Зелдокс®

General characteristics. Structure:

International (unlicensed) name (MNN): Ziprasidon
Dosage form: capsules
Active agent: a ziprasidona of a hydrochloride of monohydrate of 22,65 mg, 45,30 mg, 67,95 mg or 90,60 mg 20 mg, 40 mg, 60 mg or 80 mg of a ziprasidon are equivalent.
Excipients: lactoses monohydrate, starch corn prezhelatinizirovanny, magnesium stearate.
The case and lid the capsule contains titanium dioxide, indigo carmine (except for a dosage of 60 mg), gelatin, ink (Tek SW – 9008) (shellac, ethanol, isopropanol, butanol, propylene glycol, water, ammonia water, potassium hydroxide, dye ferrous oxide black).
Description: solid gelatin capsules with "lock" and a text of "Pfizer" on a capsule lid.
Dosage of 20 mg: the size No. 4, a lid of blue color with Pfizer text, the case of white color with a text of "ZDX 20". Both texts are put with black ink.
Dosage of 40 mg: the size No. 4, a lid of blue color with Pfizer text, the case of blue color with a text of "ZDX 40". Both texts are put with black ink.
Dosage of 60 mg: the size No. 3, a lid of white color with Pfizer text, the case of white color with a text of "ZDX 60". Both texts are put with black ink.
Dosage of 80 mg: the size No. 2, a lid of blue color with Pfizer text, the case of white color with a text of "ZDX 80". Both texts are put with black ink.
Contents of capsules: loose crystal powder of color, almost white with a pinkish shade.

Pharmacological properties:

Pharmacodynamics. Researches of linkng with receptors
Ziprasidon has high affinity to dofaminergichesky receptors 2 types (D2) and considerable more expressed affinity to serotoninovy receptors 2A of type (5-HT2A). Ziprasidon interacts also with serotoninovy 5-HT2C, 5-HT1D and 5-HT1A receptors; affinity of drug to these receptors is comparable to affinity to D2 to receptors or exceeds it. Ziprasidon oppresses the return neyronalny serotonin reuptake and noradrenaline. Also affinity to H1-histamine and alfa1-adreno-receptors to which antagonism is connected with drowsiness and orthostatic hypotension respectively is noted. Ziprasidon practically does not interact with muskarinovy m1-receptors. Antagonism to these receptors is connected with a memory impairment.
Researches of function of receptors
Ziprasidon is an antagonist both serotoninovy receptors 2A (5-HT2A) of type, and dofaminergichesky receptors 2 types (D2). Antipsychotic activity of drug, apparently, is partially caused by blockade of both types of receptors.
Ziprasidon is also powerful antagonist 5-HT2C, 5-HT1D and a powerful agonist of 5-HT1A receptors and inhibits the return capture of noradrenaline and serotonin in neurons. Serotoninergichesky activity of a ziprasidon and its influence on the return capture of neurotransmitters in neurons are connected with antidepressive activity. Blockade of 5-HT1A receptors causes anxiolytic effects. Powerful antagonism to 5-HT2C receptors defines possible antipsychotic activity.
Researches using PET at people
According to the positron emission tomography (PET), extent of blockade of serotoninovy receptors 2A of type in 12 h after a single dose of drug inside in a dose of 40 mg made 80%, and D2 of receptors – 50%.

