Inspraa 25mg and 50mg FC tablet

INSPRA is indicated to reduce the risk of cardiovascular death in stable patients with left ventricular dysfunction (ejection fraction u2264 40 %) and clinical evidence of heart failure after an acute myocardial infarction.

Posology
INSPRA is usually administered in combination with standard therapies. The recommended maintenance dose of INSPRA is 50 mg once daily. The maximum dose is 50 mg daily for heart failure. Treatment should be initiated at 25 mg once daily and titrated in one step to the target dose of 50 mg once daily preferably within 4 weeks, as tolerated by the patient, taking into account the serum potassium level (see Table 1). After initiation, the dose should be adjusted based on the serum potassium level as shown in Table 1.

Table 1. Dose adjustment table in heart failure u2013 post MI
Serum potassium (mmol/L or mEq/L) Action Dose adjustment
< 5,0 Increase 25 mg EOD to 25 mg OD 25 mg OD to 50 mg OD
5,0 u2013 5,4 Maintain No dose adjustment
5,5 u2013 5,9 Decrease 50 mg OD to 25 mg OD 25 mg OD to 25 mg EOD 25 mg EOD to withhold
u2265 6,0 Withhold N/A
EOD (every other day), OD (once daily)
Following withholding INSPRA due to serum potassium u2265 6,0 mmol/L (or > 6,0 mEq/L), INSPRA can be re-started at a dose of 25 mg every other day when potassium levels have fallen below 5,0 mmol/L (or 5,0 mEq/L).

Special populations
Elderly population
No dose adjustment is required in the elderly.
Renal impairment
No initial dose adjustment is required in patients with mild renal impairment (see section 4.4). The rates of hyperkalaemia increase with declining renal function. Periodic monitoring of serum potassium with dose adjustment according to Table 1 is recommended (see section 4.4).
Hepatic impairment
No initial dosage adjustment is necessary for patients with mild to moderate hepatic impairment.
Paediatric population
There are insufficient data to recommend the use of INSPRA in the paediatric population, and therefore, use in this age group is not recommended.
Method of administration
For oral use. INSPRA may be administered with or without food.

INSPRA is contraindicated in patients with the following:
u2022 Hypersensitivity to eplerenone or to any of the excipients of INSPRA.
u2022 Clinically significant hyperkalaemia or with conditions associated with hyperkalaemia.
u2022 Serum potassium level > 5,0 mmol/L (mEq/L) at initiation.
u2022 Moderate to severe renal impairment (creatinine clearance < 50 mL/min).
u2022 Severe hepatic impairment (Child-Pugh Class C).
u2022 Concomitant use with potassium-sparing diuretics or strong inhibitors of CYP3A4 such as ketoconazole, itraconazole and ritonavir (see section 4.5).

Hyperkalaemia
Hyperkalaemia may occur with INSPRA. Serum potassium levels should be monitored in all patients at initiation of treatment and with a change in dosage. Thereafter, periodic monitoring is recommended in patients at risk for the development of hyperkalaemia. Dose reduction of INSPRA has been shown to decrease serum potassium levels. In one study, the addition of hydrochlorothiazide to INSPRA therapy has been shown to offset increases in serum potassium. The risk of hyperkalaemia may increase when INSPRA is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB).
Impaired renal function
Potassium levels should be monitored regularly in patients with impaired renal function, including patients with diabetic microalbuminuria. Patients who have serum creatinine levels > 221 u03bcmol/L (> 2,5 mg/dL) or creatinine clearance < 50 mL/min should be treated with caution. INSPRA should be used with caution in patients with type 2 diabetes mellitus (see section 4.3).
Impaired hepatic function
No elevations of serum potassium above 5,5 mmol/L were observed in patients with mild to moderate hepatic impairment. Electrolyte levels should be monitored in patients with mild to moderate hepatic impairment. The use of INSPRA in patients with severe hepatic impairment (Child-Pugh Class C) has not been evaluated and is therefore contraindicated (see section 4.3).
Non-steroidal anti-inflammatory drugs (NSAIDS)
The administration of other potassium-sparing medicines with NSAIDs has been shown to result in hyperkalaemia in patients with impaired renal function (see section 4.5).
Lithium
Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Serum lithium levels should be monitored frequently if INSPRA is administered concomitantly with lithium (see section 4.5).
CYP3A4 inducers
Co-administration of INSPRA with potent CYP3A4 inducers is not recommended (see section 4.5).
General considerations
Potassium Serum potassium should be measured before initiating INSPRA therapy, within the first week and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed periodically thereafter.
Elderly
Due to age-related decline in renal function, the risk of hyperkalaemia is increased in elderly patients. Periodic monitoring of serum potassium is recommended.
Information about the excipients of INSPRA
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Potassium-sparing diuretics
INSPRA should not be administered to patients receiving other potassium-sparing diuretics (see section 4.3).
ACE inhibitors, angiotensin receptor blockers (ARB)
The risk of hyperkalaemia may increase when INSPRA is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB). Close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function e.g. the elderly.
CYP3A4 inhibitors
Significant drug-drug pharmacokinetic interactions may occur when INSPRA is administered concomitantly with medicines that inhibit the CYP3A4 enzyme. Significant drug-drug pharmacokinetic interactions have been observed with ketoconazole, erythromycin, saquinavir, verapamil, fluconazole and ritonavir (see section 4.3). INSPRA dosing should therefore not exceed 25 mg when mild to moderate inhibitors of CYP3A4 are co-administered with INSPRA.
CYP3A4 substrates
Results of pharmacokinetic studies with CYP3A4 probe-substrates i.e. midazolam and cisapride, showed no significant pharmacokinetic interactions when these medicines were co-administered with INSPRA.
CYP3A4 inducers
Co-administration of St Johnu2019s Wort (a potent CYP 3A4 inducer) with INSPRA caused a 30 % decrease in eplerenone AUC. A more pronounced decrease in eplerenone AUC may occur with more potent CYP3A4 inducers and the concomitant use of potent CYP3A4 inducers with INSPRA is not recommended (see section 4.4).
No clinically significant drug-drug pharmacokinetic interactions have been found with digoxin or warfarin. Medicine interaction studies of INSPRA have not been conducted with NSAIDs. The administration of other potassium-sparing medicines with NSAIDs has been shown to result in severe hyperkalaemia in patients with impaired renal function (see section 4.4).
Medicine interaction studies of INSPRA have not been conducted with lithium. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors (see section 4.4).
In vitro studies indicate that INSPRA is not an inhibitor of CYP1A2, CYP2C19, CYP2C9 or CYP2D6 isozymes. INSPRA is not a substrate or an inhibitor of P-glycoprotein.

