ZAARIO Film-coated tablet Ref.[108829] Active ingredients: Losartan

Should a woman become pregnant while receiving ZAARIO, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine. Should a woman contemplate pregnancy, the doctor should consider alternative medication (see section 4.6).

Serum potassium levels should be monitored regularly.

Hypersensitivity

Angioedema may occur in patients treated with ZAARIO. Patients with a history of angioedema (swelling of the face, lips, throat and/or tongue) should be monitored closely (see section 4.8).

Hypotension and electrolyte/fluid imbalance

Symptomatic hypotension may occur after initiation of ZAARIO.

Symptomatic hypotension, especially after the first dose and after increasing of the dose, may occur in patients who are volume- and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Volume depletion and electrolyte imbalances should be corrected prior to administration of ZAARIO or a lower starting dose should be used (see section 4.2).

Electrolyte imbalances are common in patients with renal impairment, with or without diabetes and should be addressed.

Hepatic impairment

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a dose of 25 mg should be considered for patients with a history of hepatic impairment (see section 4.2).

Renal impairment

When impaired renal function is present, changes in renal function as a consequence of inhibiting the renin-angiotensin system, including renal failure, have been reported in susceptible individuals; in some patients these changes in renal function may be reversible upon discontinuation of therapy.

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (less frequently) with acute renal failure and/or death. Similar outcomes have been reported with ZAARIO.

Medicines affecting the renin-angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with ZAARIO; these changes in renal function may be reversible upon discontinuation of therapy (see section 4.3).

There is no experience in patients who have received kidney transplantation.

Acute kidney injury

Concomitant use of fluoroquinolones and angiotensin-converting enzyme (ACE) inhibitors or renin-angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with and ACE inhibitors or renin-angiotensin receptor blockers.

Primary hyperaldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medical products acting through inhibition of the renin-angiotensin system. Therefore, the use of ZAARIO is not recommended.

Hyperkalaemia

Since hyperkalaemia may occur, serum-potassium concentrations should be monitored, especially in the elderly and patients with renal impairment and the concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicines that may increase serum potassium (e.g., trimethoprim-containing products) should be avoided (see section 4.3 and section 4.5).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers (ARBs) or renin inhibitors, such as aliskiren may increase the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ZAARIO and renin inhibitors, such as aliskiren is therefore contraindicated (see section 4.3).

ZAARIO should not be used concomitantly with renin inhibitors, such as aliskiren (see section 4.3). 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.

Other conditions with stimulation of the renin-angiotensin-aldosterone system (RAAS)

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors has been associated with oliguria and/or progressive uraemia and (less frequently) with acute renal failure and/or death. Similar outcomes are likely with ZAARIO therapy. As with other angiotensin converting enzyme inhibitors, losartan, as in ZAARIO, is apparently less effective in lowering blood pressure in the black population than in the non-black population, possibly because of higher prevalence of low-renin states in the black hypertensive population.

Coronary heart disease and cerebrovascular disease

As with any antihypertensive agents, excessive blood pressure decrease in patients with ischaemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke.

Heart failure

In patients with heart failure with or without renal impairment, there is a risk of severe arterial hypotension and renal impairment. There is no sufficient therapeutic experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA class IV) as well as in patients with heart failure and symptomatic life-threatening cardiac arrhythmias. Therefore, losartan should be used with caution in these patient groups. The combination of losartan with a beta-blocker should be used with caution.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Porphyria

Limited information is available regarding the effect of antihypertensive medicine in patients with porphyria. Safety of ZAARIO has not been established.

ZAARIO contains lactose monohydrate:

Patients with the rare hereditary conditions of lactose or galactose intolerance, e.g. galactosaemia, Lapp lactase deficiency, or glucose-galactose malabsorption should not take ZAARIO.

Other antihypertensive agents may increase the hypotensive action of losartan. Concomitant use with other medicines which may induce hypotension as an adverse reaction (like tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of hypotension.

Dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or renin inhibitors, such as aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function compared to the use of a single RAAS-acting medicine (see section 4.3 and section 4.4). Concomitant use of fluoroquinolones and angiotensin-converting enzyme (ACE) inhibitors or reninangiotensin receptor blockers may precipitate acute kidney injury (see section 4.3 and section 4.4).

Potassium-sparing diuretics, potassium-containing medicine or potassium supplements used concurrently with ZAARIO may result in hyperkalaemia since reduction of aldosterone production induced by ZAARIO may lead to elevation of serum potassium. Co-medication is not advisable.

As with other medicines which affect the excretion of sodium, lithium excretion may be reduced and serum lithium concentrations increased during concomitant administration of lithium with ACE inhibitors and with angiotensin II antagonists, including losartan, as in ZAARIO. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists (see section 4.3).

Nonsteroidal anti-inflammatory medicines (NSAIDs), including cyclo-oxygenase-2 inhibitors, may reduce the effect of diuretics and the antihypertensive effect of ZAARIO. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors. Patients taking NSAIDs concomitantly with ZAARIO should be adequately hydrated and renal function should be monitored.

ZAARIO is predominantly metabolised by cytochrome P450 CYP2C9 to the active carboxy-acid metabolite and interactions may occur with medicines that effect these enzymes. Fluconazole (inhibitor of CYP2C9) decreases the exposure to the active metabolite by approximately 50%. Concomitant treatment of ZAARIO with rifampicin (inducer of metabolism enzymes) provides a 40% reduction in plasma concentration of the active metabolite. No difference in exposure was found with concomitant treatment with fluvastatin (weak inhibitor of CYP2C9).

Women of childbearing potential

Women of childbearing age should ensure adequate contraception. ZAARIO should be discontinued immediately, when pregnancy is planned or suspected.

Pregnancy

ZAARIO should not be used in pregnancy (see section 4.3). When pregnancy is detected, ZAARIO should be discontinued as soon as possible.

Medicines affecting the renin-angiotensin system, such as ZAARIO, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women. Infants whose mothers have taken losartan should be closely observed for hypotension

Lactation

Safety has not been established. ZAARIO should not be used during breastfeeding. Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a new-born or preterm infant.

Patients should not drive, operate machinery, or do anything else that requires attention until they know how ZAARIO will affect them. It must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Reporting can also be done directly to Unicorn Pharmaceuticals (Pty) Ltd at: vigilance@unicornpharma.co.za

Not applicable.