Pharmacological properties of the drug Inspra
Eplerenone is relatively selective for binding to recombinant mineralocorticoid receptors compared to binding to recombinant human glucocorticoid, progesterone and androgen receptors. Prevents the binding of aldosterone, a key hormone of the renin-angiotensin-aldosterone system, which is involved in the regulation of blood pressure and the development of cardiovascular diseases. Eplerenone leads to a long-term increase in plasma renin and aldosterone levels, which is associated with the negative feedback regulation of renin secretion by aldosterone. However, increases in plasma renin activity and circulating aldosterone levels do not affect the effect of eplerenone on blood pressure. In studies, eplerenone significantly reduced blood pressure (measured in a sitting position) compared to placebo. This effect was confirmed by 24-hour ambulatory blood pressure monitoring. The hypotensive effect of the drug appeared after 2 weeks and reached a maximum after 4 weeks of use. The magnitude of the antihypertensive effect persisted for 8–24 weeks and did not depend on the age, gender or race of patients, or on concomitant use with drugs such as ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, β-adrenergic receptor blockers and hydrochlorothiazide. When using the drug, there was a significant reduction in mortality from cardiovascular diseases and the frequency of hospitalization for the treatment of cardiovascular diseases. This effect was especially evident at the beginning of therapy in patients under the age of 75 years. The effect of the drug in patients over 75 years of age has not been studied sufficiently. The incidence of hyperkalemia or hypokalemia with eplerenone did not differ from their frequency with placebo. Eplerenone does not affect heart rate, the length of the Q–R–S , P–R or Q–T . The absolute bioavailability of eplerenone is not known. The maximum concentration of the drug in the blood plasma is achieved 2 hours after administration. The maximum drug plasma concentration and AUC value are dose proportional in the 10–100 mg dose range and less proportional when used in doses of 100 mg. Equilibrium concentration is achieved within 2 days. Absorption does not depend on simultaneous food intake. The binding of eplerenone to plasma proteins is about 50%, mainly due to binding to α1-acid glycoproteins. The apparent volume of distribution at steady state is 50±7 l. Eplerenone does not bind selectively to red blood cells. Eplerenone is biotransformed primarily with the participation of CYP 3A4. No active metabolites of eplerenone have been identified in blood plasma. Less than 5% of the eplerenone dose is excreted unchanged in urine and feces. With a single dose of a radiolabeled drug, approximately 32% of the dose is excreted in the feces, and about 67% in the urine. The half-life of eplerenone is 3–5 hours. The apparent clearance from blood plasma is approximately 10 l/h. The pharmacokinetics of eplerenone do not differ significantly between men and women. At steady-state concentrations in elderly people, there is an increase in the maximum concentration of the drug in the blood plasma by 22% and the AUC value by 45% compared with similar indicators in people aged 18–45 years. At steady state concentration, a decrease in maximum concentration (19%) and a decrease in AUC (26%) are observed in individuals of the Negroid race. The pharmacokinetics of eplerenone were studied in patients with renal failure of varying severity and in patients on hemodialysis. Compared with the control group, steady-state maximum concentrations and AUC increased by 38 and 24%, respectively, in patients with severe renal impairment and decreased by 26 and 3%, respectively, in patients on hemodialysis. No correlation was found between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not excreted during hemodialysis. The pharmacokinetics of eplerenone at a dose of 400 mg was studied in patients with moderately severe hepatic impairment (Child-Pugh class B) compared with healthy individuals. The steady-state maximum concentration and AUC of eplerenone in this group of patients increased by 3.6 and 42%, respectively. Since the drug has not been studied in patients with severe hepatic impairment, the use of eplerenone in such patients is contraindicated. The pharmacokinetics of eplerenone at a dose of 50 mg was studied in patients with heart failure (NYHA functional class II–IV). Compared with age-, sex-, and race-matched healthy controls, steady-state AUC and peak concentrations in patients with heart failure were increased by 38% and 30%, respectively. Consistent with these results, a population pharmacokinetic analysis of eplerenone in subgroups of patients in the EPHESUS Project confirmed that clearance of the drug in patients with heart failure is similar to clearance in healthy elderly subjects.
Inspra®
Pharmacodynamic interactions
Potassium-sparing diuretics and potassium supplements:
Given the increased risk of hyperkalemia, eplerenone should not be prescribed to patients receiving potassium-sparing diuretics and potassium supplements. Potassium-sparing diuretics may enhance the effects of antihypertensive agents and other diuretics.
Preparations containing lithium:
The interaction of eplerenone with lithium has not been studied. However, cases of lithium intoxication have been described in patients receiving lithium in combination with diuretics and ACE inhibitors. Concomitant use of eplerenone and lithium should be avoided. If such a combination is necessary, it is advisable to monitor plasma lithium concentrations.
Cyclosporine, tacrolimus:
cyclosporine and tacrolimus may cause renal dysfunction and increase the risk of hyperkalemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus is required during treatment with eplerenone, close monitoring of serum potassium concentrations and renal function is recommended.
NSAIDs:
Treatment with NSAIDs can lead to acute renal failure due to direct suppression of glomerular filtration, especially in patients at risk (elderly patients and/or patients with dehydration). When using these drugs together, it is necessary to ensure adequate fluid intake and monitor renal function before and during treatment.
Trimethoprim:
simultaneous use of trimethoprim with eplerenone increases the risk of developing hyperkalemia. It is recommended to monitor serum potassium concentrations and renal function, especially in patients with renal failure and in the elderly.
ACE inhibitors and angiotensin II receptor antagonists:
Use eplerenone with ALP inhibitors or angiotensin II receptor antagonists with caution. Such a combination may lead to an increased risk of developing hyperkalemia, especially in patients with impaired renal function, incl. in older people. It is recommended to carefully monitor renal function and serum potassium concentrations.
