Canarb, 60 mg 30 pcs.

Fimasartan is a non-peptide angiotensin II receptor antagonist (type AT1) for oral administration.

Angiotensin II is a key effector compound of the RAAS, which plays an important role in BP regulation and pathogenesis of arterial hypertension. Angiotensin II increases BP due to a significant vasoconstrictor effect and increase of ROS, activation of epinephrine production, release of aldosterone, influence on sodium reabsorption in distal parts of renal tubules and increase of the blood pressure. Its action is mediated through specific angiotensin receptors, while the main physiological effects, including adverse ones, are mediated by AT1-receptors.

The action of fimasartan is due to selective binding to AT1-receptors of angiotensin II: fimasartan has no partial agonist effect on angiotensin II receptors, which is typical for peptide blockers of angiotensin II receptors (such as saralazine). In studies of various animal models, fimasartan effectively and dose-dependently reduced BP after single or repeated oral and IV administration.

In humans, fimasartan increased plasma renin activity combined with an increase in angiotensin I and II concentration, confirming specific angiotensin II receptor blockade. Thus, after single oral administration of fimasartan at doses ranging from 20 to 480 mg, it caused an increase in plasma renin, angiotensin I, and angiotensin II activity with a maximum increase usually between 6 and 8 h after dose administration, which was long-lasting (up to 48 h after administration).

No drug-related changes in ACE activity and aldosterone were observed. Fimasartan increased plasma renin activity and angiotensin II concentrations after multiple uses, over 7 days, of 120 and 360 mg daily. The maximum increase in these parameters was generally observed 6-8 h after administration, and was prolonged (up to 24 h after administration). A decrease in plasma aldosterone levels was observed with longer fimasartan administration (for 28 days).

The efficacy of fimasartan in therapeutic doses of 60 and 120 mg in reducing BP has been proven in comparative randomized clinical trials. It was established that BP is decreased during 2 weeks after initiation of therapy with maximal effect after approximately 8-12 weeks. Fimasartan acts on BP for 24 h, providing a stable and smooth BP profile, the achievement of which is also facilitated by taking fimasartan at the same time of day (to minimize BP fluctuations). No tolerance to fimasartan developed when prescribed for a prolonged period (24 weeks).

Pharmacokinetics

Absorption

Fimasartan is rapidly absorbed after oral administration: Tmax in plasma after administration in healthy subjects and patients with arterial hypertension was 0.5-3 h and 0.5-1.3 h, respectively. In study of pharmacokinetic characteristics of drug directly in population of Russian patients with arterial hypertension Tmax was also determined in the range from 0.5 to 4 h (at a single drug dose of 60 mg).

After reaching Cmax a biphasic decrease in plasma concentration of fimasartan was observed, with the beginning of the elimination phase observed 2.5-8 h after drug administration in all patients. Quantifiable plasma fimasartan concentrations were observed up to the last time point of sample collection 24 h after drug administration, ranging from 1.33 to 11.2 ng/mL. Inter-patient variability (geometric mean CV%), was high, with values for AUC0-1last, AUC0-∞ and Cmax of 50.1%, 53.9% and 86.8%, respectively.

In the Russian study #CC09042014, pharmacokinetic parameters were obtained in female patients. Comparison of data with a population of healthy male volunteers showed that after a single oral dose of 60 mg of fimasartan, healthy volunteers had a 2-hour longer Tmax compared to patients with arterial hypertension. Peak systemic exposure (Cmax) was 1.4 times greater in patients with arterial hypertension. Total systemic exposure (AUC0-∞ and AUC0-tlast) was comparable in both populations.

Comparison of data with the Korean population of patients with arterial hypertension showed that after a single oral dose of 60 mg of fimasartan, the median Tmah in the Russian and Korean patient populations was approximately 1 h with individual values ranging from 0.5 to 4.0 h and from 0.5 to 6.0 h after drug administration, respectively. The peak systemic exposure (Cmax) and total systemic exposure (AUC0-∞ and AUC0-tlast) of fimasartan were comparable in Russian and Korean patient populations.

