Vespireit^® (Tablets) Instructions for Use

Marketing Authorization Holder

Valenta Pharm, JSC (Russia)

Contact Information

VALENTA PHARM JSC (Russia)

ATC Code

N05BE01 (Buspirone)

Active Substance

Buspirone (Rec.INN registered by WHO)

Dosage Form

Vespireit®

Extended-release tablets 15 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Extended-release tablets from white to almost white, round, flat-cylindrical, with a bevel.

Excipients: lactose monohydrate – 75 mg, microcrystalline cellulose, hypromellose, colloidal silicon dioxide, magnesium stearate.

10 pcs. – blister packs (3) – cardboard packs.

Clinical-Pharmacological Group

Anxiolytic

Pharmacotherapeutic Group

Psycholeptics; anxiolytics; azaspirodecanedione derivatives

Pharmacological Action

Mechanism of action

Buspirone is a derivative of the azapirone chemical group. The action of buspirone is associated with effects on the brain serotonin receptor (5-HT) system. Buspirone is an agonist of presynaptic and a partial agonist of postsynaptic 5-HT_1A receptors. Buspirone also exhibits D₂ receptor antagonist properties. Buspirone does not have a significant effect on benzodiazepine receptors and does not affect GABA binding.

The detailed mechanism by which buspirone reduces the manifestations of functional dizziness (also known as persistent postural-perceptual dizziness) – a non-systemic (non-vestibular), chronic, subjective, anxiety-phobic, postural disorder characterized by vestibular symptoms (false or distorted sensation of movement, feeling of swaying, sensation of disordered spatial orientation) in the absence of an organic substrate of damage or dysfunction of the vestibular system – is not fully understood. It is assumed that the mechanism of action of buspirone is realized, among other things, through an effect on the hypothalamic-pituitary-adrenal system, accompanied by a stimulating effect on the processes of vestibular compensation. In addition, the anxiolytic effect of buspirone is accompanied by a reduction in anxiety disorders (constant “anxious” monitoring of one’s own postural stability due to fear of a possible fall), which, on the one hand, are one of the causes, and on the other, a consequence of the clinical manifestations of functional dizziness.

Pharmacodynamic effects

The action of buspirone is manifested in a reduction of the manifestations of functional dizziness (persistent postural-perceptual dizziness), emotional tension, and a weakening of anxiety, fear, and restlessness.

Unlike benzodiazepines, Buspirone does not possess muscle relaxant and anticonvulsant properties, and its sedative effect is significantly weaker than that of typical anxiolytics and does not impair psychomotor functions. In terms of anxiolytic activity, Buspirone is comparable to the effect of benzodiazepines. Buspirone does not cause tolerance and dependence, and withdrawal symptoms do not develop after completion of the course of treatment. Buspirone does not potentiate alcohol-induced CNS depression.

Clinical efficacy and safety

In a clinical study of the drug in adult patients with autonomic dysfunction syndrome accompanied by dizziness (functional dizziness), when assessing dizziness relief on the Likert scale and the severity of dizziness on the Dizziness Handicap Inventory and the numerical rating scale, the use of buspirone statistically significantly (p <0.05) led to an improvement in the assessed parameters between baseline and at the end of the study, compared with placebo. These differences became more pronounced with increasing duration of therapy.

Pharmacokinetics

Absorption

After oral administration, Buspirone is rapidly and almost completely absorbed from the gastrointestinal tract. Buspirone undergoes intensive first-pass metabolism in the liver. Simultaneous food intake slows down the absorption of buspirone, but, due to a decrease in presystemic clearance (the “first-pass” effect), the bioavailability of buspirone is significantly increased.

After a single dose of buspirone 15 mg in the extended-release tablet dosage form after a meal, the mean maximum concentration (C_max) of buspirone was 2.914±1.87 ng/ml, and the median time to reach it (T_max) was 2.25 h. The mean C_max of 6-hydroxybuspirone was 13.5±3.22 ng/ml, the median T_max of 6-hydroxybuspirone was 2.75 h. The mean C_max of 1-PP was 3.696±1.48 ng/ml, the median T_max of 1-PP was 3.5 h.

The mean AUC_0-∞ for buspirone was – 15.81±11.56 h×ng/ml; the mean AUC_0-∞ of 6-hydroxybuspirone was 129.22±42.47 h×ng/ml; the mean AUC_0-∞ of 1-PP – 39.40±31.22 h×ng/ml.

Distribution

Approximately 95% of buspirone binds to plasma proteins (86% to plasma albumin, the remainder to α₁-acid glycoprotein).

After a single dose of buspirone 15 mg in the extended-release tablet dosage form after a meal, the V_d of buspirone was – 11563.94±7313.89 L; V_d of 6-hydroxybuspirone – 1328.86±282.94 L; V_d of 1-PP – 3357.94±1635.29 L.