Pharmacokinetics. At use of a ziprasidon inside during food concentration in serum usually reaches a maximum during 6-8 h. Pharmacokinetics of a ziprasidon linear at reception of doses from 40 to 80 mg 2 times a day after food. Absolute bioavailability of a dose of 20 mg after food makes 60%. At reception on an empty stomach absorption of a ziprasidon decreases by 50%.
Administration of drug twice a day leads, as a rule, to achievement of an equilibrium state within 3 days. Duration of deduction of an equilibrium state depends on a dose.
In an equilibrium state the terminal elimination half-life of a ziprasidon after intake makes 6,6 h. The clearance of a ziprasidon at intravenous administration made 7,5 ml/min., and distribution volume – 1,5 l/kg. Ziprasidon more than for 99% contacts proteins of plasma and extent of binding does not depend on concentration.
Ziprasidon is substantially metabolized at intake; in not changed look kidneys and intestines remove very small part of drug (<1% and <4%, respectively). Believe that there are three ways of biotransformation of a ziprasidon which lead to formation of four main metabolites – benzisothiazolpiperazin (BITP) of sulphoxide, BITP of sulphone, a ziprasidon of sulphoxide and
S-metildigidroziprasidona. About 20% of a dose are removed by kidneys and about 66% – intestines. The share of not changed ziprasidon from the general content of drug and its metabolites in serum makes about 44%. The isoenzyme of CYP3A4 catalyzes oxidizing transformation of a ziprasidon. S-metildigidroziprasidon is formed as a result of two reactions catalyzed by aldehyde oxidase and tiolmetiltransferazy.
Ziprasidon, S-metildigidroziprasidon and a ziprasidona sulphoxide have similar properties which can cause lengthening of an interval of QT. S-metildigidroziprasidon is removed mainly with a stake, and also is exposed to further metabolism with participation of an isoenzyme of CYP3A4. Ziprasidona sulphoxide is brought by kidneys and also metabolized with participation of an isoenzyme of CYP3A4.
Clinically significant dependence of pharmacokinetics of a ziprasidon on age or floor, smoking at intake is noted.
Significant changes of pharmacokinetics of a ziprasidon at intake at patients with heavy and moderate renal failures in comparison with healthy volunteers were not revealed. Whether serumal concentration of metabolites increase at such patients, it is unknown.
At patients with an easy and moderate abnormal liver function (classes A or B on classification of Chayld-Pyyu) against the background of cirrhosis serumal concentration of a ziprasidon after intake were 30% higher, than at healthy volunteers, and the terminal elimination half-life is about 2 h more.

Indications to use:

Treatment of schizophrenia.
Drug is effective in therapy of productive and negative symptoms, and also affective frustration (at the patients receiving зипрасидон in a dose of 60 mg and 80 mg two times a day statistically reliable improvement on MADRS scale (Montgomery – Asberg Depression Rating Scale – the Rating scale of Montgomery-Asberg) (p <0,05) in comparison with placebo is noted).
Treatment of the maniacal and mixed episodes caused by bipolar disorder with psychotic symptoms or without those.

Route of administration and doses:

Ziprasidon accept inside during food (see Pharmacokinetics).
Adults
At treatment of acute schizophrenia and bipolar disorder the recommended starting dose makes 40 mg 2 times a day during meal. In the subsequent the dose is increased taking into account a clinical state. The maximum daily dose of 160 mg (80 mg 2 times a day). If necessary the daily dose can be raised to maximum within 3 days. The Sredneterapevtichessky dose of Zeldoks of 120 mg divided into two receptions.
As a maintenance therapy of schizophrenia it is necessary to appoint a minimal effective dose; in most cases reception of 20 mg of drug 2 times a day suffices
Change of a dose at elderly people (65 years are also more senior), patients with a renal failure, is not required from the smoking patients.

Features of use:

Influence on ability of driving of the car and control of mechanisms
As well as other neuroleptics, зипрасидон drowsiness causes. It is necessary to warn patients who can drive the car or dangerous mechanisms about it. It is necessary to be careful until is confidence that drug does not influence negatively ability to drive the car and to manage difficult mechanisms.

Side effects:

The undesirable phenomena noted with a frequency ≥ in 1% among the patients receiving зипрасидон in short-term placebos - controlled researches of its use at schizophrenia.


Class of systems of bodies Undesirable reactions and their frequency
Mental disturbances Often: agitation, insomniya.
Disturbances from a nervous system Very often: drowsiness.
Often: akathisia, dizziness, dystonia, extrapyramidal syndrome, headache, hyper tone, tremor.
Disturbances from organs of sight Often: vision disorder.
Disturbances from the alimentary system Often: a lock, dryness in a mouth, dyspepsia, strengthening of a sialosis, nausea, vomiting.
System disturbances and complications in an injection site it is frequent: adynamy.
Very often ≥10%; often ≥1%, but <10%

Extremely seldom there were spasms (less, than at 1% of the patients receiving зипрасидон).
The index of disturbance of movements (Movement Disorder Burden Score) reflecting expressiveness of extrapyramidal symptoms at use of a ziprasidon is much lower (p <0,05), than at use of a haloperidol or risperidon. Comparable changes were observed on a scale of assessment of an akathisia (Simpson Angus and Barnes akathisia scales) at use of a ziprasidon and placebo. Besides, at treatment by a haloperidol and risperidony the frequency of an akathisia and use of anticholinergics was higher, than at treatment ziprasidony.
It was reported about fluctuation of body weight towards increase on average on 0,5 kg at short-term reception (within 4-6 weeks) and towards decrease by 1,3 kg at patients with initially high index of body weight at long reception (within a year) in comparison with the patients who were not accepting drug.
Against the background of a maintenance therapy ziprasidony increase in level of prolactin was sometimes observed, however in most cases it was normalized without the treatment termination.

