Aviandr^® (Tablets) Instructions for Use

Marketing Authorization Holder

Avineiro LLC (Russia)

Manufactured By

Chemical Diversity Research Institute LLC (Russia)

Contact Information

PharmFirma Sotex ZAO (Russia)

ATC Code

N05BX (Other anxiolytics)

Active Substance

Maritupirdine (Rec.INN registered by WHO)

Dosage Form

Aviandr®

Film-coated tablets, 20 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; the tablet core on the cross-section is white or almost white.

Excipients: tablet core: lactose anhydrous, hydrogenated castor oil, potato starch; film coating (Opadry 03F180011 white): hypromellose, titanium dioxide (E171), macrogol 6000.

10 pcs. – blister packs (3) – cardboard packs.
30 pcs. – polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Anxiolytic (tranquilizer)

Pharmacotherapeutic Group

Psycholeptics; anxiolytics; other anxiolytics

Pharmacological Action

The active substance of the drug Aviandr^® is Maritupirdine.

Maritupirdine has multi-target activity, in particular, the ability to inhibit some groups of receptors, including adrenergic, dopaminergic, serotonergic, and histaminergic, which determines the presence of anxiolytic and antidepressant properties in the drug Aviandr^®.

Maritupirdine has a very high affinity for 5-HT₇ receptors and lower affinity for 5-HT₆, 5-HT_2A and 5-HT_2C receptors.

Maritupirdine inhibits presynaptic α-adrenergic receptors (α_2A, α_2B and α_2C) and histaminergic H₁ receptors.

Maritupirdine has a very low affinity for dopamine receptors compared to its affinity for 5-HT₇ receptors.

At the same time, Maritupirdine does not inhibit neurotransmitter transporter proteins (reuptake), does not interact with gamma-aminobutyric acid (GABA) receptors, and does not have anticholinergic action.

These pharmacological properties allow the drug Aviandr^® to be classified as a non-benzodiazepine anxiolytic with a multimodal mechanism of action.

Clinical efficacy and safety

Conducted clinical studies have demonstrated the efficacy of the drug for anxiety disorders, including generalized anxiety disorder, and anxiety arising, including as a consequence of the novel coronavirus infection (COVID-19).

It was shown that the clinical effect in the form of a reduction in anxiety symptoms occurred starting from the first week of taking the drug and was not accompanied by pronounced sedation, impairment of cognitive functions or psychomotor skills.

Maritupirdine showed efficacy regarding somatic symptoms of anxiety at the initial stage of therapy, efficacy in reducing mental symptoms of anxiety, asthenia, a reduction in depressive symptoms was observed, the dynamics of the patients’ general clinical impression improved, the duration of disability was reduced and satisfaction with the quality of life increased.

The conducted clinical studies showed that the drug was well tolerated, including by elderly patients.

No cases of withdrawal syndrome or dependence were observed upon treatment completion.

Preclinical safety data

In preclinical data obtained from the results of standard studies of pharmacological safety, toxicity after repeated administration, genotoxicity, carcinogenic potential, and reproductive and ontogenetic toxicity, no particular harm to humans was identified.

Based on the results of chronic toxicity studies, the no observed adverse effect level (NOAEL) of maritupirdine was established to be 20 mg/kg, which corresponds to a human equivalent dose (HED) of 800 mg/person.

Also, in safety pharmacology studies, the absence of potential addictive properties of the drug, as well as the absence of a significant effect on the CNS, was revealed.

Pharmacokinetics

Absorption

C_max of maritupirdine in blood plasma is 84.1 pg/ml after a single oral dose of 20 mg, T_max is about 1 h. Plasma concentrations and AUC increase proportionally to the dose (dose-dependent linear pharmacokinetics).

With multiple administration of the drug 2 times/day, the concentration of the active substance in blood plasma increases on average by 1.8 times compared to a single dose. The residual concentration of maritupirdine stabilizes 2 days after the start of regular drug intake. With multiple administration of a daily dose of 40 mg (20 mg 2 times/day), T_max is 0.4 h.

After a single dose of the drug Aviandr^® at a dose of 20 mg, the C_max of metabolite M1 is on average 149 pg/ml.

With multiple administration of the drug at a daily dose of 40 mg, the C_max of metabolite M1 increases on average by 1.5 times compared to a single dose.

The median T_max of metabolite M1 is 1.3 h, both after single and multiple administration of the drug. T_max of metabolite M1 is observed within 0.5-4 h, i.e., within the same time frame as the active substance of the drug Aviandr^®. This may indicate its rapid formation from the parent substance.