The absolute bioavailability of fimasartan in healthy subjects with oral administration of 60 mg was approximately 19%.

Distribution

Preclinical studies have shown limited distribution of the drug after oral administration.

At fimasartan concentrations of 0.01 to 100 µg/ml in vitro, plasma protein binding in humans ranges from 95.6 to 97.2% and is independent of dose.
Metabolism
CYP3A4 was the main enzyme metabolizing fimasartan. However, the role of metabolism in the excretion of fimasartan is insignificant because the initial drug is ≥85% of the forms of fimasartan found in human plasma, in addition the level of systemic exposure to fimasartan is slightly increased by specific CYP3A4 inhibitors. Desulfo-fimasartan and fimasartan-S-oxide have been identified as the most common circulating plasma metabolites of fimasartan in healthy men. Fimasartan is not an inducer or inhibitor of other cytochrome P450 family enzymes.

Excretion

After a single administration of fimasartan at doses of 20 to 480 mg in healthy subjects, the T1/2 is 5 to 16 h; in the Korean population of patients with essential hypertension when administered at doses of 20 to 180 mg the T1/2 was between 7 and 10 h; in the population of Russian patients with hypertension it was between 44 to 7.9 h when administered in a single dose of 60 mg. The systemic effects are estimated to be linear over a wide dose range. The accumulation index was 1.20 to 1.26 in healthy subjects and 1.02 to 1.08 in those with arterial hypertension. When assessed in healthy men and in patients with arterial hypertension, approximately 3-5% of the administered dose of fimasartan was detected in the urine within 24 or 144 h after oral administration.

Thus, there is little renal involvement in excretion of fimasartan. The main route of excretion is with the feces. Thus, after a single oral dose of 120 mg of 14C-labeled radioactive isotope fimasartan in a group of 6 healthy men, the average total excretion of the radioactive drug in feces and urine was about 86% of the prescribed dose, with urinary excretion of about 4.6%.

Pharmacokinetics in Special Clinical Cases

Elderly Patients. In elderly patients (over 65 years of age) the systemic effects of the drug are 1.69 times more pronounced than in younger patients. However the increase of systemic action in elderly patients does not seem to result in a more significant BP reduction because the RAAS activity in this group is generally lower than in young people.

Patients with renal insufficiency. The pharmacokinetic parameters of fimasartan were studied in patients with renal impairment; patients on hemodialysis were excluded from the study. When administered in 120 mg dose with severe renal impairment (estimated GFR less than 30 ml/min/1.73m2 body surface area) Cmax and AUC were compared to those of healthy volunteers: Cmax and AUC in patients with renal impairment were increased 1.87 and 1.73 times respectively. No differences were found in the safety profile of the two groups. Dose adjustment is required for patients with severe renal impairment (CK<30 ml/min).

Patients with hepatic impairment. Fimasartan 120 mg was administered to patients with hepatic impairment (Child-Pugh class A and B). Cmax and AUC were compared with those of healthy volunteers. The geometric mean ratios of Cmax and AUC were 0.77 and 1.10, respectively, when calculating values for patients with hepatic insufficiency class A and healthy volunteers. When values in groups of patients with hepatic insufficiency of class B and healthy volunteers were calculated – 6.55 for Cmax and 5.2 for AUC. There were no significant differences in BP and safety profile between the three groups. For patients with mild hepatic impairment initial dose adjustment of the drug is not required.

In patients with moderate and severe hepatic impairment the drug is not recommended.

Indications

Arterial hypertension 1 and 2 degrees.

Pharmacological effect

Fimasartan is a non-peptide angiotensin II receptor antagonist (type AT1) for oral administration.

Angiotensin II is a key effector compound of the RAAS, which plays an important role in the regulation of blood pressure and the pathogenesis of arterial hypertension. Angiotensin II increases blood pressure due to a pronounced vasoconstrictor effect and an increase in OPPS, activation of epinephrine production, aldosterone release, an effect on sodium reabsorption in the distal renal tubules and an increase in circulating volume. Its action is carried out through specific angiotensin receptors, with the main physiological effects, incl. and unfavorable, mediated by AT1 receptors.

