Amizon

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMIZON® (AMIZON®)

Composition:

Active substance: amizon® (enisamium iodide);

1 tablet contains amizon® (enisamium iodide) 125 mg (0.125 g) or 250 mg (0.25 g);

Excipients: lactose monohydrate, microcrystalline cellulose, povidone, sodium croscarmellose, calcium stearate;

coating: OPADRY II Clear 85F19250 (polyethylene glycol, polysorbate 80, polyvinyl alcohol, talc).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: round, biconvex, yellow or yellow-green film-coated tablets. Minor specks on the surface of tablet cores are permissible.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Direct-acting antiviral agents.

ATC code J05A X17.

Pharmacological Properties

Mechanism of Action

The antiviral activity of enisamium is associated with direct inhibition of RNA-dependent RNA polymerase of influenza virus and SARS-CoV-2.

Pharmacodynamics

Enisamium exhibits antiviral activity against various strains of influenza virus A (H1N1, H3N2, H5N1, H7N9), influenza virus B, respiratory syncytial virus, as well as alpha-coronavirus NL-63 and beta-coronavirus SARS-CoV-2 in vitro.

Enisamium iodide has demonstrated efficacy against influenza virus A and B strains in in vitro studies using differentiated normal human bronchoepithelial cells (NHBE), human hepatocellular carcinoma cells (HepG2), human rhabdomyosarcoma cells (RD), and human colorectal adenocarcinoma cells (Caco-2). In ferrets, as a representative animal model for influenza research, enisamium iodide reduced the duration of influenza virus shedding in nasal washes compared to the placebo control group.

Clinical Efficacy

In a study involving patients with acute viral respiratory infections, including influenza, treatment with enisamium iodide tablets at a daily dose of 1500 mg (2 tablets of 250 mg three times daily) resulted in positive disease progression, manifested as a more pronounced reduction in viral infection symptoms compared to placebo (Table 1).

Early and statistically significant reduction in viral antigens in nasal swabs was observed in patients treated with Amizon® compared to placebo (Table 2).

Treatment with enisamium led to increased levels of serum interferon compared to the placebo group.

Table 1

Alleviation of viral infection symptoms after treatment with Amizon**®** (number of patients / %)

Table 2

Dynamics of viral antigen detection (number of patients / %)

Results of a phase 3 clinical study showed that enisamium iodide is well tolerated and clinically effective, as demonstrated by:

• reduction in the duration of elevated temperature by 1.1 days;
• reduction in the duration of catarrhal and constitutional symptoms;
• reduced use of expectorants and decongestants;
• reduction in the number of days of work incapacity;
• reduction in the duration of viral shedding and a significant decrease in the number of patients in whom viral antigens were detected, compared to the placebo group.

Greater efficacy of enisamium was observed when treatment was initiated earlier.

A multicenter, double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of enisamium iodide included 592 patients with moderate severity COVID-19 who received either enisamium iodide or placebo in combination with standard background therapy. The primary efficacy endpoint of the study was time to clinical improvement, measured as an increase of 2 points from baseline in the patient's status score on the modified WHO scale (see Table 3).

Patients in the placebo group received one placebo capsule orally every 6 hours, 4 times daily. Patients receiving enisamium iodide were administered 500 mg of enisamium iodide every 6 hours, 4 times daily. Treatment lasted for a full 7 days (168 hours).

Table 3

Modified WHO Patient Severity Scale

The study results demonstrated that therapy using enisamium iodide significantly (p = 0.00945) accelerated improvement in the condition of patients with COVID-19 by 2 points on the modified WHO scale described above, compared to the placebo group. The superior efficacy of combined therapy with enisamium iodide in treating patients with COVID-19 is also confirmed by the results regarding secondary efficacy endpoints, namely:

• On day 15 of the study, 85.7% of patients in the placebo group had been discharged, compared to 94.4% in the enisamium iodide group. The difference in proportions was 8.6%, and these differences were statistically significant (p = 0.018), indicating superior efficacy of enisamium iodide compared to placebo;
• A significantly faster reduction in cough severity was observed in the enisamium iodide group compared to the placebo group on days 3, 4, and 5 of treatment (p = 0.009; 0.018; and 0.007, respectively);
• The use of enisamium iodide in combined therapy for COVID-19 significantly (p = 0.016) prevented clinical deterioration and worsening of respiratory insufficiency during treatment. Thus, the proportion of patients who experienced clinical worsening by 1 point on the modified WHO scale was 8.4% in the placebo group and 2.1% in the enisamium iodide group, with statistically significant differences between groups (p = 0.016). Kaplan-Meier analysis of time to clinical deterioration by 1 point, using the log-rank test to compare groups, demonstrated greater efficacy of enisamium iodide compared to placebo (p = 0.009) in preventing clinical deterioration, development of more severe respiratory insufficiency, and complications;
• In the group of patients receiving enisamium iodide as part of combined therapy, there were no fatal cases, and all patients recovered within 21 days, whereas in the placebo group there were three (3) deaths and one patient did not reach the primary endpoint during the study period, providing strong evidence in favor of using enisamium iodide in combined therapy for COVID-19.

Pharmacokinetics

Absorption

Enisamium iodide is rapidly absorbed: peak plasma concentration was reached within 1.6–2.4 hours after single administration. Absolute bioavailability in humans has not been studied, while relative bioavailability was less than 5%. Steady-state levels following oral administration of 500 mg three times daily or 1000 mg twice daily were achieved within 3 days. No drug accumulation was observed.

Studies in dogs showed that 35% of the administered dose of enisamium iodide was absorbed from the gastrointestinal tract after oral administration. Absorption in rodents was less than 5%.

Food significantly reduced the bioavailability of enisamium iodide. Mean Cmax and AUCinf values after administration of 1500 mg with food were reduced by 46.8% and 26.6%, respectively, compared to administration of 1500 mg on an empty stomach. The mean tmax was prolonged after food intake: 0.75 hours when administered fasting versus 2.75 hours when administered with food.

Distribution

The extent of plasma protein binding of enisamium iodide in humans is low.

Metabolism

The parent compound (enisamium iodide) undergoes partial conversion in humans via hydroxylation and conjugation with glucuronic acid (less than 5%). CYP2D6 likely plays a minor role in the metabolism of enisamium iodide. Other studied cytochrome P450 enzymes have no significant influence on the metabolic transformation of the parent compound.

Elimination

Enisamium iodide is primarily excreted unchanged in urine. After oral administration of radiolabeled enisamium iodide to dogs, fecal excretion accounted for 32–35%. The median elimination half-life of single doses of enisamium iodide ranged from 2.69 to 3.35 hours, and from 6.00 to 7.34 hours after multiple doses administered over 10 days.

Pharmacokinetics in specific patient populations

Elderly patients

Pharmacokinetic studies involving elderly patients have not been conducted.

Patients with hepatic or renal impairment

The pharmacokinetics of enisamium iodide in special populations has not been studied. However, based on pharmacokinetic study results, considering the presence of renal and intestinal elimination pathways and the low level of metabolism of enisamium iodide, significant accumulation of enisamium in plasma is not expected in subjects with organic liver or kidney disease during short-term use (up to 7 days) of this medicinal product. Therefore, a worsening of the safety profile in patients with the aforementioned organic diseases is unlikely.

Clinical characteristics.

Indications.

Amizon® is indicated for:

• treatment and prevention of influenza and acute respiratory viral infections in children and adults;
• treatment of adult patients with moderate severity COVID-19 in combination with background therapy.

Contraindications.

Hypersensitivity to drugs containing iodide, molecular iodine or covalently bound iodine, as well as to other components of the drug.

Interaction with other medicinal products and other forms of interaction.

Enisamium iodide may reduce thyroid gland uptake of radioactive iodine isotopes for up to 6 weeks.

Concomitant use of iodine-containing medicinal products, contrast agents and medicinal products containing covalently bound iodine should be avoided, as well as treatment of large-area wounds using iodine-containing antiseptics (e.g., molecular iodine), due to the possible increased risk of thyroid dysfunction.

Special precautions for use.

Administration of enisamium iodide leads to an increase in plasma iodide levels. The secondary rise in circulating iodide triggers a self-regulating mechanism of thyroid function, in which the uptake of inorganic iodide by thyrocytes is suppressed, thus preventing excessive production of thyroid hormones; during this process, a transient increase in thyroid-stimulating hormone (TSH) levels may occur (the Wolff–Chaikoff effect). This effect lasts for several days; after completion of the treatment course, thyroid function returns to normal. In individual cases, a transient increase in TSH has been observed for several weeks.

