Spitomin®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CПІТОМІН® (SPITOMIN®)

Composition:

Active substance: buspirone;

1 tablet contains buspirone hydrochloride 5 mg or 10 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets: white or almost white, round, flat tablets with a bevel, engraved with a stylized letter E and the number 151 on one side and a line on the other side, odorless or with a weak characteristic odor;

10 mg tablets: white or almost white, round, flat tablets with a bevel, engraved with a stylized letter E and the number 152 on one side and a line on the other side, odorless or with a weak characteristic odor.

The line is intended only for breaking the tablet to facilitate swallowing and not for dividing it into equal doses.

Pharmacotherapeutic group. Agents acting on the nervous system. Anxiolytics.

ATC code N05BE01.

Pharmacological Properties.

Pharmacodynamics.

Buspirone is an anxiolytic agent used for the treatment of anxiety disorders of various origins, particularly neuroses associated with feelings of anxiety, restlessness, tension, and irritability. The mechanism of anxiolytic action of buspirone and other azaspirodecanedione derivatives differs from that of benzodiazepines. These agents do not act on the benzodiazepine-GABA-chloride ionophore receptor complex; however, as partial agonists at 5-HT({1A}) receptors, they exert their effects by modulating the serotonergic system. This action leads to inhibition of 5-HT turnover and reduced firing rate of 5-HT neurons in the dorsal raphe nuclei. Buspirone exhibits high affinity for presynaptic 5-HT({1A}) receptors and acts as a partial agonist at postsynaptic 5-HT(_{1A}) receptors in the central nervous system. Buspirone has been shown to possess properties typical of both anxiolytics and antidepressants.

Buspirone does not exhibit significant activity at benzodiazepine receptors and does not affect GABA binding. Unlike benzodiazepines, buspirone lacks myorelaxant or anticonvulsant properties. In contrast to benzodiazepines, buspirone does not cause tolerance or dependence, and withdrawal symptoms do not occur after discontinuation of treatment. The effect of buspirone develops gradually. Therapeutic benefits begin to appear between 7 and 14 days of therapy, with maximum efficacy achieved only after 4 weeks of treatment.

Pharmacokinetics.

After oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract. Buspirone undergoes extensive first-pass metabolism in the liver. Therefore, unchanged drug is found in systemic circulation at low concentrations, with considerable individual variability.

Bioavailability is 4%. Peak plasma concentration is reached within 60–90 minutes after administration. The main metabolite—dealkylated metabolite—is active. Its anxiolytic activity is 4–5 times lower than that of the parent compound, but its plasma levels are higher and its elimination half-life is approximately twice as long as that of buspirone. Approximately 29–63% of buspirone is excreted in urine within 24 hours, primarily as metabolites. About 18–38% of the administered dose is eliminated via feces. The elimination half-life from plasma is approximately 2–3 hours.

Concomitant food intake slows the absorption of buspirone from the gastrointestinal tract.

Steady-state plasma concentration is achieved approximately 2 days after repeated administration.

Buspirone penetrates into breast milk. Data on placental passage of buspirone are lacking.

Elevated plasma levels of buspirone and increased AUC values, as well as prolonged elimination half-life, may occur in patients with impaired liver function. Due to biliary excretion of unchanged drug, a secondary peak may appear in plasma levels of buspirone. Patients with hepatic cirrhosis should receive lower individual doses or the same doses but less frequently.

Renal insufficiency may reduce buspirone clearance by up to 50%. Buspirone should be administered with caution and at reduced doses in patients with renal impairment.
Pharmacokinetics of buspirone is not altered in elderly patients.

Clinical characteristics.

Indications.

Symptomatic treatment of anxiety disorders with predominant symptoms: anxiety, inner restlessness, tension.

Contraindications.

Hypersensitivity to buspirone or to any of the excipients. Acute angle-closure glaucoma, myasthenia gravis, severe liver disease, severe hepatic insufficiency (prothrombin time greater than 18 seconds); severe renal insufficiency (glomerular filtration rate less than 10 mL/min), epilepsy, acute alcohol intoxication, sedative drugs, analgesics, and neuroleptics.

Concomitant use of monoamine oxidase inhibitors (MAOIs), and within 14 days after discontinuation of an irreversible MAOI inhibitor, or within 1 day after discontinuation of a reversible MAOI inhibitor.

Interaction with other medicinal products and other forms of interaction.

Due to insufficient clinical data, concomitant use of buspirone with antihypertensive agents, neuroleptics, antidepressants, antidiabetic agents, anticoagulants, oral contraceptives, and cardiac glycosides is possible only under strict medical supervision. Buspirone must not be used concurrently with benzodiazepines or other sedative agents.

Combination with MAO inhibitors is not recommended due to the risk of hypertensive crisis. Since buspirone is primarily metabolized by cytochrome P450, potent inhibitors of this enzyme may increase the bioavailability of buspirone.

