Mylan Captopril 12,5 mg/25 mg/50 mg Tablets

u2022 MYLAN CAPTOPRIL is indicated for the treatment of mild to moderate hypertension in adult patients.

u2022 It may be used alone or in combination with other antihypertensive medicines, especially thiazide-type diuretics. The blood pressure lowering effects of MYLAN CAPTOPRIL and thiazides are additive.

u2022 MYLAN CAPTOPRIL is indicated for the treatment of patients with congestive heart failure who have not responded adequately to, or cannot be controlled by conventional therapy with diuretics and/or digitalis and in whom vasodilation is indicated.

u2022 MYLAN CAPTOPRIL has been used with diuretics and digitalis.

Posology

u2022 The medicine should be taken 1 hour before meals.

u2022 The recommended initial dosage for adults is 25 mg two or three times a day.

u2022 This is increased as necessary, after 2 weeks to 50 mg three times daily.

u2022 The maximum daily dosage should not exceed 150 mg daily.

Congestive heart failure:

u2022 MYLAN CAPTOPRIL therapy must be started under close medical supervision.

u2022 It should be added to conventional therapy with diuretic (and digitalis where indicated). A much smaller dosage, 6,25 mg - 12,5 mg, three times daily is appropriate for the initiation of therapy in patients with heart failure, or in others who have received intensive therapy with diuretics.

Special populations

Renal impairment:

u2022 Reduced dosage is also indicated for patients with impaired renal function.

u2022 After the desired therapeutic effect has been achieved, the total daily dose should be reduced, or the dose intervals increased.

The following maximum daily doses are suggested as a guide to minimise accumulation:

Creatinine clearance (mu2113/min/1,75 mm 3 ) Maximum total daily dose (mg)

more than 80 450

80 - 41 300

40 - 21 150

20 - 11 75

less than 10 37,5

Method of administration

Oral use.

u2022 Hypersensitivity to the active substance captopril or to any of the excipients of MYLAN CAPTOPRIL.

u2022 Patients with a history of angioedema related to previous ACE-inhibitor therapy or angiotensin receptor blocker (ARBs). These patients must never again be given these medicines.

u2022 Hereditary or idiopathic angioedema.

u2022 Aortic stenosis.

u2022 Hypertrophic obstructive cardiomyopathy (HOCM) ( see section 4.4 ).

u2022 Severe renal function impairment (creatinine clearance below 30 ml/min).

u2022 Bilateral renal stenosis or renal artery stenosis in patients with a single kidney.

u2022 Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride ( see section 4.5).

u2022 Porphyria.

u2022 Lithium therapy: Concomitant administration with MYLAN CAPTOPRIL may lead to toxic blood concentration of lithium (see section 4.5) .

u2022 Pregnancy and lactation ( see section 4.6 ).

u2022 The concomitant use of MYLAN CAPTOPRIL with aliskiren-containing products is contraindicated (see section 4.4 and 4.5) .

u2022 Concomitant use of fluoroquinolones with ACE inhibitors/Renin-Angiotensin blockers is contraindicated in patients with moderate to severe renal impairment.

u2022 Concomitant use with sacubitril/valsartan therapy. MYLAN CAPTOPRIL must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan ( see section 4.4 and 4.5).

MYLAN CAPTOPRIL should be used with caution in the following conditions:

Pregnancy:

u2022 If a woman is contemplating pregnancy, a different class of medicine should be used ( see section 4.6 ).

u2022 ACE-inhibitors pass through the placenta and can be presumed to cause disturbances in foetal blood pressure regulatory mechanisms. Oligohydramnios, as well as hypotension, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors such as MYLAN CAPTOPRIL in the second and third trimesters.

u2022 Cases of defective skull ossification have been observed.

u2022 Prematurity and low birth mass can occur.

