Active ingredients: Eplerenone
Inspra 25 mg and 50 mg film-coated tablets
Why is Inspra used? What is it for?
Inspra belongs to the class of medicines known as selective aldosterone blocking agents. These agents inhibit the action of aldosterone, a substance produced by the body that controls blood pressure and heart function. High levels of aldosterone can cause changes in the body that cause heart failure.
Inspra is used to treat your heart failure, to prevent it from getting worse and to reduce hospitalization if:
- you have recently had a heart attack, in combination with other medicines used to treat heart failure
- he has moderate and persistent symptoms despite the treatment he has carried out so far.
Contraindications When Inspra should not be used
Do not take Inspra:
- If you are allergic to eplerenone or any of the other ingredients of this medicine
- If you have elevated potassium levels in the blood (hyperkalaemia)
- If you are taking medicines that help eliminate excess body fluids (potassium-sparing diuretics) or 'salt tablets' (such as potassium supplements)
- If you have severe kidney disease
- If you have severe liver disease
- If you are taking medicines used to treat fungal infections (ketoconazole or itraconazole)
- If you are taking antiviral medicines to treat HIV (nelfinavir or ritonavir)
- If you are taking antibiotics to treat bacterial infections (clarithromycin or telithromycin)
- If you are taking nefazodone to treat depression
- If you are taking medicines to treat certain heart conditions or hypertension (called angiotensin converting enzyme inhibitors [ACE inhibitors] and angiotensin receptor blockers [ARB]) together.
Precautions for use What you need to know before you take Inspra
Talk to your doctor, pharmacist or nurse before taking Inspra
- If you have kidney or liver disease (see also "Do not take Inspra")
- If you are taking lithium (generally used for manic-depressive disorders, also called bipolar disorders)
- If you are taking tacrolimus or cyclosporine (used to treat skin conditions such as psoriasis or eczema and to prevent rejection after organ transplantation)
Children and adolescents
The safety and efficacy of eplerenone in children and adolescents have not been established.
Interactions Which drugs or foods can change the effect of Inspra
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
You should not take Inspra with the following medicines (see section 'Do not take Inspra'):
- itraconazole or ketoconazole (to treat fungal infections), ritonavir, nelfinavir (antiviral medicines to treat HIV), clarithromycin, telithromycin (to treat bacterial infections) or nefazodone (for depression), as these medicines reduce the "elimination of Inspra, prolonging its effect.
- potassium-sparing diuretics (medicines that help eliminate excess body fluids) and potassium supplements (salt tablets) as these medicines increase the risk of high blood potassium levels.
- angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) together (used to treat high blood pressure, heart disease or particular kidney conditions) because these medicines may increase the risk of blood levels high blood potassium.
Tell your doctor if you are taking any of the following medicines:
- Lithium (usually used for manic-depressive disorders, also called bipolar disorders). The use of lithium together with diuretics and ACE inhibitors (used in the treatment of high blood pressure and heart disease) has been shown to increase blood lithium levels which can cause the following side effects: loss of appetite, decreased vision , fatigue, muscle weakness, muscle cramps.
- Ciclosporin or tacrolimus (used to treat skin conditions such as psoriasis or eczema and to prevent organ transplant rejection). These medicines can cause kidney problems and therefore increase the risk of high blood potassium levels.
- Non-steroidal anti-inflammatory drugs (NSAIDs - some pain relievers such as ibuprofen, used to relieve pain, stiffness and inflammation). These drugs can cause kidney problems and therefore increase the risk of high blood potassium levels.
- Trimethoprim (used to treat bacterial infections) can increase the risk of high blood potassium levels.
- Alpha-1-blockers, such as prazosin or alfuzosin (used to treat high blood pressure and for particular prostate conditions) can cause a drop in blood pressure and dizziness when standing up.
- Tricyclic antidepressants such as amitriptyline or amoxapine (for the treatment of depression), antipsychotics (also known as neuroleptics) such as chlorpromazine or haloperidol (for the treatment of psychiatric disorders), amifostine (used in anticancer chemotherapy) and baclofen (used for the treatment of spasms muscles). These medicines can cause a drop in blood pressure and dizziness when standing up.