The action of fimasartan is due to selective binding to the AT1 receptors of angiotensin II: fimasartan does not have a partial agonistic effect on the angiotensin II receptors, which is typical for peptide blockers of angiotensin II receptors (for example, saralazine). In studies of various animal models, fimasartan, after single or repeated oral and intravenous administration, effectively and dose-dependently reduced blood pressure.

In humans, fimasartan increased plasma renin activity in combination with an increase in the concentrations of angiotensin I and II, which confirms the specific blockade of angiotensin II receptors. Thus, after a single oral administration of fimasartan in a dose of 20 to 480 mg, it caused an increase in the activity of plasma renin, angiotensin I and angiotensin II with a maximum increase, usually between 6 and 8 hours after dosing, which persisted for a long time (up to 48 hours after administration).

However, no drug-related changes in ACE and aldosterone activity were observed. Fimasartan increased plasma renin activity and angiotensin II concentrations after repeated use of 120 and 360 mg per day for 7 days. The maximum increase in these parameters was observed, as a rule, 6-8 hours after administration, and persisted for a long time (up to 24 hours after administration). A decrease in plasma aldosterone levels was observed with longer administration of fimasartan (for 28 days).

The effectiveness of fimasartan in therapeutic doses of 60 and 120 mg in reducing blood pressure has been proven in comparative randomized clinical trials. It was found that blood pressure when taking the drug decreases within 2 weeks from the start of treatment, the maximum effect is observed after approximately 8-12 weeks. Fimasartan acts on blood pressure for 24 hours, providing a stable and smooth blood pressure profile, the achievement of which is also facilitated by taking fimasartan at the same time of day (to minimize pressure fluctuations). When fimasartan was prescribed for a long period (24 weeks), tolerance to it did not develop.

Pharmacokinetics

Suction

Fimasartan is rapidly absorbed after oral administration: Tmax in blood plasma after administration in healthy individuals and patients with arterial hypertension was 0.5-3 hours and 0.5-1.3 hours, respectively. When studying the pharmacokinetic characteristics of the drug directly in the population of Russian patients with arterial hypertension, Tmax was also determined within the range from 0.5 to 4 hours (with a single dose of the drug 60 mg).

After reaching Cmax, a two-phase decrease in the concentration of fimasartan in plasma was observed, with the onset of the elimination phase observed 2.5-8 hours after taking the drug in all patients. Quantitative fimasartan plasma concentrations were observed up to the last sample collection time point 24 hours after dosing, ranging from 1.33 to 11.2 ng/mL. Interpatient variability (geometric mean CV%) was high, with values ​​for AUC0-1last, AUC0-∞ and Cmax being 50.1%, 53.9% and 86.8%, respectively.

In the Russian study No. СС09042014, pharmacokinetic parameters were obtained in female patients. Comparison of data with a population of healthy male volunteers showed that after a single oral dose of fimasartan at a dose of 60 mg, Tmax was 2 hours longer in healthy volunteers compared to patients with arterial hypertension. Peak systemic exposure (Cmax) was 1.4 times higher in patients with arterial hypertension. However, the total systemic exposure (AUC0-∞ and AUC0-tlast) was comparable in both populations.

Comparison of data with the Korean population of patients with arterial hypertension showed that after a single oral dose of fimasartan at a dose of 60 mg, the median Tmax in the populations of Russian and Korean patients was approximately 1 hour with an individual range of values ​​from 0.5 to 4.0 hours and from 0.5 to 6.0 hours after taking the drug, respectively. Peak systemic exposure (Cmax) and total systemic exposure (AUC0-∞ and AUC0-tlast) of fimasartan are comparable in Russian and Korean patient populations.

The absolute bioavailability of fimasartan in healthy subjects after oral administration of 60 mg is about 19%.

Distribution

Preclinical studies have shown limited distribution of the drug after oral administration.

