Composition, form of production and packaging
Hard gelatin capsules with a "lock", size 4, the lid of blue color with the inscription "Pfizer", the body of white color with the inscription "ZDX 20", both inscriptions are marked with black ink; the contents of the capsules are a loose crystalline powder of almost white color with a pinkish tinge.
1 caps.
ziprasidone hydrochloride monohydrate 22.65 mg,
which corresponds to the content of ziprasidone 20 mg
Excipients: lactose monohydrate - 66.1 mg, corn pregelatinised corn starch - 10 mg, magnesium stearate - 1.25 mg.
The composition of the capsule body: titanium dioxide - 3%, gelatin - qs 100%.
Composition of capsule capsule: titanium dioxide - 3.2841%, indigocarmine - 0.3821%, gelatin - qs 100%.
The composition of the ink (Tek SW - 9008): shellac - 24-27%, ethanol 23-26%, isopropanol 1-3%, butanol 1-3%, propylene glycol 3-7%, water 15-18% , ammonia water - 1-2%, potassium hydroxide - 0.05-0.1%, iron dye oxide black - 24-28%.
7 pcs. - blisters (2) - packs of cardboard with the control of the first opening.
7 pcs. - blisters (8) - packs of cardboard with the control of the first opening.
10 pieces. - blisters (2) - packs of cardboard with the control of the first opening.
10 pieces. - blisters (3) - packs of cardboard with control of the first opening.
10 pieces. - blisters (5) - packs of cardboard with the control of the first opening.
10 pieces. - blisters (6) - packs of cardboard with the control of the first opening.
10 pieces. - blisters (10) - packs of cardboard with the control of the first opening.
14 pcs. - blisters (1) - packs of cardboard with control of the first opening.
14 pcs. - blisters (2) - packs of cardboard with the control of the first opening.
14 pcs. - blisters (4) - packs of cardboard with the control of the first opening.
Hard gelatin capsules with a "lock", size 4, a blue lid with the inscription "Pfizer", a casing of blue color with the inscription "ZDX 40", both inscriptions are marked with black ink; the contents of the capsules are a loose crystalline powder of almost white color with a pinkish tinge.
1 caps.
ziprasidone hydrochloride monohydrate 45.3 mg,
which corresponds to the content of ziprasidone 40 mg
Excipients: lactose monohydrate - 87.83 mg, corn pregelatinized corn starch - 15 mg, magnesium stearate - 1.87 mg.
The composition of the capsule body: titanium dioxide - 3.2841%, indigocarmine - 0.3821%, gelatin - qs 100%.
Composition of capsule capsule: titanium dioxide - 3.2841%, indigocarmine - 0.3821%, gelatin - qs 100%.
The composition of the ink (Tek SW - 9008): shellac - 24-27%, ethanol 23-26%, isopropanol 1-3%, butanol 1-3%, propylene glycol 3-7%, water 15-18% , ammonia water - 1-2%, potassium hydroxide - 0.05-0.1%, iron dye oxide black - 24-28%.
10 pieces. - blisters (3) - packs of cardboard with control of the first opening.
Hard gelatin capsules with a "lock", size 3, a white cap with the inscription "Pfizer", a white body with the inscription "ZDX 60", both inscriptions are in black ink;the contents of the capsules are a loose crystalline powder of almost white color with a pinkish tinge.
1 caps.
ziprasidone hydrochloride monohydrate 67.95 mg,
which corresponds to the content of ziprasidone 60 mg
Excipients: lactose monohydrate - 131.74 mg, corn pregelatinized starch - 22.5 mg, magnesium stearate - 2.81 mg.
The composition of the capsule body: titanium dioxide - 3%, gelatin - qs 100%.
Composition of capsule capsule: titanium dioxide - 3%, gelatin - qs 100%.
