Zyprexa

Zyprexa is a psycholeptic drug that contains the active ingredient oxazepine.

Indications Zyprexa

It is used to quickly prevent the development of agitation reactions, as well as behavioral disorders in people suffering from schizophrenia or the occurrence of manic attacks (in situations where treatment by oral administration is inappropriate).

When the possibility of switching to oral use of the substance olanzapine arises, it is necessary to stop treatment with the drug in the form of an injection solution.

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Release form

Released as a lyophilisate for the preparation of injections in 10 mg vials. The pack contains 1 vial with powder.

Zyprexa Adera is an antipsychotic drug in powder form, from which injection suspensions are made. It is available in vials of 210, 300 or 405 mg. The powder comes with a vial of solvent (3 mg), 3 needles, and a syringe.

Zyprexa Zydis is available in dispersible tablets of 5 or 10 mg, in blister packs of 28 pieces.

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Pharmacodynamics

Olanzapine is an antipsychotic with antimanic action. This substance helps stabilize mood and has a wide range of activity, affecting various receptors. Preclinical tests have found that the component is synthesized with receptors of serotonin (types 5HT2A/2C, as well as 5HT3 with 5HT6), dopamine (types D1 with D2, and together with D3 with D4 and D5), acetylcholine (muscarinic M1-M5), and together with them with α1-adrenergic receptors and the H1-receptor of histamine.

When observing the behavior of animals that were pre-administered with olanzapine, it was discovered that this element has antagonism with respect to 5HT type serotonin receptors, and in addition to this, with respect to acetylcholine and dopamine receptors.

The element olanzapine has good synthesis with serotonin endings of the 5HT2 type (better than with dopamine endings of the D2 type) in vitro and in vivo tests. In addition, electrophysiological tests have demonstrated a selective decrease in the excitability of mesolimbic type dopaminergic neurons (A10) under the influence of the drug. However, a weak effect on the pathways of action related to motor skills - striatal (type A9) - was also noted.

The drug slows down avoidance (a conditioned reflex), which is a confirmation of its antipsychotic properties after use in lower doses than those that provoke the appearance of catalepsy (this is a manifestation of a negative motor reaction). Olanzapine is able to potentiate the response to stimuli during anxiolytic testing, which some antipsychotics cannot do.

After a single 10 mg dose of the drug, PET imaging in volunteers showed that the active ingredient in Zyprexa had a higher synthesis rate at 5HT2A terminals than at dopamine D2 terminals. In addition, after analyzing the images obtained, SPECT imaging showed that people with hypersensitivity to olanzapine had a lower synthesis rate at striatal D2 terminals than other people with sensitivity to respiridone and other antipsychotics (compared to people with sensitivity to clozapine).

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Pharmacokinetics

The component is well absorbed as a result of oral administration, reaching a plasma peak after 5-8 hours. Food does not affect the degree of absorption. The level of bioavailability of the drug in oral form in comparison with intravenous injections could not be established.

The plasma protein synthesis rates of olanzapine are approximately 93% when using dosages in the range of 7-1000 ng/ml. The component is mainly synthesized with albumin, and also with α1-acid glycoprotein.

The drug undergoes hepatic metabolism, where it is oxidized and conjugated. The main circulating breakdown product is the element 10-N-glucuronide, which does not pass through the BBB. Hemoproteins of the P450-CYP1A2 types, as well as P450-CYP2D6, help form the breakdown products N-desmethyl with 2-hydroxymethyl (these elements, compared with olanzapine, have significantly lower medicinal activity in vivo in animal tests). The predominant medicinal effect is due to olanzapine of the primary type.

When the drug was administered orally, its half-life in volunteers varied according to age and gender.

In elderly volunteers (aged 65 years and over), compared with younger subjects, a longer half-life was observed (51.8 vs. 33.8 hours, respectively), and the plasma clearance rate was reduced (17.5 vs. 18.2 L/hour, respectively). The pharmacokinetic variability in elderly volunteers was distributed within the same range as in younger subjects.

