Lisinopril

Concomitant treatment of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or neutral endopeptidase (NEP) inhibitors (e.g. racecadotril), vildagliptin or tissue plasminogen activator may increase the risk of angioedema.

When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. These effects are usually reversible. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic 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 patients with impaired renal function, diabetes mellitus and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), other drugs associated with increase in serum potassium (e.g. heparin, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole) and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see section 4.5).

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with lisinopril. Use of potassium sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. Care should also be taken when lisinopril is co-administered with other agents that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of lisinopril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

If lisinopril is given with a potassium-losing diuretic, diuretic-induced hypokalaemia may be ameliorated.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

When lisinopril is combined with other antihypertensive agents (e.g. glyceryl trinitrate and other nitrates, or other vasodilators), additive falls in blood pressure may occur.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.

When a diuretic is added to the therapy of a patient receiving lisinopril 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 lisinopril is added. The possibility of symptomatic hypotension with lisinopril can be minimised by discontinuing the diuretic prior to initiation of treatment with lisinopril.

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 therefore, since these patients may be volume and/or salt depleted. If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with lisinopril.

In hypertensive patients in whom the diuretic cannot be discontinued, therapy with lisinopril should be initiated with a 5 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of lisinopril should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.

There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAASthrough the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure.

Dosage in patients with renal impairment should be based on creatinine clearance as outlined in the table below.

Dosage adjustment in renal impairment:

* Dosage and/or frequency of administration should be adjusted depending on the blood pressure response.

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

Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased lithium toxicity with ACE inhibitors. Use of lisinopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.

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 re-administration of the medicinal product.

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 different class of antihypertensive agent.

Rarely, patients receiving ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

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.

As with other ACE inhibitors, lisinopril should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.

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 those in 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.

Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contra-indicated during the second and third trimester of pregnancy.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitors therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.

Because no information is available regarding the use of lisinopril during breast-feeding, lisinopril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or tiredness may occur.

The following undesirable effects have been observed and reported during treatment with lisinopril and other ACE inhibitors with the following frequencies: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Blood and the lymphatic system disorders

Rare: decreases in haemoglobin, decreases in haematocrit

Very rare: bone marrow depression, anaemia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis, haemolytic anaemia, lymphadenopathy, autoimmune disease.

Immune system disorders

Frequency not known: anaphylactic/anaphylactoid reaction

Metabolism and nutrition disorders

Very rare: hypoglycaemia

Nervous system and psychiatric disorders

Common: dizziness, headache

Uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances, hallucinations

Rare: mental confusion, olfactory disturbance

Frequency not known: depressive symptoms, syncope

Cardiac and vascular disorders

Common: orthostatic effects (including hypotension)

Uncommon: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, palpitations, tachycardia, Raynaud’s phenomenon

Respiratory, thoracic and mediastinal disorders

Common: cough

Uncommon: rhinitis

Very rare: bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia

Gastrointestinal disorders

Common: diarrhoea, vomiting

Uncommon: nausea, abdominal pain and indigestion

Rare: dry mouth

Very rare: pancreatitis, intestinal angioedema, hepatitis – either hepatocellular or cholestatic, jaundice and hepatic failure

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus

Rare: urticaria, alopecia, psoriasis, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx

Very rare: sweating, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, cutaneous pseudolymphoma

A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.

Renal and urinary disorders

Common: renal dysfunction

Rare: uraemia, acute renal failure

Very rare: oliguria/anuria

Endocrine disorders

Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Reproductive system and breast disorders

Uncommon: impotence

Rare: gynaecomastia

General disorders and administration site conditions

Uncommon: fatigue, asthenia

Investigations

Uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia

Rare: increases in serum bilirubin, hyponatraemia.

Safety data from clinical studies suggest that lisinopril is generally well tolerated in hypertensive paediatric patients, and that the safety profile in this age group is comparable to that seen in adults.