At fimasartan concentrations from 0.01 to 100 μg/ml in vitro, protein binding in human plasma ranges from 95.6 to 97.2% and is independent of dose.
Metabolism
CYP3A4 was the main enzyme metabolizing fimasartan. However, the role of metabolism in the elimination of fimasartan is negligible, since the parent drug constitutes ≥85% of the forms of fimasartan found in human plasma, in addition, the level of systemic exposure to fimasartan is slightly increased by specific inhibitors of CYP3A4. Desulfo-fimasartan and fimasartan-S-oxide were identified as the most abundant circulating metabolites of fimasartan in plasma in healthy men. Fimasartan is not an inducer or inhibitor of other enzymes of the cytochrome P450 family.

Removal

After a single dose of fimasartan in a dose of 20 to 480 mg in healthy subjects, T1/2 ranged from 5 to 16 hours, in the Korean population of patients with essential hypertension when administered in doses of 20 to 180 mg, T1/2 ranged from 7 to 10 hours, in the population of Russian patients with hypertension – from 4.4 to 7.9 hours with a single dose of the drug 60 mg. Systemic exposure is estimated to be linear over a wide dose range. The accumulation index ranged from 1.20 to 1.26 in healthy individuals and from 1.02 to 1.08 in individuals with arterial hypertension. When assessed in healthy men and in patients with hypertension, approximately 3-5% of the administered dose of fimasartan was found in the urine within 24 or 144 hours after oral administration.

Thus, the participation of the kidneys in the elimination of fimasartan is insignificant. The main route of elimination is with feces. Thus, after oral administration of a single dose of 120 mg of 14C radiolabeled fimasartan in a group of 6 healthy men, the average total excretion of the radioactive drug in feces and urine was about 86% of the prescribed dose, while urinary excretion was about 4.6%.

Pharmacokinetics in special clinical situations

Elderly patients. In elderly patients (over 65 years of age), the systemic effect of the drug is 1.69 times more pronounced than in young people. However, increasing systemic exposure in elderly patients does not appear to lead to a greater reduction in blood pressure because RAAS activity in this population group is generally lower than in young people.

Patients with renal failure. The pharmacokinetic parameters of fimasartan have been studied in patients with renal failure; patients on hemodialysis were excluded from the study. When taking the drug at a dose of 120 mg in severe renal impairment (estimated GFR less than 30 ml/min/1.73 m2 body surface area), Cmax and AUC were compared with those in healthy volunteers: Cmax and AUC in patients with renal failure increased by 1.87 and 1.73 times, respectively. When assessing the safety profile in the two groups, no differences were found. For patients with severe renal failure (creatinine clearance <30 ml/min), dose adjustment is required.Patients with liver failure. Fimasartan at a dose of 120 mg was prescribed to patients with liver failure (class A and B on the Child-Pugh scale). Cmax and AUC were compared with the same parameters in healthy volunteers. Geometric mean Cmax and AUC ratios were 0.77 and 1.10, respectively, when calculated for patients with class A hepatic impairment and healthy volunteers. When calculating the indicators in groups of patients with class B liver failure and healthy volunteers – 6.55 for Cmax and 5.2 for AUC. However, no significant differences in blood pressure and safety profile were found between the three groups. For patients with mild liver failure, no initial dose adjustment is required.The drug is not recommended for use in patients with moderate to severe liver failure.

Special instructions

Arterial hypotension and water-electrolyte imbalance. In patients with decreased blood volume or salt depletion (for example, patients receiving high doses of diuretics, following a diet with limited salt intake, patients with diarrhea or vomiting), symptomatic hypotension may occur, especially when fimasartan therapy is initiated or the dose of the drug is increased. A decrease in intravascular volume or salt depletion should be corrected before fimasartan therapy is started, or therapy should be started at a lower dose and subsequently increased. This requires careful monitoring of the patient’s condition.

If symptomatic arterial hypotension occurs, the patient should be placed in a horizontal position and, if necessary, begin infusion therapy. Taking fimasartan can be resumed after stabilization of blood pressure.