Distribution

Plasma protein binding of maritupirdine is 40.8%. According to preclinical data, the maximum distribution of the drug is observed in the brain, the minimum – in the blood.

Metabolism

Maritupirdine is partially transformed in the liver into metabolite M1, the C_max of the metabolite in blood was 6.9±2.2 times higher than the concentration of maritupirdine. Taking into account the shorter T_1/2, the AUC of metabolite M1 was 2.9±0.6 times higher than the AUC of maritupirdine.

According to preclinical studies, Maritupirdine interacts with cytochromes CYP1A2, CYP2C19 and CYP2D6, and is likely metabolized by these isoenzymes. Also, clinical studies have recorded the influence of CYP2D6 polymorphism on the pharmacokinetic parameters of the studied drug. In patients who can be classified as poor metabolizers for CYP2D6, an increase in the concentration before the next dose (C_trough) and the average concentration in the dosing interval after steady-state distribution is established (C_avr) of maritupirdine and its metabolite M1 by 1.5-2 times may be observed. At the same time, clinical drug interaction studies have shown that co-administration of the CYP2D6 inhibitor duloxetine with the drug Aviandr^® does not lead to significant changes in the most important pharmacokinetic parameters of maritupirdine and its metabolite M1 (see section “Drug Interactions”).

Excretion

T_1/2 of maritupirdine after a single dose is about 8 h. With multiple administration (20 mg 2 times/day), T_1/2 is about 15 h. Metabolite M1 is eliminated from the blood faster (T_1/2=4.7 h).

Linearity

Studies involving volunteers demonstrated linear pharmacokinetics in the dose range from 2 to 20 mg.

Special patient groups

Elderly individuals. Special pharmacokinetic studies of the drug Aviandr^® in elderly individuals have not been conducted. In clinical studies of the drug Aviandr^®, safety in elderly patients was comparable to safety in patients of other age groups, but data are still limited.

Patients with renal impairment. The drug is contraindicated in patients with CrCl <60 ml/min.

Patients with hepatic impairment. The pharmacokinetics of maritupirdine in patients with hepatic impairment has not been studied.

Indications

Adults over 18 years old

• Treatment of generalized anxiety disorder;
• For anxiety conditions after suffering from coronavirus infection (COVID-19): in patients with stress reaction and adjustment disorders, mild and moderate severity.

ICD codes

Dosage Regimen

Administered orally, 30 minutes before meals. The tablet should be swallowed whole, without chewing.

Treatment of generalized anxiety disorder

Orally, 1 tablet (20 mg) 2 times/day (morning and evening). Since generalized anxiety disorder is a chronic condition, the duration of treatment is determined by the physician.

Treatment of anxiety conditions, including after suffering from coronavirus infection (COVID-19): in patients with a leading complaint of anxiety, change in mood background, irascibility and irritability; in patients with stress reaction and adjustment disorders, mild and moderate severity

Orally, 1 tablet (20 mg) 2 times/day (morning and evening). The duration of the course of drug administration is 4 weeks. If necessary, depending on the patient’s condition, the duration of treatment can be increased to 6 weeks.

Missed dose

If a dose is missed, the drug Aviandr^® is taken at the usual dose at the next scheduled time (the missed dose should not be taken).

Treatment discontinuation

In case of treatment discontinuation, there is no need for gradual dose reduction.

Special patient groups

Children

Data on efficacy and safety in children and adolescents under 18 years of age are lacking. The drug should not be prescribed to children under 18 years of age.

Elderly individuals

In clinical studies of the drug Aviandr^®, safety in elderly patients was comparable to safety in patients of other age groups. Dose adjustment for patients over 65 years of age is not required.

Renal impairment

Contraindicated for use in patients with moderate and severe renal failure (GFR< 60 ml/min).

Hepatic impairment

Contraindicated for use in patients with mild, moderate and severe hepatic failure (Child-Pugh class A, B and C).

Adverse Reactions

Adverse reactions (ARs) were most often mild or moderate and were observed in the first days of taking the drug. The most frequently reported were dizziness, drowsiness and asthenia. These ARs were usually transient and, for the most part, did not require therapy discontinuation. In the conducted clinical studies in different patient populations (patients with generalized anxiety disorder, patients with anxiety syndrome in Alzheimer’s disease, as well as a study in patients with stress reaction and adjustment disorders as a consequence of the novel coronavirus infection (COVID-19)), increased anxiety and insomnia were also infrequently noted at the beginning of the use of the drug Aviandr^®, however, these adverse events could be related to the course of the underlying disease.