- Glucocorticoids, such as hydrocortisone or prednisone (used to treat inflammation and some skin conditions) and tetracosactide (mainly used to diagnose and treat disorders of the adrenal cortex) can reduce the effect of Inspra.
- Digoxin (used in the treatment of heart ailments). Levels of digoxin in the blood may increase when given together with Inspra.
- Warfarin (an anti-coagulant medicine): Caution is advised with warfarin, as high levels of warfarin in the blood may change the effects of Inspra.
- Erythromycin (used to treat bacterial infections), saquinavir (antiviral medicine to treat HIV), fluconazole (used to treat fungal infections), amiodarone, diltiazem and verapamil (to treat heart disease and high blood pressure) they reduce the elimination of Inspra and prolong its effect.
- St. John's wort (herbal medicinal product), rifampicin (used to treat bacterial infections), carbamazepine, phenytoin and phenobarbital (also used to treat epilepsy) can increase the elimination of Inspra and therefore decrease its effects.
Inspra with food and drink Inspra can be taken with or without food.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
The effect of Inspra has not been evaluated during pregnancy in humans.
It is not known whether eplerenone is excreted in breast milk. Your doctor will have to decide whether to discontinue breast-feeding or to stop taking the medicine.
Driving and using machines
You may feel dizzy after taking Inspra. If this happens, do not drive or use machines.
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Inspra contains lactose monohydrate
Inspra contains lactose monohydrate (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Inspra: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Inspra tablets can be taken on a full or empty stomach. The tablets should be swallowed whole with a large quantity of water.
Inspra is usually given together with other medicines for heart failure such as beta-blockers. Usually the starting dose is one 25 mg tablet once a day, then increasing the dose after 4 weeks to 50 mg once a day. per day (one 50 mg tablet or two 25 mg tablets) The maximum daily dose is 50 mg.
Blood potassium levels should be measured before starting Inspra therapy, within the first week and within the first month of treatment or after a change in dosage. The dosage can be adjusted by the doctor based on the potassium levels in the blood.
If you have mild kidney disease you should start therapy with one 25 mg tablet once a day. If your kidney disease is moderate you should start therapy with one 25 mg tablet every other day. If your doctor deems it and based on your serum potassium levels, these doses may be adjusted. Inspra is not recommended in patients with severe kidney disease.
No initial dosage adjustments are required in patients with mild to moderate liver function problems. If you have kidney or liver problems you may need to have your blood potassium levels checked more frequently (see also "Do not take Inspra").
For the elderly: No initial dose adjustment is required.
For children and adolescents: the use of Inspra is not recommended.
If you forget to take
Inspra If it is almost time for your next tablet, skip the missed dose and take the next tablet at the correct time. Otherwise, you can take it as soon as you remember, bearing in mind that at least 12 hours must pass before taking the next dose. Then resume your medicine as you normally would.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Inspra
It is important to take Inspra as prescribed unless your doctor tells you to stop treatment.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Inspra
If you have taken too many Inspra tablets, contact your doctor or pharmacist straight away.
If you have taken too many tablets, the most likely symptoms will be low blood pressure (feeling lightheaded, dizzy, blurred vision, weakness, sudden loss of consciousness) or hyperkalaemia, elevated potassium levels in the blood (manifested by muscle cramps, diarrhea , nausea, dizziness or headache).
Side Effects What are the side effects of Inspra
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you have any of the following symptoms:
Tell your doctor immediately
- Swelling of the face, tongue or throat
- Difficulty swallowing
- Hives and difficulty in breathing.
These are symptoms of angioneurotic edema, an uncommon side effect (may affect up to 1 in 100 people).