The composition of the ink (Tek SW - 9008): shellac - 24-27%, ethanol 23-26%, isopropanol 1-3%, butanol 1-3%, propylene glycol 3-7%, water 15-18% , ammonia water - 1-2%, potassium hydroxide - 0.05-0.1%, iron dye oxide black - 24-28%.
10 pieces. - blisters (3) - packs of cardboard with control of the first opening.
Hard gelatin capsules with a "lock", size 2, a blue lid with the inscription "Pfizer", a white body with the inscription "ZDX 80", both inscriptions are marked with black ink; the contents of the capsules are a loose crystalline powder of almost white color with a pinkish tinge.
1 caps.
ziprasidone hydrochloride monohydrate 90.6 mg,
which corresponds to the content of ziprasidone 80 mg
Excipients: lactose monohydrate - 175.65 mg, corn pregelatinized corn starch - 30 mg, magnesium stearate - 3.75 mg.
The composition of the capsule body: titanium dioxide - 3%, gelatin - qs 100%.
Composition of capsule capsule: titanium dioxide - 3.2841%, indigocarmine - 0.3821%, gelatin - qs 100%.
The composition of the ink (Tek SW - 9008): shellac - 24-27%, ethanol 23-26%, isopropanol 1-3%, butanol 1-3%, propylene glycol 3-7%, water 15-18% , ammonia water - 1-2%, potassium hydroxide - 0.05-0.1%, iron dye oxide black - 24-28%.
7 pcs. - blisters (2) - packs of cardboard with the control of the first opening.
7 pcs. - blisters (8) - packs of cardboard with control of the first opening.
10 pieces. - blisters (2) - packs of cardboard with the control of the first opening.
10 pieces. - blisters (3) - packs of cardboard with control of the first opening.
10 pieces. - blisters (5) - packs of cardboard with the control of the first opening.
10 pieces. - blisters (6) - packs of cardboard with the control of the first opening.
10 pieces. - blisters (10) - packs of cardboard with the control of the first opening.
14 pcs. - blisters (1) - packs of cardboard with control of the first opening.
14 pcs. - blisters (2) - packs of cardboard with the control of the first opening.
14 pcs. - blisters (4) - packs of cardboard with the control of the first opening.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2010.
PHARMACHOLOGIC EFFECT
Antipsychotic drug (antipsychotic).
Receptor binding studies
Has a high affinity for dopamine D 2 receptors and a much more pronounced affinity for serotonin 5HT 2A receptors. Ziprasidone also interacts with serotonin 5HT 2C-, 5HT ID -, 5HT 1A - receptors; the affinity of the drug for these receptors is comparable to or greater than that for D 2 receptors. Ziprasidone has a moderate affinity for the neuronal carriers of serotonin and noradrenaline, as well as for histamine H 1 receptors and? 1- adrenoreceptors. Antagonism to these receptors is associated, respectively, with drowsiness and orthostatic hypotension.
Ziprasidone practically does not interact with muscarinic m 1 -cholinoreceptors, the manifestation of antagonism to which is associated with memory impairment.
Research of receptor function
Ziprasidone is an antagonist of both serotonin 5HT 2A receptors and dopamine D 2 receptors. Antipsychotic activity of the drug, apparently, is partly due to blockade of both types of receptors.
Ziprasidone is a potent 5HT 2C- , 5HT ID- receptor antagonist and a potent 5HT 1A receptor agonist and inhibits the reuptake of norepinephrine and serotonin in neurons. Serotonergic activity of ziprasidone and its effect on the reuptake of neurotransmitters in neurons are associated with antidepressant activity. The blockade of 5HT 1A receptors causes the anxiolytic effect of ziprasidone. A powerful antagonism to 5HT 2C receptors determines antipsychotic activity.
Studies using PET in humans
According to positron emission tomography (PET), the degree of blockade of serotonin 5HT 2A -receptors was 80% at 12 hours after a single oral dose of 40 mg, and 50% of dopamine D 2 receptors.
PHARMACOKINETICS
The pharmacokinetics of ziprasidone is linear when taken in doses of 40 to 80 mg 2 times / day after meals.