Cerebrovascular disease or ischaemic heart disease:

u2022 Reduction in blood pressure could aggravate these conditions and may result in myocardial infarction and cerebrovascular accidents. Should a woman become pregnant while receiving MYLAN CAPTOPRIL, the treatment must be stopped promptly and switched to a different antihypertensive medicine ( see section 4.3 & 4.6 ).

u2022 Myocardial infarction and cerebrovascular accidents may be due to severe fall in blood pressure in high-risk patients, e.g. those with ischaemic heart disease or cerebrovascular disease.

u2022 In volume depleted patients or patients with ischaemic heart disease or cerebrovascular disease, therapy should be monitored, especially when the dose of MYLAN CAPTOPRIL or diuretic is adjusted (see sub-header u2018 Volume depleted patients u2019).

u2022 If hypotension occurs, the patient should be placed in the supine position, and if necessary, receive an intravenous infusion of 0,9 % saline.

Volume depleted patients (e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting):

u2022 Although it may occur in normo volumic patients, hypotension is more likely in volume depleted patients.

u2022 A sudden reduction in angiotensin II may result in sudden and severe hypotension. There is also an increased risk of MYLAN CAPTOPRIL induced renal failure, especially in those with congestive heart failure.

u2022 Patients at a high risk of symptomatic hypotension, e.g., patients with salt or volume depletion, with or without hyponatraemia, should have these conditions corrected before therapy with MYLAN CAPTOPRIL. Monitoring is required after initiating therapy.

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

u2022 There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers (ARBs) or 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 MYLAN CAPTOPRIL and aliskiren is therefore contraindicated (see section 4.3 ).

u2022 MYLAN CAPTOPRIL should not be used concomitantly with aliskiren (see section 4.3 )

Hypotension in acute myocardial infarction:

u2022 Treatment with MYLAN CAPTOPRIL must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator.

u2022 These include patients with systolic blood pressure of 100 mmHg or lower or cardiogenic shock.

u2022 During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mmHg or lower.

u2022 Maintenance doses should be reduced to 5 mg or temporarily to 2,5 mg if systolic blood pressure is 100 mmHg or lower.

u2022 If hypotension persists (systolic blood pressure less than 90 mmHg or more than 1 hour) then MYLAN CAPTOPRIL should be withdrawn.

u2022 In acute myocardial infarction, treatment with MYLAN CAPTOPRIL should not be initiated in patients with evidence of renal dysfunction (serum creatinine concentrations exceeding 177 micromol/l or proteinuria exceeding 500 mg/24 hours). If renal dysfunction develops during treatment (serum creatinine concentrations exceeding 177 micromol/l or doubling of the pre-treatment value) then MYLAN CAPTOPRIL may need to be withdrawn (see section 4.3 ).

u2022 In acute myocardial infarction, patients may develop persistent hypotension and/or impaired renal function.

Bone marrow depression:

u2022 Increased risk of agranulocytosis and neutropaenia.

Diabetic patients:

u2022 Diabetes mellitus u2013 Increased risk of hyperkalaemia, as well as hypoglycaemia may occur.

Hyperkalaemia:

u2022 MYLAN CAPTOPRIL may cause an increase in serum potassium levels.

u2022 Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene and amiloride is contraindicated ( see section 4.3) . Concomitant use may lead to hyperkalaemia, which may be severe and lead to cardiac conduction abnormalities, dysarrythmias and cardiac arrest ( see section 4.5 ).

u2022 Diabetics, and elderly diabetics particularly, may be at increased risk of hyperkalaemia. It is recommended that patients taking an ACE inhibitor, such as MYLAN CAPTOPRIL, should have serum electrolytes (including potassium, sodium, and urea) measured frequently.

Renovascular disease:

u2022 MYLAN CAPTOPRIL should not be used in patients with renovascular disease or suspected renovascular disease, but it may be used cautiously in severe resistant hypertension in such patients. In this instance MYLAN CAPTOPRIL should only be used under specialist supervision.

u2022 The elderly, patients with peripheral vascular diseases or generalised atherosclerosis may have asymptomatic renovascular disease (see section 4.2).

u2022 Increases in blood urea and serum creatinine have been seen in patients with no apparent pre-existing vascular disease, especially when MYLAN CAPTOPRIL has been given concomitantly with a diuretic. Dosage reduction or discontinuation of MYLAN CAPTOPRIL or the diuretic may be required.

Renal artery stenosis:

u2022 Renal artery stenosis, bilateral or in one kidney or renal transplant u2013 Increased risk of renal function impairment which may lead to an increase in blood urea and serum creatinine concentrations which may be reversible upon discontinuation of therapy.

u2022 There is also an increased risk of agranulocytosis and neutropaenia when immunosuppressants are concurrently administered ( see sub-header u2018 N eutropenia/Agranulocytosisu2019).