Metabolism

Buspirone undergoes oxidative metabolism, mainly involving cytochrome P450 CYP3A4 isoenzymes. Various hydroxylated metabolites are formed, including the pharmacologically active metabolite 6-hydroxybuspirone, which contributes significantly to the therapeutic effects of the drug. The dealkylated metabolite 1-PP is also pharmacologically active, but its anxiolytic activity is 4-5 times lower than that of buspirone. Furthermore, 1-PP partially contributes to the manifestation of buspirone’s adverse reactions.

Oral extended-release formulations of buspirone allow for a reduction in the AUC of 1-PP, as well as an increase in the T_1/2 and MRT of 6-hydroxybuspirone.

Elimination

Buspirone is excreted by the kidneys and through the intestines.

After a single dose of buspirone 15 mg in the extended-release tablet dosage form, the T_1/2 of buspirone was 6.07±2.19 h, the mean total clearance (Cl/F) was 1356.45±761 L/h; the T_1/2 of 6-hydroxybuspirone was 7.55±1.64 h, Cl/F was 126.82±36.22 L/h; the T_1/2 of 1-PP was 4.73±1.59 h, Cl/F was – 556.52±311.76 L/h.

Indications

Adults from 18 years

• Autonomic dysfunction syndrome accompanied by dizziness (functional dizziness).

ICD codes

Dosage Regimen

Orally. The tablets should be taken whole, without breaking or chewing.

1 tablet once/day, at the same time in the morning, after a meal.

The recommended duration of the treatment course is 28 days.

Elderly patients (over 65 years): based on available data, advanced age or patient gender alone does not require a change in the dosage regimen.

Patients with renal failure: use of the drug in patients with renal failure is contraindicated.

Patients with hepatic impairment: use of the drug in patients with hepatic impairment is contraindicated.

Children: safety and efficacy in children aged 0 to 18 years have not been established. Data are not available.

Adverse Reactions

The determination of the frequency of adverse reactions is carried out in accordance with the following criteria: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

In clinical studies in patients with autonomic dysfunction syndrome accompanied by dizziness (functional dizziness), the following adverse reactions were registered

Psychiatric disorders frequency unknown – depression.

Nervous system disorders frequency unknown – dizziness, headache, drowsiness, impaired coordination.

Ear and labyrinth disorders frequency unknown – tinnitus.

Vascular disorders frequency unknown – increased blood pressure, arterial hypotension.

Gastrointestinal disorders frequency unknown – nausea, vomiting.

General disorders frequency unknown – weakness.

The following adverse reactions are also known for buspirone

Psychiatric disorders common – nervousness, insomnia, impaired concentration, depression, confusion, sleep disorders, irritability; very rare – psychotic state, hallucinations, depersonalization, affective disorders.

Nervous system disorders very common – dizziness (including lightheadedness), headache, drowsiness; common – paresthesia, impaired coordination, tremor; very rare – serotonin syndrome, seizures, extrapyramidal disorders, cogwheel rigidity, dyskinesia, dystonia, syncope, amnesia, ataxia, parkinsonism, akathisia, restless legs syndrome, restlessness.

Eye disorders: common – blurred vision; very rare – tunnel vision.

Ear and labyrinth disorders common – tinnitus.

Cardiac disorders: common – tachycardia, chest pain.

Respiratory, thoracic and mediastinal disorders common – nasal congestion, pharyngeal and laryngeal pain.

Gastrointestinal disorders common – nausea, abdominal pain, dry mouth, diarrhea, constipation, vomiting.

Skin and subcutaneous tissue disorders common – cold sweat, skin rash; rare – angioedema, ecchymosis, urticaria.

Musculoskeletal and connective tissue disorders common – musculoskeletal pain.

Renal and urinary disorders very rare – urinary retention.

Reproductive system and breast disorders very rare – galactorrhea.

General disorders common – fatigue.

Contraindications

• Hypersensitivity to buspirone or any of the excipients included in the drug;
• Concomitant use with inhibitors and inducers of cytochrome P450 CYP3A4 isoenzyme;
• Renal failure;
• Hepatic impairment;
• Epilepsy;
• Acute intoxication caused by alcohol, hypnotics, analgesics, antipsychotics;
• Age under 18 years.

With caution

• Concomitant use of MAO inhibitors or a 14-day period after discontinuation of an irreversible MAO inhibitor or 1 day after discontinuation of a reversible MAO inhibitor;
• Myasthenia gravis;
• Angle-closure glaucoma;
• Drug dependence;
• Impaired renal function;
• Impaired liver function.