Other reported side effects include:
Common (may affect up to 1 in 10 people):
- high levels of potassium in the blood (symptoms include muscle cramps, diarrhea, nausea, dizziness or headache)
- dizziness
- fainting
- increase in the amount of cholesterol in the blood
- insomnia (difficulty sleeping)
- headache
- heart problems eg. irregular heartbeat, heart failure
- cough
- constipation
- low blood pressure
- diarrhea
- nausea
- He retched
- impaired renal function
- rash
- itch
- backache
- weakness
- muscle spasms
- increased blood urea levels
- increased blood creatinine levels which may indicate kidney problems
Uncommon (may affect up to 1 in 100 people):
- infections
- eosinophilia (increase in some white blood cells)
- dehydration
- increase in the amount of triglycerides (fats) in the blood
- low levels of sodium in the blood
- rapid heartbeat
- inflammation of the gallbladder
- decrease in pressure which can cause dizziness when standing up
- thrombosis (blood clots) in the legs
- sore throat
- flatulence
- reduced thyroid function
- increased blood sugar
- reduced sensitivity to touch
- increased sweating
- musculoskeletal pain
- generalized feeling of malaise
- kidney inflammation
- breast enlargement in men
- changes in blood test values.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at: www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
This medicinal product does not require any special storage conditions.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What Inspra contains
The active ingredient in Inspra film-coated tablets is eplerenone. Each tablet contains 25 mg or 50 mg of eplerenone.
The other ingredients are:
lactose monohydrate, microcrystalline cellulose (E460), croscarmellose sodium (E468), hypromellose (E464), sodium lauryl sulfate, talc (E553b) and magnesium stearate (E470b).
The opadry yellow coating of Inspra 25 mg and 50 mg film-coated tablets contain: hypromellose (E464), titanium dioxide (E171), macrogol 400, polysorbate 80 (E433), yellow iron oxide (E172), iron oxide red (E172).
What Inspra looks like and what is in the box
Inspra 25 mg tablets are yellow, film-coated tablets debossed with "Pfizer" on one side and "NSR" and "25" on the other side.
Inspra 50 mg tablets are yellow, film-coated tablets debossed with "Pfizer" on one side and "NSR" and "50" on the other side.
Packs of Inspra 25 mg and 50 mg film-coated tablets are available in opaque PVC / Al blisters containing 10, 20, 28, 30, 50, 90, 100 or 200 tablets and in packs of 10x1, 20x1, 30x1, 50x1, 90x1, 100x1 or 200x1 (10 packs of 20x1) tablets in opaque PVC / Al blisters divisible for unit dose.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
INSPRA TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 25 mg or 50 mg of eplerenone.
For excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
25 mg tablets: Yellow tablets with "Pfizer" on one side of the tablet and "NSR" and "25" on the other side.
50 mg tablets: Yellow tablets with "Pfizer" on one side of the tablet and "NSR" and "50" on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Eplerenone is indicated for the reduction of the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (LVEF ≤ 40%) and clinical evidence of heart failure following recent myocardial infarction, in addition to standard therapy including beta blockers. .
04.2 Posology and method of administration
Strengths of 25 mg and 50 mg are available for individual dose adjustment.
The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should be initiated at 25 mg once daily and titrated to the recommended dose of 50 mg once daily preferably within 4 weeks, taking into account serum potassium levels (see Table 1). Eplerenone therapy should normally begin within 3-14 days of an acute myocardial infarction episode.
Patients with serum potassium levels> 5.0 mmol / L should not initiate therapy with eplerenone (see section 4.3).
Serum potassium should be measured prior to initiation of eplerenone therapy, within the first week of treatment and one month after initiation of treatment or dose adjustment. Thereafter, serum potassium should be assessed as needed on a periodic basis.
After initiation of therapy, the dose should be adjusted according to the serum potassium level as indicated in Table 1.
Table 1: Table for dosage adjustment after initiation of treatment
Following discontinuation of eplerenone due to serum potassium levels ≥ 6.0 mmol / L, eplerenone treatment can be resumed at a dose of 25 mg every other day when potassium levels have fallen below 5.0 mmol /L.
Children and adolescents
No data are available to recommend the use of eplerenone in the pediatric population, therefore use in this patient group is not recommended.
Senior citizens
No starting dose adjustment is necessary in elderly patients. Due to age-related impairment of renal function, the risk of hyperkalaemia increases in elderly patients. This risk may increase when there is co-morbidity associated with increased systemic exposure, particularly in the presence of mild to mild hepatic impairment. moderate Periodic monitoring of serum potassium is recommended in these patients (see section 4.4).