The half-life of the drug in women is longer than in men (36.7 and 32.3 hours, respectively), and the plasma clearance value is reduced (18.9 and 27.3 l/hour, respectively). However, the drug in a dose of 5-20 mg demonstrates a comparable level of safety profile - N = 467 (women) and N = 869 (men).

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Dosing and administration

The medicine must be administered intramuscularly. Subcutaneous or intravenous injections are prohibited.

The initial adult dosage for intramuscular injection is 10 mg (administered once). Taking into account the patient's condition, another injection (also no more than 10 mg) may be administered 2 hours after the procedure. The third dose (maximum 10 mg) may be administered at least 4 hours after the 2nd injection. The safety parameters of a daily dose exceeding 30 mg were not studied during clinical trials.

If there are indications for prolonging the treatment course, it is necessary to abandon intramuscular injections of the drug and use the oral form of olanzapine (in the amount of 5-20 mg) as soon as possible after deciding on the advisability of using this form of treatment.

Elderly patients.

For people over 60 years of age, the initial dosage should be 2.5-5 mg. Taking into account all clinical indications, the 2nd injection (its size is also within 2.5-5 mg) can be administered 2 hours after the 1st procedure. The number of injections in a 24-hour period is no more than 3; no more than 20 mg of the drug can be administered per day.

People with liver/kidney problems.

It is recommended to use reduced initial dosages (5 mg). If the patient has moderate liver failure, the initial dosage may be increased, but this should be done with caution.

Reduced initial dosages may be prescribed to people with a combination of individual factors (elderly people, women, non-smokers) that can reduce the metabolism of the drug. If it is necessary to increase the dose, this should be done with caution.

A method for preparing a medicinal solution for intramuscular injection.

The powder must be dissolved exclusively in sterile injection fluid using standard aseptic materials required for dissolving parenteral substances. The use of any other solvents is prohibited.

It is necessary to fill the syringe with sterile liquid (2.1 ml), and then inject it into the vial containing the lyophilisate.

After this, shake the contents of the container until the lyophilisate is completely dissolved, turning into a yellow liquid. The vial contains 11 mg of the active substance in the form of a 5 mg/ml solution (1 mg of the drug remains inside the syringe and the vial, so the patient is given a dose of 10 mg).

The injection volumes that yield the required dosages of the drug are listed below:

• injection of 2 ml – 10 mg of medicine;
• injection of 1.5 ml – 7.5 mg of medicine;
• a dose of the drug in the amount of 1 ml - 5 mg of the drug;
• injection of 0.5 ml – 2.5 mg of medicine.

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Use Zyprexa during pregnancy

There have been no carefully controlled and adequate tests of the effects of the active component of Zyprexa on pregnant women. During the period of using olanzapine, the patient must inform the attending physician about the onset of pregnancy or about its planning. Since at the moment the experience of using the drug in pregnant women is limited, its use during this period is allowed only in case of urgent need.

If a pregnant woman has used antipsychotics in the 3rd trimester (this includes olanzapine), the newborn may develop certain negative effects, including extrapyramidal disorders or withdrawal syndrome (after birth, the signs of these disorders may change in duration and strength). There have also been reports of hypotonia, a feeling of drowsiness or agitation, increased blood pressure, tremors, problems with feeding, or hyaline membrane disease. Because of this, it is necessary to carefully monitor the condition of the baby.

In healthy women taking olanzapine (during the study) during lactation, the substance was observed in the milk. The average dose that does not have a negative effect on the child is 1.8% of the dose taken by the mother (estimated in mg / kg). But in any case, it is not recommended to use the drug during lactation.

Contraindications

Main contraindications: intolerance to the active component and any additional elements of the drug, as well as a diagnosed probability of developing closed-angle glaucoma. There is also no information on the use of the drug in children. Zyprexa in the form of a lyophilisate for injection solutions is prohibited for use by adolescents and children (under 18 years of age), because there is only limited information regarding the effectiveness and safety of the drug in this category of patients.

