Amizart 50mg & 100mg FC Tablets

AMIZART is indicated for the treatment of hypertension. Renal protection in type 2 diabetic patients with hypertension and proteinuria.

AMIZART may be administered with or without food. AMIZART may be administered with other antihypertensive medicines.

Hypertension
The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 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).

No initial dosage adjustment is necessary for the elderly patients or for patients with renal impairment, including patients on dialysis. 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 based on blood pressure response. AMIZART may be administered with other antihypertensive medicines (e.g. diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting medicines) as well as with insulin and other commonly used hypoglycaemic medicines (e.g. sulfonylureas, glitazones and glucosidase inhibitors).

Method of administration
For oral use.

AMIZART is contraindicated in patients:

• who are hypersensitive to losartan or any of the ingredients of AMIZART listed in section 6.1.
• with a history of angioedema related to previous therapy with ACE-inhibitors or angiotensin receptor antagonists. These patients must never again be given these medicines.
• with hereditary or idiopathic angioedema.
• with hypertrophic obstructive cardiomyopathy (HOCM).
• with severe renal impairment (creatinine clearance less than 30 ml/min) or for patients with hepatic impairment.
• with aortic stenosis, left ventricular outflow track obstruction.
• with bilateral renal artery stenosis.
• with renal artery stenosis in patients with a single kidney.
• taking concomitant therapy with potassium sparing diuretics such as spirinolactone, triamterene and amiloride.
• the concomitant use of fluoroquinolones with ACE inhibitors/angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (creatinine clearance u2264 30 ml/min) and in elderly patients.
• with porphyria.
• on lithium therapy - concomitant administration with AMIZART may lead to toxic blood concentrations of lithium.
• pregnancy and lactation (see section 4.6).
• the concomitant use of AMIZART with aliskiren-containing medicines is contraindicated.

Should a woman become pregnant while receiving AMIZART, the treatment must be stopped promptly and changed to a different medicine. If a woman is contemplating pregnancy, a different class of medicine should be used (see section 4.6).

Hypersensitivity
Angioedema. Patients with a history of angioedema (swelling of the face, lips, throat, and/or tongue) should be closely monitored (see section 4.8).

Hypotension and electrolyte/fluid imbalance
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. These conditions should be corrected prior to administration of AMIZART, or a lower starting dose should be used. This also applies to children 6 to 18 years of age.

Electrolyte imbalances
Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with nephropathy, the incidence of hyperkalaemia was higher in the group treated with losartan as compared to the placebo group (see section 4.8). Therefore, the plasma concentrations of potassium as well as creatinine clearance values should be closely monitored, especially patients with heart failure and a creatinine clearance between 30 - 50 mL/min should be closely monitored. 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) with losartan is not recommended (see section 4.5).

Hepatic impairment
Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore, AMIZART must not be administered in patients with severe hepatic impairment (see sections 5.2).

Renal impairment
As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported (in particular, in patients whose renal function is dependent on the renin-angiotensin-aldosterone system such as those with severe cardiac insufficiency or pre-existing renal dysfunction). Increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; these changes in renal function may be reversible upon discontinuation of therapy. AMIZART is contraindicated in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Concomitant use of fluoroquinolones and ACE inhibitors/angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or ACE inhibitors/angiotensin receptor blockers whether used separately and/or concomitantly.

Use in paediatric patients with renal impairment
Losartan is not recommended in children with glomerular filtration rate < 30 mL/min/1.73 m2 as no data are available. Renal function should be regularly monitored during treatment with AMIZART as it may deteriorate. This applies particularly when AMIZART is given in the presence of other conditions (fever, dehydration) likely to impair renal function. Concomitant use of AMIZART and ACE-inhibitors has been shown to impair renal function. Therefore, concomitant use is not recommended (see section 4.5).

Renal transplantation
There is no experience in patients with recent kidney transplantation.

Primary hyperaldosteronism
Patients with primary aldosteronism generally will not respond to antihypertensive medicines acting through inhibition of the renin-angiotensin system. Therefore, the use of losartan is not recommended.

Coronary heart disease and cerebrovascular disease
Excessive blood pressure decreases in patients with ischaemic cardiovascular and cerebrovascular disease and 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 (often acute) 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 dysrhythmias. Therefore, AMIZART should be used with caution in these patient groups. The combination of AMIZART with a beta-blocker should be used with caution (see section 5.1).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
Special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Other warnings and precautions
Losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

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 aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore contraindicated (see section 4.3). AMIZART should not be used concomitantly with aliskerin (see section 4.3).

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

Excipients
AMIZART contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take AMIZART.

Other antihypertensive medicines may increase the hypotensive action of losartan. Concomitant use with other substances which may induce hypotension as an adverse reaction (like tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of hypotension. Losartan is predominantly metabolised by cytochrome P450 (CYP) 2C9 to the active carboxy-acid metabolite. In a clinical trial it was found that fluconazole (inhibitor of CYP2C9) decreases the exposure to the active metabolite by approximately 50 %. It was found that concomitant treatment of losartan with rifampicin (inducer of metabolism enzymes) gave a 40 % reduction in plasma concentration of the active metabolite. The clinical relevance of this effect is unknown. No difference in exposure was found with concomitant treatment with fluvastatin (weak inhibitor of CYP2C9). Concomitant use of other medicines which retain potassium (e.g. potassium-sparing diuretics: amiloride, triamterene, spironolactone) or may increase potassium levels (e.g. heparin, trimethoprim-containing products), potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium. Co-medication is not advisable. Concomitant use of fluoroquinolones and ACE inhibitors/angiotensin receptor blockers may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3). Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Very rare cases have also been reported with angiotensin II receptor antagonists. Co-administration of lithium and losartan should be undertaken with caution. If this combination proves essential, serum lithium level monitoring is recommended during concomitant use. When angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonists or diuretics 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. 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. Clinical trial data have 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 medicine (see sections 4.4 and 5.1).