Neflazodone.

Concomitant administration of buspirone and nefazodone resulted in a 20-fold increase in the maximum plasma concentration (Cmax) of buspirone and a 50-fold increase in the area under the concentration-time curve (AUC).

Erythromycin.

Concomitant administration of buspirone and erythromycin resulted in a 5-fold increase in Cmax and a 6-fold increase in AUC of buspirone.

Itraconazole.

Concomitant administration of buspirone and itraconazole resulted in a 13-fold increase in Cmax and a 19-fold increase in AUC of buspirone.

Diltiazem.

Concomitant administration of buspirone and diltiazem resulted in a 4-fold increase in Cmax and a 5.3-fold increase in AUC of buspirone.

Verapamil.

Concomitant administration of buspirone and verapamil resulted in a 3.4-fold increase in both Cmax and AUC of buspirone.

Cimetidine.

Concomitant administration of buspirone and cimetidine resulted in a 40% increase in Cmax of buspirone and a doubling of tmax, while AUC remained practically unchanged.

When buspirone is used concomitantly with the above-mentioned agents, the therapeutic effect and toxicity of buspirone may increase; therefore, dose reduction of buspirone is recommended (e.g., 2.5 mg twice daily).

Rifampicin.

Concomitant administration of buspirone and rifampicin resulted in an 83.9% decrease in Cmax and an 89.6% decrease in AUC of buspirone.

Inhibitors and inducers of CYP3A4.

Ketoconazole or ritonavir inhibit the metabolism of buspirone and increase its plasma levels.

If buspirone is used concomitantly with a CYP3A4 inhibitor, its dose should be reduced.

Inducers of CYP3A4, such as dexamethasone, phenytoin, phenobarbital, or carbamazepine, may increase the rate of buspirone metabolism. In such cases, the dose of buspirone may need to be increased to maintain its anxiolytic efficacy.

Serotonin reuptake inhibitors.

No dangerous interaction has been reported with concomitant use of buspirone and antidepressants that are selective serotonin reuptake inhibitors. However, isolated reports have described seizures occurring during long-term combined use of these agents with buspirone.

Haloperidol.

Concomitant administration of buspirone and haloperidol resulted in increased serum concentration of haloperidol.

Trazodone.

There have been reports of a 3-fold increase in ALT activity in some patients receiving trazodone concomitantly with buspirone. However, this elevation in liver transaminases has not been confirmed in clinical studies.

Diazepam.

When diazepam and buspirone are administered concomitantly, plasma levels of diazepam may slightly increase, and adverse effects such as dizziness, headache, and nausea may occur.

Alcoholic beverages should be avoided during treatment with buspirone.

Patients undergoing treatment should avoid consuming large amounts of grapefruit juice, as this may lead to increased plasma levels of buspirone and an increased frequency or severity of adverse effects.

Special precautions for use.

Hepatic impairment.

Buspirone undergoes extensive hepatic metabolism. In a pharmacokinetic study, administration of a single 30 mg dose of buspirone to patients with liver cirrhosis resulted in increased plasma buspirone levels, increased AUC values, and prolonged elimination half-life of buspirone. Due to biliary excretion of the drug, a secondary peak in plasma buspirone concentration may occur. The use of the drug is contraindicated in patients with severe hepatic impairment. In patients with liver cirrhosis, the drug should be administered at lower doses or at the same doses but with extended dosing intervals.

Renal impairment. Buspirone clearance may be reduced by 50% in patients with moderate or severe renal impairment. The drug is contraindicated in patients with severe renal impairment (glomerular filtration rate (GFR) < 10 mL/min). Buspirone may be administered in patients with mild (GFR > 30 mL/min) and moderate (GFR = 10–30 mL/min) renal impairment; however, reduced doses should be used and carefully monitored.

Elderly patients. Dose adjustment is not required; however, caution should be exercised when administering the drug (e.g., due to possible decreased renal and/or hepatic function and increased sensitivity to adverse effects). The lowest effective dose should be prescribed, and close monitoring is recommended if dose escalation is necessary.

Patients should be advised to avoid consuming grapefruit or drinking grapefruit juice in significant amounts during treatment, as these products may increase plasma buspirone levels and lead to an increased frequency or severity of adverse effects.

Switching from benzodiazepines to buspirone. Buspirone cannot alleviate benzodiazepine withdrawal symptoms. If switching a patient to buspirone therapy after prolonged benzodiazepine treatment, buspirone should only be initiated after completion of a gradual benzodiazepine dose reduction period.

Buspirone does not cause drug dependence; however, its use in patients with known or suspected susceptibility to substance dependence requires careful medical supervision.