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Side effects Zyprexa

Using the medicine may cause some side effects:

• manifestations in the area of general blood flow and lymph: leuko- or neutropenia or eosinophilia often occur. Thrombocytopenia is rarely observed;
• immune disorders: sometimes hypersensitivity develops;
• problems with nutrition and metabolic processes: mainly weight gain, less often there is an increase in appetite, an increase in sugar, cholesterol, and triglyceride levels, and in addition, glucosuria develops. Sometimes diabetes develops or worsens (rarely this leads to ketoacidosis or coma, as well as death). Hypothermia rarely develops;
• disorders in the nervous system: mainly a feeling of drowsiness develops. Parkinsonism, akathisia, dizziness or dyskinesia may often occur. Sometimes, due to a history or the presence of risk factors, epileptic seizures have developed; in addition, late-stage dyskinesia, dysarthria, dystonia (including the ocular symptom), and amnesia may sometimes develop. Withdrawal syndrome or NMS may occasionally occur;
• Cardiac disorders: prolongation of the QT interval and bradycardia are sometimes observed. Rarely, tachycardia/ventricular fibrillation occurs or sudden death may occur;
• disorders in the functioning of the cardiovascular system: mainly orthostatic collapse is observed. Thromboembolism is sometimes observed (this also includes pulmonary embolism or deep vein thrombosis);
• dysfunction of the respiratory system, mediastinum and sternum: sometimes nosebleeds occur;
• Gastrointestinal disorders: often there are short-term cholinolytic manifestations in a mild form (including dry mouth and constipation). Sometimes flatulence is observed. Pancreatitis develops occasionally;
• problems with the hepatobiliary system: often there is a temporary increase in liver transaminase levels (AST and ALT), especially at the initial stage of the course (proceeds without symptoms), and in addition, peripheral edema is observed. Rarely, hepatitis develops (also in the hepatocellular form) and liver disorder of cholestatic or mixed type;
• skin and subcutaneous lesions: rashes often appear. Sometimes alopecia or photosensitivity occurs;
• Disorders of the connective tissues, as well as the structure of muscles and bones: arthralgia often occurs. Rhabdomyolysis is rarely observed;
• manifestations in the area of the urinary organs and kidneys: sometimes there are problems with urination, as well as urinary retention/incontinence;
• disorders in the area of the mammary glands with reproductive organs: impotence often develops in men, and in addition, both men and women experience a decrease in libido. Sometimes men experience breast enlargement, and galactorrhea or amenorrhea in women is observed. Priapism occasionally occurs;
• systemic disorders: a feeling of fatigue often arises, swelling appears, asthenia or pyrexia develops;
• Test results and analyses: mainly the plasma prolactin level increases. Often the values of CPK, uric acid, alkaline phosphatase and GGT increase. Sometimes the total bilirubin level increases.

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Overdose

Signs of intoxication: mainly a feeling of excitement/aggressiveness, tachycardia, dysarthria, and in addition to this, a weakening of the level of consciousness and the development of extrapyramidal manifestations are observed. A state of coma is possible.

Other significant complications include the development of CNS, cardiopulmonary shock, cardiac arrhythmia, and coma. In addition, convulsions may occur, blood pressure may decrease/increase, and respiratory depression may occur. Fatalities were observed in cases of acute poisoning - the use of 450 mg of the drug, although there is information about survival in cases of acute intoxication using 2 g of the drug.

The drug has no specific antidote. In accordance with clinical symptoms, it is necessary to monitor vital signs of the body (among other things, support of the respiratory process, elimination of circulatory failure, as well as hypotension) and eliminate the disorders that have appeared. It is necessary to refuse the use of dopamine and epinephrine, as well as other sympathomimetics with properties characteristic of ß-agonists - due to the fact that ß-stimulation can increase hypotension.

To detect possible arrhythmia, it is necessary to monitor the CVS function indicators. It is necessary to monitor the condition of the victim and keep him under medical supervision until he has fully recovered.

