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Data Sheet

PRINIVIL®

lisinopril

5 mg, 10 mg, 20 mg tablets

Presentation

5 mg tablet: A white shield shaped tablet, flat faced with a bevelled edge. The tablet is scored on one side and engraved PRINIVIL on the other. Dimensions 6.0 mm x 6.8 mm (0.2377 x 0.2677 inches).

10 mg tablet: A pale yellow shield shaped tablet, flat faced with a bevelled edge. The tablet is scored on one side and engraved PRINIVIL on the other. Dimensions 7.6 mm x 8.6 mm (0.3000 x 0.3378 inches).

20 mg tablet: A pale orange shield shaped tablet, flat faced with bevelled edge. The tablet is scored on one side and engraved PRINIVIL on the other. Dimensions 7.6 mm x 8.6 mm (0.3000 x 0.3378 inches).

Indications

Dosage and Administration

Since absorption of PRINIVIL tablets is not affected by food, the tablets may be administered before, during or after meals. PRINIVIL should be administered in a single daily dose. As with all single daily dose medications, PRINIVIL should be taken at approximately the same time each day.

Essential Hypertension

In patients with essential hypertension the usual 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. In some patients, achievement of optimal blood pressure reduction may require two to four weeks of therapy. The maximum dose used in long term, controlled clinical trials was 80 mg/day.

A lower starting dose is required in the presence of renal impairment, in patients in whom diuretic therapy cannot be discontinued, patients who are volume and/or salt-depleted for any reason, and in patients with renovascular hypertension and may be required in some elderly patients.

Diuretic Treated Patients

Symptomatic hypotension may occur following initiation of therapy with PRINIVIL; this is more likely in patients who are being treated currently with diuretics. Caution is recommended, therefore, since these patients may be volume- and/or salt-depleted. The diuretic should be discontinued 2 to 3 days before beginning therapy with PRINIVIL (see Warnings and Precautions). In hypertensive patients in whom the diuretic cannot be discontinued, therapy with PRINIVIL should be initiated with a 5 mg dose. The subsequent dosage of PRINIVIL should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.

Dosage Adjustment in Renal Impairment

Dosage in patients with renal impairment should be based on creatinine clearance as outlined in Table 1.

Table 1

Creatinine Clearance
(mL/min)		 Starting Dose
(mg/day)
≤70 > 30 mL/min 5 mg - 10 mg
≤ 30 ≥ 10 mL/min 2.5 mg - 5 mg
< 10 mL/min
(including patients on dialysis)**		 2.5 mg*

* Dosage and/or frequency of administration should be adjusted depending on the blood pressure response.
** See Warnings and Precautions - Haemodialysis Patients

The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

Renovascular Hypertension

Some patients with renovascular hypertension, especially those with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, may develop an exaggerated response to the first dose of PRINIVIL. Therefore, a lower starting dose of 2.5 or 5 mg is recommended. Thereafter, the dosage may be adjusted according to the blood pressure response.

Congestive Heart Failure

As adjunctive therapy with diuretics and where appropriate digitalis PRINIVIL may be initiated with a dose of 2.5 mg once a day. The usual effective dosage range is 5 to 20 mg per day administered in a single daily dose. In clinical trials, dosages were adjusted at 4 week intervals in patients requiring additional therapeutic effect. Dosage adjustments should be based on clinical response of each individual patient.

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, if possible, prior to therapy with PRINIVIL. The effect of the starting dosage of PRINIVIL on blood pressure should be monitored carefully.

Acute Myocardial Infarction

Treatment with PRINIVIL may be started within 24 hours of the onset of symptoms. The first dose of PRINIVIL 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 mm Hg or less) when treatment is started or during the first 3 days after the infarct should be given a lower dose - 2.5 mg orally (see Warnings and Precautions). If hypotension occurs (systolic blood pressure less than or equal to 100 mm Hg) 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 mm Hg for more than 1 hour) PRINIVIL should be withdrawn. Dosing for patients with acute myocardial infarction should continue for six weeks. (For patients who develop symptoms of heart failure, see Dosage and Administration, Congestive Heart Failure).

PRINIVIL is compatible with intravenous or transdermal glyceryl trinitrate.

Children

Not recommended for children.

Contraindications

PRINIVIL is contraindicated in patients who are hypersensitive to any component of this 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.

All angiotensin-converting enzyme inhibitors, including lisinopril, are contraindicated in pregnancy because of the potential risk of foetotoxicity.

Warnings and Precautions

Symptomatic Hypotension

Symptomatic hypotension was seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving PRINIVIL 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 (see Interactions and Adverse Effects). 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, therapy should be started under medical supervision and the patient should be followed closely whenever the dose of PRINIVIL and/or diuretic is adjusted.

Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in 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 congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with PRINIVIL. This effect is anticipated and it not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of PRINIVIL 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 mm Hg 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 mm Hg or lower. Maintenance doses should be reduced to 5 mg or temporarily 2.5 mg if systolic blood pressure is 100 mm Hg or lower. If hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour) then PRINIVIL should be withdrawn.

Aortic Stenosis/Hypertrophic Cardiomyopathy

As with all vasodilators, ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.

Renal Function Impairment

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, usually reversible, 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, usually 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, usually minor and transient, especially when PRINIVIL has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or PRINIVIL 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 proteinuria exceeding 500 mg/24 h. If renal dysfunction develops during treatment with PRINIVIL (serum creatinine concentration exceeding 265 micromol/l or a doubling from the pre-treatment value) then the physician should consider withdrawal of PRINIVIL.

Hypersensitivity/Angioneurotic Oedema

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL. This may occur at any time during treatment. In such cases, PRINIVIL should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient.

Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy which may include subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures to ensure a patent airway, should be administered promptly.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-Blacks.

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).

Anaphylactoid Reactions During Hymenoptera Desensitisation

Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.

Haemodialysis Patients

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g. 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 a different class of antihypertensive agent.

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, PRINIVIL 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.

Hyperkalaemia

Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, 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. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias.

If concomitant use of PRINIVIL and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium. (See Interactions, Serum Potassium).

Hypoglycaemia

Diabetic patients treated with oral anti-diabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycaemia, especially during the first month of combined use. (See Interactions.)

Use in the Elderly

In clinical studies, there was no age-related change in the efficacy or safety profile of lisinopril. When advanced age is associated with decrease in renal function, however, the guidelines set out in Table 1 (see Dosage and Administration, Dosage Adjustment in Renal Impairment) should be used to determine the starting dose of PRINIVIL. Thereafter, the dosage should be adjusted according to the blood pressure response.

Use in Pregnancy

The use of PRINIVIL during pregnancy is contraindicated. When pregnancy is detected, PRINIVIL should be discontinued as soon as possible.

In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor drug during the first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been repeated.

ACE inhibitors can cause foetal 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 foetal and neonatal injury including hypotension, renal failure, hyperkalaemia, and/or skull hypoplasia in the newborn. Maternal oligohydramnios, presumably representing decreased foetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development.

These adverse effects to the embryo and foetus do not appear to have resulted from intrauterine ACE-inhibitor exposure limited to the first trimester.

Infants whose mothers have taken PRINIVIL should be closely observed for hypotension, oliguria and hyperkalaemia. Lisinopril, 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.

Nursing Mothers

It is not known whether PRINIVIL is secreted in human milk. Because many medicines are secreted in human milk, caution should be exercised if PRINIVIL is given to a nursing mother.

Paediatric Use

Safety and effectiveness of PRINIVIL in children have not been established.

Pancreatitis

Pancreatitis may occur with angiotensin converting enzyme inhibitors and patients with abdominal pain on ACE inhibitors should be tested accordingly.

Animal Toxicity

The safety of lisinopril has been thoroughly investigated in laboratory animals. The oral LD50 of lisinopril was greater than 20 g/kg in mice and rats.

The toxicity of lisinopril in rats and dogs appears to be related principally to an exaggeration of the pharmacologic effects. There was a wide separation between the therapeutic dose in humans and toxic doses in animals.

The ratio of the non-toxic dose in dogs (5 mg/kg/day) to a recommended human dose of 40 mg/day was greater than 6 in this sensitive species.

With a dose of 40 mg/day in humans, the maximum plasma lisinopril concentration was 468 ng/mL, well below the 11,370 ng/mL plasma level produced by a nephrotoxic dose in dogs.

The principal signs of toxicity in dogs were related to changes in renal function (elevated serum urea nitrogen and creatinine concentrations), sometimes associated with renal tubular degeneration. This last change was not observed in rats, but increases in serum urea nitrogen were recorded.

The changes in renal function probably represent a medicine-induced pre-renal azotaemia related to the pharmacologic activity of lisinopril. Saline-supplementation ameliorated or prevented the toxicity of lisinopril in rats as well as dogs, further substantiating a mechanism-based toxicity.

There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day (about 110 times the maximum recommended daily human dose).

Lisinopril has also been administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about 170 times the maximum recommended daily human dose) and showed no evidence of carcinogenicity.

Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.

There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg/kg/day of lisinopril.