Alpha1-blockers (prazosin, alfuzosin):
with simultaneous use of alpha1-blockers with eplerenone, the hypotensive effect may be enhanced and/or the risk of developing orthostatic hypotension may increase, and therefore it is recommended to monitor blood pressure when changing body position.
Tricyclic antidepressants, neuroleptics, amifostine, baclofen:
When these drugs are used concomitantly with eplerenone, the antihypertensive effect may be enhanced or the risk of developing orthostatic hypotension may increase.
Glucocorticoids, tetracosactide:
simultaneous use of these drugs with eplerenone may lead to a weakening of the antihypertensive effect (sodium and fluid retention).
Pharmacokinetic interactions
In vitro studies indicate that eplerenone does not inhibit the isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. Eplerenone is not a substrate or inhibitor of P-glycoprotein.
Digoxin:
The AUC of digoxin when coadministered with eplerenone increases by 16% (90% CI: 4-30%). Caution must be exercised if digoxin is used in doses close to the maximum therapeutic dose.
Warfarin:
no clinically significant pharmacokinetic interaction with warfarin was identified. Caution must be exercised if warfarin is used in doses close to the maximum therapeutic dose.
CYP3A substrates:
In special studies, no evidence of pharmacokinetic interaction of eplerenone with CYP3A4 substrates, for example, midazolam and cisapride, was identified.
CYP3A4 inhibitors:
— Potent CYP3A4 inhibitors:
When eplerenone is used with drugs that inhibit CYP3A4, significant pharmacokinetic interactions are possible. A potent inhibitor of CYP3A4 (ketoconazole 200 mg 2 times / day) caused an increase in eplerenone AUC by 441%. Concomitant use of eplerenone with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone is contraindicated;
— weak and moderate CYP3A4 inhibitors:
simultaneous use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole was accompanied by significant pharmacokinetic interactions (the degree of increase in AUC ranged from 98% to 187%). When using these drugs simultaneously with eplerenone, the dose of the latter should not exceed 25 mg.
CYP3A4 inducers:
simultaneous administration of St. John's wort tincture (a powerful inducer of CYP3A4) with eplerenone caused a decrease in the AUC of the latter by 30%. When using more potent inducers of CYP3A4, such as rifampicin, a more pronounced decrease in the AUC of eplerenone is possible. Given the possible decrease in the effectiveness of eplerenone, the simultaneous use of powerful CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort tincture) is not recommended.
Antacids:
Based on a pharmacokinetic clinical study, significant interactions between antacids and eplerenone when used concomitantly are not expected.
Indications for use of the drug Inspra
Heart failure after myocardial infarction. The drug is used as a component of standard therapy to reduce the risk of cardiovascular morbidity and mortality in patients with a stable clinical condition with left ventricular dysfunction (left ventricular ejection fraction ≤40%) and clinical manifestations of heart failure after myocardial infarction. AH (arterial hypertension). Treatment of hypertension (arterial hypertension). The drug can be prescribed either as monotherapy or in combination with other antihypertensive drugs.
Espiro
Pharmacodynamic interaction
Potassium-sparing diuretics and potassium supplements: Given the increased risk of hyperkalemia, eplerenone should not be administered to patients receiving potassium-sparing diuretics and potassium supplements. Potassium-sparing diuretics may enhance the effects of antihypertensive drugs and other diuretics.
Lithium preparations: The interaction of eplerenone with lithium preparations has not been studied. However, cases of lithium intoxication have been described in patients receiving lithium preparations in combination with diuretics and ACE inhibitors. If such a combination is necessary, it is advisable to monitor the concentration of lithium in the blood plasma.
Cyclosporine, tacrolimus: Cyclosporine and tacrolimus may cause renal impairment and increase the risk of hyperkalemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus is required during treatment with eplerenone, regular monitoring of serum potassium concentrations and renal function is recommended.
NSAIDs: Treatment with NSAIDs may lead to acute renal failure due to direct inhibition of glomerular filtration, especially in at-risk patients (elderly patients and/or patients with dehydration). When using these drugs together, it is necessary to ensure adequate fluid intake and monitor renal function before and during treatment.
Trimethoprim: Concomitant use of trimethoprim with eplerenone increases the risk of hyperkalemia. It is recommended to monitor serum potassium concentrations and renal function, especially in patients with renal insufficiency and in elderly patients.
ACE inhibitors and angiotensin II receptor antagonists: When using eplerenone with ACE inhibitors or angiotensin II receptor antagonists, serum potassium concentrations should be regularly monitored. This combination may lead to an increased risk of developing hyperkalemia, especially in patients with impaired renal function, including elderly patients. The triple combination of an ACE inhibitor and an ARA II with eplerenone should not be used.
Alpha1-blockers (prazosin, alfuzosin): with simultaneous use of alpha1-blockers with eplerenone, the antihypertensive effect may be enhanced and/or the risk of developing orthostatic hypotension may increase, and therefore it is recommended to monitor blood pressure when changing body position.
Tricyclic antidepressants, antipsychotics, amifostine, baclofen: the antihypertensive effect may be enhanced or the risk of orthostatic hypotension may increase.
Glucocorticoids, tetracosactide: Concomitant use of these drugs with eplerenone may result in sodium and fluid retention.
Pharmacokinetic interaction
In vitro studies indicate that eplerenone does not inhibit the isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. Eplerenone is not a substrate or inhibitor of P-glycoprotein.
Digoxin: Caution should be used if digoxin is used in doses close to the maximum therapeutic dose.
Warfarin: No clinically significant pharmacokinetic interaction with warfarin has been identified. Caution must be exercised if warfarin is used in doses close to the maximum therapeutic dose.
CYP3A4 substrates: In specific studies, there was no evidence of pharmacokinetic interaction between eplerenone and CYP3A4 substrates, such as midazolam and cisapride.