The undesirable phenomena noted with a frequency ≥ 5% among the patients receiving зипрасидон in short-term placebos - controlled researches of its use at maniacal episodes of bipolar disorder.


Disturbances from a nervous system Very often: akathisia, dizziness, extrapyramidal syndrome, headache, drowsiness.
Often: dystonia, hyper tone, tremor.
Disturbances from an organ of sight Often: vision disorder.
Disturbances from the alimentary system Very often: nausea.
Often: lock.
System disturbances and complications in an injection site it is frequent: adynamy.
Very often ≥10%; often ≥1%, but <10%.

The side effects noted during post-marketing use of drug.

Disturbances from immune system: allergic reaction.
Mental disturbances: insomniya, mania and hypomania.
Disturbances from a nervous system: paresis of a facial nerve, malignant antipsychotic syndrome; a serotoninovy syndrome (when using a ziprasidon in monotherapy or in a combination with serotonergic medicines) late dyskinesia.
Cardiological disturbances: tachycardia, paroxysmal ventricular arrhythmia (torsade des pointes)
Disturbances from vascular system: postural hypotension, syncope.
Disturbances from the alimentary system: dysphagy, paraglossa.
Disturbances from skin and hypodermic cellulose: Quincke's disease, skin rashes.
Disturbances from an urinary system: enuresis, urine incontience
Disturbances from reproductive system and a mammary gland: galactorrhoea, priapism.

Malignant Antipsychotic Syndrome (MAS).
At use of antipsychotic means observed cases of ZNS which is rare, but potentially deadly complication. Clinical manifestations of ZNS are fervescence (hyper pyrexia), muscular rigidity, change of the mental status and instability of the autonomic nervous system (arrhythmia, fluctuations of arterial pressure, tachycardia, profuse sweating, disturbance of a heart rhythm). Accessory signs can include increase in level of a kreatininfosfokinaza, a myoglobinuria (рабдомиолиз) and an acute renal failure. If at the patient symptoms which can be carried to ZNS signs develop, or unexpectedly there was a high temperature (hyper pyrexia) which is not accompanied with emergence of other symptoms of ZNS, it is necessary to cancel immediately all antipsychotic means, including зипрасидон.
Cases of ZNS are noted at post-marketing use of Zeldoksa®.
Late dyskinesia
At prolonged use of a ziprasidon, as well as other antipsychotic means, there is a risk of development of late diskineziya and other remote extrapyramidal syndromes. At emergence of symptoms of dyskinesia it is reasonable to lower a dose of a ziprasidon or to cancel it.
Increase in frequency of mortality against the background of reception of neuroleptics at the elderly patients having dementia which is combined with psychosis.
In researches of a number of neuroleptics increase, in comparison with placebo, risk of approach of death at the elderly patients having the psychosis caused by dementia was revealed. The results received during the researches of a ziprasidon do not allow to draw a conclusion on increase in risk of approach of death at elderly patients with the psychosis caused by dementia against the background of administration of drug. Nevertheless, зипрасидон it is not recommended for treatment of this category of patients.

Interaction with other medicines:

Antiarrhytmic means of IA and the III class and other drugs causing lengthening of an interval of QT (see the section "With Care". QT interval).
The drugs operating on TsNS / alcohol
Ziprasidon has primary effect on TsNS therefore it is necessary to be careful at its use in combination with other drugs of the central action, including the means operating on dofaminergichesky and serotonergic systems.
During treatment ziprasidony alcohol intake is not recommended.
Influence of a ziprasidon on other medicines
Ziprasidon does not exert the inhibiting impact on isoenzymes of CYP1A2, CYP2C9 or CYP2C19. The concentration of a ziprasidon causing inhibition of isoenzymes of CYP2D6 and CYP3A4 in vitro, at least, by 1000 times exceeded concentration of drug which could be expected in vivo. It indicates lack of probability of clinically significant interaction between ziprasidony and medicines, the metabolized these isoenzymes.
Dextromethorphan
According to results of the researches in vitro and data of clinical tests on healthy volunteers it was shown that зипрасидон did not render CYP2D6 of influence on metabolism of dextromethorphan and its main metabolite of a dekstrorfan mediated through an isoenzyme.


