QUALITATIVE AND QUANTITATIVE COMPOSITION: Each tablet contains

FIBSOL  5

Active ingredient:  Lisinopril dihydrate equivalent to 5.0 mg Lisinopril

Inactive ingredient: Calcium hydrogen phosphate, Magnesium stearate, Mannitol, Silica – colloidal anhydrous, Starch – Maize, Starch – pregelatinised maize.

FIBSOL  10

Active ingredient:  Lisinopril dihydrate equivalent to 10mg Lisinopril

Inactive ingredient:  Calcium hydrogen phosphate,  Magnesium stearate, Mannitol, Silica – colloidal anhydrous, Starch – Maize, Starch – pregelatinised maize.

FIBSOL  20 

Active ingredient:  Lisinopril dihydrate equivalent to 20mg Lisinopril

Inactive ingredient:  Calcium hydrogen phosphate,  Magnesium stearate, Mannitol, Silica – colloidal anhydrous, Starch – Maize, Starch – pregelatinised maize.

PHARMACOKINETIC PROPERTIES

Following oral administration of lisinopril, peak serum concentrations of lisinopril occur within about seven hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients.  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 does not appear to be bound to other serum proteins. 

Lisinopril does not undergo metabolism and absorbed drug is excreted unchanged entirely in the urine.  Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with large interpatient variability (6 to 60%) at all doses tested (5 to 80 mg).  Lisinopril absorption is not affected by the presence of food in the gastrointestinal tract. 

Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12.6 hours. 

Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease, becomes clinically important only when the glomerular filtration rate (GFR) is below 30 mL/minute.  Above this GFR, the elimination half-life is little changed.  With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged.  Older patients, on average, have higher (approximately doubled) blood levels and higher values for the area under the plasma concentration time curve (AUC) than younger patients.   Lisinopril can be removed by haemodialysis. 

PHARMACODYNAMIC PROPERTIES

Administration of lisinopril to patients with hypertension results in a reduction of supine and standing blood pressure to about the same extent, with no compensatory tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt depleted patients.  When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive. 

In most patients studied, onset of antihypertensive activity was seen one to two hours after oral administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved by six hours.  Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. 

However, in all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was six hours after dosing. 

In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy. The antihypertensive effects of lisinopril are maintained during long-term therapy. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure or a significant increase in blood pressure compared to pretreatment levels.

THERAPEUTIC INDICATIONS

Hypertension.

Treatment of hypertension. Lisinopril may be used alone or concomitantly with other classes of antihypertensive agents. Sufficient data have not been provided to support the use of lisinopril in severe hypertension or renovascular hypertension.

Congestive heart failure.

Treatment of heart failure. In such patients, it is recommended that lisinopril be administered together with a diuretic.

Acute myocardial infarction.

Treatment of acute myocardial infarction in haemodynamically stable patients, defined as patients who are not in cardiogenic shock and who have a systolic blood pressure greater than 100 mmHg. Lisinopril may be initiated within 24 hours of an acute myocardial infarction.

ADMINISTRATION

Since there is no clinically significant effect of food on the absorption of lisinopril, the tablets may be administered before, during or after meals.  Lisinopril should be administered in a single daily dose.

Essential hypertension.

In-patients with uncomplicated essential hypertension not on diuretic therapy, the usual recommended starting dose is 5 to 10 mg.  The usual maintenance dosage is 10 to 20 mg/day administered in a single daily dose.  Dosage should be adjusted at two to four week intervals according to blood pressure response.  In some patients, doses up to 40 mg/day may be required. If blood pressure is not controlled with lisinopril, a low dose of a diuretic may be added.  Hydrochlorothiazide (12.5 mg) has been shown to provide an additive effect.  After addition of a diuretic, the dose of lisinopril may be reduced.

Diuretic treated or severely salt or volume depleted patients.  Symptomatic hypotension following the initial dose of lisinopril may occur occasionally in-patients receiving concomitant diuretics.  The diuretic should be discontinued, if possible, for two to three days before beginning therapy with lisinopril  . In hypertensive patients in whom the diuretic cannot be discontinued, the initial dose of lisinopril should be 2.5 mg, followed then by 5 mg.  The subsequent dosage of lisinopril should be adjusted according to blood pressure response.  If required, diuretic therapy may be resumed gradually.