CYP3A4 inhibitors:
- strong CYP3A4 inhibitors: simultaneous use of eplerenone with strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone, is contraindicated;
- weak and moderate inhibitors of CYP3A4: simultaneous use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole was accompanied by significant pharmacokinetic interactions (the degree of increase in AUC ranged from 98% to 187%). When using these drugs simultaneously with eplerenone, the dose of the latter should not exceed 25 mg.
CYP3A4 inducers: given the possible decrease in the effectiveness of eplerenone, the simultaneous use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, drugs containing St. John's wort) is not recommended.
Antacids: Based on a pharmacokinetic clinical study, significant interactions between antacids and eplerenone when used concomitantly are not expected.
Use of the drug Inspra
AH (arterial hypertension). Inspru can be prescribed as monotherapy or in combination with other antihypertensive drugs. The recommended initial dose of the drug is 50 mg once a day. If the reduction in blood pressure is insufficient, the dose can be increased to 100 mg once a day. Heart failure after myocardial infarction. The recommended maintenance dose is 50 mg 1 time per day. Treatment should begin with a dose of 25 mg once a day. Subsequently, the dose is titrated over 4 weeks until the required dose of 50 mg is reached once a day, taking into account the level of potassium ions in the blood serum, as indicated in the table.
Serum potassium level, mmol/l | Action | Dose adjustment |
| ≤5 | Increasing the dose | From 25 mg once every 2 days to 25 mg once daily From 25 mg once daily to 50 mg once daily |
| 5–5,4 | Dose maintenance | The dose does not change |
| 5,5–5,9 | Dose reduction | From 50 mg once a day to 25 mg once a day From 25 mg once a day to 25 mg once every 2 days From 25 mg once every 2 days until discontinuation of the drug |
| ≥6 | Withdrawal of the drug | — |
After stopping the use of the drug if the potassium concentration in the blood serum increases to 6 mmol/l, the use of Inspra at a dose of 25 mg once every 2 days can be resumed when the potassium concentration decreases to a level of ≤5 mmol/l. Serum potassium levels should be determined before Inspra is prescribed, during the first week of treatment, and one month after starting use or changing the dose of the drug. In the future, potassium levels should be periodically monitored. The drug can be used regardless of meals. A dose of 25 mg/day is recommended for patients who are concomitantly taking weak CYP3A4 inhibitors such as erythromycin, saquinavir, verapamil, or fluconazole. Use for the treatment of patients with mild and moderately severe liver dysfunction. No initial dose adjustment is required for patients with mild to moderate hepatic impairment. For mild dysfunction, no adjustment of the initial dose is required. In case of moderate to severe renal dysfunction or type II diabetes mellitus with microalbuminuria, see CONTRAINDICATIONS and SPECIAL INSTRUCTIONS. No adjustment of the initial dose is required for the elderly. The safety and effectiveness of the drug when used in children have not been studied.
The drug 'Inspra' - instructions for use, description and reviews
Pharmacodynamic interactions Potassium-sparing diuretics and potassium supplements. Given the increased risk of hyperkalemia, eplerenone should not be prescribed to patients receiving potassium-sparing diuretics and potassium supplements (see section "Contraindications"). Potassium-sparing diuretics may enhance the effects of antihypertensive agents and other diuretics.
Preparations containing lithium. The interaction of eplerenone with lithium has not been studied. However, cases of lithium intoxication have been described in patients receiving lithium in combination with diuretics and ACE inhibitors. Concomitant use of eplerenone and lithium should be avoided. If such a combination is necessary, it is advisable to monitor the concentration of lithium in the blood plasma (see section "Special instructions").
Cyclosporine, tacrolumus. These drugs may cause renal dysfunction and increase the risk of hyperkalemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus is required during treatment with eplerenone, it is recommended to carefully monitor serum potassium concentrations and renal function (see section "Special Instructions").
NSAIDs. Treatment with NSAIDs can lead to acute renal failure due to direct suppression of glomerular filtration, especially in patients at risk (elderly patients and/or patients with dehydration). When using these drugs together, it is necessary to ensure adequate fluid intake and monitor renal function before and during treatment.
Trimethoprim. Concomitant use of trimethoprim with eplerenone increases the risk of developing hyperkalemia. It is recommended to monitor serum potassium concentrations and renal function, especially in patients with renal failure and in the elderly.
ACE inhibitors and angiotensin II receptor antagonists. Eplerenone should be used with caution with ACE inhibitors or angiotensin II receptor antagonists. Such a combination may lead to an increased risk of developing hyperkalemia, especially in patients with impaired renal function, incl. in older people. It is recommended to carefully monitor renal function and serum potassium concentrations.
Alpha1-blockers (prazosin, alfuzosin). With simultaneous use of alpha1-blockers with eplerenone, the hypotensive effect may be enhanced and/or the risk of developing orthostatic hypotension may increase, and therefore it is recommended to monitor blood pressure when changing body position.
Tricyclic antidepressants, neuroleptics, amifostine, baclofen. When these drugs are used concomitantly with eplerenone, the antihypertensive effect may be enhanced or the risk of developing orthostatic hypotension may increase.
GCS, tetracosactide. Concomitant use of these drugs with eplerenone may lead to a weakening of the antihypertensive effect (sodium and fluid retention).
Pharmacokinetic interactions
In vitro studies indicate that eplerenone does not inhibit the isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. Eplerenone is not a substrate or inhibitor of P-glycoprotein.
Digoxin. The AUC of digoxin when used concomitantly with eplerenone increases by 16% (90% CI - 4-30%). Caution must be exercised if digoxin is used in doses close to the maximum therapeutic dose.
Warfarin. No clinically significant pharmacokinetic interaction with warfarin has been identified. Caution must be exercised if warfarin is used in doses close to the maximum therapeutic dose.
CYP3A4 substrates. In specific studies, no evidence of pharmacokinetic interaction between eplerenone and CYP3A4 substrates, such as midazolam and cisapride, was identified.