Oral contraceptives
Use of a ziprasidon did not cause significant changes of pharmacokinetics of estrogen (the ethinylestradiol which is CYP3A4 isoenzyme substrate) or the components containing progesterone.
Lithium
Ziprasidon does not influence lithium pharmacokinetics at combined use.
Communication with proteins
Ziprasidon substantially contacts proteins of a blood plasma. In the researches in vitro warfarin and propranolol, two drugs with high extent of linkng with proteins, did not exert impact on binding of a ziprasidon proteins of plasma, as well as зипрасидон did not influence binding of these drugs proteins of plasma. Thus, the possibility of interaction of medicines with ziprasidony owing to replacement from communication with proteins of plasma, is represented improbable.
Influence of other drugs on зипрасидон
Ziprasidon is metabolized by aldehyde oxidase and to a lesser extent CYP3A4 isoenzyme. Clinically significant inhibitors or inductors of aldehyde oxidase are unknown.
Purpose of a ketokonazol (CYP3A4 isoenzyme inhibitor) in a dose of 400 mg/days leads to increase in concentration of a ziprasidon in blood serum for less than 40% and Cmax of a ziprasidon. Concentration of S-metildigidroziprasidona in serum increases by 55% during reception of a ketokonazol. Additional lengthening of an interval of QT is noted.
Carbamazepine use (200 mg two times a day) as CYP3A4 isoenzyme inductor, led, in turn, to reduction of influence of a ziprasidon by 36%.
Cimetidinum - nonspecific inhibitor of an isoenzyme of CYP, did not exert considerable impact on pharmacokinetics of a ziprasidon.
Antacids
Use of the antacids containing aluminum and magnesium did not influence pharmacokinetics of a ziprasidon.
Serotonergic medicines
The development of a serotoninovy syndrome matching on time reception of a ziprasidon in a combination with other serotonergic medicines was in some cases noted. Confusion of consciousness, agitation, fervescence, perspiration, an ataxy, a hyperreflexia, a myoclonus and diarrhea can be signs of a serotoninovy syndrome.
Benzatropine, propranolol, lorazepam - clinical tests of a ziprasidon at the patients accepting benzatropine, propranolol and lorazepam did not show clinically significant influence of these drugs on pharmacokinetic indicators of concentration of a ziprasidon in blood serum.

Contraindications:

Use of a ziprasidon is contraindicated in the following cases:

- hypersensitivity to a ziprasidon or any inactive component of drug;
- lengthening of an interval of QT in the anamnesis, including an inborn syndrome of the extended QT interval;
- recently postponed acute myocardial infarction;
- dekompensirovanny heart failure;
- the arrhythmias demanding reception of antiarrhythmic means of IA and the III class (see the section Special instructions);
- pregnancy, feeding period breast.
- Lactose intolerance, insufficiency of lactase, glyukozo-galaktozny malabsorption
- Joint reception of the medicines extending QT interval, in particular antiarrhytmic means of the classes IA and III, arsenic of trioxide, a galofantrin, methadone, a mezoridazin, thioridazine, Pimozidum, a sparfloksatsin, a gatifloksatsin, a moksifloksatsin, a dolasetron, a meflokhin, a sertindol or a tsizaprid.
Efficiency and safety of a ziprasidon at patients aged up to 18 years was not studied.