Renal function impairment:

u2022 Concomitant use of fluoroquinolones and ACE inhibitors/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 fluoroquinolones or ACE inhibitors/renin-angiotensin receptor blockers.

u2022 Decreased elimination of MYLAN CAPTOPRIL resulting in an increased risk of hyperkalaemia. These patients may require lower doses ( see sub-header u2018Hyperkalaemiau2019).

Anaphylactoid reactions during desensitisation:

u2022 Anaphylactoid reactions have occurred in patients using ACE inhibitors, including MYLAN CAPTOPRIL during desensitising protocols involving for example, hymenoptera venom.

Anaphylactoid reactions during high-flux dialysis / lipoprotein apheresis membrane exposure:

u2022 Anaphylactoid reactions have been reported in patients exposed to either high-flux membrane dialysis or low-density lipoprotein apheresis with dextran sulfate absorption.

Hypersensitivity/Angioedema:

u2022 If angioedema of the face, extremities, lips, tongue, glottis and/or larynx is observed in patients treated with MYLAN CAPTOPRIL, MYLAN CAPTOPRIL should be discontinued promptly. These patients should be monitored to ensure complete resolution of symptoms.

u2022 Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate emergency therapy should be administered. This may include the administration of adrenaline and/or the maintenance of a patientu2019s airway.

u2022 The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.

u2022 These patients should never receive any MYLAN CAPTOPRIL, ACE-inhibitors or angiotensin-receptor blockers again.

u2022 Concomitant use of ACE inhibitors with sacubitril/valsartan is not recommended due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of captopril. Treatment with MYLAN CAPTOPRIL must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan ( see sections 4.3 and 4.5).

u2022 Intestinal angioedema may occur in patients treated with MYLAN CAPTOPRIL with symptoms such as abdominal pain (with or without nausea or vomiting).

u2022 Patients receiving coadministration of an ACE inhibitor such as MYLAN CAPTOPRIL and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or vildagliptin may be at increased risk for angioedema ( see section 4.5).

u2022 Ethnic differences: MYLAN CAPTOPRIL causes a higher rate of angioedema in black patients than in non-black patients.

Surgery/Anaesthesia:

u2022 In patients undergoing major surgery or during anaesthesia with agents medicines that produce hypotension, MYLAN CAPTOPRIL may block angiotensin II formation secondary to complementary rennin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Neutropenia/Agranulocytosis:

MYLAN CAPTOPRIL should be used with caution in the following conditions:

u2022 Autoimmune disease, especially systemic lupus erythematosus, other collagen vascular disease or scleroderma, increase the risk for development of neutropaenia or agranulocytosis.

u2022 All patients receiving MYLAN CAPTOPRIL should be instructed to report any signs of infection (e.g.: sore throat or fever) to their doctor.

u2022 If MYLAN CAPTOPRIL is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately two-week intervals for about three months, then periodically (see sub- header u2018Renal artery stenosisu2019).

Proteinuria:

u2022 Patients with prior renal disease or those receiving MYLAN CAPTOPRIL should have urinary protein estimations (dipstick on first morning urine) prior to treatment, and periodically thereafter.

Anaemia:

u2022 Anaemia with reduced haemoglobin levels was reported in renal transplants or haemodialysis patients. It is reversible upon MYLAN CAPTOPRIL discontinuation.

Cough:

u2022 A persistent dry (non-productive) cough may occur with MYLAN CAPTOPRIL.

Use in hepatic impairment:

u2022 Patients receiving MYLAN CAPTOPRIL who develop jaundice or marked elevations of hepatic enzymes should discontinue MYLAN CAPTOPRIL.

Effects on laboratory tests:

u2022 MYLAN CAPTOPRIL may cause a false-positive urine test for acetone.

Paediatric Population:

u2022 Safety and efficacy in children have not been established.

Lactose warning:

u2022 MYLAN CAPTOPRIL contains lactose which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take MYLAN CAPTOPRIL.