CYP3A4 inhibitors
Potent CYP3A4 inhibitors. When eplerenone is used with drugs that inhibit CYP3A4, significant pharmacokinetic interactions are possible. A potent CYP3A4 inhibitor (ketoconazole 200 mg twice daily) caused an increase in eplerenone AUC by 441%. Concomitant use of eplerenone with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone is contraindicated (see section "Contraindications").
Weak and moderate inhibitors of CYP3A4. Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole was accompanied by significant pharmacokinetic interactions (the degree of increase in AUC ranged from 98 to 187%). When using these drugs simultaneously with eplerenone, the dose of the latter should not exceed 25 mg (see section “Dosage and Administration”).
CYP3A4 inducers
Concomitant use of St. John's wort tincture (a powerful CYP3A4 inducer) with eplerenone caused a decrease in the AUC of the latter by 30%. When using more potent inducers of CYP3A4, such as rifampicin, a more pronounced decrease in the AUC of eplerenone is possible. Given the possible decrease in the effectiveness of eplerenone, the simultaneous use of powerful CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort tincture) is not recommended (see section "Special instructions").
Antacids. Based on a pharmacokinetic clinical study, significant interactions between antacids and eplerenone when used concomitantly are not expected.
Contraindications to the use of the drug Inspra
Hypersensitivity to eplerenone or to any other component of the drug, hyperkalemia with or without clinical manifestations and a potassium level of 5 mmol/l (mEq/l) before treatment, moderate to severe renal failure (creatinine clearance ≤50 ml/min), severe liver failure (Child-Pugh class C), pregnancy and lactation, childhood. The drug is contraindicated during concomitant use of potassium-sparing diuretics, potassium supplements or potent P450 3A4 inhibitors such as ketoconazole, itraconazole and ritonavir. The drug is contraindicated in patients with hypertension (arterial hypertension) and concomitant type II diabetes mellitus with microalbuminuria and an increase in serum creatinine levels to 2 mg/dl (or 177 μ mol/l) in men or 1.8 mg/dl (or 159 μ mol/l) in women.
Instructions for use of INSPRA
Pharmacodynamic interactions
Potassium-sparing diuretics and potassium supplements:
Due to the increased risk of hyperkalemia, eplerenone should not be administered to patients receiving potassium-sparing diuretics and potassium supplements. Potassium-sparing diuretics may potentiate the effect of antihypertensive agents and other diuretics.
Lithium:
Drug interaction studies between eplerenone and lithium have not been conducted. However, lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Concomitant use of eplerenone and lithium should be avoided. If this combination is necessary, plasma lithium concentrations should be monitored.
Cyclosporine, tacrolimus:
the use of cyclosporine and tacrolimus may lead to impaired renal function and an increased risk of hyperkalemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If it is necessary to prescribe cyclosporine and tacrolimus during treatment with eplerenone, it is recommended to carefully monitor serum potassium levels and renal function.
NSAIDs:
Treatment with NSAIDs may lead to the development of acute renal failure through a direct effect on glomerular filtration, especially in patients at risk (elderly and/or patients with dehydration). Patients taking eplerenone and NSAIDs should be adequately hydrated and have their renal function checked before starting treatment.
Trimethoprim:
concomitant administration of trimethoprim and eplerenone increases the risk of hyperkalemia. Serum potassium and renal function should be monitored, especially in patients with impaired renal function and the elderly.
ACE inhibitors, angiotensin II receptor antagonists:
Eplerenone should be prescribed with caution in combination with ACE inhibitors and angiotensin II receptor antagonists. Combining eplerenone with these drugs may increase the risk of hyperkalemia in patients at risk for renal impairment, such as the elderly.
Careful monitoring of serum potassium and renal function is recommended.
Alpha1 blockers (eg, prazosin, alfuzosin):
with the combined use of alpha1-blockers and eplerenone, there is a possibility of increased hypotensive effect and/or postural hypotension. During concomitant use of an alpha1-blocker, clinical monitoring is recommended for timely diagnosis of postural hypotension.
Tricyclic antidepressants, neuroleptics, amifostine, baclofen:
when these drugs are co-administered with eplerenone, an enhanced antihypertensive effect and an increased risk of postural hypotension are likely.
Glucocorticoids, tetracosactide:
when these drugs are co-administered with eplerenone, a decrease in the antihypertensive effect (salt and fluid retention) is likely.
Pharmacokinetic interaction
In vitro studies indicate that eplerenone is not an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6 or CYP3A4. Eplerenone is not a substrate or inhibitor of P-glycoprotein.
Digoxin:
systemic exposure (AUC) of digoxin increases by 16% (90% CI:
- 4% -30%) when co-administered with eplerenone. Caution is necessary if the digoxin dose is close to the upper limit of the therapeutic range.
Warfarin:
no clinically significant pharmacokinetic interaction with warfarin was observed. Use this combination with caution if the warfarin dose is close to the upper limit of the therapeutic range.
CYP3A4 substrates:
According to the results of pharmacokinetic studies with CYP3A4 substrates, for example, midazolam and cisapride, there is no significant pharmacokinetic interaction between these drugs and eplerenone when used together.
CYP3A4 inhibitors:
- strong CYP3A4 inhibitors: Significant pharmacokinetic interactions may be observed with concomitant use of eplerenone and drugs that inhibit the CYP3A4 enzyme. The use of a strong CYP3A4 inhibitor (ketoconazole 200 mg 2 times / day) leads to an increase in the AUC of eplerenone to 441%. Concomitant use of eplerenone and strong CYP3A4 inhibitors such as ketoconazole, intraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone is contraindicated;
- weak to moderate CYP3A4 inhibitors: Coadministration with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole resulted in a significant pharmacokinetic interaction with a linear increase in AUC ranging from 98% to 187%. Therefore, when used concomitantly with weak to moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg.
