Zeldox

557 9 minutes read

Active material: Ziprasidon
When ATH: N05AE04
CCF: Antipsychotic drug (anxiolytic)
ICD-10 codes (testimony): F20, F21, F22, F23, F25, F29
When CSF: 02.01.02.05
Manufacturer: PFIZER GmbH (Germany)

Pharmaceutical form, composition and packaging

Capsules hard gelatin, size №4, from “Castle”, white hull and blue Cap, with an inscription “ZDX 20” housing and inscription “Pfizer” of krыshechke.

	1 caps.
ziprasidon (in the form of hydrochloride monohydrate)	20 mg

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

7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (8) – packs cardboard.
10 PC. – blisters (2) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (5) – packs cardboard.
10 PC. – blisters (6) – packs cardboard.
10 PC. – blisters (10) – packs cardboard.
14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.

Capsules hard gelatin, size №4, from “Castle”, Blue shell and blue Cap, with an inscription “ZDX 40” housing and inscription “Pfizer” of krыshechke.

	1 caps.
ziprasidon (in the form of hydrochloride monohydrate)	40 mg

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

Capsules hard gelatin, size №3, from “Castle”, white hull and White Cap, with an inscription “ZDX 60” housing and inscription “Pfizer” of krыshechke.

	1 caps.
ziprasidon (in the form of hydrochloride monohydrate)	60 mg

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

Capsules hard gelatin, size №2, from “Castle”, white hull and blue Cap, with an inscription “ZDX 80” housing and inscription “Pfizer” of krыshechke.

	1 caps.
ziprasidon (in the form of hydrochloride monohydrate)	80 mg

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

Pharmacological action

Antipsychotic drug (anxiolytic).

Study of binding to receptors

It has a high affinity for dopamine D₂-receptors and significantly more pronounced affinity for serotoninergic 5HT_2A-Receptor. Ziprasidone also interacts with serotonin 5HT_2FROM-, 5HT_ID-, 5HT_1A-receptors; drug affinity for these receptors with an affinity comparable to D₂-receptors or exceeds. Ziprasidone has moderate affinity for the serotonin and norepinephrine carriers nejronal'nym, as well as the histamine H₁-рецепторам и a₁-adrenoceptor. Antagonism at these receptors is associated respectively with sleepiness and orthostatic hypotension.

Ziprasidone practically does not interact with muscarinic m₁-holinoretseptorami, antagonism which is associated with memory impairment.

Study of the function of receptors

Ziprasidone is an antagonist as serotonin 5HT_2A-receptors, and dopamine D₂-receptors. Antipsihoticheskaja activity of the preparation, apparently, partly due to blockade of both types of receptors.

Ziprasidone is a potent antagonist of 5HT_2FROM-, 5HT_ID-receptors and potent agonist 5HT_1A-receptor and inhibits reuptake of norepinephrine and serotonin neurons. Ziprasidone serotonergic activity and its effect on the reuptake of neurotransmitters in neurons associated with antidepressant activity. Blockade of 5HT_1A– receptors results in an anxiolytic effect of ziprasidone. Powerful antagonism to 5NT_2FROM-receptors determines the antipsychotic activity.

Studies using PET people

According to Positron Emission Tomography (PET) degree of blockade of serotonin 5HT_2A-receptors through 12 h after a single reception of the drug inside the dose 40 mg was 80%, and dopaminovykh (D)₂-receptors – 50%.

Pharmacokinetics

Pharmacokinetics: linear when taking the drug in doses of 40 to 80 mg 2 times / day after meals.

Absorption

When taken into ziprasidone with meals C_max It reached within 6-8 no. The absolute bioavailability of a dose 20 mg when given after a meal is 60%, in the fasting state is reduced by the absorption of ziprasidone 50%.

Distribution

Before the drug 2 times / day equilibrium state is reached within 3 days. Duration Retention equilibrium dose dependent. V_d at equilibrium – 1.5 l / kg. Plasma protein binding is 99% and does not depend on the concentration of.

Metabolism and excretion

If ingestion of ziprasidone is largely metabolized, unchanged in the urine and feces displayed a small fraction of the dose (<1% and <4% respectively). In equilibrium, the T_1/2 is 6.6 no, clearance of ziprasidone at / introduction – 7.5 ml / min / kg. It is believed, that there 3 biotransformation way ziprasidone, which lead to the formation of four main metabolites – benzizotiazolpiperazin (BITP) sulfoxide, BITP sulfone, зипрасидона сульфоксида и S-метилдигидрозипрасидона. About 20% excreted in the urine and about 66% – with 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 is formed by two reactions, catalyzed al'degidoksidazoj and tiometiltransferazoj.