Safety and efficacy of INSPRA have not been demonstrated in pregnancy and lactation.
Pregnancy
INSPRA should not be used during pregnancy.
Breastfeeding
INSPRA should not be used during lactation. INSPRA is excreted in animal breast milk. Mothers on INSPRA should not breastfeed their infants.

No studies on the effect of INSPRA on the ability to drive or use machines have been performed. INSPRA does not cause drowsiness or impairment of cognitive function but when driving vehicles or operating machines it should be taken into account that dizziness and syncope may occur during treatment. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.

Summary of the safety profile
INSPRA has been evaluated for safety in 3 307 patients treated for heart failure post-myocardial infarction (see section 5.1). In the INSPRA post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS), the overall incidence of adverse events reported with INSPRA (78,9 %) was similar to placebo (79,5 %). The discontinuation rate due to adverse events in these studies was 4,4 % for patients receiving INSPRA and for 4,3 % patients receiving placebo.
Tabulated summary of adverse reactions
Adverse events reported below are those with suspected relationship to treatment and in excess of placebo, taken from EPHESUS. Adverse events are listed according to the system organ class and absolute frequency. Frequencies are defined as: Very common ( u2265 1/10); common ( u2265 1/100 to < 1/10); uncommon ( u2265 1/1 000 to < 1/100); rare ( u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000).

MedDRA System organ class Frequency Adverse drug reactions
Infections and infestations Common Infection Uncommon Pharyngitis
Blood and lymphatic system disorders Uncommon Eosinophilia
Endocrine disorders Uncommon Hypothyroidism
Metabolism and nutrition disorders Common Hyperkalaemia, dehydration Uncommon Hypercholesterolaemia, hypertriglyceridaemia, hyponatraemia
Psychiatric disorders Uncommon Insomnia
Nervous system disorders Common Dizziness, syncope Uncommon Hypoaesthesia, headache
Cardiac disorders Common Myocardial infarction Uncommon Left ventricular failure, atrial fibrillation
Vascular disorders Common Hypotension Uncommon Postural hypotension
Respiratory, thoracic and mediastinal disorders Common Cough
Gastrointestinal disorders Common Diarrhoea, nausea, constipation Uncommon Flatulence, vomiting
Hepatobiliary disorders Uncommon Cholecystitis
Skin and subcutaneous tissue disorders Common Pruritus Uncommon Increased sweating
Musculoskeletal and connective tissue disorders Common Muscle spasms, musculoskeletal pain Uncommon Back pain, leg cramps
Renal and urinary disorders Common Renal impairment
General disorders and administration site conditions Uncommon Asthenia, malaise
Investigations Common Increased blood urea nitrogen (BUN) Uncommon Increased blood creatinine, decreased epidermal growth factor receptor, increased blood glucose
Post-marketing side effects
MedDRA System organ class Adverse drug reactions
Skin and subcutaneous tissue disorders Angioedema, rash
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.

No cases of human overdosage with INSPRA have been reported. The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalaemia. INSPRA cannot be removed by haemodialysis. INSPRA has been shown to bind extensively to charcoal. If symptomatic hypotension should occur, supportive treatment should be initiated. If hyperkalaemia develops, standard treatment should be initiated.