Impaired renal function.

The usual dose of lisinopril is recommended for patients with a creatinine clearance > 70 mL/minute. Dosage in-patients with renal impairment should be based on creatinine clearance as outlined below.

If creatinine clearance is between 70 and 30 mL/minute then the starting dose should be 5 to 10 mg/day.

If creatinine clearance is between 30 and 10 mL/minute then the starting dose should be 2.5 to 5 mg/day.

If creatinine clearance is less than 10 mL/minute (including patients on dialysis) then the starting dose should be 2.5 mg/day.

The dosage may be titrated upward until blood pressure is controlled or to a maximum of 20 mg daily.

Congestive cardiac failure.

Treatment of heart failure with lisinopril should be initiated under close medical supervision. In-patients not adequately controlled by diuretics (and digitalis, where indicated), lisinopril may be added with a starting dose of 2.5 mg once a day. Dose adjustment should be increased by increments of no greater than 10mg and at intervals of no less than 2 weeks. 

The usual dosage is 5 to 20 mg/day administered as a single dose. The dose of lisinopril should not be titrated according to symptoms, as higher doses may not give additional symptomatic relief.  The optimal upper dose has not been determined; 35mg/day has been shown to be more effective than 5mg/day but there is no evidence regarding the effectiveness of intermediate doses. 

Patients at a 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 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) when treatment is started or during the first three days after the infarct should be given a lower dose (2.5 mg) orally. 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 < 90 mmHg for more than one hour), lisinopril should be withdrawn.

In the elderly:

In general, blood pressure response and adverse experiences were similar in younger and older patients given similar dose of Lisinopril. Pharmacokinetic studies however, indicate that maximum blood levels and AUC are doubled in old patients, so that dosage adjustments should be made with particular caution.

CONTRAINDICATIONS

• Hypersensitivity to lisinopril or any other component of lisinopril.
• History of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an ACE inhibitor.
• Patients with hereditary or idiopathic angioedema.
• Pregnancy  
• Patients undergoing haemodialysis with polyacrylonitrile metalylsulfonate high flux membranes. There is a risk of anaphylactoid reaction (hypersensitivity reactions which may be severe, e.g. shock) with the simultaneous use of an ACE inhibitor and polyacrylonitrile metalylsulfonate high flux dialysis membranes (e.g. AN69) or during low-density lipoproteins (LDL) apharesis with dextran sulphate within the framework of dialysis treatment. This combination thus needs to be avoided, either by using other medical products to control high blood pressure or cardiac insufficiency or by using other membranes during dialysis.
• Lisinopril should not be used in patients with aortic stenosis or outflow tract obstruction ( obstructive car-diomyopathy), renal artery stenosis, bilateral or in a solitary kidney.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Hyperkalaemia:  Because the ACE inhibitors decrease the formation of angiotensin II and the subsequent production of aldosterone, serum potassium concentrations exceeding 5.5 mEq/L may occur. Hyperkalaemia is more likely in-patients with some degree of renal impairment, those treated with potassium sparing diuretics or potassium supplements, and in those consuming potassium containing salt substitutes. Diabetic patients, and elderly diabetic patients particularly, may be at increased risk of hyperkalaemia. In some patients, hyponatraemia may coexist with hyperkalaemia. It is recommended that patients taking an ACE inhibitor should have serum electrolytes (including potassium, sodium and urea) measured from time to time.

Surgery and anaesthesia:  In patients undergoing major surgery or who require anaesthesia, hypotension due to anaesthetic agents may be greater in patients receiving ACE inhibitors because of interference with compensatory mechanisms associated with the renin-angiotensin system. If perioperative hypotension occurs, volume expansion would be required.

Cough:  A persistent dry (nonproductive) irritating cough has been reported with ACE inhibitors. In various studies, the incidence of cough varies depending on the drug, dosage, duration of use and method of analysis. The cough is most likely due to stimulation of the pulmonary cough reflex by kinins (bradykinin) and/or prostaglandins, which accumulate because of ACE inhibition. A change to another class of drugs may be required in severe cases.