There is no available information regarding the effect of enisamium iodide in patients with impaired thyroid function or in patients who have previously developed hypothyroidism. However, it is advisable to monitor thyroid function during treatment with enisamium iodide.

Other iodine-containing medications should not be used during treatment and for 7 days after completion of enisamium iodide therapy.

Excipients

Lactose content in the Amizon® 0.125 g tablet: 5.225 mg/tablet or 0.0153 mmol/tablet or 3.37% of the total tablet mass.

Lactose content in the Amizon® 0.250 g tablet: 10.45 mg/tablet or 0.0306 mmol/tablet or 3.37% of the total tablet mass.

If you have been diagnosed with intolerance to certain sugars, consult your physician before taking Amizon®. Capsules, which do not contain lactose, may be prescribed for such patients.

Sodium content in the Amizon® 0.125 g tablet: 0.285 mg/tablet or 0.0124 mmol/tablet or 0.18% of the total tablet mass.

Sodium content in the Amizon® 0.250 g tablet: 0.570 mg/tablet or 0.0248 mmol/tablet or 0.18% of the total tablet mass.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

The use of this medicinal product is contraindicated during pregnancy, as clinical studies of enisamium iodide have not been conducted in pregnant women. Animal studies have not revealed any direct or indirect adverse effects on reproductive function/fertility.

Breastfeeding

It is unknown whether enisamium iodide or its metabolites are excreted in human breast milk. It is not possible to exclude the risk of enisamium iodide exposure to a newborn or infant.

Ability to affect reaction rate when driving or operating machinery.

Administration of Amizon® does not affect the ability to drive or operate machinery.

Administration and Dosage

Enisamium iodide tablets should be swallowed whole, without chewing, 2 hours before meals.

Maximum single dose – 1000 mg (1 g); maximum daily dose – 2000 mg (2 g).

Treatment of influenza and acute respiratory viral infections.
For adults: enisamium iodide is administered at a dose of 500 mg (0.5 g) three times daily or 1000 mg (1 g) twice daily.
For children aged 12 years and older: enisamium iodide is administered at a dose of 500 mg (0.5 g) three times daily.
For children aged 6 to 12 years: 125 mg (0.125 g) two to three times daily.

Treatment of adult patients with moderate COVID-19.
Enisamium iodide should be administered in combination with standard therapy at a dose of 500 mg (0.5 g) four times daily.
Treatment duration – 7 days.

Prophylaxis of influenza and acute respiratory viral infections.
For adults and adolescents aged 16 years and older: 250 mg (0.25 g) once daily for 3–5 days, followed by 250 mg (0.25 g) every 2–3 days for 2–3 weeks.
For children aged 12 to 16 years: 250 mg (0.25 g) every other day for 2–3 weeks.
For children aged 6 to 12 years: 125 mg (0.125 g) every other day for 2–3 weeks.

Children.
This medicinal product in the given pharmaceutical form is not recommended for children under 6 years of age.
There is insufficient data on the use of Amizon® in children with COVID-19 caused by SARS-CoV-2 virus; therefore, its use in this patient group is not recommended.

Overdose.
No cases of overdose with Amizon® have been reported in clinical trials or during post-marketing use.
There is no specific antidote.

Adverse reactions

The most commonly reported adverse reactions (ARs) were taste disturbances, folliculitis, nasopharyngitis, headache, and lymphadenopathy (in phase I placebo-controlled studies). Most of these ARs were reported as single occurrences and resolved spontaneously. In the majority of patients, these ARs did not lead to discontinuation of enisamium iodide.

In the phase III placebo-controlled study, mild gastrointestinal disorders were recorded (bitter taste in mouth), heartburn, and burning sensation in the throat.

Only adverse events occurring more frequently in the enisamium iodide group compared to the placebo group and reported in more than two individuals were considered.

Table 4 lists the adverse reactions observed during clinical trials and post-marketing use of the drug. The frequency is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (>1/1,000, <1/100), and frequency not known (cannot be estimated from available data).

Table 4

* Reports in the post-marketing period.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization of a medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in a place protected from light at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

Tablets, coated, 0.125 g. 10 tablets per blister, 1 or 2 blisters per carton; or 20 tablets per blister, 1 blister per carton.

Tablets, coated, 0.25 g. 10 tablets per blister, 1 blister per carton; or 20 tablets per blister, 1 or 2 blisters per carton.

Availability category. Over-the-counter.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.