Expiration date: 03/2026

Release form and composition:

Hard gelatin capsules, size ?4, with lock, white body and blue cap with the inscription ZDX 20 on the body and the inscription on the lid Pfier.

1 capsule contains:

ziprasidone (hydrochloride monohydrate) 40 or 60 mg

Excipients: lactose monohydrate, pregelatinized corn starch, magnesium stearate.

Pharmachologic effect:

The antipsychotic (neuroleptic).

Receptor binding studies

It has a high affinity for dopamine D2-receptor agonism and significantly greater affinity for the serotonin 5HT2A-receptors. Ziprasidone also interacts with serotonin 5HT2S-, 5HTID-, 5HT1A-receptors drug affinity to these receptors with affinities comparable to the D2-receptor or exceeds it. Ziprasidone has moderate affinity for neuronal serotonin and norepinephrine transporters as well as the histamine H1-receptor and apha1-adrenoceptors. Antagonism of these receptors is associated respectively with drowsiness and orthostatic hypotension.

Ziprasidone is practically not interact with muscarinic M1-cholinergic receptors, antagonism which is associated with memory impairment.

Research receptor function

Ziprasidone is an antagonist of a serotonin 5HT2A-receptors and dopamine D2-receptor. The antipsychotic activity of the drug, presumably in part due to blockade of both types of receptors.

Ziprasidone is a potent antagonist 5HT2S-, 5HTID-receptor agonist and a potent 5HT1A-receptors and inhibits reuptake of norepinephrine and serotonin in neurons. Serotonergic activity of ziprasidone and its effect on the reuptake of neurotransmitters in neurons associated with antidepressant activity. Blockade 5HT1A- receptors causes anxiolytic effect of ziprasidone. A powerful antagonism to the 5HT2C receptor determines the antipsychotic activity.

Studies using PET in humans

According to a positron emission tomography (PET), the degree of blockade of serotonin 5HT2A-receptors 12 h after a single oral dose of the drug in 40 mg of 80%, and D2-dopamine receptors - 50%.

Pharmacokinetics:

Linear pharmacokinetics of ziprasidone when receiving the drug in doses of 40 to 80 mg 2 times / day after meals.

Suction

When receiving ziprasidone inside during food Cmax is reached within 6-8 hours. The absolute bioavailability of 20 mg when administered to 60% in the fasting state ziprasidone absorption is reduced by 50%.

Distribution

Before the drug two times / day equilibrium state is achieved within 3 days. Duration Retention equilibrium depends on the dose. Vd at steady state - 1.5 l / kg. Plasma protein binding is 99% and is independent of concentration.

Metabolism and excretion

The ingestion of ziprasidone is largely metabolized, unchanged in the urine and feces displayed a small fraction of the dose (t1% and t4% respectively). In equilibrium, the T1 / 2 of 6.6 h, the clearance of ziprasidone with a / in the introduction - 7.5 ml / min / kg. It is believed that there are 3 ways biotransformation ziprasidone, which lead to the formation of four major metabolites - benzizotiazolpiperazin (BITP) sulfoxide, sulfone BITP, ziprasidone sulphoxide and S-metildigidroziprasidona. About 20% is excreted in urine and about 66% - with the feces. The proportion of unchanged total of ziprasidone drug and its metabolites in serum is about 44%. CYP3A4 catalyzes the oxidative conversion of ziprasidone. S-metilgidroziprasidon formed by two reactions, catalyzed by aldehyde oxidase and tiometiltransferazoy.

Ziprasidone, S-metildigidroziprasidon and ziprasidone sulphoxide have similar properties that may cause prolongation of the interval QT. S-metildigidroziprasidon derived mainly from the faeces, and is also subject to further metabolism with the participation of CYP3A4, ziprasidone sulfoxide excreted by the kidneys and is also metabolized by CYP3A4.

Pharmacokinetics in special clinical situations

Purpose of ketoconazole at a dose of 400 mg / day (CYP3A4 inhibitor) causes an increase in the serum concentration of ziprasidone at approximately 40%. S-metildigidroziprasidona concentration in serum is increased by 55% while receiving ketoconazole. Additional prolongation of the QTc interval were observed.

Clinically significant relationship ziprasidone pharmacokinetics of age or gender, smoking, ingestion is not observed.

No significant changes in the pharmacokinetics of ziprasidone when administered in patients with severe and moderate renal impairment have been identified. It is unknown whether these patients metabolite concentrations in serum are increased.