Ziprasidon, S-metildigidroziprasidon sulfoxide, ziprasidone and possess similar properties, that may make the elongation QT interval. S-metildigidroziprasidon write mainly from faeces, as well as being exposed to further metabolism involving CYP3A4, ziprasidone sulfoxide appears kidneys and also with the participation of CYP3A4 metabolized.

Pharmacokinetics in special clinical situations

Appointment of ketoconazole in the dose 400 mg / day (CYP3A4 inhibitor) leads to an increase in the concentration of serum: approximately 40%. The concentration of S-metildigidroziprasidona in serum is increased by 55% at the time of admission ketokonazola. Additional elongation QT interval_c not observed.

Clinically significant dependence pharmacokinetics: from age or gender, smoking ingestion is not marked.

Significant changes pharmacokinetics: ingestion in patients with severe and moderate kidney dysfunction have not been identified. Unknown, whether such patients are increasing the concentration of metabolites in serum.

In patients with mild or moderate impaired hepatic function (class a or b on a scale Child-Pugh) against the background of cirrhosis: concentration in blood serum were on 30% higher, than in healthy patients, and Terminal T_1/2 about 2 h more.

Testimony

-Prevention and treatment of schizophrenia and other mental disorders. The drug is effective in the treatment of negative symptoms of productive and, as well as mood disorders (patients, treated with ziprasidone dose 60 mg 80 mg 2 times/day observed statistically reliable improvement scale MADRS/r<0.05/ compared to placebo) schizophrenia.

Dosage regimen

The drug is taken orally with meals.

The recommended starting dose for Adult is 40 mg 2 times / day. In a subsequent dose picked on the basis of the clinical condition. If necessary, the daily dose can be increased up to the maximum for 3 days. The maximum daily dose is 160 mg (by 80 mg 2 times / day).

Correction mode in the elderly, smokers are patients and in violation of the kidney is not required.

In patients light or moderately expressed violations of the liver It is advisable to reduce the dose of the drug. Application experience: u patients with severe hepatic insufficiency missing, Therefore, this category of patients, the drug should be used with caution.

Side effect

Adverse events, noted in clinical trials, encountered more than 1% patients, took ziprasidone

From the central and peripheral nervous system: asthenia, headache, extrapyramidal syndrome, insomnia or drowsiness, tremor, blurred vision, psychomotor agitation, akathisia, dizziness, dystonic reactions. Very rarely appeared convulsions (less than 1% patients, treated with ziprasidone). Index movements violations (Movement Disorder Burden Score), reflecting the severity extrapiramidale symptoms when you apply:, significantly below (p<0.05), than when applying haloperidol or risperidone. Comparable changes were observed in applying the rating scales akatizia (The Simpson Angus and Barnes akathisia scales). Besides, When treating aminazin and risperidonom frequency akatizia and use of antiholinergicakih funds was higher, than in the treatment of ziprasidonom.

Neuroleptic malignant syndrome (NMS): When applying antipsychotic means observed cases of CSN, that is a rare, but a potentially fatal complication. Clinical manifestations of CSNS are increased body temperature (hyperpyrexia), muscle rigidity, altered mental status and instability of the autonomic nervous system (arrhythmia, changes in blood pressure, tachycardia, panhydrosis, heart rhythm disturbance). Additional signs may include increasing the level of CPK, mioglobinuriju (raʙdomioliz) and acute kidney failure. When symptoms, which can be attributed to the grounds of the CSN, or unexpectedly high body temperature, not accompanied by the emergence of other symptoms of CSN, You should immediately revoke all antipsychotic means, including ziprasidone.

Cases marked postmarketingovom with application of the CSN Zeldoksa^®.

Slow dyskinesia: with long-term use:, like other antipsychotic means, There is a risk of slow dyskinesias and other remote extrapyramidal syndromes. When signs of psoriasis it is advisable to reduce the dose or discard it:.

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

Other: against the backdrop of maintenance therapy ziprasidonom sometimes, there was an increase in prolactin levels (in most cases, normal without stopping treatment), arterial hypertension. Body mass fluctuations were reported in average 0.5 kg with a short admission (during 4-6 weeks) and downwards 1-3 kg in the long admission (in the course of the year) compared to patients, not taking medication.

Adverse events, in postmarketingovyh tests ziprasidona: postural hypotension, tachycardia (incl. the type of arrhythmia “pirouette”), insomnia, skin rash, allergic reactions, galactorrhea.

Contraindications

-elongation QT interval (incl. congenital long QT syndrome);

— recently moved myocardial infarction;

- Decompensated heart failure;

- Arrhythmia, requiring the admission of antiarrhythmics class IA and III;

- Pregnancy;

- Lactation (breast-feeding);

-hypersensitivity to ziprasidonu or to any active component of the drug.

