Zeldox^® (Capsules, Lyophilisate) Instructions for Use

ATC Code

N05AE04 (Ziprasidone)

Active Substance

Ziprasidone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Psycholeptics; antipsychotic agents; indole derivatives

Pharmacological Action

Antipsychotic agent (neuroleptic). It has high affinity for dopamine D₂ receptors and a significantly more pronounced affinity for serotonin 5-HT_2A receptors. It also interacts with serotonin 5-HT_2C-, 5-HT_1D-, 5-HT_1A receptors; the drug’s affinity for these receptors is comparable to or exceeds its affinity for D₂ receptors.

It has moderately expressed affinity for neuronal serotonin and norepinephrine transporters, as well as for histamine H₁ receptors and α₁-adrenoceptors. Antagonism to these receptors is associated with drowsiness and orthostatic hypotension, respectively.

Ziprasidone practically does not interact with M₁-cholinergic receptors, the manifestation of antagonism to which is associated with memory impairment.

Ziprasidone is an antagonist of both serotonin 5-HT_2A receptors and dopamine D₂ receptors. Antipsychotic activity appears to be partly due to the blockade of both types of receptors.

Ziprasidone is a potent antagonist of 5-HT_2C-, 5-HT_1D-, 5-HT_1A receptors and inhibits the reuptake of norepinephrine and serotonin in neurons. The serotonergic activity of ziprasidone and its effect on neurotransmitter reuptake in neurons are associated with antidepressant activity. Blockade of 5-HT_1A receptors causes the anxiolytic effect of ziprasidone. Pronounced antagonism to 5-HT_2C receptors determines antipsychotic activity.

Pharmacokinetics

The pharmacokinetics of ziprasidone are linear when taken in doses from 40 to 80 mg twice daily after meals. When ziprasidone is taken orally with food, C_max is reached within 6-8 hours. The absolute bioavailability of a 20 mg dose when taken after a meal is 60%; when taken on an empty stomach, the absorption of ziprasidone is reduced by 50%.

When taken twice daily, steady state is reached within 3 days. The duration of steady-state retention is dose-dependent. V_d at steady state is 1.5 L/kg. Plasma protein binding is 99% and is concentration-independent.

When taken orally, Ziprasidone is extensively metabolized, with a small portion of the dose excreted unchanged in urine and feces (<1% and <4%, respectively). At steady state, T_1/2 is 6.6 hours, the clearance of ziprasidone after IV administration is 7.5 mL/min/kg. It is believed that there are 3 pathways of ziprasidone biotransformation, leading to the formation of four main metabolites – benzisothiazolpiperazine (BITP) sulfoxide, BITP sulfone, ziprasidone sulfoxide, and S-methyldihydroziprasidone. Approximately 20% is excreted in the urine and approximately 66% in the feces. The proportion of unchanged ziprasidone from the total content of the drug and its metabolites in serum is about 44%. CYP3A4 catalyzes the oxidative conversion of ziprasidone. S-methylhydroziprasidone is formed as a result of 2 reactions catalyzed by aldehyde oxidase and thiol methyltransferase.

Ziprasidone, S-methyldihydroziprasidone, and Ziprasidone sulfoxide have similar properties that may cause QT interval prolongation. S-methyldihydroziprasidone is excreted mainly in the feces and also undergoes further metabolism involving CYP3A4; Ziprasidone sulfoxide is excreted by the kidneys and is also metabolized with the participation of CYP3A4.

In patients with mild or moderate hepatic impairment (Child-Pugh class A or B) due to cirrhosis, serum ziprasidone concentrations were 30% higher than in healthy patients, and the terminal phase T_1/2 was approximately 2 hours longer.

Indications

Prevention and treatment of schizophrenia and other mental disorders.

ICD codes

Dosage Regimen

Administer Zeldox^® orally twice daily with food, as absorption is significantly reduced on an empty stomach.

Initiate treatment at the recommended dose of 40 mg twice daily.

If clinically necessary, titrate the dose upward. Do not exceed a maximum daily dose of 160 mg, administered as 80 mg twice daily.

Complete any dose titration within a three-day period to reach the target maintenance dose.

For patients with mild to moderate hepatic impairment (Child-Pugh class A or B), initiate therapy at a reduced dose.

Do not use in patients with severe hepatic impairment due to a lack of clinical data.

Regularly monitor the QT interval in patients with known cardiovascular disease or risk factors. Discontinue therapy if the QTc interval exceeds 500 msec.

Assess efficacy and tolerability periodically. For the management of persistent adverse reactions, consider a dose reduction or discontinuation of therapy.

Adverse Reactions

From the central and peripheral nervous system asthenia, headache, extrapyramidal syndrome, insomnia or drowsiness, tremor, blurred vision, psychomotor agitation, akathisia, dizziness, dystonic reactions; rarely – seizures.

With long-term use of ziprasidone, as with other antipsychotic agents, there is a risk of developing dyskinesias and other long-term extrapyramidal syndromes. If signs of dyskinesia appear, it is advisable to reduce the dose of ziprasidone or discontinue it.

From the digestive system constipation, dry mouth, dyspepsia, increased salivation, nausea, vomiting.

Other possible increase in prolactin levels, arterial hypertension, slight increase in body weight, postural hypotension, tachycardia, skin rash.

Contraindications

Prolongation of the QT interval (including congenital long QT syndrome), recent acute myocardial infarction, decompensated heart failure, arrhythmias requiring the use of class IA and III antiarrhythmic drugs, pregnancy, lactation (breastfeeding), hypersensitivity to ziprasidone.

Use in Pregnancy and Lactation

Use during pregnancy is contraindicated. If it is necessary to use during lactation, breastfeeding should be discontinued.

Women of reproductive age should use adequate methods of contraception during treatment due to the lack of clinical data on the safety of ziprasidone use during pregnancy.

Use in Hepatic Impairment

There is no experience with the use of ziprasidone in patients with severe hepatic insufficiency.

Pediatric Use

The efficacy and safety of ziprasidone in patients under 18 years of age have not been studied.

Special Precautions

If symptoms that can be attributed to signs of neuroleptic malignant syndrome (NMS) or an unexpectedly high body temperature not accompanied by other symptoms of NMS appear, antipsychotic agents, including Ziprasidone, should be discontinued immediately.

Use with caution in patients with bradycardia, electrolyte disturbances, as this may lead to QT interval prolongation or the development of paroxysmal ventricular tachycardia. If the QT interval exceeds 500 msec, it is recommended to discontinue Ziprasidone.

Use with caution in patients with a history of seizure disorders.

Effect on ability to drive vehicles and operate machinery

Use with caution in patients engaged in potentially hazardous activities requiring increased attention and speed of psychomotor reactions. Patients should be warned about the possible occurrence of drowsiness while taking ziprasidone.

Drug Interactions

When ziprasidone is used concomitantly with drugs that cause QT interval prolongation (including class IA and III antiarrhythmic drugs), the risk of QT interval prolongation and paroxysmal ventricular tachycardia increases (the combination is contraindicated).

When ziprasidone is used concomitantly with drugs that have a depressant effect on the central nervous system, mutual enhancement of this effect is possible (the combination requires caution).

The use of ketoconazole at a dose of 400 mg/day (a CYP3A4 inhibitor) leads to an increase in serum ziprasidone concentration by approximately 40%. The serum concentration of S-methyldihydroziprasidone increases by 55% during ketoconazole administration.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.