Use in Pregnancy and Lactation

Pregnancy

Due to the lack of clinical data, the use of the drug during pregnancy and in women planning a pregnancy is contraindicated. If pregnancy occurs, the drug should be discontinued.

Breastfeeding

It is not known whether Buspirone or its metabolites are excreted in breast milk. Before starting the use of buspirone in nursing mothers, a decision should be made either to discontinue breastfeeding or to discontinue buspirone treatment, taking into account either the benefit for the child (breastfeeding without taking the drug) or the benefit of treatment for the mother.

Fertility

There are no data on the effect of the drug on fertility.

Use in Hepatic Impairment

Contraindicated in hepatic impairment.

Use in Renal Impairment

Contraindicated in renal failure.

Pediatric Use

Safety and efficacy in children aged 0 to 18 years have not been established.

Geriatric Use

Based on available data, advanced age alone does not require a change in the dosage regimen.

Special Precautions

Impaired renal function

After a single dose in patients with mild to moderate renal impairment (CrCl 20-49 ml/min/1.73 m²), a slight increase in buspirone blood concentration is noted without an increase in T_1/2. Administration of buspirone to patients with anuria causes an increase in the blood concentration of its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP); performed hemodialysis does not affect either the concentration of buspirone or the concentration of 1-PP. Due to the dosage regimen, which does not provide for individual dose selection and the use of buspirone doses less than 15 mg, the use of the drug Vespireit^® in patients with renal failure is contraindicated (see section “Contraindications”).

Impaired liver function

In case of impaired liver function, the “first-pass” effect is reduced for drugs of the buspirone series. When using buspirone in patients with liver cirrhosis, an increase in the blood concentration of unchanged buspirone and T_1/2 is observed. Due to the dosage regimen, which does not provide for individual dose selection and the use of buspirone doses less than 15 mg, the use of the drug Vespireit^® in patients with hepatic impairment is contraindicated (see section “Contraindications”).

Drug dependence/drug abuse

Based on experimental data and clinical studies, it has been shown that Buspirone does not cause drug dependence and does not lead to abuse. Nevertheless, the use of buspirone in patients with known or suspected drug dependence requires strict control.

Serotonin syndrome

When buspirone is used concomitantly with buprenorphine, serotonin syndrome, a potentially life-threatening condition, may develop. If concomitant use of these drugs is clinically necessary, careful monitoring of the patient is recommended, especially at the beginning of treatment. Symptoms of serotonin syndrome include: changes in mental status, autonomic nervous system disorder (instability), neuromuscular disorders, and gastrointestinal symptoms.

If serotonin syndrome is suspected, it is advisable to discontinue treatment depending on the severity of symptoms.

Possible withdrawal reactions in patients dependent on sedative-hypnotic and anxiolytic drugs

Buspirone cannot eliminate benzodiazepine withdrawal symptoms because it does not have cross-tolerance to benzodiazepines and other sedative-hypnotic drugs. If a patient is switched to Buspirone after long-term benzodiazepine therapy, Buspirone should be prescribed only after the period of gradual dose reduction of the benzodiazepine has been completed, especially in patients who chronically took CNS depressant drugs.

Duration of use and repeated courses

The duration of use of the drug Vespireit^® in patients with autonomic dysfunction syndrome accompanied by dizziness (functional dizziness) in the study was 28 days. In studies, the drug Vespireit^® was studied for use for up to 6 weeks; use for more than 6 weeks has not been studied. The efficacy and safety, as well as the rationality of repeated courses of the drug Vespireit^®, have not been studied.

Alcohol

During treatment with buspirone, consumption of alcoholic beverages should be avoided, despite the lack of reports of impaired psychomotor function caused by alcohol. There are no data on the concomitant use of alcohol with a single dose of buspirone exceeding 20 mg.

Excipients

The drug Vespireit^® contains lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take the drug Vespireit^®.

Effect on the ability to drive vehicles and operate machinery

Buspirone has a moderate effect on the ability to drive vehicles and operate machinery. The risk associated with the development of drowsiness or other adverse reactions should be taken into account. This drug may impair cognitive functions and affect the patient’s ability to drive vehicles. Depending on drug tolerance, caution should be exercised or driving should be refrained from.

Overdose

Symptoms in healthy volunteers, the maximum tolerated dose was 375 mg/day. In case of overdose, gastrointestinal symptoms, nausea, vomiting, dizziness, drowsiness (these symptoms may be severe), loss of consciousness, miosis may develop. Mild bradycardia and hypotension have also been reported. The occurrence of extrapyramidal symptoms is possible (such symptoms were observed when taking buspirone in therapeutic doses; overdose increases the risk of their occurrence). In rare cases, seizures may develop.

Treatment gastric lavage should be performed as soon as possible and symptomatic and supportive therapy should be prescribed. A specific antidote is unknown, dialysis is ineffective. Concomitant ingestion of several drugs should be suspected.