Pregnancy and lactation

Use Zeldoksa^® contraindicated during pregnancy, except, when the intended benefits to the mother outweighs the potential risk to the fetus.

Women of reproductive age must use adequate contraception during the Zeldoksa^® due to the lack of clinical data on the safety of its use in pregnancy.

If you must use Zeldoksa^® lactation breastfeeding should be discontinued.

Cautions

Ziprasidone is causing a slight elongation QT interval, so Zeldoks^® should be cautious appoint patients with bradycardia, electrolytic disorders, tk. This can lead to longer QT interval or the development of paroxysmal ventricular tachycardia. If the QT interval is greater than 500 Ms, It is recommended that you cancel Zeldoks^®.

When applying Zeldoksa^® patients, with a history of convulsive status, Caution should be exercised.

Ziprasidone has a primary effect on the central nervous system, so be careful when applying it in combination with other drugs central action, including funds, acting on the dopaminergicheskie and serotoninergicakie system.

During treatment is not recommended reception alcohol ziprasidonom.

Use in Pediatrics

The efficacy and safety of: patients aged 18 years I have not been studied.

Effects on ability to drive vehicles and management mechanisms

Patients, engaged in potentially hazardous activities, require increased attention and psychomotor speed reactions, Caution should be exercised. Patients should be warned of the possible occurrence of sleepiness in the face of the reception Zeldoksa^®.

Overdose

Information about overdose: limited.

Symptoms: in pre-registration clinical trials when taking the drug inside the maximum confirmed dose (12800 mg) the patient has manifested sedative drug, slowing of speech and passing arterial hypertension (FROM 200/95 mm Hg. Art.). Clinically significant changes in heart rate or functional changes were observed.

Treatment: If overdose is suspected, it is necessary to take into account the possible role of concomitant therapy. Specific antidote: none. 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 the introduction of activated charcoal in conjunction with laxatives drugs. Possible cramps or distonicheskaja reaction of muscles of the head and neck following overdose may create risk of aspiration with induced vomiting. You must immediately start monitoring functions of cardiovascular system, including continuous registration of ECG to detect possible arrhythmias. Considering, that ziprasidone is largely associated with the plasma protein, hemodialysis is ineffective in the case of an overdose.

Drug Interactions

In a joint application: medicines, causing QT prolongation (including antiarimicheskie preparations class IA and III), increases the risk of fracture QT interval and paroxysmal ventricular tachycardia (This combination is contraindicated).

When coupled with drugs:, have a depressing effect on the CNS, Perhaps a mutual enhancement of this action (this combination requires caution).

Ziprasidone has no inhibitory effect on CYP1A2, CYP2C9 or CYP2C19. Concentration:, causing inhibition of CYP2D6 and CYP3A4 in vitro, by at least 1000 times higher than the concentration of the preparation, that could be expected in vivo. This indicates that there is no likelihood of clinically meaningful interaction between ziprasidonom and drugs, those those izofermentami.

In accordance with the results of in vitro studies and data from clinical trials in healthy volunteers has been shown, that ziprasidone was not mediated through effects on the metabolism of CYP2D6 dextromethorphan and its main metabolite dekstrofana.

Ziprasidone when coupled with the use of oral hormonal contraceptives did not produce significant changes in the pharmacokinetics of estrogen, or ethinyl estradiol (which is a substrate of CYP3A4), or progesteronosoderzhashhih components.

Ziprasidone did not affect the farmakokinetiku lithium in a joint application.

Ziprasidone is largely associated with blood plasma proteins. The studies in vitro warfarin and propranolol (drugs with a high degree of bonding with the squirrels) did not affect binding protein with the plasma:, and ziprasidone did not affect the binding of these drugs with plasma protein. Thus, the ability to interact with drugs ziprasidonom due to displacement of the blood plasma is unlikely.

Ziprasidone is metabolized and al'degidoksidazoj, less, CYP3А4. Clinically relevant inhibitors or inducers of unknown al'degidoksidazy.

The combined use of ketoconazole (400 mg / day) as a potential inhibitor of CYP3A4 leading to an increase of approximately 35% AUC and C_max ziprasidona, that hardly has clinical significance.

Combined use with carbamazepine (200 mg 2 times / day), as the inductor CYP3A4, led, in turn, to a decrease in AUC and c_max : on 36%, that hardly has clinical significance.

When combined with the application of cimetidine, nonspecific inhibitor of Isoenzymes, had no significant effect on farmakokinetiku:.

Simultaneous application antatsidov, containing aluminum and magnesium, not affect the farmakokinetiku:.

During clinical studies are not clinically meaningful effect simultaneous application benstropina, propranolola and lorazepama on pharmacokinetic performance and concentration in serum:.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

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

Vladimir Andreevich Didenko

557 9 minutes read