Lisinopril was not teratogenic in mice treated on days 6-15 of gestation with up to 1000 mg/kg/day (1250 times the maximum recommended human dose). There was an increase in foetal resorptions at doses down to 100 mg/kg; at doses of 1000 mg/kg this was prevented by saline supplementation. There was no foetotoxicity or teratogenicity in rats treated with up to 300 mg/kg/day (375 times the maximum recommended dose) of lisinopril at days 6-17 of gestation. In rats receiving lisinopril from day 15 of gestation through day 21 postpartum, there was an increased incidence of pup deaths on days 2-7 postpartum. The increase in pup deaths and decrease in pup weight did not occur with maternal saline supplementation.

Lisinopril at doses up to 1 mg/kg/day, was not teratogenic when given throughout the organogenic period in saline supplemented rabbits. Saline supplementation (physiologic saline in place of tap water) was used to eliminate maternotoxic effects and enable evaluation of the teratogenic potential at the highest possible dosage level.

The rabbit has been shown to be extremely sensitive to angiotensin converting enzyme inhibitors (captopril and enalapril), with materno- and foetotoxic effects apparent at or below the recommended therapeutic dosage levels in humans.

Foetotoxicity was demonstrated in rabbits by an increased incidence of foetal resorptions at an oral dose of lisinopril of 1 mg/kg/day and by an increased incidence of incomplete ossification at the lowest dose tested (0.1 mg/kg/day). A single intravenous dose of 15 mg/kg/day of PRINIVIL administered to pregnant rabbits during gestation days 16, 21 or 26 resulted in 88% to 100% foetal death.

Adverse Effects

PRINIVIL has been found in controlled clinical trials to be generally well tolerated. For the most part, adverse effects were mild and transient in nature.

The most frequent clinical adverse effects of PRINIVIL in controlled trials were: dizziness, headache, diarrhoea, fatigue, cough and nausea.

Other adverse effects occurring less frequently were: orthostatic effects (including hypotension), rash, and asthenia.

Hypersensitivity/Angioneurotic Oedema

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely (see Warnings and Precautions). In very rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including lisinopril.

Adverse effects which occurred rarely, either during controlled clinical trials or after the medicine was marketed, include:

Cardiovascular: myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients (see Warnings and Precautions), palpitation, tachycardia

Digestive: abdominal pain, dry mouth, pancreatitis (see Warnings and Precautions), hepatitis - either hepatocellular or cholestatic, jaundice

Endocrine: syndrome of inappropriate anti-diuretic hormone secretion (SIADH)

Metabolic: Cases of hypoglycaemia in diabetic patients on oral anti-diabetic agents or insulin have been reported (see Interactions).

Nervous System: mood alterations, mental confusion, paresthesia

Respiratory: bronchospasm

Skin: urticaria, pruritus, diaphoresis, alopecia

Urogenital: uraemia, oliguria/anuria, renal dysfunction, acute renal failure, impotence

A symptom complex has been reported which may include some or all of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, an elevated ESR, eosinophilia and leukocytosis, rash, photosensitivity or other dermatologic manifestations may occur.

Laboratory Test Findings

Clinically important changes in standard laboratory parameters were rarely associated with administration of PRINIVIL. Increases in blood urea, serum creatinine, liver enzymes and serum bilirubin usually reversible upon discontinuation of PRINIVIL, have been seen.

Bone marrow depression, manifest as anaemia and/or thrombocytopaenia and/or leukopaenia, has been reported.

Small decreases in haemoglobin and haematocrit, rarely of clinical importance unless another cause of anaemia coexisted, have occurred.

Hyperkalaemia and hyponatraemia have occurred.

The following additional events have been reported but a causal relationship to PRINIVIL has not been established.

Body as a Whole : chest pain, flushing, syncope

Cardiovascular System: angina pectoris, rhythm disturbances

Digestive System: anorexia, constipation, dyspepsia, flatulence, vomiting, hepatic failure

Metabolic: gout

Musculoskeletal System: back pain, joint pain, muscle cramps, shoulder pain

Nervous System and Psychiatric: decreased libido, depression, insomnia, somnolence, stroke, vertigo

Respiratory System: bronchitis, dyspnoea, nasal congestion, pharyngeal pain, rhinitis, sinusitis, upper respiratory symptoms

Skin: erythema multiforme, pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous pseudolymphoma

Urogenital: urinary tract infection

Other: blurred vision, taste disturbances

Laboratory Test findings: haemolytic anaemia

Interactions

Diuretics

When a diuretic is added to the therapy of a patient receiving PRINIVIL, the antihypertensive effect is usually additive.