Data were obtained from 422 patients who took the drug Aviandr^® in clinical studies (patients with generalized anxiety disorder, patients with anxiety syndrome in Alzheimer’s disease, patients with stress reaction and adjustment disorders as a consequence of the novel coronavirus infection (COVID-19)), as well as taking into account data from 64 healthy volunteers who took the drug Aviandr^® in clinical safety, pharmacokinetic and drug interaction studies.

Adverse reactions are classified by clinical manifestations (according to affected organs and organ systems) and by frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000). Presented are ARs (related and possibly related, in the investigators’ opinion, to the intake of the study drug) that occurred in clinical studies in patients in the treatment groups with the drug Aviandr^®.

Table 1. Adverse reactions that occurred in clinical studies in patients and healthy volunteers during treatment with the drug Aviandr^®

¹ Dizziness, drowsiness, asthenia were observed at the beginning of treatment, did not require drug discontinuation and resolved on their own.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients included in the drug;
• Epilepsy and organic brain diseases;
• Concomitant use with MAO inhibitors and within 2 weeks after their discontinuation;
• Moderate and severe renal failure (GFR< 60 ml/min);
• Mild, moderate and severe hepatic failure (Child-Pugh class A, B and C).

Use in Pregnancy and Lactation

The use of the drug Aviandr^® during pregnancy and breastfeeding is contraindicated.

Pregnancy

Currently, there are no data on the use of the drug Aviandr^® in pregnant women. In preclinical studies, no signs of embryotoxicity or teratogenic effects of the drug Aviandr^® were found (see subsection “Preclinical safety data”). The drug Aviandr^® should not be prescribed during pregnancy, except in cases where the potential benefit to the mother outweighs the possible risk to the fetus, and there are no other alternative treatment methods. If a woman takes the drug Aviandr^® during the first trimester of pregnancy or pregnancy occurs during the use of the drug, the patient should be warned about the potential harm to the fetus.

Breastfeeding period

The drug Aviandr^® is contraindicated during breastfeeding. If it is necessary to use the drug Aviandr^® during lactation, the issue of discontinuing breastfeeding or discontinuing therapy should be decided, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

Preclinical studies of male and female fertility did not reveal adverse effects of the use of the drug Aviandr^® (see subsection “Preclinical safety data”).

Use in Hepatic Impairment

Contraindicated for use in patients with mild, moderate and severe hepatic failure (Child-Pugh class A, B and C).

Use in Renal Impairment

Contraindicated for use in patients with moderate and severe renal failure (GFR< 60 ml/min).

Pediatric Use

Data on efficacy and safety in children and adolescents under 18 years of age are lacking. The drug should not be prescribed to children under 18 years of age.

Geriatric Use

Dose adjustment for patients over 65 years of age is not required.

Special Precautions

Cardiovascular disorders

In conducted preclinical and clinical studies, no negative effect of the drug Aviandr^® on the cardiovascular system was identified. The drug Aviandr^® does not have an anticholinergic effect and does not prolong the QT interval. However, due to insufficient clinical data, the drug Aviandr^® should be used with caution in patients with cardiovascular diseases.

Endocrine diseases

In conducted clinical studies, no clinically significant increase in prolactin levels or effect on blood glucose levels were identified.

Hyponatremia

In conducted clinical studies, no cases of hyponatremia were identified with the use of the drug Aviandr^®.

Use in elderly patients

Elderly patients are usually more sensitive, especially regarding side effects. In clinical studies of the drug Aviandr^®, safety in elderly patients was comparable to safety in patients of other age groups.

Drug dependence and withdrawal syndrome

In conducted clinical studies with the use of the drug Aviandr^®, no cases of dependence or occurrence of withdrawal syndrome were identified, but, as with the use of any other psychotropic drugs, the development of drug dependence or withdrawal syndrome is possible with the use of the drug Aviandr^®.

Excipients

The medicinal product Aviandr^® contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Given the minimal amount of castor oil in one tablet of the drug, no adverse reactions associated with the action of this excipient are expected.

Effect on the Ability to Drive Vehicles and Operate Machinery

The drug may cause dizziness and drowsiness. If dizziness and drowsiness occur, you should refrain from driving vehicles and operating machinery.