Dermatological reactions:  Dermatological reactions characterised by maculopapular pruritic rashes and sometimes photosensitivities have been reported rarely with ACE inhibitors. Rare and occasionally severe skin reactions (e.g. lichenoid eruptions, psoriasis, pemphigus-like rash, Stevens-Johnson syndrome) have also been reported with some ACE inhibitors. A causal relationship is sometimes difficult to assess. Patients who develop a cutaneous reaction with one ACE inhibitor might not when switched to another drug of the same class, but there are reports of cross reactivity.

Taste disturbances (dysgeusia):  The incidence of taste disturbance was reported to be high (up to 12.5%) with high doses of another ACE inhibitor but the overall incidence for the class is probably low. However, the relevant data are scarce and difficult to interpret. The taste disturbance has been described as a suppression of taste or a metallic sensation in the mouth. The dysgeusia usually occurs in the first few weeks of treatment and may disappear within one to three months despite continued treatment.

Impaired renal function:  Changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive cardiac failure, whose renal function may depend on the activity of the renin angiotensin aldosterone system, treatment with ACE inhibitors may be associated with oliguria and/or progressive azotaemia and rarely with acute renal failure and/or death.

Impaired hepatic function:  Hepatitis (hepatocellular and/or cholestatic) and elevations of hepatic enzymes and/or serum bilirubin have occurred during therapy with other ACE inhibitors in-patients with or without pre-existing hepatic abnormalities. In most cases the changes were reversed on discontinuation of the drug. There are no adequate studies in-patients with cirrhosis and/or hepatic dysfunction. Lisinopril should be used with particular caution in-patients with pre-existing hepatic abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Anaphylactoid reactions during Hymenoptera desensitisation:  Patients receiving ACE inhibitors during desensitisation (e.g. Hymenoptera venom) have experienced anaphylactoid reactions. These reactions have been avoided when ACE inhibitors were temporarily withheld.

Angioedema:  Severe life-threatening angioedema has been reported rarely with most of the ACE inhibitors. There seems to be no sex difference in the incidence of angioedema or in the predisposition to angioedema in patients with heart failure or hypertension. Most commonly, angioedema occurs during the first week of therapy but it has also been reported after long-term therapy. Patients may have multiple episodes of angioedema with long symptom free intervals.

Symptomatic hypotension:  Hypotension may occur in-patients commencing treatment with ACE inhibitors. Excessive hypotension is rarely seen in patients with uncomplicated hypertension but can develop in patients with impaired renal function, in those who are salt or volume depleted because of renovascular disease, diuretic therapy, vomiting or diarrhoea, and in patients undergoing dialysis.   In-patients with severe congestive cardiac failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with syncope, neurological deficits, oliguria and/or progressive azotaemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started at low doses under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dosage is increased or diuretic therapy is commenced or increased.

Neutropenia/agranulocytosis:  Another ACE inhibitor has been shown to cause agranulocytosis and bone marrow depression (including leucopenia and neutropenia). These reports generally involve patients who have pre-existing renal dysfunction and/or collagen vascular disease, some of whom have received concomitant immunosuppressant therapy. Most reports describe transient episodes for which a causal relationship to the ACE inhibitor could not be established. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not cause agranulocytosis at similar rates. International marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to lisinopril cannot be excluded.

INTERACTIONS WITH OTHER DRUGS

Diuretics:  When a diuretic is added to the therapy of a patient receiving an ACE inhibitor, the antihypertensive effect is usually additive. Patients receiving diuretics, especially those in whom diuretic therapy was recently instituted or those with intravascular volume depletion, may sometimes experience an excessive reduction of blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects may be minimised by discontinuing the diuretic and ensuring adequate hydration and salt intake prior to commencing ACE inhibitor therapy. If it is not possible to discontinue the diuretic, the starting dose of the ACE inhibitor should be reduced and the patient closely observed for several hours following the initial dose of the ACE inhibitor and until the blood pressure has stabilised.

Lithium:  Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Nonsteroidal anti-inflammatory drugs:  Drugs with prostaglandin synthetase inhibitory properties (e.g. indomethacin) may diminish the antihypertensive efficacy of concomitantly administered ACE inhibitors. In some patients with compromised renal function who are being treated with nonsteroidal anti-inflammatory drugs (NSAIDs), the co-administration of lisinopril may result in a further deterioration in renal function.