Patients already on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure when PRINIVIL is added. The possibility of symptomatic hypotension with PRINIVIL can be minimised by discontinuing the diuretic prior to initiation of treatment with PRINIVIL (see Warnings and Precautions and Dosage and Administration).

Other Agents

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.

In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory medicines including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function. These effects are usually reversible.

PRINIVIL has been used concomitantly with nitrates without evidence of clinically significant adverse interactions.

As with other medicines which eliminate sodium, the lithium elimination may be reduced. Therefore the serum lithium levels should be monitored carefully if lithium salts are to be administered.

Serum Potassium

Although in clinical trials, serum potassium usually remained within normal limits, hyperkalaemia did occur in some cases.

Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride) or 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 PRINIVIL and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

If PRINIVIL is given with a potassium-losing diuretic diuretic-induced hypokalaemia may be ameliorated. (See Precautions, Hyperkalaemia.)

Anti-diabetics

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and anti-diabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients treated with oral anti-diabetic agents or insulin, glycaemic control should be closely monitored for hypoglycaemia, especially during the first month of treatment with an ACE inhibitor.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including lisinopril.

Overdosage

The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. If available, angiotensin II may be beneficial. Lisinopril may be removed from the general circulation by haemodialysis (see Warnings and Precautions, Haemodialysis Patients).

Actions

Lisinopril has been shown to inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyses the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was less than 0.1 mEq/L. However, approximately 10% of patients had increases in serum K+ of >0.5 mEq/L and approximately 6% had decreases of 0.5m Eq/L. In patients treated with lisinopril plus a thiazide diuretic, there was essentially no change in serum potassium (see Warnings and Precautions).

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

ACE is identical to kininase, the enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated.

While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril has been shown to be antihypertensive even in patients with low-renin hypertension. Although lisinopril was anti-hypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non-black patients. This difference was eliminated with concomitant administration of lisinopril and hydrochlorothiazide.

In most patients studied, onset of antihypertensive activity was seen at 1-2 hours after oral administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved by six hours.

In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy.

At recommended single daily doses, antihypertensive effects have been maintained for up to 24 hours.

Pharmacokinetics

In clinical studies, peak serum concentrations occur within about 6 to 8 hours following oral administration. Declining serum concentrations exhibited a prolonged terminal phase which did not contribute to medicine accumulation. This terminal phase probably represents saturable binding to ACE and was not proportional to dose. Lisinopril does not appear to be bound to other plasma proteins.

Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the extent of absorption of lisinopril is approximately 25 percent. Lisinopril absorption was not influenced by the presence of food in the gastrointestinal tract.

Conventional pharmacokinetic calculations including half-life of elimination are precluded by the non-linear binding of lisinopril to ACE. However, upon multiple dosing, lisinopril exhibited an effective half-life of accumulation of 12 hours. This value is predictive of steady state parameters in the plasma.

In elderly healthy subjects (65 years and above), a single dose of lisinopril 20 mg produced higher serum concentrations than those seen in young healthy adults given a similar dose. In another study, single daily doses of lisinopril 5 mg were given for seven consecutive days to young and elderly healthy volunteers and to elderly patients with congestive heart failure. Maximum serum concentrations of lisinopril on Day 7 were higher in the elderly volunteers than in the young, and still higher in the elderly patients with congestive heart failure. These findings are consistent with the concept that medicines of low lipid solubility (such as lisinopril) achieve a reduced volume of distribution in the elderly, who have a decreased lean body mass/fat ratio; and renal clearance of lisinopril was decreased in the elderly, particularly in the presence of congestive heart failure.

The disposition of lisinopril in patients with renal insufficiency was similar to that in patients with normal renal function until the glomerular filtration rate reached 30 mL/min or less, when peak and trough lisinopril levels then increased, time to peak concentration was increased and time to steady state sometimes prolonged (see Dosage and Administration).

Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contained radioactivity following administration of 14C lisinopril. Radioactivity was found to cross the placenta following administration of labelled lisinopril to pregnant rats, but none was found in the foetuses.

Radioactivity was found to cross the placenta following administration of labelled lisinopril to pregnant hamsters.

Pharmaceutical Precautions

Store in a dry place below 30°C.

Medicine Classification

Prescription Medicine.

Package Quantities

PRINIVIL 5 mg, 10 mg and 20 mg tablets are available in blister platforms of 30 tablets each, either as a single platform or in a pack of three platforms (90 tablets).

Further Information

None

Name and Address

Merck Sharp & Dohme (New Zealand) Limited
P O Box 99 851
Newmarket
Auckland
NEW ZEALAND
Tel: 0800 500 673

Date Of Preparation

29 April 2008

DP-PNV-0408(290408)

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