In patients with mild or moderate hepatic impairment (Class A or B on the scale of Child-Pugh) on the background of cirrhosis of ziprasidone serum concentrations were 30% higher than in healthy patients, and a terminal T1 / 2 of about 2 hours more.

Indications:

• Prevention and treatment of schizophrenia and other psychiatric disorders. The drug is effective in the treatment of productive and negative symptoms and affective disorders (for patients receiving a dose of ziprasidone of 60 mg and 80 mg 2 times / day was a statistically significant improvement on the MADRS scale /rt0.05/ compared to placebo) in schizophrenia.
  

Dosage and administration:

The drug is taken orally with meals.

The recommended starting dose for adults is 40 mg 2 times / day. Subsequently, the dose is selected taking into account the clinical condition. If necessary, the daily dose may be increased to the maximum within 3 days. The maximum daily dose is 160 mg (80 mg of 2 times / day).

Correction of dosage regimen in the elderly, smokers, and patients with impaired renal function is not required.

In patients with mild or moderate hepatic impairment it is advisable to reduce the dose of the drug. Experience with ziprasidone in patients with severe hepatic impairment is not, therefore in these patients the drug should be used with caution.

Side effects:

Adverse events reported in clinical trials, encountered more than 1% of patients treated with ziprasidone

From the central and peripheral nervous system: asthenia, headache, extrapyramidal syndrome, insomnia or drowsiness, tremor, blurred vision, agitation, akathisia, dizziness, dystonic reactions. Rarely appear seizures (less than 1% of patients treated with ziprasidone). movement disorders Index (Mvement Disrder Burden Scre), reflecting the severity of extrapyramidal symptoms when using ziprasidone, significantly lower (rt0.05) than with haloperidol or risperidone. Comparable changes were observed in the application of akathisia rating scale (Simpsn Angus and Barnes akathisia scaes). Furthermore, the treatment with haloperidol and risperidone frequency akathisia and anticholinergics use was higher than in the treatment of ziprasidone.

Neuroleptic malignant syndrome (NMS): The use of antipsychotics observed cases of NMS, which is a rare but potentially fatal complication. Clinical manifestations of NMS are fever (hyperpyrexia), muscle rigidity, altered mental status, and autonomic instability (irregular, changes in blood pressure, tachycardia, profuse sweating, heart rhythm disturbance). Additional signs may include raising the level of CPK, myoglobinuria (rhabdomyolysis) and acute renal failure. If you have symptoms that can be attributed to the signs of NMS, or unexpectedly high body temperature, not accompanied by the appearance of the other symptoms of NMS, you should immediately cancel all antipsychotic drugs, including ziprasidone.

Cases were observed in postmarketing NMS application of Zeldox.

Slow dyskinesia: long-term use of ziprasidone, as with other antipsychotics, there is a risk of slow development of dyskinesias and other remote extrapyramidal syndromes. If signs of dyskinesia advisable to reduce the dose of ziprasidone, or cancel it.

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

Other: against maintenance therapy ziprasidone sometimes increase in prolactin levels were observed (in most cases returned to normal without treatment), hypertension. Reported weight swing upward on average 0.5 kg for intermittent reception (for 4-6 weeks) and downward by 1-3 kg for chronic administration (for years) than patients not taking the drug.

Adverse events noted in post-marketing trials, ziprasidone: postural hypotension, tachycardia (including arrhythmia type pirouette), insomnia, skin rashes, allergic reactions, galactorrhea.

Contraindications:

• Lengthening the interval QT (including congenital long QT syndrome)
  
• Recent history of acute myocardial infarction
  
• Decompensated heart failure
  
• Arrhythmia requiring admission antiarrhythmics IA and Class III
  
• pregnancy
  
• Lactation (breastfeeding)
  
• Hypersensitivity to ziprasidone or any inactive components of the drug.
  

Pregnancy and lactation:

Application of Zeldox contraindicated during pregnancy, except in those cases where the intended benefits to the mother outweighs the potential risk to the fetus.

Women of childbearing age should use adequate contraception methods during the period of application of Zeldox due to the lack of clinical data on the safety of its use during pregnancy.

If necessary, use Zeldox during lactation should stop breastfeeding.

Special instructions:

Ziprasidone causes a slight lengthening of the interval QT, so Zeldox should be used with caution in patients with bradycardia, electrolyte disturbances, as this can cause QT interval elongation or development of paroxysmal ventricular tachycardia. If the QT interval greater than 500 ms, it is recommended to cancel Zeldox.