Agents causing renin release:  The antihypertensive effect of lisinopril is augmented by antihypertensive agents that cause renin release (e.g. diuretics).

Agents affecting sympathetic activity:  Agents affecting sympathetic activity (e.g. ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. Beta-Adrenergic blocking drugs are also antihypertensive in action, hence if they are combined with an ACE inhibitor the patient should be closely monitored.

Serum potassium:  ACE inhibitors can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. The concomitant therapy of an ACE inhibitor with a potassium sparing diuretic (e.g. spironolactone, triamterene or amiloride), potassium supplement or potassium containing salt substitute can increase the risk of hyperkalaemia. Therefore, if coadministration is indicated these agents should be used with caution and the patient's serum potassium should be monitored frequently.

Other antihypertensive agents:  When combined with other antihypertensive agents, additive falls in blood pressure may occur.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics:  The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment.  This includes use in fixed-combination products containing more than one class of drug.  Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination.  The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Antidiabetics:  Epidemiological studies have suggested that concomitant administration of an ACE inhibitor and antidiabetic medicines (such as insulins, oral hypoglycaemic agents) may cause increased blood glucose lowering effect with the risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first few weeks of combined treatment and in patients with renal impairment.

USES IN PREGNANCY AND LACTATION

As with all ACE inhibitors, Fibsol should not be taken during pregnancy.  Pregnancy should be excluded before starting treatment with Fibsol and avoided during the treatment.

If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced with another form of treatment.

USE IN LACTATION.

It is not known whether this drug is secreted in human milk. Because the possibility exists that lisinopril may be secreted in human milk, lisinopril should not be given to a breastfeeding mother.

EFFECTS ON ABILITY TO DRIVE AND OPERATE MACHINES

When driving vehicles or operating machines, patients may experience dizziness or tiredness.

UNDESIRABLE EFFECTS

Lisinopril has been found to be generally well tolerated in controlled clinical trials. For the most part, adverse experiences were mild and transient in nature.  In patients with congestive heart failure high doses of lisinopril may predispose to symptoms related to hypotension (dizziness, syncope) and biochemical changes related to impaired renal function (hyperkalaemia and increased serum creatinine), as would be expected with ACE inhibitor therapy.

Hypertension. Adverse reactions reported in 2,633 patients with hypertension follow.

More common reactions (3 to 10%)

Nervous system.        Dizziness, headache.

Less common reactions (1 to 3%)

Body as a whole.        Asthenia/ fatigue.

Cardiovascular.          Chest pain.

Gastrointestinal.        Diarrhoea, nausea, vomiting.

Respiratory.               Cough.

Dermatological.         Rash.

Rare reactions (< 1%)

Cardiovascular           Hypotension, orthostatic effects, angina, oedema, palpitation, rhythm disturbances.

Gastrointestinal         Dyspepsia, anorexia, constipation, flatulence.

Nervous system.        Paraesthesia, depression, somnolence, insomnia, vertigo.

Respiratory.               Dyspnoea, orthopnoea.

Dermatological.         Pruritus.

Musculoskeletal.        Muscle cramps, back pain, leg pain, shoulder pain.

Other.                                                 Blurred vision, fever, flushing, gout, decreased libido, malaise.

Congestive cardiac failure.

Adverse reactions reported in 636 patients with congestive cardiac failure. The most common adverse reaction occurring in this patient population was dizziness (14.2%). The other adverse reactions follow.

More common reactions (3 to 10%)

Nervous system.        Headache.

Cardiovascular.          Hypotension, chest pain, angina.

Gastrointestinal.        Diarrhoea, nausea.

Respiratory.               Cough, dyspnoea.

Dermatological.         Rash.

Body as a whole.        Asthenia/ fatigue.

Less common reactions (1 to 3%)

Cardiovascular.          Orthostatic effects, oedema, palpitation.

Gastrointestinal.        Vomiting, dyspepsia, anorexia.

Nervous system.        Paraesthesia, depression, insomnia.