Suction
When taking ziprasidone inside while eating, C max is reached within 6-8 hours. Absolute bioavailability of 20 mg dose after admission after eating is 60%; when taken on an empty stomach, the absorption of ziprasidone is reduced by 50%.
Distribution
When taking the drug 2 times / day, the equilibrium state is reached within 3 days. The duration of retention of the equilibrium state depends on the dose. V d in the equilibrium state is 1.5 l / kg. The binding with plasma proteins is 99% and does not depend on concentration.
Metabolism and excretion
When administered ziprasidone is largely metabolized, in an unchanged form with urine and feces a small portion of the dose (<1% and <4%, respectively) is excreted. In the equilibrium state, T 1/2 is 6.6 hours, the ziprasidone clearance for intravenous administration is 7.5 ml / min / kg. It is believed that there are 3 ways of biotransformation of ziprasidone that lead to the formation of four main metabolites - benzothiazole piperazine (BITP) sulfoxide, BITP sulfone, ziprasidone sulfoxide and S-methyldihydroziprasidone. Approximately 20% is excreted in the urine and approximately 66% - with feces. The proportion of unchanged ziprasidone from the total drug and its metabolites in the serum is about 44%. CYP3A4 catalyzes the oxidative conversion of ziprasidone. S-methylhydroziprasidone is formed as a result of two reactions catalyzed by aldehyde oxidase and thiomethyltransferase.
Ziprasidone, S-methyldihydroziprasidone and ziprasidone sulfoxide have similar properties that can cause prolongation of the QT interval. S-methyldihydrosiprasidone is excreted mainly with feces, and also undergoes a further metabolism involving CYP3A4, ziprasidone sulfoxide is excreted by the kidneys and is also metabolized with the participation of CYP3A4.
Pharmacokinetics in special clinical cases
The administration of ketoconazole 400 mg / day (inhibitor CYP3A4) leads to an increase in the concentration of ziprasidone in the blood serum by approximately 40%. The concentration of S-methyldihydrosiprasidone in serum increases by 55% during the administration of ketoconazole. There was no additional elongation of the QT c interval.
Clinically significant dependence of the pharmacokinetics of ziprasidone on age or sex, smoking with ingestion was not noted.
Significant changes in the pharmacokinetics of ziprasidone for oral administration in patients with severe and moderate impairment of renal function have not been identified. It is not known whether the concentration of metabolites in serum increases in such patients.
In patients with mild or moderate hepatic impairment (class A or B on the Child-Pugh scale), the ziprasidone concentration in the serum was 30% higher than in healthy patients with cirrhosis, and the terminal T 1/2 was approximately 2 hours greater .
INDICATIONS
- prevention and treatment of schizophrenia and other mental disorders. The drug is effective in the treatment of productive and negative symptoms, as well as affective disorders (in patients who received ziprasidone at a dose of 60 mg and 80 mg 2 times / day, there was a statistically significant improvement in the MADRS scale / СЂ<0.05 / compared with placebo) in schizophrenia.
DOSING MODE
The drug is taken orally during a meal.
The recommended starting dose for adults is 40 mg 2 times / day. Subsequently, the dose is selected taking into account the clinical state. If necessary, the daily dose can be increased to the maximum within 3 days. The maximum daily dose is 160 mg (80 mg 2 times / day).
Correction of the dosing regimen in the elderly, smoking patients and renal dysfunction is not required.
In patients with mild or moderate impairment of liver function, it is advisable to reduce the dose of the drug. The experience of using ziprasidone in patients with severe hepatic insufficiency is absent, therefore in this category of patients the drug should be used with caution.