Renal impairment
No starting dose adjustment is necessary in patients with mild renal impairment. Periodic monitoring of serum potassium is recommended in these patients (see section 4.4).
Eplerenone is not dialysable.
Hepatic impairment
No starting dose adjustment is necessary in patients with mild to moderate hepatic impairment. Due to an increase in systemic exposure to eplerenone, frequent and regular monitoring of serum potassium is recommended in patients with mild to moderate hepatic impairment, especially when elderly (see section 4.4).
Concomitant use
In case of concomitant treatment with weak or moderate inhibitors of CYP3A4, eg. amiodarone, diltiazem and verapamil, treatment can be started with 25 mg per day. The dose should not exceed 25 mg per day (see section 4.5).
Eplerenone can be administered with or without food (see section 5.2).
04.3 Contraindications
• Hypersensitivity to eplerenone or to any of the excipients (see section 6.1).
• Patients with serum potassium levels> 5.0 mmol / L at the start of treatment.
• Patients with moderate to severe renal insufficiency (creatinine clearance
• Patients with severe hepatic insufficiency (Child-Pugh Score C).
• Patients taking potassium-sparing diuretics, potassium supplements or strong CYP3A4 inhibitors (eg itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromacin and nefazodone) (see section 4.5).
04.4 Special warnings and appropriate precautions for use
Hyperkalaemia: According to its mechanism of action, hyperkalaemia may occur with the administration of eplerenone. Serum potassium levels should be monitored in all patients at the initiation of treatment and following dose modification. Thereafter, periodic monitoring is recommended especially in patients at risk for hyperkalaemia, such as (elderly) patients with renal insufficiency (see section 4.2) and diabetic patients. The use of potassium supplements after eplerenone treatment has been started is not recommended due to an increased risk of hyperkalaemia. Reduction in the dose of eplerenone was observed to reduce serum potassium levels. In a study. The addition of hydrochlorothiazide to eplerenone treatment was observed to compensate for the increases in serum potassium.
Renal impairment: Potassium levels should be monitored regularly in patients with impaired renal function, including patients with diabetic microalbuminuria. The risk of hyperkalaemia increases with decreased renal function. Although data from the EPHESUS study in patients with type 2 diabetes and microalbuminuria are limited, an increase in hyperkalaemia was observed in this small number of patients. Therefore, these patients should be treated with caution. Eplerenone is not eliminated by hemodialysis.
Hepatic impairment: No increases in serum potassium above 5.5 mmol / l were observed in patients with mild to moderate hepatic impairment (Child Pugh Score A and B). Electrolyte levels should be monitored in patients with mild to moderate hepatic impairment. The use of eplerenone in patients with severe hepatic function has not been evaluated and its use is therefore contraindicated (see section 4.3).
CYP3A4 inducers: co-administration of eplerenone with strong CYP3A4 inducers is not recommended (see section 4.5)
Lithium, cyclosporine, tacrolimus should be avoided during treatment with eplerenone (see section 4.5).
Lactose: The tablets contain lactose and patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Potassium-sparing diuretics and potassium supplements: Due to the increased risk of hyperkalaemia, eplerenone should not be administered in patients receiving potassium-sparing diuretics and potassium supplements (see section 4.3). Potassium-sparing diuretics may potentiate the effect of antihypertensive agents and other diuretics.
Lithium: No interaction studies have been conducted with lithium. However, lithium toxicity has been reported in patients taking lithium concomitantly with diuretics and ACE inhibitors (see section 4.4). Concomitant administration of eplerenone and lithium should be avoided. If this combination is necessary, plasma lithium concentrations should be monitored (see section 4.4).
Ciclosporin, tacrolimus: cyclosporine and tacrolimus can lead to impaired renal function and increase the risk of hyperkalaemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If necessary, careful monitoring of serum potassium and renal function is recommended when cyclosporine and tacrolimus are administered during treatment with eplerenone (see section 4.4).