With care. Use at an abnormal liver function
At patients with the slight or moderately expressed liver failure it is reasonable to lower a drug dose. Experience of use of a ziprasidon for patients with a heavy liver failure is absent therefore in this group drug should be used with care (see the section Pharmacokinetics).
QT interval
Ziprasidon causes small or moderate lengthening of an interval of QT.
It is considered that there is a communication in emergence of lengthening of an interval of QT more than on 500 ms and paroxysmal ventricular arrhythmia (torsade des pointes) which is potentially life-threatening (similar effect some drugs, including antiarrhythmic means of IA and the III class cause (see the section of the Contraindication)).
Exceptional cases of developing of such arrhythmia at the patients with the multiple mixed risk factors accepting зипрасидон (post-marketing use) though to relationship of cause and effect with administration of drug it was not established were celebrated.
Ziprasidon patients should appoint with care with below the listed risk factors which can aggravate possibility of similar arrhythmia:
- bradycardia,
- electrolytic imbalance,
- use with other drugs extending QT interval.
If the interval of QT exceeds 500 ms, it is recommended to stop treatment (see the section of the Contraindication).
Spasms
At treatment of patients in the anamnesis it is necessary to be careful with spasms.
Diabetes mellitus
At the patients suffering from a diabetes mellitus after the beginning of therapy by atypical neuroleptics, regular monitoring of concentration of glucose in blood is necessary. With risk factors of a diabetes mellitus (in particular, obesity, existence of a diabetes mellitus in the family anamnesis) at the patients who began treatment with atypical neuroleptics it is necessary to define concentration of glucose in blood on an empty stomach during the beginning of such therapy and periodically during it. Monitoring of all patients receiving atypical neuroleptics regarding manifestations of a hyperglycemia, including polydipsia, polyuria, polyphagia and weakness is necessary. At development of these manifestations against the background of reception of atypical neuroleptics definition of concentration of glucose in blood on an empty stomach is necessary. In certain cases the hyperglycemia is stopped after cancellation of an atypical neuroleptic; however some patients need continuation of hypoglycemic therapy even after cancellation of the estimated drug which caused this disturbance.
Arterial hypotension.
Ziprasidon can provoke the arterial hypotension which is followed by dizziness, tachycardia and, at some patients, faints, especially during the initial stage of a titration of a dose that is probably caused it α1-адреноблокирующей by activity. Cases of a faint were noted at 0,6% of the patients receiving зипрасидон.
Ziprasidon it is necessary to use with extra care at the patients having the known cardiovascular pathology (with existence in the anamnesis of a myocardial infarction or coronary heart disease, heart failure or disturbances of conductivity), the cerebrovascular pathology or other states contributing to hypotension (dehydration, a hypovolemia, and also receiving other antihypertensives).
Aspiration pneumonia
Aspiration pneumonia is the frequent state taking place at the patients of advanced age, in particular, having the expressed dementia caused by Alzheimer's disease. Ziprasidon and other antipsychotic means have to be used with care at patients of risk group of aspiration pneumonia.
Pregnancy and feeding by a breast
Use at pregnancy
Researches at pregnant women were not conducted. In this regard women of reproductive age should use a reliable method of contraception. Considering limited experience of use of drug for the person, зипрасидон it is not recommended to appoint during pregnancy.
Use when feeding by a breast
It is unknown whether it is allocated зипрасидон with breast milk. At treatment ziprasidony women should be warned about the feeding termination by a breast.

Overdose:

Data on overdose of a ziprasidon are limited. In preregistration clinical tests at oral administration of drug in most confirmed dose (12800 mg) at the patient extrapyramidal manifestations, lengthening of an interval of QT to 446 ms were shown (without dysfunction of heart) the Most frequent manifestations of overdose are: extrapyramidal disturbances, drowsiness, tremor, alarm.
At suspicion on overdose it is necessary to consider a possible role of many drugs if the patient received the accompanying therapy. There is no specific antidote of a ziprasidon. At acute overdose it is necessary to provide passability of respiratory tracts and adequate ventilation and oxygenation. Are possible a gastric lavage (after an intubation if the patient is unconscious) and reception of absorbent carbon in a combination to a purgative. Possible spasms or dystonic reaction of muscles of the head and neck after overdose can create threat of aspiration at the induced vomiting. It is necessary to begin immediately monitoring of function of cardiovascular system, including continuous registration of an ECG for the purpose of detection of possible arrhythmias. Considering what зипрасидон substantially contacts proteins of plasma, the hemodialysis in case of overdose is ineffective.

Storage conditions:

To store at a temperature not above 30 °C. To store in the places unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules 7, 10 or 14 of capsules in the blister from PVC and aluminum foil.
2 or 8 blisters on 7 capsules; 1 or 4 blisters on 14 capsules; 2, 3, 5, 6 or 10 blisters on 10 capsules in a cardboard pack together with the application instruction.