Overdose

Symptoms There are no data on overdose cases. In case of overdose, general symptoms characteristic of an overdose of psychotropic drugs with a sedative effect may occur.

Treatment There is no specific antidote for intoxication or overdose. In case of overdose, symptomatic therapy should be administered to maintain vital body functions. Activated charcoal should be taken or gastric lavage should be performed.

Drug Interactions

Medicinal Products with Sedative Properties

Given the pharmacological properties and mechanism of action, Aviandr^® may enhance the sedative effect of benzodiazepine derivatives, neuroleptics, barbiturates, and histamine H₁-receptor blockers. Caution should be exercised when prescribing these medicinal products concomitantly with Aviandr^®.

Serotonergic Medicinal Products

Clinical drug interaction studies have shown that co-administration of Aviandr^® with a drug from the selective serotonin and norepinephrine reuptake inhibitor group (duloxetine) did not cause clinical manifestations associated with enhanced serotonergic transmission. Nevertheless, considering the receptor profile of Aviandr^® and the class pharmacological effects, it is assumed that the use of Aviandr^® concomitantly with serotonergic drugs may cause effects due to increased serotonergic stimulation (serotonin syndrome). Caution should be exercised when taking Aviandr^® with other serotonergic drugs (L-tryptophan, triptans, tramadol, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, lithium, fentanyl, and St. John’s wort).

Monoamine Oxidase Inhibitors (MAOIs)

Aviandr^® should not be used in combination with MAO inhibitors, or within 2 weeks of discontinuing MAO inhibitor treatment.

Alcohol and Ethanol-Containing Medicinal Products

Aviandr^® may enhance the CNS depressant effect of alcohol. Therefore, patients should be warned to avoid consuming alcohol and ethanol-containing medicinal products.

Inhibitors of the CYP2D6 Isoenzyme

Clinical drug interaction studies have shown that co-administration of the CYP2D6 inhibitor duloxetine with Aviandr^® does not lead to significant changes in the key pharmacokinetic parameters of Aviandr^® and its metabolite M1 (C_max, AUC_0-t, T_1/2). Nevertheless, considering that according to preclinical studies Aviandr^® is metabolized with the participation of the hepatic isoenzyme CYP2D6, drugs that are its inhibitors may lead to an increase in the blood concentration of Aviandr^®. Caution should be exercised when using Aviandr^® with CYP2D6 inhibitors (e.g., diphenhydramine, terbinafine, quinidine, hydroxychloroquine, SSRIs).

Substrates of the CYP2D6 Isoenzyme

Results from clinical drug interaction studies have shown that co-administration of Aviandr^® with the CYP2D6 substrate metoprolol does not lead to significant changes in the key pharmacokinetic parameters of metoprolol (C_max, AUC_0-t, T_1/2).

No drug interaction in the form of enhanced pharmacodynamic effects of metoprolol – for example, a clinically significant decrease in heart rate or blood pressure – was detected during co-administration of Aviandr^® and metoprolol. It is assumed that Aviandr^® does not have a significant effect on the pharmacokinetic parameters of other CYP2D6 substrates (e.g., atomoxetine, imipramine, venlafaxine, nebivolol, propranolol, propafenone, tramadol).

Inhibitors of the CYP1A2 Isoenzyme

Clinical drug interaction studies have established that co-administration of the strong CYP1A2 inhibitor ciprofloxacin with Aviandr^® does not lead to significant changes in the key pharmacokinetic parameters of Aviandr^® and its metabolite M1 (C_max, AUC_0-t, T_1/2). It is assumed that other CYP1A2 inhibitors (e.g., fluvoxamine, acyclovir, combined oral contraceptives) do not have a significant effect on the pharmacokinetics of Aviandr^®.

Inhibitors of the CYP2C19 Isoenzyme

Clinical drug interaction studies have established that co-administration of the strong CYP2C19 inhibitor fluconazole (which is also an inhibitor of the P-glycoprotein transporter) with Aviandr^® does not lead to significant changes in the key pharmacokinetic parameters of Aviandr^® and its metabolite M1 (C_max, AUC_0-t, T_1/2). It is assumed that other CYP2C19 inhibitors (e.g., fluvoxamine, fluoxetine, ticlopidine, omeprazole) do not have a significant effect on the pharmacokinetics of Aviandr^®.

Incompatibility

Due to the lack of compatibility studies, this medicinal product should not be mixed with other medicinal products.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F) in the original packaging (bottle, blister) to protect from light.

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.