Non-steroidal anti-inflammatory drugs (NSAIDs): treatment with NSAIDs can cause acute renal failure through a direct action on glomerular filtration, especially in patients at risk (elderly and / or dehydrated patients). Patients treated with eplerenone and NSAIDs must be adequately hydrated and renal function must be checked before starting treatment.
Trimethoprim: Concomitant administration of trimethoprim and eplerenone increases the risk of hyperkalaemia. Monitoring of serum potassium and renal function should be performed, especially in patients with renal impairment and in the elderly.
ACE inhibitors, angiotensin II receptor antagonists (AIIA): Concomitant administration of eplerenone with ACE inhibitors or angiotensin II receptor antagonists should be done with caution. The combination of eplerenone with these medicinal products may increase the risk of hyperkalaemia in patients at risk of renal impairment, eg. seniors. Close monitoring of serum potassium levels and renal function is recommended.
Alpha-1 blockers (eg. prazosin, alfuzosin): when alpha-1 blockers are administered in combination with eplerenone, increased hypotensive effect and / or postural hypotension may occur. Clinical monitoring of postural hypotension is therefore recommended in case of concomitant administration with alpha-1 blockers.
Tricyclic antidepressants, neuroleptics, amifostine, baclofen: Concomitant administration of these medicinal products with eplerenone may potentially increase the antihypertensive effects and the risk of postural hypotension.
Glucocorticoids, tetracosactide: concomitant administration of these medicinal products with eplerenone may potentially decrease the antihypertensive effects (sodium and fluid retention).
Pharmacokinetic interactions:
Studies in vitro indicate that eplerenone is not an inhibitor of the isoenzymes of CYP1A2, CYP2C19, CYP2C9, CYP2D6 or CYP3A4. Eplerenone is not a substrate or inhibitor of P-glycoprotein.
Digoxin: Systemic exposure (AUC) to digoxin increases by 16% (90% CI: 4% - 30%) when given together with eplerenone. Caution is advised when digoxin is administered at doses close to the upper therapeutic limit.
Warfarin: No clinically significant pharmacokinetic interactions have been observed with warfarin. Caution is advised when warfarin is administered at doses close to the upper therapeutic limit.
CYP3A4 substrates: the results of pharmacokinetic studies on specific substrates of CYP3A4, eg. midazolam and cisapride did not show any significant pharmacokinetic interaction when these drugs were co-administered with eplerenone.
CYP3A4 inhibitors:
- Strong CYP3A4 inhibitorsSignificant pharmacokinetic interactions may occur when eplerenone is co-administered with medicinal products that inhibit the CYP3A4 enzyme. A potent CYP3A4 inhibitor (ketoconazole 200 mg BID) resulted in a 441% increase in the AUC of eplerenone (see section 4.3). The concomitant use of eplerenone with strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone is contraindicated (see section 4.3).
- Weak-moderate inhibitors of CYP3A4: Concomitant administration of erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole resulted in significant pharmacokinetic interactions with increases in AUC from 98% to 187%. Therefore, the dose of eplerenone should not exceed 25 mg when weak to moderate inhibitors of CYP3A4 are administered together with eplerenone (see section 4.2).
CYP3A4 inducers: Co-administration of St. John's wort (a potent CYP3A4 inducer) with eplerenone caused a 30% decrease in eplerenone AUC. A more pronounced decrease in eplerenone "AUC" may occur with more potent inducers of CYP3A4, such as rifampicin. Due to the risk of reduced efficacy of eplerenone, the concomitant use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) with eplerenone is not recommended (see section 4.4).
Antacids: Based on the results of a clinical pharmacokinetic study, no significant interactions are expected when antacids are administered with eplerenone.
04.6 Pregnancy and breastfeeding
Pregnancy: There are insufficient data on the use of eplerenone in pregnant women. Animal studies did not indicate direct or indirect adverse events on pregnancy, embryofoetal development, parturition or postnatal development (see section 5.3). Caution is warranted. when prescribing eplerenone to pregnant women.
