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

Active ingredient

Composition

1 tablet contains:

Active ingredients:

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;

– Hydroxypropyl cellulose – 3.5 mg;

– Magnesium stearate – 2.25 mg.

Shell composition:

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

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

– Carnauba wax (E903) – 0.25 mg.

How to take, the dosage

Interaction

Special Instructions

Contraindications

Side effects

Safety of fimasartan in a 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 (ie, whose information formed the safety database). Eighty-five patients received fimasartan for 6 months or longer.

The majority of adverse events noted were mild to moderate in severity and transient, with frequency of occurrence independent of drug dose. The most frequent adverse events were headache and dizziness. Table 1 lists the adverse reactions (i.e., adverse events considered to be definitely related, probably related, or possibly related to fimasartan) according to the WHO classification of adverse reactions by frequency of occurrence in clinical trials with fimasartan in Korea.

Table 1. Adverse reactions due to the use of fimasartan1

Overdose