Hyperkalemia. Drugs that affect the RAAS may cause hyperkalemia in patients with chronic heart failure or renal failure. If fimasartan is used in these patients, regular monitoring of blood potassium levels is recommended.

Renovascular hypertension. In patients with unilateral or bilateral renovascular hypertension, cases of increased serum creatinine and urea nitrogen levels have been reported with the use of angiotensin II receptor antagonists such as fimasartan. Although fimasartan itself has not been used in patients with unilateral or bilateral renovascular hypertension, similar effects may occur if such use occurs.

Dual inhibition of the RAAS. When taking drugs that inhibit the RAAS system, especially if they are used simultaneously with drugs that can also affect the RAAS, changes in kidney function are possible
including the development of acute renal failure in patients with hypersensitivity to these drugs. Therefore, double inhibition of the RAAS, i.e. Concomitant use of an angiotensin II receptor antagonist and an ACE inhibitor is usually not recommended. However, if necessary, such therapy can be carried out in a number of patients after confirming its safety.

During therapy with fimasartan, transient symptomatic arterial hypotension (for example, shock, loss of consciousness, shortness of breath) may occur. If these symptoms appear, the drug should be discontinued and the necessary symptomatic therapy should be started.
Arterial hypotension may also develop in patients receiving an angiotensin II receptor antagonist during anesthesia (anesthesia) and surgery due to inhibition of the RAAS. In very rare cases, severe hypotension may occur, requiring fluid resuscitation and vasopressors.

As with the use of other antihypertensive drugs, a pronounced decrease in blood pressure in patients with coronary artery disease or cerebral ischemia may worsen the course of the underlying disease. Special care must be taken when treating this patient population.

– There is no experience with the use of the drug Kanarb in patients after kidney transplantation;

– In patients of the Negroid race, there is a decrease in the antihypertensive effectiveness of angiotensin II receptor antagonists;

– Impact on the ability to drive vehicles and machinery;

– The effect of fimasartan on the ability to drive vehicles and machines has not been studied. However, sometimes drowsiness and dizziness may occur during the use of antihypertensive drugs, so patients taking fimasartan should be warned about the existence of this risk.

Active ingredient

Fimasartan

Composition

1 tab. contains:

Active substances:

fimasartan potassium trihydrate – 66.01 mg, mg, which corresponds to the content of fimasartan potassium 60 mg

Excipients:

– Lactose monohydrate – 43.99 mg;

– Microcrystalline cellulose – 11.75 mg;

– Croscarmellose sodium – 22.5 mg;

– Hydroxypropylcellulose – 3.5 mg;

– Magnesium stearate – 2.25 mg.

Shell composition:

– Opadry 03B62599 yellow – 3.75 mg (hypromellose (E464) 62.5%, titanium dioxide (E171) 25.52%, macrogol (E1521) 6.25%,

food dye tartrazine (E102) 3%, iron oxide yellow dye (E172) 2.7%, brilliant blue dye (E133) 0.02%, charming red dye (E129) 0.01%);

– Carnauba wax (E903) – 0.25 mg.

Contraindications

Hypersensitivity to any of the components of the drug;
patients on hemodialysis (there is no experience with the drug in this patient population);
moderate and severe liver dysfunction (more than 7 points on the Child-Pugh scale);
patients with biliary obstruction;
simultaneous use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2);
patients with diabetic nephropathy taking ACE inhibitors;
patients with genetic disorders such as galactose intolerance, congenital lactase deficiency or glucose-galactose malabsorption syndrome (the drug contains lactose);
pregnancy;
breastfeeding period;
women planning pregnancy;
age up to 18 years.
With caution
Special precautions should be taken when using fimasartan in patients with the following conditions/diseases.

Decreased blood volume or salt depletion: In these patients (for example, patients receiving high doses of diuretics) with an activated RAAS, symptomatic hypotension may occur when fimasartan therapy is initiated or when the dose of the drug is increased. Such patients require careful monitoring.