When using Zeldox in patients with a history of convulsive conditions, care must be taken.

Ziprasidone has a primary effect on the central nervous system, so care must be taken when it is used in combination with other centrally acting drugs, including agents acting on the dopaminergic and serotonergic systems.

During treatment with ziprasidone alcohol is not recommended.

Use in Pediatrics

Efficacy and safety of ziprasidone use in patients under the age of 18 years have not been studied.

Effects on ability to drive vehicles and management mechanisms

The patients involved in potentially hazardous activities that require increased attention and psychomotor speed reactions, caution should be exercised. Patients should be warned of the possible occurrence of somnolence in patients receiving Zeldox.

Overdose:

Data on ziprasidone overdosage is limited.

Symptoms: in pre-registration clinical trials while taking the drug orally at a maximum dose of confirmed (12800 mg) in a patient manifested sedative effect of the drug, slow speech and transitory hypertension (blood pressure 200/95 mm Hg..). No clinically significant changes in heart rate or functional changes were noted.

Treatment: If overdose is suspected, it is necessary to take into account the possible role of concomitant therapy. Ziprasidone no specific antidote. In acute overdose should ensure airway and adequate ventilation and oxygenation of the lungs. Perhaps gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal together with laxatives. Possible seizures or dystonic reaction of the head and neck muscles after overdose may endanger aspiration with induced emesis. It is necessary to immediately start monitoring the function of the cardiovascular system, including continuous ECG recording to detect possible arrhythmias. Given that ziprasidone is largely bound to plasma proteins, hemodialysis is ineffective in the case of an overdose.

Drug Interactions:

In a joint application ziprasidone and drugs causing prolongation of the interval QT (including antiarimicheskie IA and Class III drugs), increased risk of QT interval prolongation and ventricular paroxysmal tachycardia (this combination is contraindicated).

In a joint application with ziprasidone drugs, have a depressing effect on the CNS, probably mutual reinforcement of actions (such a combination requires caution).

Ziprasidone has no inhibitory effect on CYP1A2, CYP2C9 and CYP2C19. The concentrations of ziprasidone, causing inhibition of CYP2D6 and CYP3A4 in vitr, n at least 1000 paz higher than the concentration of drug that could be expected in viv. This indicates the absence of likelihood of clinically significant interaction between ziprasidone and drugs metabolized by these isoenzymes.

In accordance with the results of studies in vitr data and clinical trials on healthy volunteers showed that the ziprasidone had no CYP2D6 mediated through effects on the metabolism of dextromethorphan and its main metabolite Dextrorphan.

Ziprasidone or combined with oral hormonal contraceptives did not cause significant changes in the pharmacokinetics of estrogen, or ethinyl estradiol (a substrate of CYP3A4), or progesteronosoderzhaschih components.

Ziprasidone has no effect on the pharmacokinetics of lithium when used together.

Ziprasidone largely bound to plasma proteins. In studies in vitr warfarin and propranolol (drugs with high protein binding) had no effect on the binding of ziprasidone to plasma proteins, and ziprasidone did not affect the binding of these drugs to plasma proteins. Thus, the possibility of interaction with drugs of ziprasidone consequence of displacement due to plasma proteins is unlikely.

Ziprasidone is metabolized by aldehyde oxidase, and to a lesser extent, CYP3A4. Clinically relevant inhibitors or inducers of aldehyde oxidase are unknown.

The combined use of ketoconazole (400 mg / day) as a potential inhibitor of CYP3A4 resulted in an increase of approximately 35% AUC and Cmax of ziprasidone that is unlikely to have clinical significance.

Combined use of carbamazepine (200 mg 2 times / day) as an inducer of CYP3A4, led in turn to a decrease in AUC and Cmax of ziprasidone at 36%, which is unlikely to have clinical significance.

If concomitant use of cimetidine, a nonspecific inhibitor of isozymes, had no significant effect on the pharmacokinetics of ziprasidone.

Concomitant use of antacids containing aluminum and magnesium, had no effect on the pharmacokinetics of ziprasidone.

In clinical studies found no clinically significant effect of the simultaneous use of benztropine, propranolol and lorazepam on the pharmacokinetic parameters and the concentration of ziprasidone in the blood serum.

Conditions and terms:

The drug should be stored out of reach of children at or above 30 ° C. Shelf life - 4 years.