CYP3A4 inducers:
co-administration of St. John's wort (a strong CYP3A4 inducer) and eplerenone caused a 30% decrease in the AUC of eplerenone. A more pronounced decrease in eplerenone AUC may be observed with the use of stronger CYP3A4 inducers, such as rifampicin. Concomitant use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbitol, St. John's wort) and eplerenone is not recommended due to the risk of reducing the effectiveness of eplerenone.
Antacids:
Based on the results of a pharmacokinetic clinical study, no significant interaction is expected with the concomitant use of antacids and eplerenone.
Side effects of the drug Inspra
Hypertension (arterial hypertension) These side effects were observed with a frequency of 1% in 4 placebo-controlled studies of eplerenone monotherapy in patients with hypertension (arterial hypertension) in doses of 25 to 400 mg. Infections and infestations. Often - flu-like syndrome. Metabolic disorders. Often - hypercholesterolemia, hypertriglyceridemia. From the nervous system. Often - dizziness. From the respiratory system. Often - cough. From the gastrointestinal tract. Often - abdominal pain, diarrhea. From the hepatobiliary system. Often - increased activity of gamma-glutamyltransferase and ALT. From the urinary system. Often - albuminuria. General disorders. Often - increased fatigue. Other clinical studies have observed: Metabolic and metabolic disorders. Often - hyperkalemia. Heart failure after myocardial infarction In the Eplerenone Efficacy and Prognosis Study in Patients with Heart Failure After Acute Myocardial Infarction (EPHESUS), the total number of side effects with eplerenone (78.9%) was comparable to that with placebo (79.5%). ). Discontinuation rates due to side effects were 4.4% for patients treated with eplerenone and 4.3% for patients treated with placebo. The following adverse events in the EPHESUS study were treatment related and occurred more frequently than with placebo. Side effects are listed according to body system and absolute frequency of occurrence. Side effects were classified as common (1% but ≤10%) or uncommon (0.1% but ≤1%). From the blood system. Uncommon: eosinophilia. Metabolic disorders. Often - hyperkalemia; uncommon - dehydration, hypercholesterolemia, hypertriglyceridemia, hyponatremia. Mental disorders. Uncommon: insomnia. From the nervous system. Often - dizziness; infrequently - headache. From the cardiovascular system. Often - hypotension; uncommon - atrial fibrillation, myocardial infarction, left ventricular heart failure, postural hypotension. From the respiratory system. Uncommon: pharyngitis. From the gastrointestinal tract. Often - diarrhea, nausea; infrequently - flatulence, vomiting. Changes in the skin and subcutaneous tissue. Uncommon: itching, increased sweating. From the musculoskeletal system. Uncommon: back pain, calf muscle cramps. From the kidneys and urinary tract. Uncommon: renal dysfunction. General disorders. Uncommon: asthenia, increased fatigue. Changes in research results. Uncommon: increased levels of urea nitrogen and creatinine in the blood. During the period after the introduction of the drug into widespread medical practice, the following side effects on the skin and its appendages were recorded: angioedema, rash.
Inspra, tablets 25 mg, 30 pcs.
FDV
Potassium-sparing diuretics and potassium supplements. Given the increased risk of hyperkalemia, eplerenone should not be prescribed to patients receiving potassium-sparing diuretics and potassium supplements (see “Contraindications”). Potassium-sparing diuretics may enhance the effects of antihypertensive agents and other diuretics.
Preparations containing lithium. The interaction of eplerenone with lithium preparations has not been studied. However, in patients receiving lithium preparations in combination with diuretics and ACE inhibitors, cases of increased concentrations and lithium intoxication have been described. If such a combination is necessary, it is advisable to monitor the concentration of lithium in the blood plasma (see “Special Instructions”).
Cyclosporine, tacrolimus. These drugs may cause renal dysfunction and increase the risk of hyperkalemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus is required during treatment with eplerenone, it is recommended to carefully monitor serum potassium concentrations and renal function (see "Special Instructions").
NSAIDs. Treatment with NSAIDs can lead to acute renal failure due to direct suppression of glomerular filtration, especially in patients at risk (elderly patients and/or patients with dehydration). When using these drugs together, it is necessary to ensure adequate fluid intake and monitor renal function before and during treatment.
Trimethoprim. Concomitant use of trimethoprim with eplerenone increases the risk of developing hyperkalemia. It is recommended to monitor serum potassium concentrations and renal function, especially in patients with renal insufficiency and elderly patients.
ACE inhibitors and angiotensin II receptor antagonists. When using eplerenone with ACE inhibitors or angiotensin II receptor antagonists, serum potassium concentrations should be carefully monitored. Such a combination may lead to an increased risk of developing hyperkalemia, especially in patients with impaired renal function, incl. in elderly patients. The triple combination of an ACE inhibitor and angiotensin II receptor antagonist with eplerenone should not be used.
α1-blockers (prazosin, alfuzosin). With simultaneous use of α1-blockers with eplerenone, the hypotensive effect may be enhanced and/or the risk of developing orthostatic hypotension may increase, and therefore it is recommended to monitor blood pressure when changing body position.
Tricyclic antidepressants, neuroleptics, amifostine, baclofen. When these drugs are used concomitantly with eplerenone, the antihypertensive effect may be enhanced or the risk of developing orthostatic hypotension may increase.
GCS, tetracosactide. Concomitant use of these drugs with eplerenone may lead to a weakening of the antihypertensive effect (sodium and fluid retention).
FKV
In vitro studies indicate that eplerenone does not inhibit the isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. Eplerenone is not a substrate or inhibitor of P-glycoprotein.
Digoxin. The AUC of digoxin when used concomitantly with eplerenone increases by 16% (90% CI - 4-30%). Caution must be exercised if digoxin is used in doses close to the maximum therapeutic dose.
Warfarin. No clinically significant pharmacokinetic interaction with warfarin has been identified. Caution must be exercised if warfarin is used in doses close to the maximum therapeutic dose.