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Interactions with other drugs

People who use medications that can increase blood pressure or suppress breathing or the nervous system should be given Zyprexa with caution.

Potential interactions following olanzapine injection.

When the drug is administered intramuscularly in combination with lorazepam, the feeling of drowsiness increases (compared to using these two drugs separately).

The administration of olanzapine by the intramuscular method together with a parenteral injection of a benzodiazepine is prohibited.

Potential interactions that may affect the efficacy of olanzapine.

Since the metabolism of the active substance Zyprexa is carried out with the participation of the CYP1A2 element, components that inhibit/activate this isoenzyme are capable of affecting the pharmacokinetics of oral olanzapine.

Induction of CYP1A2 activity.

When combined with carbamazepine and as a result of smoking, the clearance rate of olanzapine increased from low to moderate. This is unlikely to have a significant impact on the treatment process, but it is still recommended to monitor the drug indicators in order to increase its dose if necessary.

Slowing down the activity of the CYP1A2 element.

Fluoxamine, an inhibitor of the CYP1A2 component, reduces the clearance rates of the drug. Due to this, an average increase in its peak values after using fluoxamine is observed: in non-smoking women by 54%, and in smokers by 77%. The corresponding average increase in the AUC level of olanzapine is 52% and 108%. People using fluoxamine or any other inhibitor of the CYP1A2 element (for example, ciprofloxacin) need to coordinate with them reduced initial dosages of Zyprexa. If there is a need to use an inhibitor of the CYP1A2 element, an option with a reduced portion of olanzapine should be considered.

Medicines that inhibit the activity of the CYP2D6 element.

When using fluoxetine (a single dose of 60 mg or multiple doses of the same dose over 8 days), an average increase in peak olanzapine values (by 16%) and a decrease in average clearance values (by 16%) are observed. These factors are insignificant compared to individual differences between patients, which is why dose changes are often not required.

Decreased bioavailability.

When activated carbon is used, a decrease in the bioavailability of oral olanzapine is observed (by approximately 50-60%), so it is recommended to take it either 2 hours before using Zyprexa or 2 hours after using the drug.

Potential interactions of the drug with other drugs.

The drug can act as an antagonist with respect to the properties of indirect and direct dopamine agonists.

Combining the drug with antiparkinsonian drugs in people with dementia and shaking palsy is prohibited.

Olanzapine has an antagonist effect on α-1-adrenergic receptors. Individuals using drugs that can lower blood pressure (and have a mechanism of action other than antagonism on α-1-adrenergic receptors) should use them with caution in combination with olanzapine.

Since the drug can help reduce blood pressure, it is necessary to take into account that in combination with certain antihypertensive drugs it will potentiate their effect.

The drug is capable of demonstrating an antagonistic effect on the properties of dopamine agonists, as well as levodopa.

The drug does not change the pharmacokinetic characteristics of diazepam with its active breakdown product N-desmethyldiazepam, but the combined use of these agents potentiates orthostatic hypotension (compared to the use of each of these drugs separately).

Effect on QT interval length.

Zyprexa should be co-administered with drugs that can prolong the QT interval with extreme caution.

Storage conditions

Zyprexa should be kept out of the reach of children at temperatures no higher than 25°C.

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Special instructions

Reviews

Zyprexa receives a large number of positive reviews - almost all doctors say that the drug shows very good results when used for a long time in maintenance doses during outpatient treatment.

Among the negative reviews regarding the drug, the most common complaints are about the large number and high risk of developing side effects. People complain mainly about metabolic disorders and a high probability of developing diabetes.

Men note an increase in mammary glands, but this disorder goes away even without stopping treatment. Some patients suffered from dizziness, constipation, and dry mouth. There are also reviews that note the high price of the drug.

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Shelf life

Zyprexa in the form of a lyophilisate can be used for 3 years from the date of manufacture of the drug. However, the shelf life of the already prepared solution is only 1 hour.