Women of childbearing potential
Women of childbearing age should ensure adequate contraception.

Pregnancy
The use of AMIZART is contraindicated during pregnancy (see section 4.3). Patients planning pregnancy should be changed to alternative anti-hypertensive treatments, which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with losartan should be stopped immediately and, if appropriate, alternative therapy should be started.

Breastfeeding
AMIZART is contraindicated during lactation (see section 4.3). It is not known whether losartan is excreted in human milk. Safety of breastfeeding in mothers, taking AMIZART has not been established. However, significant levels of losartan and the active metabolite were shown to be present in rat milk.

Fertility
No data is available on fertility.

No studies on the effects of the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, 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.

Adverse reaction Frequency of adverse reaction by indication Other Hypertension Hypertensive patients with left-ventricular hypertrophy Chronic heart failure Hypertension and type 2 diabetes with renal disease Post-marketing experience

• Blood and lymphatic system disorders
  Anaemia Frequent Frequency not known
  Thrombocytopaenia Frequency not known
• Immune system disorders
  Hypersensitivity reactions, anaphylactic reactions, angioedema*, and vasculitis** Less frequent
• Psychiatric disorders
  Depression Frequency not known
• Nervous system disorders
  Dizziness Frequent Frequent Frequent Frequent
  Somnolence Less frequent
  Headache Less frequent Less frequent
  Sleep disorders Less frequent
  Paraesthesia Less frequent
  Migraine Frequency not known
  Dysgeusia Frequency not known
• Ear and labyrinth disorders
  Vertigo Frequent Frequent
  Tinnitus Frequency not known
• Cardiac disorders
  Palpitations Less frequent
  Angina pectoris Less frequent
  Syncope Less frequent
  Atrial fibrillation Less frequent
  Cerebrovascular accident Less frequent
• Vascular disorders
  (Orthostatic) hypotension (including dose-related orthostatic effects) u2551 Less frequent Frequent Frequent
• Respiratory, thoracic and mediastinal disorders
  Dyspnoea Less frequent
  Cough Less frequent
  Frequency not known
• Gastrointestinal disorders
  Abdominal pain Less frequent
  Obstipation Less frequent
  Diarrhoea Less frequent
  Frequency not known
  Nausea Less frequent
  Vomiting Less frequent
• Hepatobiliary disorders
  Pancreatitis Frequency not known
  Hepatitis Less frequent
  Liver function abnormalities Frequency not known
• Skin and subcutaneous tissue disorders
  Urticaria Less frequent
  Frequency not known
  Pruritus Less frequent
  Frequency not known
  Rash Less frequent Less frequent
  Frequency not known
  Photosensitivity Frequency not known
• Musculoskeletal and connective tissue disorders
  Myalgia Frequency not known
  Arthralgia Frequency not known
  Rhabdomyolysis Frequency not known
• Renal and urinary disorders
  Renal impairment Frequent
  Renal failure Frequent
• Reproductive system and breast disorders
  Erectile dysfunction/ impotence Frequency not known
• General disorders and administrative site conditions
  Asthenia Less frequent Frequent Less frequent Frequent
  Fatigue Less frequent Frequent Less frequent Frequent
  Oedema Less frequent
  Malaise Frequency not known
• Investigations
  Hyperkalaemia Frequent Less frequentu2020 Frequentu2021
  Increased alanine aminotransferase (ALT) u00a7 Less frequent
  Increase in blood urea, serum creatinine, and serum potassium Frequent
  Hyponatraemia Frequency not known
  Hypoglycaemia Frequent

* Including swelling of the larynx, glottis, face, lips, pharynx, and/or tongue (causing airway obstruction); in some of these patientsu2019 angioedema had been reported in the past in connection with the administration of other medicines, including ACE inhibitors. **Including Henoch-Schu00f6nlein purpura. u2551Especially in patients with intravascular depletion, e.g. patients with severe heart failure or under treatment with high dose diuretics. u2020Common in patients who received 150 mg losartan instead of 50 mg. u2021In a clinical study conducted in type 2 diabetic patients with nephropathy, 9.9 % of patients treated with Losartan tablets developed hyperkalaemia > 5.5 mmol/l and 3.4 % of patients treated with placebo.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function including renal failure have been reported in patients at risk; these changes in renal function may be reversible upon discontinuation of therapy (see section 4.4).

Paediatric population
The adverse reaction profile for paediatric patients appears to be similar to that seen in adult patients. Data in the paediatric population are limited.

Reporting of suspected adverse reactions
Reporting of 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

Symptoms of overdose
Limited data are available with regard to overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia. Bradycardia could occur from parasympathetic (vagal) stimulation.

Treatment of overdose
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 losartan nor the active metabolite can be removed by haemodialysis.