SIDE EFFECT
Adverse events observed during clinical trials occurred in more than 1% of patients taking ziprasidone
From the central nervous system and peripheral nervous system: asthenia, headache, extrapyramidal syndrome, insomnia or drowsiness, tremor, blurred vision, psychomotor agitation, akathisia, dizziness, dystonic reactions. Very rarely there were seizures (less than 1% of patients receiving ziprasidone). The Movement Disorder Burden Score, which reflects the severity of extrapyramidal symptoms with ziprasidone, is significantly lower (p <0.05) than with haloperidol or risperidone. Comparable changes were observed with the use of the akathisia scales (Simpson Angus and Barnes akathisia scales). In addition, with the treatment of haloperidol and risperidone, the frequency of akathisia and the use of anticholinergic agents was higher than with ziprasidone.
Malignant neuroleptic syndrome (CNS): with the use of antipsychotic agents, cases of CNS have been observed, which is a rare but potentially fatal complication.Clinical manifestations of CNS are fever (hyperpyrexia), muscle rigidity, changes in mental status and instability of the autonomic nervous system (arrhythmia, changes in blood pressure, tachycardia, profuse sweating, heart rhythm disturbance). Additional signs may include increased levels of CK, myoglobinuria (rhabdomyolysis), and acute renal failure. When symptoms appear that can be attributed to signs of the NSA, or unexpectedly high body temperature, not accompanied by the emergence of other symptoms of the NSA, all antipsychotics, including ziprasidone, should be immediately discontinued.
The cases of CNS are noted in the post-marketing application of Zeldox.
Slow dyskinesia: with prolonged use of ziprasidone, like other antipsychotics, there is a risk of developing slow dyskinesia and other distant extrapyramidal syndromes. When there are signs of dyskinesia, it is advisable to reduce the dose of ziprasidone or to cancel it.
From the digestive system: constipation, dry mouth, dyspepsia, increased salivation, nausea, vomiting.
Other: on the background of maintenance therapy with ziprasidone, an increase in the level of prolactin was sometimes observed (in most cases it was normalized without discontinuing treatment), hypertension. Weight fluctuations in the body were reported to increase by an average of 0.5 kg for short-term admission (within 4-6 weeks) and downward by 1-3 kg with prolonged admission (during the year) compared with patients who did not take the drug.
Adverse events noted in post-marketing trials of ziprasidone: postural hypotension, tachycardia (including pirouette-type arrhythmia), insomnia, skin rash, allergic reactions, galactorrhea.
CONTRAINDICATIONS
- prolongation of QT interval (including congenital syndrome of prolonged QT interval);
- recently suffered acute myocardial infarction;
Decompensated heart failure;
- arrhythmias requiring the use of antiarrhythmic drugs IA and III class;
- Pregnancy;
- lactation (breastfeeding);
- Hypersensitivity to ziprasidone or any inactive component of the drug.
PREGNANCY AND LACTATION
The use of Zeldox during pregnancy is contraindicated, except when the intended benefit to the mother exceeds the potential risk to the fetus.
Women of reproductive age should use adequate methods of contraception during the period of application of Zeldox in connection with the lack of clinical data on the safety of its use in pregnancy.
If you need Zeldox during lactation, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
Correction of the dosing regimen for renal dysfunction is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with mild or moderate impairment of liver function, it is advisable to reduce the dose of the drug. The experience of using ziprasidone in patients with severe hepatic insufficiency is absent, therefore in this category of patients the drug should be used with caution.
APPLICATION FOR CHILDREN
The efficacy and safety of ziprasidone in patients under the age of 18 years has not been studied.
APPLICATION IN ELDERLY PATIENTS
Correction of the dosing regimen in the elderly is not required.
SPECIAL INSTRUCTIONS
Ziprasidone causes a slight prolongation of the QT interval, so Zeldox В® should be used with caution in patients with bradycardia, electrolyte disorders, this can lead to an elongation of the QT interval or the development of paroxysmal ventricular tachycardia. If the QT interval exceeds 500 ms, it is recommended to cancel ZeldoxВ® .
Care should be taken when using Zeldox in patients who have a history of seizures.
Ziprasidone has a primary effect on the central nervous system, so care must be taken when it is used in combination with other central-action drugs, including agents acting on dopaminergic and serotonergic systems.