Since the anxiolytic effect of the drug becomes apparent after 7–14 days of treatment, and the full therapeutic effect develops approximately after 4 weeks, patients with pronounced anxiety require careful medical monitoring during the initial phase of therapy.

Alcoholic beverages should be avoided throughout the course of buspirone treatment.

In patients with lactose intolerance, the lactose content in tablets should be considered when planning a diet (55.7 mg in 5 mg tablets and 111.4 mg in 10 mg tablets).

Spitomin® contains lactose and therefore should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Clinical and experimental studies have not revealed any evidence that buspirone causes risk of dependence or addiction; however, the prescription of the drug should be justified.

Buspirone is not intended for the treatment of withdrawal symptoms caused by benzodiazepines or other sedative/hypnotic agents. Therefore, these medications should be gradually discontinued before initiating buspirone therapy. This is particularly important for patients taking central nervous system (CNS)-depressant drugs.

The combination of buspirone with monoamine oxidase inhibitors (MAOIs) is not recommended. Cases of increased blood pressure have been reported with concomitant use of these drugs.

Buspirone is contraindicated in patients with a history of epileptic seizures.

Long-term toxicity. Since the mechanism of action is not fully understood, long-term toxic effects on the CNS or other organ systems cannot be predicted.

Use during pregnancy or breastfeeding.

There are no data available on the use of buspirone during pregnancy; therefore, the drug should be prescribed only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus. Buspirone passes into breast milk; therefore, breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving or operating machinery.

During treatment, patients should refrain from driving or operating machinery, as adverse reactions affecting the central nervous system and mental function may occur (see section "Adverse reactions").

Dosage and Administration

The dosage is determined individually by a physician for each patient depending on the condition being treated. At the beginning of therapy, administer 5 mg of buspirone hydrochloride 2–3 times daily. To achieve the maximum therapeutic effect, the daily dose should be gradually increased to 20–30 mg of buspirone, divided into several individual doses.

The maximum single dose should not exceed 30 mg.

The maximum daily dose should not exceed 60 mg.

Food increases the bioavailability of buspirone. Tablets should always be taken at the same time of day, without chewing, with a small amount of liquid, either before or after meals.

If it is necessary to divide the tablet into two halves, place it on a firm surface with the score line facing upwards and press gently with the thumb.

If buspirone is used concomitantly with a strong CYP3A4 inhibitor, its initial dose should be reduced and only gradually increased after medical evaluation of the patient (see section "Interaction with other medicinal products and other forms of interaction").

Special patient groups.

Available data do not indicate the need for dosage adjustment based on age or gender.

Renal impairment

In patients with mild to moderate renal impairment (creatinine clearance 20–49 mL/min/1.72 m²), single-dose administration of buspirone results in increased plasma levels without prolongation of elimination half-life. Buspirone should be used with caution in these patients at reduced doses administered twice daily. The patient's response to treatment and symptoms should be carefully monitored before increasing the dose. In patients with anuric syndrome, single-dose administration leads to increased plasma levels of the metabolite 1-pyrimidinyl/piperazine (1-PP). Dialysis has no effect on plasma levels of either buspirone or 1-PP. Buspirone should not be administered to patients with creatinine clearance below 20 mL/min/1.72 m², especially those with anuric syndrome, due to the potential for increased levels of buspirone and its metabolites.

Hepatic impairment

The use of drugs such as buspirone in patients with impaired liver function demonstrates reduced first-pass metabolism. In patients with liver cirrhosis, single-dose administration of buspirone leads to increased plasma levels of unchanged drug and prolonged elimination half-life. Buspirone should be used with caution in these patients, following individual dose titration, to reduce the risk of serious adverse reactions that may occur with high doses of buspirone. Dose escalation should be considered only after careful patient evaluation and not earlier than 4–5 days after administration of the previous dose.

Treatment duration.

Anxiolytics should not be used for prolonged periods without monitoring. Therefore, treatment duration with buspirone 5 mg and/or 10 mg should not exceed 4 months. Dosage is determined individually by a physician for each patient depending on the condition being treated. If prolonged treatment (up to 6 months) is required, careful medical monitoring should be performed.

Psychological and social therapeutic measures should be considered in parallel with buspirone treatment.

Children.

Buspirone should not be administered to children due to lack of data on safety and efficacy.

Overdose.

Symptoms: nausea, vomiting, dizziness, drowsiness, increased fatigue, miosis, gastrointestinal disturbances, loss of consciousness. More severe complications have not been observed, even with daily doses up to 2400 mg.

Treatment: gastric lavage, monitoring of respiration, pulse, and blood pressure. Symptomatic therapy. There is no specific antidote. Buspirone is not removed by hemodialysis. Based on clinical experience, overdose with high doses (single oral dose of 375 mg) does not necessarily result in severe symptoms.

