Zaario 50 mg & 100 mg FC tablets

ZAARIO is indicated for the following:

• Treatment of hypertension.
• Renal protection in type 2 diabetic patients with hypertension and proteinuria.

Posology

ZAARIO may be administered with other antihypertensive medicines of a different class. Hypertension: The usual starting and maintenance dose is 50 mg once daily for most patients. The maximum antihypertensive effect is achieved 3 to 6 weeks after initiation of therapy. The dose may be increased to 100 mg once daily. For patients with intravascular volume-depletion (e.g. those treated with high-dose diuretics), a starting dose of 25 mg once daily should be considered (see section 4.4). Another formulation should be used for patients requiring a dose of 25 mg. No initial dosage adjustment is necessary for elderly patients including patients on dialysis. ZAARIO is contraindicated in patients with renal impairment, A lower dose should be considered for patients with a history of hepatic impairment (see section 4.4). Renal protection in type 2 diabetic patients with hypertension and proteinuria: The usual starting dose is 50 mg once daily. The dose may be increased to 100 mg once daily if blood pressure response indicates that it is required. ZAARIO may be administered with other antihypertensive medicines (e.g. diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting agents) as well as with insulin and other commonly used hypoglycaemic medicines (e.g. sulphonylureas, glitazones and glucosidase inhibitors).

Special populations

Use in Elderly: Although consideration should be given to initiating therapy with 25 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.

Method of administration: Losartan tablets should be swallowed whole with a glass of water. ZAARIO may be administered with or without food.

• Hypersensitivity to losartan or to any of the inactive ingredients of ZAARIO (see section 6.1).
• A history of angioedema related to previous therapy with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 ml/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis, left ventricular outflow track obstruction.
• Concomitant therapy with potassium-sparing diuretics, such as spironolactone, triamterene, and amiloride (see section 4.5).
• Porphyria.
• Lithium therapy: Concomitant administration with ZAARIO may lead to toxic blood concentrations of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of ZAARIO with renin inhibitors containing products, such as aliskiren, is contraindicated (see section 4.4 and section 4.5).
• Concomitant use of fluoroquinolones with angiotensin-converting enzyme (ACE) inhibitors or renin-angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (see section 4.4).
• ZAARIO is not recommended for patients with hepatic impairment.
• Safety and efficacy has not been established in children.

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 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.

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 renin-angiotensin 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.

System Organ Class Adverse Drug Reaction Frequency

• Infections and infestations upper respiratory infection Frequent
• Blood and the lymphatic system disorders neutropenia Less frequent
• thrombocytopaenia, anaemia Frequency unknown
• Psychiatric disorders insomnia Less frequent
• depression Frequency unknown
• Nervous system disorders headache, dizziness Frequent
• Fatigue, somnolence, sleep disorders, paraesthesia Less Frequent
• migraine, dysgeusia Frequency unknown
• Ear and labyrinth disorders vertigo Frequent
• tinnitus Frequency unknown
• Cardiac disorders palpitations, tachycardia Frequent
• angina pectoris, syncope, atrial fibrillation, cerebrovascular accident Less Frequent
• Vascular disorders orthostatic hypotension Less frequent
• vasculitis, including Henoch Schu00f6nlein purpura Frequency unknown
• Respiratory, thoracic and mediastinal disorders cough, pharyngitis, nasal congestion, sinus disorder Frequent
• respiratory tract disorders, dyspnoea Less frequent
• Gastrointestinal disorders diarrhoea, nausea, abdominal pain, dyspepsia Frequent
• obstipation, vomiting Less frequent
• Skin and subcutaneous tissue disorders Rash, urticaria, pruritus Less frequent
• erythroderma, photosensitivity Frequency unknown
• Musculoskeletal, connective tissue and bone disorders back pain, muscle cramps Frequent
• leg pain Less frequent
• myalgia, arthralgia, rhabdomyolysis Frequency unknown
• Renal and urinary disorders Renal failure, renal impairment Frequent
• Hepatobiliary disorders hepatitis Less frequent
• pancreatitis, liver function abnormalities Frequency unknown
• Immune system disorders hypersensitivity reactions, anaphylactic reactions, angioedema (including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue), vasculitis Less frequent
• Reproductive system and breast disorders erectile dysfunction/impotence Frequency unknown
• General disorders and administrative site conditions asthenia, fatigue, oedema/swelling, chest pain Frequent
• malaise Frequency unknown
• Investigations hyperkalaemia, increased alanine aminotransferase (ALT), increase in blood urea, serum creatinine and serum potassium, hypoglycaemia Frequent
• liver function abnormalities, hyponatraemia Frequency unknown

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 u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8. Reporting can also be done directly to Unicorn Pharmaceuticals (Pty) Ltd at: [email protected]

Symptoms: The symptoms of an overdosage of ZAARIO would be hypotension and tachycardia. Bradycardia could occur from parasympathetic (vagal) stimulation.

Treatment: If symptomatic hypotension should occur, supportive treatment should be instituted. Measures are depending on the time of medicinal product intake and kind and severity of symptoms. Stabilisation of the cardiovascular system should be given priority. After oral intake, the administration of a sufficient dose of activated charcoal is indicated. Afterwards, close monitoring of the vital parameters should be performed. Vital parameters should be corrected if necessary. Neither ZAARIO nor the active metabolite can be removed by haemodialysis.