Composition, form of production and packaging
Capsules 1 caps.
ziprasidone 20 mg
10 pieces. - packings cellular planimetric (3) - packs cardboard.
14 pcs. - packings cellular planimetric (2) - packs cardboard.
14 pcs. - packings cellular planimetric (4) - packs cardboard.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
10 pieces. - packings cellular planimetric (9) - packs cardboard.
Capsules 1 caps.
ziprasidone 40 mg
10 pieces. - packings cellular planimetric (3) - packs cardboard.
14 pcs. - packings cellular planimetric (2) - packs cardboard.
14 pcs. - packings cellular planimetric (4) - packs cardboard.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
10 pieces. - packings cellular planimetric (9) - packs cardboard.
Capsules 1 caps.
ziprasidone 60 mg
10 pieces. - packings cellular planimetric (3) - packs cardboard.
14 pcs. - packings cellular planimetric (2) - packs cardboard.
14 pcs. - packings cellular planimetric (4) - packs cardboard.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
10 pieces. - packings cellular planimetric (9) - packs cardboard.
Capsules 1 caps.
ziprasidone 80 mg
10 pieces. - packings cellular planimetric (3) - packs cardboard.
14 pcs. - packings cellular planimetric (2) - packs cardboard.
14 pcs. - packings cellular planimetric (4) - packs cardboard.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
10 pieces. - packings cellular planimetric (9) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Ziprasidone has a high affinity for type 2 dopamine receptors (D 2 ) and a high affinity for serotonin 2A receptors (5HT 2A ). According to the positron emission tomography (PET) data, 80% of the serotonin 2A receptors and more than 50% of the D 2 receptors were blocked 12 hours after a single dose of 40 mg. Ziprasidone also interacts with serotonin 5HT 2C , 5HT 1D and 5HT 1A receptors, and the affinity for these receptors is comparable or exceeds the affinity for D 2 receptors.Ziprasidone has a moderate affinity for neuronal serotonin and norepinephrine transports, exhibits moderate affinity for histamine H 1 and alpha 1- adrenoreceptors.The affinity of ziprasidone for muscarinic M 1 -receptors is negligible.
Ziprasidone is an antagonist of both receptors - serotonin 2A and dopamine D 2 . Ziprasidone is also a potent antagonist of 5HT 2C and 5HT 1D receptors and a 5HT1A receptor agonist. Suppresses the reverse neuronal seizure of norepinephrine and serotonin.
PHARMACOKINETICS
Suction. After ingestion of ziprasidone with food, Cmax in blood plasma is usually achieved in 6-8 hours. Absolute bioavailability of 20 mg dose is 60%.Pharmacokinetic studies have shown that the bioavailability of ziprasidone during food intake rises to 100%, so the drug is recommended to be taken with meals.
Distribution. V d is about 1.1 l / kg. Ziprasidone binds more than 99% to blood proteins.
Biotransformation and excretion. T 1/2 of ziprasidone after ingestion is 6.6 hours. The equilibrium state is reached within 1-3 days. The average clearance of ziprasidone administered intravenously is 5 ml / min / kg. Approximately 20% of the dose is excreted by the kidneys and 66% is excreted with bile through the intestine.
When receiving therapeutic doses from 40 to 80 mg 2 times a day, the pharmacokinetic schedule of ziprasidone is linear.
Ziprasidone is metabolized mainly in three ways, with the formation of four major circulating metabolites: benzothiazole piperazine (BITP) sulfoxide, BITP sulfone, ziprasidone sulfoxide and S-methyldihydroziprasidone. Unchanged ziprasidone accounts for approximately 44% of the total drug circulating in the serum. In invivo studies, it has been established that conversion to S-methyldihydroziprasidone is the main route of drug metabolism. Studies in vitro testify that this metabolite is formed by reduction catalyzed by aldehyde oxidase, followed by S-methylation. There is also an oxidative metabolism, mainly involving the isoenzyme CYP3A4 and the potential participation of the CYP1A2 isoenzyme.