Side effects

Adverse effects usually occur at the beginning of treatment and typically diminish with continued use. In some cases, dose reduction may be necessary. The most commonly observed side effects were those affecting the nervous system, such as dizziness, insomnia, nervousness, drowsiness, and semiconscious state, as well as those affecting the gastrointestinal tract, such as nausea, and other effects such as headache and increased fatigue.

Less frequently observed were anger and hostility, confusion, blurred vision, diarrhoea, muscle and bone pain, numbness, paraesthesia, coordination disturbances, tremor, skin rash, dry mouth, weakness, asthenia, increased sweating, and clammy skin.

Adverse reactions are classified according to frequency of occurrence: very common (≥ 1/10); common (≥1/100, < 1/10); uncommon (≥1/1000, < 1/100); rare (≥1/10,000, < 1/1000); very rare (< 1/10,000); unknown (frequency cannot be estimated due to lack of data).

Infections and infestations:

frequency unknown – influenza-like illness.

Cardiovascular system:

common – non-specific chest pain;

uncommon – transient loss of consciousness, arterial hypotension and/or hypertension, tachycardia/palpitations;

rare – cerebrovascular accident, heart failure, myocardial infarction, cardiomyopathy, bradycardia, cerebrovascular disorders.

Blood and lymphatic system:

rare – blood count abnormalities (eosinophilia, leucopenia, thrombocytopenia).

Psychiatric disorders:

common – nightmares, somnolence, insomnia, dizziness, nervousness, decreased concentration, emotional lability, irritability, hostility, confusion, depression;

uncommon – depersonalisation, discomfort, pathological intolerance to normal sounds, euphoria, hyperkinesia, restlessness, loss of interest, associative disturbances, hallucinations, suicidal ideation, epileptic seizures, dysphoria, fear;

rare – sudden mood changes, claustrophobia, stupor, slurred speech, transient memory problems, serotonin syndrome, psychosis.

Nervous system:

uncommon – numbness, paraesthesia (e.g. tingling, burning sensation), coordination disturbances, tremor, epileptic seizures, dysgeusia, dysosmia, prolonged reaction time;

rare – involuntary movements, retardation, extrapyramidal symptoms including early and late dyskinesia, tone disturbances, fever, parkinsonism, akathisia, tinnitus.

Eye disorders:

common – blurred vision;

uncommon – redness and itching in the eye area, conjunctivitis;

rare – photophobia, sensation of pressure in the eyes, eye pain, narrowed visual field, increased intraocular pressure.

Ear and labyrinth disorders:

common – tinnitus; rare – inner ear disorders.

Respiratory system:

common – throat inflammation, nasal congestion;

uncommon – tachypnoea, dyspnoea, chest tightness, hyperventilation, sensation of breathlessness;

rare – epistaxis, burning sensation of the tongue.

Gastrointestinal disorders:

common – nausea, xerostomia, epigastric pain, diarrhoea;

uncommon – flatulence, loss of appetite, increased appetite, hypersalivation, irritable bowel syndrome, rectal bleeding, constipation, vomiting.

Renal and urinary system:

uncommon – frequent urination, urinary retention, dysuria;

rare – enuresis, nocturia.

Skin and subcutaneous tissue:

uncommon – oedema, urticaria, hyperaemia, bruising, alopecia, dry skin, eczema, facial swelling, bullae, flushing, skin fragility, skin rash, pruritus;

rare – allergic reactions, ecchymosis, acne, nail thinning.

Musculoskeletal and connective tissue disorders:

uncommon – muscle spasms and rigidity, myalgia, arthralgia;

rare – myasthenia.

Endocrine system:

rare – galactorrhoea, gynaecomastia, thyroid dysfunction.

Metabolism and nutrition disorders:

uncommon – anorexia, increased appetite;

frequency unknown – weight gain, weight loss.

General disorders:

common – headache, asthenia;

uncommon – fever, dizziness, malaise, increased fatigue, disturbances in smell and taste, increased sweating, flushing, cold hyperesthesia;

rare – alcohol abuse tendency, coagulation disorders, voice loss, hiccups, glossalgia.

Hepatobiliary disorders:

uncommon – increased liver enzymes.

Reproductive system and breast:

uncommon – menstrual cycle disturbances, decreased or increased libido;

rare – amenorrhoea, genital inflammation, decreased ejaculation, impotence.

Laboratory investigations: elevated serum transaminase levels.

Shelf life. 5 years.

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

Storage conditions.

Store at a temperature not exceeding 30 °C in a place protected from light.

Keep out of reach of children.

Packaging.

10 tablets in a blister, 6 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer/Marketing Authorisation Holder.

Egis Pharmaceuticals PLC, Hungary.

Address of manufacturer and place of business.

Matyas kiraly str. 65, 9900 Kermend, Hungary.

Bekenyfeldi str. 118-120, 1165 Budapest, Hungary.