Eplenocard: composition and pharmaceutical form
One tablet contains 25 mg or 50 mg of eplerenone. The two strengths exist precisely so that the dose can be tailored to the individual; the maximum daily dose is 50 mg.
The medicine may be taken with food or independently of it. The tablets contain lactose, so they should not be used in rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.
How Eplenocard works
Eplerenone shows relative selectivity of binding to recombinant human mineralocorticoid receptors compared with binding to glucocorticoid, progesterone and androgen receptors. It prevents the binding of aldosterone, the key hormone of the renin-angiotensin-aldosterone system, which is involved in blood pressure regulation and in the pathophysiology of cardiovascular disease.
Eplerenone has been shown to produce a sustained rise in plasma renin activity and in serum aldosterone concentration. This follows from the reduced inhibitory effect of aldosterone on renin secretion — regulation by negative feedback. The resulting increase in plasma renin activity and in circulating aldosterone does not weaken the action of eplerenone.
Indications
Eplerenone is prescribed as therapy added to standard treatment, and both indications concern heart failure with impaired left ventricular function.
The aim in both cases is the same: to reduce the risk of cardiovascular mortality and morbidity.
- an addition to standard treatment including beta-blockers in stable patients with left ventricular dysfunction — ejection fraction of no more than 40% — and clinical signs of heart failure after a recent myocardial infarction;
- an addition to standard treatment in adult patients with chronic heart failure of NYHA class II and left ventricular dysfunction with an ejection fraction of no more than 30%.
Method of use and dosage
The regimen is the same for both indications: treatment starts at 25 mg once daily and is raised gradually, preferably over 4 weeks, to the target of 50 mg once daily, with monitoring of serum potassium. After myocardial infarction treatment is usually started within 3 to 14 days of the diagnosis. If serum potassium is above 5.0 mmol/l, treatment is not started at all.
| Serum potassium | What to do with the dose |
| Below 5.0 mmol/l | increase: from 25 mg every other day to 25 mg once daily, and from 25 mg once daily to 50 mg once daily |
| 5.0–5.4 mmol/l | leave unchanged |
| 5.5–5.9 mmol/l | decrease: from 50 mg to 25 mg once daily, from 25 mg once daily to 25 mg every other day, and from 25 mg every other day to withdrawal |
| 6.0 mmol/l and above | withdraw; dosing may resume at 25 mg every other day once potassium falls below 5 mmol/l |
| When to measure | before starting treatment, in the first week, a month after starting or after a dose change, then periodically as needed |
| Moderate renal impairment, creatinine clearance 30–60 ml/min | starting dose 25 mg every other day, then adjusted according to potassium |
| Weak and moderate CYP3A4 inhibitors — amiodarone, diltiazem, verapamil | start at 25 mg once daily and do not exceed that dose |
In older people the starting dose need not be changed, but because of the age-related decline in renal function their risk of hyperkalaemia is higher, and mild to moderate hepatic impairment raises it further. In mild renal impairment the starting dose is likewise unchanged, though potassium is monitored periodically. There is no experience with creatinine clearance below 50 ml/min in patients with heart failure after infarction, and doses above 25 mg a day have not been studied in that group. In mild and moderate hepatic impairment exposure to the medicine rises, so potassium is checked often and regularly, especially in older people. Safety and efficacy in children and adolescents have not been established.
Contraindications
Hypersensitivity to eplerenone or to any excipient. Serum potassium above 5.0 mmol/l before treatment begins. Severe renal impairment with an estimated glomerular filtration rate below 30 ml/min/1.73 m². Severe hepatic impairment of Child-Pugh class C.
A separate group is formed by the forbidden combinations: potassium-sparing diuretics, potassium preparations and potent CYP3A4 inhibitors — itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone. Combined treatment in which eplerenone is given together with both an ACE inhibitor and an angiotensin receptor antagonist is also contraindicated.
Special warnings and precautions
The main risk follows directly from the mechanism of action: hyperkalaemia may occur on eplerenone. Serum potassium is monitored in all patients at the start of treatment and after each dose change, and during continued treatment periodic monitoring is particularly recommended for those predisposed to hyperkalaemia: older people, patients with renal impairment and patients with diabetes.
- potassium preparations are not recommended once eplerenone has been started, because of the increased risk of hyperkalaemia; reducing the eplerenone dose has been shown to lower serum potassium, and in one study adding hydrochlorothiazide offset its rise;
- the risk of hyperkalaemia increases when eplerenone is added to treatment with an ACE inhibitor or an angiotensin receptor antagonist, and it must not be combined with both at once;
- in renal impairment, including microalbuminuria in diabetes, potassium is monitored regularly: the risk grows as renal function declines, and in the EPHESUS study the frequency of hyperkalaemia was higher in patients with type 2 diabetes and microalbuminuria;
- in mild and moderate hepatic impairment — Child-Pugh classes A and B — no rise in potassium above 5.5 mmol/l was seen, but electrolytes in such patients are monitored; in severe hepatic impairment the medicine has not been studied and is therefore contraindicated;
- concomitant use with substances that strongly induce CYP3A4 is not recommended, and lithium, ciclosporin and tacrolimus should be avoided during treatment with eplerenone.
Eplerenone is not removed by haemodialysis — which matters both in renal impairment and in overdose. No studies have been carried out on the effect on the ability to drive or operate machinery: the medicine does not cause drowsiness and does not impair cognitive function, though the possibility of dizziness during treatment is worth bearing in mind at the wheel.