Drug Interactions

Given the pharmacokinetic properties of buspirone (low bioavailability, intensive metabolism in the liver, significant binding to plasma proteins), there is a high probability of interaction of buspirone with co-administered drugs; however, since Buspirone has a high therapeutic index, drug interactions do not lead to clinically significant pharmacodynamic changes.

Contraindicated combinations

Inhibitors and inducers of cytochrome P450 CYP3A4 isoenzyme: when buspirone is used concomitantly with rifampicin, the plasma concentration of buspirone and its pharmacodynamic effect are reduced. When used concomitantly with potent inducers of the CYP3A4 isoenzyme, for example, with phenobarbital, phenytoin, carbamazepine, St. John’s wort preparations, dose titration of buspirone may be necessary. It has been shown that when buspirone is used concomitantly with erythromycin, itraconazole, diltiazem and verapamil, the plasma concentration of buspirone increases. Due to the dosage regimen, which does not provide for individual dose selection and the use of buspirone doses less than 15 mg, the concomitant use of the drug Vespireit^® with inhibitors and inducers of cytochrome P450 CYP3A4 isoenzyme is contraindicated.

Not Recommended Combinations

MAO Inhibitors increases in blood pressure and the occurrence of hypertensive crises have been described after simultaneous administration of buspirone and drugs acting on MAO; therefore, concomitant use of buspirone with MAO inhibitors is not recommended. At least 14 days should elapse after discontinuation of an irreversible MAO inhibitor (e.g., selegiline) before starting the drug (and vice versa), or 1 day after discontinuation of a reversible MAO inhibitor (moclobemide).

Combinations Requiring Precautions

Selective Serotonin Reuptake Inhibitors (SSRIs) the concomitant use of buspirone with SSRIs has been extensively studied. Although no severe toxicity was observed, rare cases of seizures have been reported with the concomitant use of buspirone and SSRI drugs. Buspirone should be used with caution in combination with serotonergic drugs (including MAO inhibitors, L-tryptophan, triptans, tramadol, linezolid, SSRIs, lithium preparations, and products containing St. John’s wort), as there have been isolated reports of serotonin syndrome developing when buspirone was combined with SSRIs. If serotonin syndrome is suspected, Buspirone should be discontinued immediately and supportive symptomatic therapy initiated.

Fluvoxamine with short-term concomitant use of fluvoxamine and buspirone, the plasma concentration of buspirone increases 2-fold compared to its use as monotherapy.

Trazodone when used concomitantly with trazodone, some patients experience a 3- to 6-fold increase in ALT activity.

Cimetidine with concomitant use of cimetidine and buspirone, a slight increase in the concentration of the buspirone metabolite 1-PP is observed. Due to the high degree of plasma protein binding of buspirone (95%), caution should be exercised when co-administering buspirone with drugs that also have a high degree of plasma protein binding.

Other Medicines due to insufficient relevant clinical data, concomitant use of buspirone with antihypertensive drugs, cardiac glycosides, oral contraceptives, and antidiabetic agents is possible only under conditions of careful medical supervision.

Combinations to be Considered

Baclofen, lofexidine, nabilone, antihistamines may enhance any sedative effect.

Diazepam after adding buspirone to ongoing diazepam therapy, no statistically significant changes in the pharmacokinetics of diazepam (C_max, AUC, and C_min) are observed; however, a 15% increase in these parameters for nordiazepam is observed, along with the development of some minor adverse reactions (dizziness, headache, nausea).

Haloperidol concomitant use may increase the plasma concentration of haloperidol.

Plasma Protein Binding Buspirone is highly bound to plasma proteins (95%). In vitro, Buspirone does not displace other drugs that are tightly bound to plasma proteins, such as warfarin. However, in vivo, Buspirone may displace drugs that are less tightly bound to plasma proteins, such as digoxin. The clinical significance of this effect is unknown.

Warfarin prolongation of prothrombin time has been reported after adding buspirone to ongoing warfarin therapy.

Grapefruit Juice

Grapefruit juice increases the plasma concentration of buspirone. Patients taking Buspirone should avoid consuming large amounts of grapefruit juice.

CNS Depressants and Alcohol

Concomitant administration of buspirone with triazolam or flurazepam does not increase the duration or effect of these benzodiazepines. After a single 20 mg dose of buspirone, its CNS effects are not enhanced. Experience with the concomitant use of buspirone and other anxiolytics or other agents acting on the CNS (e.g., antipsychotics and antidepressants) is insufficient. Therefore, in such cases, careful medical supervision is necessary.

Storage Conditions

The drug should be stored in the original packaging (blister pack in a carton), in a place inaccessible to children, at a temperature not exceeding 30°C (86°F).

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.