Dermatological.         Pruritus.

Musculoskeletal.        Muscle cramps, back pain, leg pain.

Other.                                                 Blurred vision, fever, gout, malaise.

Rare reactions (< 1%)

Cardiovascular.          Rhythm disturbances.

Gastrointestinal.        Constipation, flatulence.

Nervous system.        Somnolence, vertigo.

Respiratory.               Orthopnoea.

Musculoskeletal.        Shoulder pain.

Other.                                                 Flushing decreased libido.

Renal and retinal complications of diabetes mellitus.

Adverse events from two clinical trials in diabetic patients (433 patients receiving lisinopril) are as follows. (The adverse events from each trial that were reported by < 1% of the patients are not included.)

More common reactions (3 to 10%)

Body as a whole.        Abdominal pain, flu syndrome.

Nervous system.        Dizziness.

Respiratory.               Bronchitis increased cough, pharyngitis.

Less common reactions (1 to 3%)

Body as a whole.        Accidental injury, asthenia, back pain, chest pain, fever, headache, infection, pain.

Cardiovascular.          Tachycardia.

Gastrointestinal.        Diarrhoea, dyspepsia, gastroenteritis, nausea.

Metabolic.                  Hyperglycaemia, hypoglycaemia.

Musculoskeletal.        Arthritis, myalgia.

Nervous system.        Vertigo.

Respiratory.               Dyspnoea, rhinitis, sinusitis, otitis media.

Dermatological.         Rash.

Genitourinary.            Cystitis, impotence, urinary tract infection.

Rare reactions (< 1%)

Body as a whole.        Generalised oedema, neck pain, pelvic pain.

Cardiovascular.          Angina pectoris, cerebral ischaemia, hypertension, palpitations.

Gastrointestinal.        Constipation, flatulence, gastritis, vomiting.

Dermatological.         Eczema.

Metabolic.                  Hyperlipidaemia, hypoglycaemic reaction, peripheral oedema.

Musculoskeletal.        Arthrosis, bursitis, pathological fracture, tendon disorder.

Nervous system.        Anxiety, depression, hypertonia, paraesthesia.

Special senses.           Ear disorder, taste perversion.

Genitourinary.            Dysuria, haematuria, kidney pain.

General.

Hypersensitivity/ angioneurotic oedema.  Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely.  In very rare cases, intestinal angioedema has been reported.

Additional adverse reactions, which occurred rarely, either during, controlled clinical trials or after the drug was marketed, include the following:

Cardiovascular.  Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, tachycardia.

Gastrointestinal.  Abdominal pain, dry mouth, hepatitis (hepatocellular and cholestatic, very rarely this may progress to hepatic failure), jaundice, pancreatitis, taste disturbance.

Musculoskeletal.  Joint pain.

Nervous system.  Mood alterations, mental confusion, stroke, sleep disturbances.

Respiratory. Bronchitis, bronchospasm, nasal congestion, pharyngeal pain, sinusitis, rhinitis.

Dermatological.  Alopecia, urticaria, diaphoresis, psoriasis and severe skin disorders have been reported, including pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme.

Genitourinary.            Uraemia, oliguria/ anuria, proteinuria, renal dysfunction, acute renal failure, impotence, urinary tract infection.

Body as a whole.  Syncope.

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/ arthritis, a positive antinuclear antibody (ANA) test, an elevated erythrocyte sedimentation rate (ESR), eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.

          Inform doctors with side effects when using medicine.

OVERDOSAGE

There are no data on overdosage in humans.  The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution.  Lisinopril may be removed from the general circulation by haemodialysis.

STORAGE: Protect from sunlight and moisture, Store below 30ºC.

HOW SUPPLIED: Box of 2 blisters x 15 tablets.

EXPIRY: 36 months from the manufacturing date.

SPECIFICATION: Manufacturer

WARNING :

• Read carefully the leaflet before use.
• For further information, please contact your doctor.
• This drug is used only by doctors’ prescription.
• Keep out of reach of children.

Manufacturer :

SIGMA PHARMACEUTICALS (AUSTRALIA) PTY LTD

7 Maitland Place, Norwest Business Park, Baulkham Hills NSW 2153, AUSTRALIA