 to 0,97) and in the combined end-point (OR 0,85; 95% CI 0,76 to 0,94). The favourable effect of lisinopril alone or with glyceryl trinitrate was clear also in the predefined high-risk populations (elderly patients and women) for the
combined end-point. These findings were obtained in a population exposed to recommended treatments (thrombolysis 72%, beta-blockade 31%, and asprin 84%).
A 6 month follow up analysis of the previous study sought to assess whether the early reduction of mortality obtained with a 6 week treatment course of lisinopril or glyceryl trinitrate or both, outlasts therapy and is still present after 6 months. The primary outcome of this 6 month follw up was the combined end-point of mortality and severe left ventricular dysfnction. The assumption was that the early benefit on the remodeling processes may be maintained over a longer period of time, even in the absence of treatment. At 6 months , among patients randomized to lisinopril, 18,1% had died or developed severe ventricular dysfunction in comparison with 19,3% of those randomized to no lisinopril. No difference was found between patients with and without glyceryl trinitrate therapy (18,4% and 18,9%). Although the systematic administration of glyceryl trinitrate started early and continued for 6 weeks after acute myocardial infarction does not yield evidence of benefit, early treatment with lisinopril appears to improve prognosis. This effect seems to carry over the first 6 mionths from randomization, even after treatment withdrawal.
Mortality of diabetic patients with acute myocardial infection remains high despite improvement in their management. There is a need to evaluate the efficacy and safety of novel treatments of myocardial infarction in this high-risk population. In a retrospective analysis of data obtained in the GISSI-3 study, information on diabetic status was analysed for 18 131 patients (approximately 94% of the total population enrolled), of whom 2790 patients had a history of diabetes. Treatment with lisinopril was associated with a decreased 6-week mortality in diabetic patients (8,7% in comparison with 12,4%; OR 0,68; 95% CI 0,53 to 0,86); this effect was significantly greater (p<0,025) than that observed in non-diabetic patients. The survival benefit in diabetics was mostly maintained at 6 months, despite withdrawal of treatment at 6 weeks (12,9% in comparison with 16,1%; OR 0,77; 95% CI 0,62 to 0,95).
In the GISSI trial, 2585 patients, >70 years of age, received lisinopril. There was a significant 12% reduction in the combined end-point with lisinopril versus no lisinopril at 6 weeks. Lisinopril plus nitroglycerin reduced total events even more than lisinopril alone. The drug had its greatest effect on mortality in elderly patients in the first 6 weeks after myocardial infarction, but its greatest effect on left ventricular function occurred over the longer six months period.

INDICATIONS
Sinoprenis indicated in the treatment of mild to moderate hypertension. It may be used alone or concomitantly with other classes of antihypertensive agents.
Sinoprenis indicated in the mangement of congestive heart failure as an adjunctive treatment with diuretics and, where appropriate, digitalis.
Sinoprenis 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-blockers. Administration is by the oral route.

CONTRA-INDICATIONS
Breast feeding mothers:
The safety of Sinopren has not been established in breast feeding mothers.
Sinoprenis contra-indicated 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 an angiotensin-converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema (See Special Precautions).
Sinoprenshould 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 and mortality 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, craniofacial deformities and hypoplastic lung development, as well as hypotension, renal failure, hyperkalaemia, oliguria and anuria in newborns 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 Sinopren should be closely observed for hypotension, oliguria and hyperkalaemia.
Sinopren crosses the human placenta. Limited experience indicates that peritoneal dialysis may be of some benefit in the clearance of Sinopren from the neonatal circulation. Sinopren can theoretically be removed from the neonatal circulation by exchange transfusion.

DOSAGE AND DIRECTIONS FOR USE
Absorption of lisinopril is not affected by food, and tablets may be administered before, during or after meals. Sinopren should be administered in a single dose. Sinopren 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 Sinopren; this is more likely in patients who are being treated concurrently 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 Sinopren (See Special Precautions). In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Sinopren should be initiated with a 5 mg dose. The subsequent dosage of Sinopren 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 cleatance as outlined below:

Creatinine Clearance
        (mL/min)
        Initial 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 is 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, Sinopren 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 effecrive dosage range is 5 to 20 mg per day administered in a single daily dose.
Patients at high risk of symptomatic hypotension, e.g. patients with salt depletion with or without hyponataemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy, should have these conditions corrected, prior to therapy with Sinopren. The effect of the starting dosage of Sinopren on blood pressire should be monitored carefully.
Acute Myocardial Infarction
Treatment with Sinopren may be started within 24 hours of the onset of symproms. The first dose of Sinopren 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 maitenance dose of 5 mg may be given with temporary reduction to 2,5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour), Sinopren 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 Sinopren (see “Dosage and Directions for Use”for Congestive Heart Failure).
Sinopren is compatible with intravenous or transdermal glyceryl trinitrate.
Paediatric Use
Safety and effeciveness of Sinopren 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 Sinopren. Thereafter, the dosage should be adjusted according to the blood pressure response.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
The following side-effects may occur more frequently:
Dizziness, headache, diarrhoea, fatigue, nausea and cough.
Other side-effects include:
Orthostatic effects (including hypotension), rash, asthenia.
Hypersensitivity/Angioneurotic Oedema
Angioneurotic oedema of the face, lips, tongue, glottis and/or larynx, which may be fatal, and extremities has been reported (see Special Precautions).
Cardiovascular:
Myocardial infarction or cerebro-vascular accident, possibly secondary to excessive hypotension in high risk patients (See Special Precautions), palpitations, tachycardia.
Digestive
Abdominal pain and indigestion , vomiting, dry mouth.
Hepatitis –either hepatocellular or cholestatic jaundice, pancreatitis.
Nervous system
Mood alterations, mental confusion, paraesthesiae, vertigo.
Taste disturbances and sleep disturbances have been reported.
Respiratory
Bronchospasm, rhinitis, sinusitis.
Skin
Urticaria, excessive sweating, 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 ANA (anti-nuclear antibody), elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis. Rash, photosensitivity, or other dematological manifestations may occur.
Laboratory Test Findings
Increases in blood urea and serum creatinine, liver enzymes and serum bilirubin, usually reversible upon discontimuation 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 thrombocytopaenia 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 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 a 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 mgHg 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 futher 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 Sinopren has been given concurrently with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Sinopren and/or discontinuation of the diuretic and/or Sinopren may be required.
In acute myocardial infarction, treatment with Sinopren should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/l and/or proteinuria exceeding 500 mg/ 24 hr. If renal dysfunction develops during treatment with Sinopren (serum creatinine concentration exceeding 265 micromol/l or a doubling from the pre-treatment value) then the doctor should consider withdrawal of Sinopren.
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, lips, tongue, glottis and/or larynx and extremities has been reported in patients treated with angiotensin converting enzyme inhibitors (including lisinopril). In such cases, Sinopren should be discontinued promptly and appropriate monitoring should instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those cases where the swelling has been confined to the face and lips, the condition generally resolves without treatment, although anti-histamines 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.
Sinopren causes a higher rate of angioedema in black patients than in non-black patients.
Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE-inhibitor (see Contra-indications )
Desensitisation
Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent rechallenge.
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, Sinopren may block the 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 Sinopren, 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 Sinopren is added. The possibility of symptomatic hypotension with Sinopren can be minimized by discontinuing the diuretic prior to initiation of treatment with Sinopren.
Other Agents
Indomethacin may diminish the antihypertensive efficacy of concomitantly-administered Sinopren. In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs (NSAIDS), the co-administration of Sinopren may result in further deterioration in renal function.
Sinopren 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 Sinopren and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

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

IDENTIFICATION
Sinopren 5 Tablets:
Light yellow coloured, uncoated, round tablets debossed with ‘5’on one side and scored on the other side.
Sinopren 10 Tablets:Light yellow coloured, uncoated, round tablets debossed with ‘10’on one side and scored on the other side.
Sinopren 20 Tablets:Light peach coloured, uncoated, round tablets debossed with ‘20’on one side and scored on the other side.

PRESENTATION
Sinopren 5 Tablets
: Carton containing three PVdC coated PVC blister strips of 10 tablets each.
Sinopren 10 Tablets: Carton containing three PVdC coated PVC blister strips of 10 tablets each.
Sinopren 20 Tablets: Carton containing three PVdC coated PVC blister strips of 10 tablets each.

STORAGE INSTRUCTIONS
Store below 25°C, protected from light and moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
Sinopren 5 Tablets
: 35/7.1.3/0209
Sinopren 10 Tablets: 35/7.1.3/0210
Sinopren 20 Tablets: 35/7.1.3/0211

NAME AND BUSINESS ADDRESS OF THE APPLICANT
RANBAXY (SA) (PTY) LTD
Third Floor
Outspan House
1006 Lenchen Avenue North
CENTURION

DATE OF PUBLICATION OF THIS PACKAGE INSERT
April 2003

Updated on this site: October 2003
Source: Community Pharmacy

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