Renal impairment: Patients with increased sensitivity to RAAS inhibition may experience changes in renal function. The use of ACE inhibitors or angiotensin II receptor antagonists may be accompanied by the development of oliguria and progressive uremia and, in rare cases, acute renal failure or death in patients whose renal function depends on the activity of the RAAS (for example, in patients with chronic heart failure, NYHA functional class IV).

Renovascular hypertension: Patients with unilateral or bilateral renal artery stenosis have an increased risk of developing severe hypotension or renal failure when taking medications that affect the RAAS, such as fimasartan.

As with other vasodilators, special care must be taken when treating patients with aortic or mitral valve stenosis, obstructive or hypertrophic cardiomyopathy.

Primary hyperaldosteronism: the use of drugs that inhibit the renin-angiotensin system is usually ineffective. Therefore, it is not recommended to prescribe fimasratan to such patients.

Hyperkalemia.

Old age.

Concomitant use of lithium preparations.

IHD.

Cerebrovascular disease..

Side Effects

The safety of fimasartan in the Korean population was studied in 406 patients out of 852 patients with essential hypertension who received fimasartan in doses ranging from 60 to 120 mg for 4 to 12 weeks and who were included in clinical trials and selected for safety analysis (i.e., information on which constituted a safety database). 85 patients received fimasartan for 6 months or more.

Most of the observed adverse events were mild or moderate and transient in nature; the frequency of occurrence of the events did not depend on the dose of the drug. The most frequently occurring adverse events were headache and dizziness. Table 1 lists the adverse reactions (i.e., adverse events judged to be definitely related, likely related, or possibly related to fimasartan) according to the WHO classification of adverse reactions by frequency of occurrence reported during clinical trials with fimasartan in Korea.

Table 1. Adverse reactions associated with the use of fimasartan1

Frequency of occurrence2
Symptoms
From the nervous system
often
headache
dizziness
infrequently
fainting
sedative effect
migraine
From the digestive system
infrequently
dyspepsia
nausea
vomiting
pain in the upper abdomen
From the respiratory system
infrequently
cough
From the musculoskeletal system
infrequently
muscle twitching
muscle stiffness
From the skin and subcutaneous tissues
infrequently
itchy skin
localized urticaria
From the side of blood vessels
infrequently
tides
hyperemia
From the genital organs and breast
infrequently
erectile dysfunction
General reactions
infrequently
asthenia
Laboratory indicators
infrequently
increased ALT activity
increased AST activity
thrombocytopenia
increased CPK activity in the blood

1 Adverse events for which a relationship with the use of fimasartan was definite, probable, or possible.

2 Very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency of occurrence is unknown (cannot be determined from available information).

In the Russian population, the safety of fimasartan was studied in 89 of 179 patients with stage I-II hypertension who received fimasartan at a dose of 60 to 120 mg for 12 weeks in a study using losartan as a comparator drug. In this study, the following adverse reactions due to the use of fimasartan were noted: nausea in 4 (4.5%) patients, increased AST activity in 1 (1.1%) patient, increased ALT activity in 1 (1.1%) patient, dizziness in 1 (1.1%) patient, headache in 4 (4.5%) patients, itching in 1 (1.1%) patient. In the Russian population of patients, adverse events were identified, the connection of which with taking the drug has not been established (anemia, diarrhea, increased levels of total cholesterol and LDL cholesterol in the blood, decreased creatinine clearance).

Interaction

Potassium-sparing diuretics and potassium-containing drugs. Concomitant use of fimasartan, as well as other drugs that affect the RAAS, and potassium-sparing diuretics (eg, spironolactone), potassium supplements, salt substitutes containing potassium, and drugs that may increase serum potassium levels (eg, heparin) may increase serum potassium levels.

The decrease in blood pressure when taking fimasartan may be enhanced when used simultaneously with other antihypertensive drugs, including diuretics. With previous use of high doses of diuretics, the initiation of fimasartan may be accompanied by an excessive decrease in blood pressure due to a decrease in intravascular volume.