Antacids. Based on a pharmacokinetic clinical study, significant interactions between antacids and eplerenone when used concomitantly are not expected.
CYP3A4 substrates. In special studies, no evidence of pharmacokinetic interaction of eplerenone with CYP3A4 substrates, such as midazolam and cisapride, was identified.
CYP3A4 inhibitors
Strong inhibitors of CYP3A4. When eplerenone is used with drugs that inhibit CYP3A4, significant PCF is possible. A strong CYP3A4 inhibitor (ketoconazole 200 mg twice daily) caused an increase in eplerenone AUC by 441%. Concomitant use of eplerenone with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone is contraindicated (see "Contraindications").
Weak and moderate inhibitors of CYP3A4. Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole was accompanied by a significant PEF (the degree of increase in AUC ranged from 98 to 187%). When using these drugs simultaneously with eplerenone, the dose of the latter should not exceed 25 mg (see “Dosage and Administration”).
CYP3A4 inducers
Concomitant use of drugs containing St. John's Wort (St John's Wort, a strong inducer of the CYP3A4 isoenzyme) with eplerenone caused a decrease in the AUC of the latter by 30%. When using stronger CYP3A4 inducers, such as rifampicin, a more pronounced decrease in the AUC of eplerenone is possible. Given the possible decrease in the effectiveness of eplerenone, simultaneous use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, drugs containing St. John's wort) is not recommended
Special instructions for the use of the drug Inspra
Hyperkalemia. Hyperkalemia may occur when using eplerenone. The risk of developing hyperkalemia can be reduced by avoiding multidrug concomitant therapy and careful monitoring. Eplerenone should not be prescribed to patients who have taken potassium supplements. Regular monitoring of serum potassium levels is necessary in patients with impaired renal function, including diabetic microalbuminuria. Reducing the dose of eplerenone may decrease serum potassium levels. Hepatic impairment: In patients with mild to moderate hepatic impairment, serum electrolyte levels should be monitored. The use of eplerenone in patients with severe hepatic impairment (Child-Pugh class C) has not been studied and is therefore contraindicated. Impaired renal function See SPECIAL INSTRUCTIONS and CONTRAINDICATIONS. Elderly Patients The risk of developing hyperkalemia is greater in older people due to age-related deterioration in renal function. Therefore, in elderly people, it is recommended to periodically monitor serum potassium levels. Pregnancy and lactation There are no data on the use of eplerenone in pregnant women. Experiments on animals did not reveal direct or indirect negative effects on the course of pregnancy, the development of the embryo and fetus, childbirth and the postpartum period. However, eplerenone should be used with caution in pregnant women. It is unknown whether eplerenone is excreted in breast milk after oral administration. The decision to stop breastfeeding or discontinue the drug is made taking into account the benefit ratio for the mother/risk for the infant. Effect on the ability to drive vehicles and operate machinery No studies have been conducted on the effect of eplerenone on the ability to drive vehicles or operate machinery.
Inspra, 30 pcs., 50 mg, film-coated tablets
Pharmacodynamic interactions
Potassium-sparing diuretics and potassium supplements.
Given the increased risk of hyperkalemia, eplerenone should not be prescribed to patients receiving potassium-sparing diuretics and potassium supplements (see section "Contraindications"). Potassium-sparing diuretics may enhance the effects of antihypertensive agents and other diuretics.
Preparations containing lithium.
The interaction of eplerenone with lithium has not been studied. However, cases of lithium intoxication have been described in patients receiving lithium in combination with diuretics and ACE inhibitors. Concomitant use of eplerenone and lithium should be avoided. If such a combination is necessary, it is advisable to monitor the concentration of lithium in the blood plasma (see section "Special instructions").
Cyclosporine, tacrolumus.
These drugs may cause renal dysfunction and increase the risk of hyperkalemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus is required during treatment with eplerenone, it is recommended to carefully monitor serum potassium concentrations and renal function (see section "Special Instructions").
NSAIDs.
Treatment with NSAIDs can lead to acute renal failure due to direct suppression of glomerular filtration, especially in patients at risk (elderly patients and/or patients with dehydration). When using these drugs together, it is necessary to ensure adequate fluid intake and monitor renal function before and during treatment.
Trimethoprim.
Concomitant use of trimethoprim with eplerenone increases the risk of developing hyperkalemia. It is recommended to monitor serum potassium concentrations and renal function, especially in patients with renal failure and in the elderly.
ACE inhibitors and angiotensin II receptor antagonists.
Eplerenone should be used with caution with ACE inhibitors or angiotensin II receptor antagonists. Such a combination may lead to an increased risk of developing hyperkalemia, especially in patients with impaired renal function, incl. in older people. It is recommended to carefully monitor renal function and serum potassium concentrations.
Alpha1-blockers (prazosin, alfuzosin).
With simultaneous use of alpha1-blockers with eplerenone, the hypotensive effect may be enhanced and/or the risk of developing orthostatic hypotension may increase, and therefore it is recommended to monitor blood pressure when changing body position.
Tricyclic antidepressants, neuroleptics, amifostine, baclofen.
When these drugs are used concomitantly with eplerenone, the antihypertensive effect may be enhanced or the risk of developing orthostatic hypotension may increase.
GCS, tetracosactide.
Concomitant use of these drugs with eplerenone may lead to a weakening of the antihypertensive effect (sodium and fluid retention).
Pharmacokinetic interactions
In vitro studies
indicate that eplerenone does not inhibit the isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. Eplerenone is not a substrate or inhibitor of P-glycoprotein.
Digoxin.
The AUC of digoxin when used concomitantly with eplerenone increases by 16% (90% CI - 4-30%). Caution must be exercised if digoxin is used in doses close to the maximum therapeutic dose.
Warfarin.