During treatment with ziprasidone, alcohol intake is not recommended.
Use in Pediatrics
The efficacy and safety of ziprasidone in patients under the age of 18 years has not been studied.
Impact on the ability to drive vehicles and manage mechanisms
Patients who engage in potentially hazardous activities requiring increased attention and speed of psychomotor reactions should be careful. Patients should be warned about the possible occurrence of drowsiness on the background of Zeldox.
OVERDOSE
Information about an overdose of ziprasidone is limited.
Symptoms: in pre-registration clinical trials, when taking the drug inside at the maximum confirmed dose (12800 mg), the patient showed a sedative effect of the drug, speech slowing and transient arterial hypertension (BP 200/95 mm Hg). Clinically significant changes in heart rate or functional changes were not noted.
Treatment: if you suspect an overdose, consider the possible role of concomitant therapy. There is no specific ziprasidone antidote. In case of acute overdose, it is necessary to provide airway patency and adequate ventilation and oxygenation of the lungs. Perhaps gastric lavage (after intubation, if the patient is unconscious) and the introduction of activated carbon in combination with laxatives. Possible seizures or dystonic reaction of the muscles of the head and neck after an overdose can create a threat of aspiration with induced vomiting. It is necessary to immediately begin monitoring the function of the cardiovascular system, including continuous registration of the ECG in order to identify possible arrhythmias. Given that ziprasidone is largely bound to plasma proteins, hemodialysis in case of an overdose is ineffective.
DRUG INTERACTION
When the joint application ziprasidone and drugs that cause QT interval prolongation (including antiarimicheskie Class IA and III drugs), increases the risk of lengthening QT interval, and paroxysmal ventricular tachycardia (this combination is contraindicated).
When ziprasidone combined use with drugs have a depressing effect on the CNS may mutual enhancement of the action (the combination requires care).
Ziprasidone has no inhibitory effect on CYP1A2, CYP2C9 and CYP2C19. Ziprasidone concentration causing inhibition of CYP2D6 and CYP3A4 in vitro, Po at least 1000 paz exceed the concentration of drug that could be expected in vivo. This indicates the absence of clinically significant probability of interaction between ziprasidone and drugs metabolized by these isoenzymes.
In accordance with the results of in vitro studies and clinical trial data in healthy volunteers have shown that the ziprasidone had no effect mediated by CYP2D6 in 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, ethinyl estradiol, or (which is the substrate CYP3A4), or progesteronosoderzhaschih components.
Ziprasidone has no effect on the pharmacokinetics of lithium when used together.
Ziprasidone is largely bound to plasma proteins. In in vitro studies, warfarin and propranolol (drugs with a high degree of protein binding) had no effect on binding to plasma proteins ziprasidone, ziprasidone and had no effect on the binding of drugs with plasma proteins. Thus, the possibility of interaction with drugs of ziprasidone result of displacement due to plasma proteins is unlikely.
Ziprasidone aldehyde and metabolized to a lesser extent, CYP3A4. Clinically significant inhibitors or inducers aldehyde unknown.
Joint application with ketoconazole (400 mg / day) as a potential inhibitor of CYP3A4 resulted in an increase of approximately 35% AUC and C max ziprasidone that hardly has clinical significance.
Joint application with carbamazepine (200 mg, 2 times / day), as an inductor CYP3A4, resulting, in turn, to a decrease in AUC and C max ziprasidone at 36%, which hardly has clinical significance.
The combined application cimetidine, nonspecific isoenzyme inhibitor, had no significant effect on the pharmacokinetics of ziprasidone.
The simultaneous use of antacids containing aluminum and magnesium, no effect on the pharmacokinetics of ziprasidone.
In clinical studies found no clinically significant effect simultaneous application benztropine, Lorazepam propranolol and the pharmacokinetic parameters and the concentration of ziprasidone in the blood serum.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 4 years.