In experiments, invitroS-methyldihydroziprasidone and ziprasidone sulfoxide exhibited properties that could cause the effect of prolonging the QTc interval. S-methyldihydroziprasidone is mainly excreted from the body through the intestine by biliary excretion with minimal participation of the CYP3A4 isoenzyme.Ziprasidone sulfoxide is excreted by renal excretion and secondary metabolism catalyzed by the CYP3A4 isoenzyme.
Special groups of patients. Pharmacokinetic screening of patients did not reveal significant pharmacokinetic differences in smokers and non-smokers.
Given that renal clearance does not affect the overall clearance of ziprasidone, when it was used by patients with different renal function, there was no increase in its content in the blood.
Exposure of 20 mg of ziprasidone 2 times / day for several days in patients with mild (creatinine clearance more than 60 ml / min), moderate (KK 30-60 ml / min) and severe renal insufficiency (the need for dialysis) respectively, 146%, 87% and 75% of the drug exposure in healthy volunteers (QC more than 70 ml / min). With mild to moderate liver failure (class A / B according to Child-Pugh classification) caused by cirrhosis, serum concentrations of ziprasidone after ingestion were 30% higher and T 1/2 increased approximately 2 hours compared to healthy volunteers. The effect of liver failure on serum concentrations of metabolites is unknown.
INDICATIONS
Schizophrenia and other psychotic conditions (treatment and prevention).
DOSING MODE
Inside, with food.
Treatment of schizophrenia
The recommended dose is 40 mg 2 times / day.
In the future, the daily dose can be changed in accordance with the clinical picture and course of the disease and brought to a maximum of -160 mg / day (2 times 80 mg). If necessary, the daily dose can be brought to maximum for 3 days.
Prevention of schizophrenia
Recommended minimum initial dose - 20 mg 2 times / day.
Elderly patients (over 65 years of age)
Dose adjustment is required for concomitant diseases and / or conditions limiting the use of ziprasidone (a minimum initial dose is recommended). Impaired renal function: dose adjustment is not required.
Dysfunction of the liver: the dose of the drug should be reduced.
SIDE EFFECT
Classification of incidence of side effects (World Health Organization): very often> 1/10; often> 1/100, <1/10; infrequently> 1/1000, <1/100; rarely> 1/10000, <1/1000; very rarely <1/10000, including single messages.
From the cardiovascular system: infrequently - palpitation, tachycardia, hypertensive crisis, increased blood pressure (BP), orthostatic hypotension, syncope; rarely - isolated systolic or diastolic hypertension, labile blood pressure.
On the part of the senses: often - impaired vision; -only: photophobia; rarely - pain in the ears, amblyopia, itching and dryness of the conjunctiva, discomfort in the eyes.
On the part of the digestive system: often - nausea, vomiting, constipation, dyspepsia, dryness of the oral mucosa, increased salivation; infrequently - diarrhea, dysphagia, gastritis, discomfort in the abdomen, swelling of the tongue, flatulence;
Disorders of metabolism and nutrition: infrequent - increased appetite; rarely - hypocalcemia.
From the musculoskeletal system: often - stiff muscles; infrequently - muscle cramps, pain in the limbs, stiffness of the joints; rarely - trimester.
From the nervous system: very often - drowsiness, akathisia; often - dystonia, extrapyramidal disorders, tardive dyskinesia, parkinsonism (including rigidity of the "cogwheel" type, bradykinesia, hypokinesia), tremor, dizziness, sedation, headache, anxiety, agitation, insomnia; - often: generalized tonic-clonic seizures, ataxia, dysarthria, oculogic crisis, attention disturbance, hypertension, tremor, sensory disturbances (hypesthesia, paresthesia), lethargy, agitation, anxiety disorders, "coma in the throat" sensation, sleep disturbances (nightmares ), mania, hypomania; rarely - serotonin syndrome, malignant neuroleptic syndrome, panic attacks, depressive syndrome, bradyphrenia, affective disorders; very rarely - torticollis, paresis of the facial nerve, akinesia, hyperkinesia, restless legs syndrome;
From the genitourinary system: rarely - urinary incontinence, dysuria, enuresis, erectile dysfunction, increased erection, galactorrhea, gynecomastia, anorgasmia, priapism.