Interaction with other medicines
The pharmacodynamic interactions come down to two lines: potassium and blood pressure. Potassium-sparing diuretics and potassium preparations must not be combined with eplerenone because of the risk of hyperkalaemia, and such diuretics also enhance the action of antihypertensives and of other diuretics. ACE inhibitors and angiotensin receptor antagonists raise that risk too: when combined, plasma potassium and renal function are monitored closely, particularly in renal impairment and in older people, and the triple combination is not recommended.
- concomitant use with lithium should be avoided: the interaction has not been studied, but lithium toxicity has been described in patients receiving diuretics and ACE inhibitors at the same time; if such treatment is necessary, lithium concentrations are monitored;
- ciclosporin and tacrolimus can impair renal function and increase the risk of hyperkalaemia, so those combinations are avoided and, where necessary, potassium and renal function are monitored closely; trimethoprim likewise increases the risk of hyperkalaemia;
- non-steroidal anti-inflammatory drugs can cause acute renal failure through their direct action on glomerular filtration, especially in older and dehydrated patients: they are kept adequately hydrated and their renal function is checked before treatment begins;
- alpha-1 blockers such as prazosin and alfuzosin, tricyclic antidepressants, neuroleptics, amifostine and baclofen enhance the hypotensive effect and the risk of orthostatic hypotension, while glucocorticoids and tetracosactide weaken it through sodium and water retention;
- potent CYP3A4 inhibitors are contraindicated: ketoconazole at 200 mg twice daily increased the area under the eplerenone curve by 441%; weak and moderate ones — erythromycin, saquinavir, amiodarone, diltiazem, verapamil, fluconazole — raised it by 98% to 187%, so with them the dose must not exceed 25 mg a day;
- CYP3A4 inducers work the other way: St John's wort reduced the area under the curve by 30%, and stronger inducers — rifampicin, carbamazepine, phenytoin, phenobarbital — may reduce it further, so their combination with eplerenone is not recommended.
Eplerenone itself barely interferes with other drugs' metabolism: in vitro it does not inhibit the CYP1A2, CYP2C19, CYP2C9, CYP2D6 or CYP3A4 isoenzymes and is neither a substrate nor an inhibitor of P-glycoprotein, and no significant interactions were found with midazolam or cisapride. Digoxin at 200 µg a day together with 100 mg of eplerenone produced a 16% rise in the area under the curve without clinical evidence of toxicity, and no clinically significant pharmacokinetic interaction was seen with warfarin — but both call for caution at doses near the upper limit of the therapeutic range.
Pregnancy and breastfeeding
There are no adequate data on the use of eplerenone in pregnant women. Animal studies revealed no direct or indirect adverse effects on pregnancy, embryonic and fetal development, delivery or the development of the newborn child. Even so, eplerenone is prescribed to pregnant women with caution.
Whether eplerenone passes into human milk after oral administration is not known, though preclinical data indicate that eplerenone and its metabolites are present in rat milk. Rat pups receiving these substances in milk developed normally. Because the possibility of adverse effects in the breastfed infant is unknown, a decision must be made whether to stop breastfeeding or to withdraw the medicine, taking into account the importance of treatment for the mother.
Adverse reactions
In two studies — EPHESUS, which examined survival and efficacy of eplerenone in acute post-infarction heart failure, and EMPHASIS-HF, which examined survival in patients hospitalised with mild heart failure — the overall frequency of adverse reactions on eplerenone was close to that in the placebo group. The most frequent in EMPHASIS-HF was hyperkalaemia: 8.7% against 4% on placebo.
- common: hyperkalaemia, infections, dizziness, fainting, myocardial infarction, arterial hypotension, cough, diarrhoea, nausea, constipation, rash, itching, painful muscle cramps, musculoskeletal pain, renal impairment, raised blood urea;
- uncommon, metabolic and endocrine: hyponatraemia, dehydration, hypercholesterolaemia, hypertriglyceridaemia, hypothyroidism, eosinophilia, raised blood creatinine and glucose;
- uncommon, cardiac and vascular: left ventricular failure, atrial fibrillation, tachycardia, arterial thrombosis of the lower limbs, orthostatic hypotension;
- other uncommon: pyelonephritis, pharyngitis, insomnia, headache, hypoaesthesia, vomiting, flatulence, excessive sweating, back pain, cholecystitis, gynaecomastia, weakness, malaise;
- frequency not known: angioedema.
The story of strokes in the very old deserves separate mention. In EPHESUS there were more strokes on eplerenone among patients aged 75 and over — 30 against 22 on placebo — but the difference was not statistically significant. In EMPHASIS-HF, in that same age group the count came out almost even: 9 against 8.
Overdose
No cases of adverse effects associated with eplerenone overdose in humans have been described. The most likely manifestations would be arterial hypotension and hyperkalaemia.
Symptomatic hypotension is treated with supportive measures and hyperkalaemia with standard treatment. Eplerenone cannot be removed by haemodialysis, but it has been shown to be strongly bound by activated charcoal.
How to get a prescription for Eplenocard online
The medicine is prescription-only, and the conversation with the doctor revolves around two numbers: the left ventricular ejection fraction and serum potassium. The first determines the indication itself — no more than 40% after a recent infarction, or no more than 30% in chronic heart failure of NYHA class II — and the second decides whether treatment can begin and at what dose.
It is therefore worth preparing recent test results for the consultation: potassium, creatinine with a calculated glomerular filtration rate, and liver function indices. The medicines being taken are listed separately — ACE inhibitors and angiotensin receptor antagonists, potassium-sparing diuretics and potassium preparations, amiodarone, diltiazem, verapamil, antifungals and macrolides, lithium, ciclosporin and tacrolimus, non-steroidal anti-inflammatory drugs — along with diabetes, kidney and liver disease, pregnancy and breastfeeding, and galactose intolerance. The doctor will assess these circumstances during the online consultation and, if there are no contraindications, will issue an electronic prescription.