Feeding time: It is not known whether eplerenone is excreted in human milk after oral administration. However, preclinical data show that eplerenone and / or its metabolites are present in the milk of rats and that young rats exposed to this route of administration develop normally. Since possible adverse events on the infant during breastfeeding are not known, a decision must be made whether to discontinue breastfeeding or treatment, taking into account the importance of the drug to the mother.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed following the use of eplerenone. Eplerenone does not cause drowsiness or impaired cognitive function, but when driving vehicles or operating machines it should be taken into account that in dizziness may occur during the course of treatment.
04.8 Undesirable effects
In the efficacy and survival study on heart failure following acute myocardial infarction (EPHESUS study), the overall incidence of adverse events reported with eplerenone (78.9%) was similar to placebo (79.5%). Discontinuation rate due to adverse events was 4.4% for patients taking eplerenone and 4.3% for those taking placebo.
The adverse events reported below, originate is from the EPHESUS study, and are those with a suspected correlation to treatment and occurring in a higher percentage than placebo, or those severe and occurring with a significantly higher percentage than placebo, or have been reported at the product marketing stage. Adverse events reported are listed by system organ class and by frequency. Frequencies are defined as: common> 1/100, 1/1000,
Infections and infestations
Uncommon: pyelonephritis
Disorders of the blood and lymphatic system
Uncommon: eosinophilia
Metabolism and nutrition disorders
common: hyperkalaemia
Uncommon: hyponatremia, dehydration, hypercholesterolemia, hypertriglyceridemia,
Psychiatric disorders
Uncommon: insomnia
Nervous system disorders
common: dizziness
Uncommon: headache
Cardiac pathologies
Uncommon: myocardial infarction, left heart failure, atrial fibrillation
Vascular pathologies
common: hypotension
Uncommon: arterial thrombosis in the legs, postural hypotension
Respiratory, thoracic and mediastinal disorders
Uncommon: pharyngitis
Gastrointestinal disorders
common: diarrhea, nausea
Uncommon: vomiting, flatulence
Skin and subcutaneous tissue disorders
Common: rash
Uncommon: itching, increased sweating
Not known: angioneurotic edema
Musculoskeletal and connective tissue disorders
Uncommon: back pain, leg cramps.
Renal and urinary tract disorders
Common: impaired renal function
Breast reproductive system disorders:
Uncommon: gynecomastia
General disorders and administration site conditions
Uncommon: asthenia, malaise
Diagnostic tests
Uncommon: increased blood urea nitrogen, increased creatinine
In the EPHESUS study, more strokes occurred in the elderly patient group (≥75 years). However, there was no significant difference between the incidence of stroke in the eplerenone group compared to placebo.
04.9 Overdose
There have been no reported cases of overdose with eplerenone. The most likely manifestation of overdose in humans is expected to be hypotension or hyperkalaemia. Eplerenone is not eliminated by hemodialysis. Eplerenone has been observed to bind to a large extent to charcoal. If symptomatic hypotension occurs, supportive treatment should be initiated. In case of hyperkalaemia, standard treatment should be started.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: aldosterone antagonists, ATC code: C03DA04
Eplerenone exhibits relative selectivity for binding to recombinant human mineralocorticoid receptors compared to binding to recombinant human glucocorticoid, progesterone and androgen receptors. Eplerenone prevents binding of aldosterone, a key hormone in the renin-system. angiotensin-aldosterone (RAAS) involved in the regulation of blood pressure and in the pathophysiology of cardiovascular diseases.
Eplerenone has been observed to cause persistent increases in plasma renin and serum aldosterone, in accordance with the inhibition of the negative regulatory feedback exerted by aldosterone on renin secretion. The consequent increase in plasma renin activity and circulating aldosterone levels do not negate the effects of eplerenone.
In studies conducted with different strengths of eplerenone in patients with chronic heart failure (NYHA classification II-IV) the addition of the latter to standard therapy resulted in predictable dose-dependent increases in aldosterone. Similarly, in a subset of patients in the EPHESUS study with cardiorenal impairment, treatment with eplerenone caused a significant increase in aldosterone. These results confirm the blockade of the mineralocorticoid receptor in these patient groups.