Lithium preparations. A reversible increase in serum lithium concentrations and toxic effects were observed when lithium was administered with ACE inhibitors. In the case of combined use of lithium preparations with angiotensin II receptor antagonists, such reactions were observed very rarely. Although the simultaneous use of fimasartan with lithium preparations is usually not recommended, if such therapy is necessary, careful monitoring of lithium blood levels should be performed.

NSAIDs. With simultaneous use of NSAIDs (for example, COX-2 inhibitors, acetylsalicylic acid at a dose of ≥3 g / day) with angiotensin II receptor antagonists, a weakening of the hypotensive effect may be observed.

When angiotensin II receptor antagonists were used in combination with a COX inhibitor, an increase in the severity of excretory dysfunction (including the development of acute renal failure, although reversible) was noted in some patients with renal failure (for example, in patients with dehydration and in elderly patients with impaired renal function). Therefore, caution must be exercised when using fimasartan with NSAIDs, especially in elderly patients. In these cases, adequate hydration and close monitoring of renal function are necessary.
Hydrochlorothiazide. With the simultaneous use of fimasartan and hydrochlorothiazide, no significant pharmacokinetic drug interactions were observed.

Amlodipine. With the simultaneous use of fimasartan and amlodipine, no significant pharmacokinetic drug interactions were observed.

Ketoconazole. The level of systemic exposure to fimasartan, determined by AUC, increased approximately 2-fold with concomitant use of ketoconazole. Caution must be exercised when using fimasartan and ketoconazole simultaneously.

Rifampicin or other inhibitors of organic anion transporter proteins (OATP1B1, OAT1). Fimasartan is not a substrate for the ABC transport system, but is a substrate for the OAT1 and OART1B1 transporters. With simultaneous use of fimasartan with rifampicin (OATP1B1 inhibitor), an increase in the AUC of fimasartan by approximately 4.6 times was observed.

Therefore, the simultaneous use of fimasartan with rifampicin is not recommended. When used in combination with other OATP1B1 transporter inhibitors (eg, cyclosporine), an increase in the systemic exposure of fimasartan may also be observed and such combinations should be used with caution.

Warfarin. Concomitant use of fimasartan did not significantly affect the pharmacokinetics and pharmacodynamics of warfarin.

Atorvastatin. Concomitant use of fimasartan did not affect the AUC of atorvastatin and its active metabolites. Cmax of atorvastatin and its active metabolites in plasma increased by 1.9 and 2.5 times, respectively. There is no data on the clinical significance of this interaction.

Digoxin. The simultaneous use of fimasartan did not affect the pharmacokinetics and clearance of digoxin, with the exception of an increase in Cmax of digoxin by 30%. In combination therapy settings, careful monitoring of digoxin concentrations may be required.

Other angiotensin receptor antagonists, ACE inhibitors or aliskiren. Dual blockade of the RAAS with angiotensin II and ACE receptor blockers or aliskiren is accompanied by a higher risk of arterial hypotension, syncope, hyperkalemia and changes in renal function (including acute renal failure) than in the case of monotherapy.

In general, concomitant use of RAAS inhibitors should be avoided. Aliskiren and fimasartan should not be used simultaneously in patients with diabetes mellitus or impaired renal function (GFR <60 ml/min/1.73 m2). It is not recommended to use ACE inhibitors and fimasartan simultaneously, and in patients with diabetic nephropathy, the simultaneous use of ACE inhibitors and fimasartan should be avoided.Other cases of drug interactions. Fimasartan does not inhibit or induce isoenzymes of the CYP450 system.

Overdose

There is no evidence of fimasartan overdose in humans.

Symptoms:

the most likely manifestations of an overdose may be arterial hypotension and tachycardia.
Bradycardia may occur as a result of stimulation of the parasympathetic nervous system (vagus nerve).

Treatment:

in case of symptomatic arterial hypotension, maintenance therapy is necessary.
It is not known whether fimasartan is eliminated from plasma by hemodialysis.

Storage conditions

The drug should be stored out of the reach of children, protected from light at a temperature not exceeding 25°C.

Shelf life

3 years.

Manufacturer

Boryung Pharmaceutical Co. Ltd., Republic of Korea