From the respiratory system: infrequently - dyspnoea.
From the side of the skin: infrequently - angioedema, urticaria, skin rash, acne; rarely - psoriasis, allergic dermatitis, alopecia, erythema, papular rash.
Laboratory indicators: infrequently - increased activity of "hepatic" enzymes in the blood; rarely - prolongation of the QT interval on the ECG, increased lactate dehydrogenase activity, eosinophilia, lymphopenia.
Common violations: often - asthenia, weakness; -nonly: violations of gait.
Other: thromboembolism, including thromboembolism of the pulmonary artery, deep vein thrombosis, the incidence of which is not established.
CONTRAINDICATIONS
- hypersensitivity to ziprasidone or any component of the drug;
- prolongation of QT interval on electrocardiogram (ECG), including congenital syndrome of elongated QT;
- myocardial infarction (acute, acute stage);
Decompensated chronic heart failure;
- Arrhythmia, requiring the use of antiarrhythmic drugs IA and III classes;
- simultaneous therapy with drugs that extend the QT interval: arsenic trioxide, halofantrine, levacetylmetadol, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron, mefloquine, sertindole or cisapride;
- pregnancy, lactation;
- the age is under 18 years;
- Congenital intolerance of galactose, deficiency of lactase, syndrome of glucose-galactose malabsorption.
Carefully. Pronounced bradycardia, electrolyte disorders (hypokalemia, hypomagnesemia), bipolar disorder, elderly age (over 65 years), history of convulsions, severe hepatic insufficiency, risk of stroke, simultaneous use of alcohol, thrombosis, due to risk of thromboembolism.
PREGNANCY AND LACTATION
The drug ZipsilaВ® is not used in pregnancy and during breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
Impaired renal function: dose adjustment is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Use with caution in severe hepatic insufficiency.
APPLICATION FOR CHILDREN
Contraindicated in children under 18 years of age.
APPLICATION IN ELDERLY PATIENTS
Use with caution in the elderly (over 65 years).
SPECIAL INSTRUCTIONS
QT interval. Ziprasidone causes an easy or moderate, dose-dependent, prolongation of the QT interval. In this regard, the drug should not be used together with drugs that also extend the QT interval. In patients with severe bradycardia, caution should be exercised when using ZipsilВ®.
Electrolyte disorders such as hypokalemia or hypomagnesemia increase the risk of developing a malignant arrhythmia, so they should be identified before starting ziprasidone therapy.
If the length of the QT interval is more than 500 msec, it is recommended to stop the use of ZipsilВ®.
Malignant neuroleptic syndrome (CNS). ZNS is a rare, potentially dangerous condition associated with the use of antipsychotics, including ziprasidone. Symptoms of ZNS: fever (hyperpyrexia), muscle rigidity, changes in mental status and instability of the autonomic nervous system (arrhythmia, fluctuations in blood pressure, tachycardia, profuse sweating, heart rhythm disturbance). When identifying the NSA, it is necessary to immediately abolish the ZipsilaВ® preparation.
Late dyskinesia. Long-term use of ziprasidone may cause the development of tardive dyskinesia and other extrapyramidal disorders. Particularly predisposed to the development of these complications are patients with bipolar disorders. The incidence of these conditions increases with age, and also depends on the duration of treatment with ziprasidone. When signs and symptoms of tardive dyskinesia appear, you either need to reduce the dose or stop using ZipsilВ®.
Convulsions. In patients with episodes of seizures in history, caution should be exercised with ZipsilaВ®.