Eplerenone was evaluated in the efficacy and survival study in heart failure following acute myocardial infarction (EPHESUS study). The EPHESUS study was a 3-year double-blind placebo-controlled study in 6,632 patients. with acute myocardial infarction (AMI), left ventricular dysfunction (measured by left ventricular ejection fraction [LVEF] ≤40%) and clinical signs of heart failure. Over the next 3-14 days (median 7 days) in acute myocardial infarction, patients were treated with eplerenone at a starting dose of 25 mg once daily or placebo, in addition to standard therapies; eplerenone dosage was then gradually increased to the recommended dose of 50 mg once daily after 4 weeks if serum potassium was acetylsalicylic acid (92%), ACE-inhibitors (90%),? -blockers (83 %), nitrates (72%), loop diuretics (66%) or HMG CoA reductase inhibitors (60%).
In the EPHESUS study, the co-primary endpoints were all-cause mortality and the combined cardiovascular mortality or hospitalization endpoint; 14.4% of patients treated with eplerenone and 16.7% of patients treated with placebo died (all causes), while 26.7% of patients treated with eplerenone and 30.0% of patients treated with placebo achieved the combined endpoint of death from cardiovascular causes or hospitalization. Thus, in the EPHESUS study, eplerenone reduced the risk of death from all causes by 15% (RR 0.85; 95% CI, 0.75-0.96; p = 0.008) compared to placebo, mainly with a reduction in cardiovascular mortality. The risk of death or hospitalization from cardiovascular causes with eplerenone was reduced by 13% (RR 0.87; 95% CI, 0.79-0.95; p = 0.002). risk for all-cause mortality and cardiovascular / hospitalization mortality endpoints were 2.3 and 3.3%, respectively. Clinical efficacy was primarily demonstrated when eplerenone treatment was initiated in patients of age 75 years are not clear. The NYHA functional classification improved or remained stable for a statistically significantly higher percentage of patients receiving eplerenone than those in the placebo group. The incidence of hyperkalaemia was 3.4% in the eplerenone group versus 2.0% in the placebo group (pipokalaemia was 0.5% in the eplerenone group versus 1.5% in the placebo group. placebo (p
No uniform effects on heart rate, QRS wave duration, or PR or QT interval were observed in 147 healthy subjects undergoing evaluation for electrocardiographic changes during pharmacokinetic studies.
05.2 Pharmacokinetic properties
Absorption and distribution:
the absolute bioavailability of eplerenone is unknown. Maximum plasma concentrations are reached after approximately two hours. Both peak plasma levels (Cmax) and area under the curve (AUC) are proportional to doses in the range of 10 to 100 mg and below a proportional increase with doses above 100 mg. Steady state is reached within 2 days. Absorption is not affected by food.
Plasma protein binding of eplerenone is approximately 50% and binds primarily to alpha-1-acid glycoproteins. The apparent volume of distribution at steady state is estimated to be 50 (± 7) liters. Eplerenone does not occur. binds preferentially to erythrocytes.
Metabolism and excretion:
The metabolism of eplerenone is mainly mediated by CYP3A4. The active metabolites of eplerenone in human plasma have not been identified.
Less than 5% of a dose of eplerenone is found in the urine and faeces as unchanged drug. Following administration of a single oral dose of radiolabelled drug, approximately 32% of the dose is eliminated in the faeces and approximately 67% in the urine. The elimination half-life of eplerenone is approximately 3-5 hours. Apparent plasma clearance is approximately 10 L / hour.
Special populations
Age, gender and race: The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been studied in elderly patients (≥ 65 years old), men and women, and in black subjects. The pharmacokinetics of eplerenone did not differ significantly between men. and women. Increases in steady-state Cmax (22%) and AUC (45%) were observed in elderly subjects compared to younger subjects (18-45 years). In black subjects, steady-state Cmax was 19% lower and AUC was 26% lower (see section 4.2).