Concomitant use of MYLAN CAPTOPRIL with:

Diuretics, alcohol, anti-hypertensive and other hypotension-producing medicines:

u2022 The antihypertensive effect is additive.

u2022 Dosage adjustments may be necessary during concurrent use or when one medicine is discontinued.

u2022 Medicines affecting sympathetic activity: The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving MYLAN CAPTOPRIL alone or with diuretics. Therefore, medicines affecting sympathetic activity (e.g.: ganglionic blocking medicines or adrenergic neuron blocking medicines) should be used with caution.

Loop, thiazide or related diuretics:

u2022 u201cFirst dose hypotensionu201d may occur (see section 4.2).

Potassium supplements or potassium sparing diuretics:

u2022 Potassium supplements or potassium sparing diuretics such as spironolactone, triamterene or amiloride is contraindicated ( see section 4.3) . Concurrent administration may result in hyperkalaemia ( see section 4.4).

Combination with non-steroidal anti-inflammatory medicines (NSAIDs):

u2022 When ACE-inhibitors are administered simultaneously with non-steroidal anti- inflammatory medicines (i.e., selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) 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.

u2022 The combination should be administered with caution, especially in the elderly and in volume depleted patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

u2022 Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with MYLAN CAPTOPRIL.

Lithium:

u2022 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 risk of lithium toxicity with ACE inhibitors.

u2022 Use of MYLAN CAPTOPRIL with lithium is not recommended ( see section 4.3).

Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury (see section 4.3).

Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren:

u2022 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 (see section 4.3 & 4.4).

Medicines with vasodilator activity:

u2022 Glyceryl trinitrate or other nitrates (as used for management of angina) or other medicines with vasodilator activity should be discontinued before starting MYLAN CAPTOPRIL.

Haemodialysis membranes:

u2022 Hypersensitivity-like (anaphylactoid) reactions have been reported with high-flux dialysis membranes ( see section 4.4).

Mammalian Target of Rapamycin (mTOR) Inhibitors:

u2022 Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) medicine may be at increased risk for angioedema.

Combination of ACE inhibitors and vildagliptin:

u2022 Patients taking concomitant vildagliptin medicine may be at an increased risk of angioedema.

Combination of ACE inhibitors and sacubitril/valsartan:

u2022 Concomitant use of MYLAN CAPTOPRIL with sacubitril/valsartan is not recommended as this increases the risk of angioedema ( see section 4.3).

Allopurinol, procainamide, cytostatic, or immuno-suppressive agents:

u2022 Concomitant administration with MYLAN CAPTOPRIL may lead to an increased risk of leukopenia.

Tricyclic anti-depressants, neuroleptics, amifostine, baclofen:

u2022 Co-administration of these medicines with MYLAN CAPTOPRIL may potentially increase antihypertensive effects and risk of postural hypotension.

Antidiabetics:

u2022 MYLAN CAPTOPRIL can potentiate the blood glucose-reducing effects of insulin and oral antidiabetics such as sulphonylurea in diabetics.

Gold:

u2022 Nitritoid reactions with symptoms such as flushing, dizziness, nausea, vomiting and drop in blood pressure up to circulatory collapse have been reported in patients treated with ACE inhibitors such as MYLAN CAPTOPRIL and injectable gold preparations (sodium aurothiomalate) at the same time.

Pregnancy

u2022 MYLAN CAPTOPRIL is contraindicated during pregnancy ( see section 4.3 ).

u2022 ACE-inhibitors, such as MYLAN CAPTOPRIL, can cause foetal morbidity and death.

u2022 Pregnant women should be informed of the potential hazards to the foetus and must not take MYLAN CAPTOPRIL during pregnancy ( see section 4.3) .

u2022 Patients planning pregnancy should be changed to alternative anti-hypertensive medicines which have an established safety profile for use in pregnancy.

u2022 When pregnancy is diagnosed, treatment with MYLAN CAPTOPRIL should be stopped immediately and if appropriate, alternative therapy should be started.

u2022 Foetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spins bifida) and of kidney malformations.

u2022 MYLAN CAPTOPRIL passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in newborns, have been reported after administration of MYLAN CAPTOPRIL during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur ( see section 4.3 ).

Breastfeeding

u2022 Safety in breastfeeding has not been established.