Dysfunction of the liver. The experience with ziprasidone in patients with severe hepatic insufficiency is limited, so the drug should be used with caution in this group of patients.
Increased risk of cerebrovascular disorders among people with dementia. Possible increased risk of cerebrovascular disorders in patients with dementia. The drug ZipsilaВ® should be used with caution in patients with risk factors for stroke.
When ziprasidone is used, it is possible to develop thromboembolism, incl. thromboembolism of the pulmonary artery and deep vein thrombosis, the incidence of which is not established.
Influence on ability of management of motor transport and work with technical devices. The drug ZipsilВ® can cause drowsiness, dizziness, tremor, sedation, anxiety, and other side effects, and therefore, during the use of the drug, it is necessary to refrain from driving and potentially dangerous activities that require concentration and speed of psychomotor reactions.
OVERDOSE
The maximum, confirmed, single application of ziprasidone was 12800 mg. In this case, extrapyramidal disorders and lengthening of QT446 msec interval were noted. (without any known complications or negative effects on the cardiovascular system). In general, the most common symptoms in overdose are extrapyramidal disorders, drowsiness and anxiety.
Reduced pain sensitivity, convulsions or dystonic reactions in the head and neck area, due to an overdose, may create a risk of aspiration with induced vomiting.
Treatment: there is no specific antidote.
In case of acute overdose, it is necessary to provide airway patency, adequate ventilation and oxygenation of the lungs. Possible gastric lavage (after intubation, if the patient is unconscious) and the use of activated carbon in combination with laxatives. It is necessary to monitor the functions of the cardiovascular system, including continuous registration of the ECG in order to identify possible arrhythmias.
Hemodialysis is ineffective.
DRUG INTERACTION
Pharmacokinetic and pharmacodynamic studies with ziprasidone and drugs extending the QT interval were not performed. It is impossible to exclude the additive effect of ziprasidone and these drugs. In this regard, ziprasidone should not be used concomitantly with drugs that extend the QT interval (antiarrhythmic drugs IA and III classes, arsenic trioxide, halofantrine, levocetylmetadol, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron, meflochin, sertindole or cisapride ).
An in vivo study with dextromethorphan has shown that ziprasidone does not mediate through the isoenzyme CYP2D6 on the metabolism of dextromethorphan and its main metabolite dextrorphan.
Inhibitor of the isoenzyme CYP3A4 ketoconazole (400 mg / day) increases the concentration of ziprasidone in serum by less than 40%. At the expected T max ofziprasidone, the serum concentration of S-methyldihydroziprasidone increases approximately by 55%, and ziprasidone-sulfoxide by 8%. An additional prolongation of the QT interval was not observed. Changes in pharmacokinetics with the simultaneous use of potent inhibitors of the isoenzyme CYP3A4 have not been identified, so dose adjustment is not required.
When ziprasidone is used with serotonergic drugs, it is possible to develop a serotonin syndrome. Symptoms of serotonin syndrome: confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus, and diarrhea.
Cimetidine, a nonspecific inhibitor of the CYP isoenzyme, has no significant effect on the pharmacokinetics of ziprasidone.
The use of antacids containing aluminum and magnesium does not affect the pharmacokinetics of ziprasidone.
Benzatropin, propranolol, lorazepam do not affect the pharmacokinetic parameters of ziprasidone concentration in blood serum.
Does not affect the pharmacokinetics of lithium.
The simultaneous use of ziprasidone and carbamazepine at a dose of 200 mg 2 times per day for 21 days resulted in a decrease in ziprasidone concentration by approximately 35%.
Given the directional effect of ziprasidone on the central nervous system, care must be taken when it is combined with other drugs that depress the central nervous system, including alcohol.
The use of ziprasidone does not cause significant changes in the pharmacokinetics of estrogens (ethinylestradiol, CYP3A4 substrate) or progesterone.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
At temperatures not higher than 30 В° C, in the original packaging. Keep out of the reach of children.
Shelf life. 3 years. Do not use the drug after the expiration date.