Kidney failure: The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of renal insufficiency and in patients undergoing hemodialysis. Compared to controls, steady-state AUC and Cmax were increased by 38% and 24%, respectively, in patients with impairment severe renal disease and decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. There was no correlation between plasma eplerenone clearance and creatinine clearance. Eplerenone is not eliminated by hemodialysis (see section 4.4).
Hepatic insufficiency: The pharmacokinetics of eplerenone 400 mg were studied in patients with moderate hepatic impairment (Child-Pugh score B) and compared to the pharmacokinetics in healthy subjects. The steady-state Cmax and AUC of eplerenone increased by 3.6%, respectively. and 42% (see section 4.2). Since the use of eplerenone has not been evaluated in patients with severe hepatic impairment, the drug is contraindicated in this patient group (see section 4.3).
Heart failure: The pharmacokinetics of eplerenone 50 mg were evaluated in patients with heart failure (NYHA classification II-IV). Compared to healthy volunteers comparable for age, weight and gender, steady-state AUC and Cmax in patients with heart failure are were 38% and 30% higher, respectively. In agreement with these results, a "pharmacokinetic analysis of eplerenone" conducted on a subgroup of patients included in the EPHESUS study indicates that the clearance of eplerenone in patients with heart failure is similar to that observed. in healthy elderly subjects.
05.3 Preclinical safety data
Preclinical studies of safety, genotoxicity, carcinogenic potential and reproductive toxicity did not reveal any special hazard for humans.
In repeat dose toxicity studies, prostate atrophy was observed in rats and dogs at exposure levels slightly above clinical exposure levels. Changes in the prostate were not associated with adverse functional consequences. The clinical relevance of these data is unknown.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet core:
Lactose monohydrate
Microcrystalline cellulose (E460)
Croscarmellose sodium (E468)
Hypromellose (E464)
Sodium lauryl sulfate
Talc (E553b)
Magnesium stearate (E470b)
Tablet coating:
Yellow Opadry:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 400
Polysorbate 80 (E433)
Yellow iron oxide (E172)
Red iron oxide (E172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Packs of 10, 20, 28, 30, 50, 90, 100 or 200 tablets in opaque PVC / Al blister.
Packs of 20x1, 30x1, 50x1, 90x1, 100x1 or 200x1 (10 packs of 20x1) tablets in opaque PVC / Al blister packs divisible for unit dose.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Italia S.r.l., Via Isonzo, 71 -04100 Latina
08.0 MARKETING AUTHORIZATION NUMBER
25 mg tablets:
10 film-coated tablets: AIC n 037298015 / M
20 film-coated tablets: AIC n 037298027 / M
28 film-coated tablets: AIC n 037298039 / M
30 film-coated tablets: AIC n 037298041 / M
50 film-coated tablets: AIC n 037298054 / M
90 film-coated tablets: AIC n 037298256 / M
100 film-coated tablets: AIC n 037298066 / M
200 film-coated tablets: AIC n 037298078 / M
20x1 film-coated tablets: AIC n 037298080 / M
30x1 film-coated tablets: AIC n 037298092 / M
50x1 film-coated tablets: AIC n 037298104 / M
90x1 film-coated tablets: AIC n 037298268 / M
100x1 film-coated tablets: AIC n 037298116 / M
200x1 film-coated tablets: AIC n 037298128 / M
50 mg tablets:
10 film-coated tablets: AIC n 037298130 / M
20 film-coated tablets: AIC n 037298142 / M
28 film-coated tablets: AIC n 037298155 / M
30 film-coated tablets: AIC n 037298167 / M
50 film-coated tablets: AIC n 037298179 / M
90 film-coated tablets: AIC n 037298270 / M
100 film-coated tablets: AIC n 037298181 / M
200 film-coated tablets: AIC n 037298193 / M
20x1 film-coated tablets: AIC n 037298205 / M
30x1 film-coated tablets: AIC n 037298217 / M
50x1 film-coated tablets: AIC n 037298229 / M
90x1 film-coated tablets: AIC n 037298282 / M
100x1 film-coated tablets: AIC n 037298231 / M
200x1 film-coated tablets: AIC n 037298243 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
January 22, 2008
10.0 DATE OF REVISION OF THE TEXT
January 22, 2008