No clinically significant pharmacokinetic interaction with warfarin has been identified. Caution must be exercised if warfarin is used in doses close to the maximum therapeutic dose.
CYP3A4 substrates.
In specific studies, no evidence of pharmacokinetic interaction between eplerenone and CYP3A4 substrates, such as midazolam and cisapride, was identified.
CYP3A4 inhibitors
Potent CYP3A4 inhibitors.
When eplerenone is used with drugs that inhibit CYP3A4, significant pharmacokinetic interactions are possible. A potent CYP3A4 inhibitor (ketoconazole 200 mg twice daily) caused an increase in eplerenone AUC by 441%. Concomitant use of eplerenone with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone is contraindicated (see "Contraindications").
Weak and moderate inhibitors of CYP3A4.
Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole was accompanied by significant pharmacokinetic interactions (the degree of increase in AUC ranged from 98 to 187%). When using these drugs simultaneously with eplerenone, the dose of the latter should not exceed 25 mg (see “Dosage and Administration”).
CYP3A4 inducers
Concomitant use of St. John's wort tincture (a powerful CYP3A4 inducer) with eplerenone caused a decrease in the AUC of the latter by 30%. When using more potent inducers of CYP3A4, such as rifampicin, a more pronounced decrease in the AUC of eplerenone is possible. Given the possible decrease in the effectiveness of eplerenone, the simultaneous use of powerful CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort tincture) is not recommended (see "Special Instructions").
Antacids.
Based on a pharmacokinetic clinical study, significant interactions between antacids and eplerenone when used concomitantly are not expected.
Interactions of the drug Inspra
The drug should not be used simultaneously with potassium-sparing diuretics and potassium supplements due to the risk of developing hyperkalemia. Digoxin. No evidence of drug interactions between eplerenone and digoxin was observed. Warfarin. No manifestations of drug interactions between eplerenone and warfarin were noted. NSAIDs. Concomitant use of other potassium-sparing diuretics with NSAIDs has led to the development of hyperkalemia in patients with impaired renal function. Lithium preparations. There have been cases of toxicity of lithium preparations when they are used simultaneously with diuretics and ACE inhibitors. In vitro studies have demonstrated that eplerenone is not an inhibitor of CYP 1A2, CYP 2C19, CYP 2C9 or CYP 2D6 isoenzymes. Eplerenone is not a substrate or inhibitor of P-glycoprotein. Substrates of CYP 3A4. Pharmacokinetic studies with CYP3A4 substrates such as midazolam and cisapride have shown no evidence of significant pharmacokinetic interactions between these substrates and eplerenone. CYP3A4 inhibitors. Powerful inhibitors. Significant pharmacokinetic interactions may occur when eplerenone is co-administered with strong CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir. The use of ketoconazole at a dose of 200 mg 2 times a day caused an increase in the AUC of eplerenone by 441%. Concomitant use of eplerenone with strong CYP3A4 inhibitors is contraindicated. Weak and moderate inhibitors of CYP 3A4. Concomitant use of eplerenone with erythromycin, saquinavir, verapamil and fluconazole may result in a significant pharmacokinetic interaction, which is manifested by an increase in eplerenone AUC by 98–187%. The daily dose of eplerenone when used simultaneously with such drugs should not exceed 25 mg. CYP 3A4 inducers. The simultaneous use of St. John's wort (a powerful inducer of CYP 3A4) with eplerenone caused a decrease in the AUC of eplerenone by 30%. Concomitant use of eplerenone with strong CYP3A4 inducers is not recommended due to the potential for a significant decrease in AUC that may occur.
Inspra
Pharmacodynamic interaction
Potassium-sparing diuretics and potassium supplements: Given the increased risk of hyperkalemia, eplerenone should not be administered to patients receiving potassium-sparing diuretics and potassium supplements. Potassium-sparing diuretics may enhance the effects of antihypertensive drugs and other diuretics.
Lithium preparations: The interaction of eplerenone with lithium preparations has not been studied. However, cases of lithium intoxication have been described in patients receiving lithium preparations in combination with diuretics and ACE inhibitors. If such a combination is necessary, it is advisable to monitor the concentration of lithium in the blood plasma.
Cyclosporine, tacrolimus: Cyclosporine and tacrolimus may cause renal impairment and increase the risk of hyperkalemia. Concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus is required during treatment with eplerenone, regular monitoring of serum potassium concentrations and renal function is recommended.
NSAIDs: Treatment with NSAIDs may lead to acute renal failure due to direct inhibition of glomerular filtration, especially in at-risk patients (elderly patients and/or patients with dehydration). When using these drugs together, it is necessary to ensure adequate fluid intake and monitor renal function before and during treatment.
Trimethoprim: Concomitant use of trimethoprim with eplerenone increases the risk of hyperkalemia. It is recommended to monitor serum potassium concentrations and renal function, especially in patients with renal insufficiency and in elderly patients.
ACE inhibitors and angiotensin II receptor antagonists: When using eplerenone with ACE inhibitors or angiotensin II receptor antagonists, serum potassium concentrations should be regularly monitored. This combination may lead to an increased risk of developing hyperkalemia, especially in patients with impaired renal function, including elderly patients. The triple combination of an ACE inhibitor and an ARA II with eplerenone should not be used.
Alpha1-blockers (prazosin, alfuzosin): with simultaneous use of alpha1-blockers with eplerenone, the antihypertensive effect may be enhanced and/or the risk of developing orthostatic hypotension may increase, and therefore it is recommended to monitor blood pressure when changing body position.
Tricyclic antidepressants, antipsychotics, amifostine, baclofen: the antihypertensive effect may be enhanced or the risk of orthostatic hypotension may increase.
Glucocorticoids, tetracosactide: simultaneous use of these drugs with the drug may lead to sodium and fluid retention.
Pharmacokinetic interaction
In vitro studies indicate that eplerenone does not inhibit the isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. Eplerenone is not a substrate or inhibitor of P-glycoprotein.