Fertility

u2022 No information available.

MYLAN CAPTOPRIL may cause dizziness and may have minor to moderate influence on mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision. Caution should therefore to be taken when driving or performing tasks requiring alertness because of possible dizziness.

MYLAN CAPTOPRIL tablets can have undesirable effects.

Tabulated list of adverse reactions

Body system Frequent Less frequent

Blood and the lymphatic system disorders: Decrease in white blood cell count, haemoglobin and haemotocrit, bone marrow suppresion, anaemia, thrombocytopaenia, haemolytic anaemia, agranulocytosis, neutropenia, eosinophilia, pancytopenia, auto- immune disease

Immune system disorders: Hypersensitivity /angioedema reactions -serious or life- threatening ( see section 4.4) , serum sickness-like syndrome

Metabolism and nutrition disorders: Hyperkalaemia, hyponatraemia, hypoglycaemia

Psychiatric disorders: Mood alterations, sleep disorders, mental confusion

Nervous system disorders: Dizziness Headache, fatigue, paraesthesia, vertigo, malaise, drowsiness

Eye disorders: Disturbed vision, itching and/or dry eyes

Cardiac disorders: Orthostatic effects (including hypotension, myocardial infarction, cerebrovascular accident, tachycardia, palpitations, schest pain, angina pectoris, Raynaud's phenomenon and congestive heart failure, cardiac arrest, rhythm disturbances/orthostatic hypotension, syncope

Respiratory, thoracic and mediastinal disorders: Cough Bronchospasm, sinusitis, rhinitis, dyspnoea

Gastrointestinal disorders: Diarrhoea, nausea, abdominal pain, indigestion, dry mouth, vomiting, taste disturbances

Glossitis, pancreatitis, intestinal angioedema and constipation, stomatitis, aphthous ulcers, tongue ulceration, peptic ulcer and a scalded sensation of the oral mucosa

Hepato-biliary disorders: Hepatitis (hepatocellular or cholestatic) jaundice, increases in serum bilirubin, increased liver enzymes

Skin and subcutaneous tissue disorders: Photosensitivity or other dermatological manifestations may occur, diaphoresis, alopecia, psoriasis, severe skin disorders including bullous pemphigus, toxic epidermal necrolysis, Stevens- Johnson Syndrome and erythema multiforme, angioedema of the face, which may be fatal, extremities, lips, tongue, glottis and/or larynx, angio-oedema, rash, urticaria, pruritus, exfoliative dermatitis

Musculoskeletal, connective tissue and bone disorders: Asthenia, myalgia

Renal and urinary disorders: Ureamia, oliguria, anuria, renal dysfuntion, acute renal failure , proteinuria ( see section 4.4 ), polyuria, increased urinary frequency, nephrotic syndrome and glomerulopathy

Reproductive system and breast disorders: Impotence, loss of libido, gynecomastia

General disorders and administrative site conditions: A symptom complex has been reported which may include: fever, vasculitis, positive antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate, eosinophilia and leucocytosis

Investigations: Increased blood urea, increased blood creatinine, increased liver transaminases, alkaline phosphatase and serum bilirubin, increases in serum potassium ( see section 4.4)

Post-marketing experience:

Body system Frequency not known

Musculoskeletal, connective tissue and bone disorders: Myasthenia

Psychiatric disorders: Ataxia, confusion, depression, somnolence

Nervous system disorders: Nervousness

Respiratory, thoracic and mediastinal disorders: Eosinophilic pneumonitis, rhinitis

As with other ACE inhibitors, a syndrome has been reported which may include fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated (erythrocyte sedimentation rate ) ESR.

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. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c 6.04 Adverse Drug Reactions Reporting Form u201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

In overdose, undesirable effects can be precipitated and/or be of increased severity ( see section 4.8) .

Symptoms of overdose: Severe hypotension, electrolyte disturbances and renal failure.

Treatment of overdose:

u2022 Treatment is supportive and symptomatic.

u2022 Activated charcoal may be given in severe overdosage if the patient presents within 1 hour of ingestion.

u2022 Treatment consists of volume expansion to correct hypotension and treating dehydration and electrolyte imbalances.

u2022 MYLAN CAPTOPRIL is removable by haemodialysis.