Digoxin: Caution should be used if digoxin is used in doses close to the maximum therapeutic dose.
Warfarin: No clinically significant pharmacokinetic interaction with warfarin has been identified. Caution must be exercised if warfarin is used in doses close to the maximum therapeutic dose.
CYP3A4 substrates: In specific studies, there was no evidence of pharmacokinetic interaction between eplerenone and CYP3A4 substrates, such as midazolam and cisapride.
CYP3A4 inhibitors:
- strong CYP3A4 inhibitors: simultaneous use of eplerenone with strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone, is contraindicated;
- weak and moderate inhibitors of CYP3A4: simultaneous use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole was accompanied by significant pharmacokinetic interactions (the degree of increase in AUC ranged from 98% to 187%). When using these drugs simultaneously with the drug, the dose of the latter should not exceed 25 mg.
CYP3A4 inducers: given the possible decrease in the effectiveness of eplerenone, the simultaneous use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, drugs containing St. John's wort) is not recommended.
Antacids: Based on a pharmacokinetic clinical study, significant interactions between antacids and eplerenone when used concomitantly are not expected.
Espiro
Pharmacodynamic interactions
Potassium-sparing diuretics and potassium supplements: Given the increased risk of hyperkalemia, eplerenone should not be administered to patients receiving potassium-sparing diuretics and potassium supplements. Potassium-sparing diuretics may enhance the effects of antihypertensives and other diuretics.
Preparations containing lithium: the interaction of eilerenone with lithium preparations has not been studied. However, in patients receiving lithium preparations in combination with diuretics and AIF inhibitors. Cases of increased concentration and lithium intoxication have been described. If such a combination is necessary, it is advisable to monitor the lithium content in the blood plasma.
Cyclosporine, tacrolimus: Cyclosporine and tacrolimus may cause disturbances in nocturnal function and increase the risk of developing hyperkalemia. Concomitant use of eplerenoid and cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus is required during treatment of eplerenomas, it is recommended to regularly monitor serum potassium levels and renal function. Nonsteroidal anti-inflammatory drugs (NSAIDs): Treatment with III1VP may lead to acute renal failure due to direct suppression of glomerular filtration, especially in patients at risk (elderly patients and/or patients with dehydration). When using these drugs together, it is necessary to ensure adequate fluid intake and monitor renal function before and during treatment.
Trimethoprim: Concomitant use of trimethoprim with eplerenoid increases the risk of developing hyperkalemia. It is recommended to monitor serum stone levels and renal function, especially in patients with renal failure and in elderly patients.
AIF inhibitors and angiotensin II receptor antagonists: When using eplerenone with ACE inhibitors or angiotensin II receptor antagonists, serum potassium levels should be regularly monitored. Such a combination may lead to an increased risk of developing hyperkalemia, especially in patients with impaired renal function, incl. in elderly patients.
The triple combination of an ACE inhibitor and an ARA II with enlereion should not be used.
Alpha1-adrenergic blockers (prazoznn, alfuzoznn): with simultaneous use of alpha1-adrenoblockers with eplerenone, the antihypertensive effect may be enhanced and/or the risk of developing orthostatic hypotension may increase, and therefore it is recommended to monitor blood pressure when changing body position.
Tricyclic antidepressants, antipsychotics, amnphostin, baclofen: with simultaneous use of these drugs with eplerenone, the antihypertensive effect may be enhanced or the risk of developing orthostatic hypotension may increase.
Glucocorticosteroids, tetracosactide: simultaneous use of these drugs with eplerenone may lead to sodium and fluid retention.
Pharmacokinetic interactions
In vitro studies indicate that eplerenone does not inhibit CYP1A2 isoenzymes. CYP2C19, CYP2C9, CYP2D6 and CYP3A4. Eplerenone is not a substrate or inhibitor of P glycoprotein.
Digoxin: The AUC of digoxin when administered concomitantly with eplerenone increased by 16% (90% CI: 4-30%). Caution must be exercised if digoxin is used in doses close to the maximum therapeutic dose.
Warfarin: No clinically significant pharmacokinetic interaction with warfarin has been identified. Caution must be exercised if warfarin is used in doses close to the maximum therapeutic dose.
CYP3A4 substrates: In specific studies, no evidence of pharmacokinetic interaction of eplerenone with CYP3A4 substrates, such as midazolam and cisapride, was identified.
CYP3A4 isoenzyme inhibitors
Strong inhibitors of the CYP3A4 isoenzyme: when using eplersion with drugs that inhibit the CYP3A4 isoenzyme, significant pharmacokinetic interaction is possible. A strong CYP3A4 inhibitor (ketoconazole 200 mg twice daily) caused a 441% increase in the AIJC of eplercion. Concomitant use of eplerenone with strong inhibitors of the CYP3A4 isoenzyme, such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithrominine and nefazadone, is contraindicated (see section "Contraindications").
Weak and moderate inhibitors of the CYP3A4 isoenzyme: simultaneous use with erythromycin, saquinavir, amiodarone, diltiazem. verapamil and fluconazole were accompanied by a significant pharmacokinetic interaction (the degree of increase in AUC ranged from 98% to 187%). When using these drugs simultaneously with eplerenone, the dose of the latter should not exceed 25 mg (see section “Dosage and Administration”).
Inducers of the CYP3A4 isoenzyme: simultaneous use of drugs containing St. John's wort (a strong CYP3A4 inducer) with eplerenone caused a decrease in the AUC of the latter by 30%. When using stronger CYP3A4 inducers, such as rifampicants, a more pronounced decrease in the AUC of eplersion is possible. Given the possible decrease in the effectiveness of eplerenone, the simultaneous use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, drugs containing St. John's wort) is not recommended.
Lntacids: based on pharmacokinetic clinical study
There is no significant interaction between antacids and eplerenone when used concomitantly.
