Zipsila^® (Capsules) Instructions for Use

Marketing Authorization Holder

Krka-Rus, LLC (Russia)

ATC Code

N05AE04 (Ziprasidone)

Active Substance

Ziprasidone (Rec.INN registered by WHO)

Dosage Forms

	Zipsila®	Capsules 20 mg: 28, 30, 56, 60 or 90 pcs.
		Capsules 40 mg: 28, 30, 56, 60 or 90 pcs.
		Capsules 60 mg: 28, 30, 56, 60 or 90 pcs.
		Capsules 80 mg: 28, 30, 56, 60 or 90 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blister packs (3) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.

10 pcs. – blister packs (3) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.

10 pcs. – blister packs (3) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.

10 pcs. – blister packs (3) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

Pharmacological Action

Ziprasidone has a high affinity for dopamine D₂ receptors and a high affinity for serotonin 5HT_2A receptors.

According to positron emission tomography (PET) data, 12 hours after a single 40 mg dose, 80% of serotonin 2A receptors and more than 50% of D₂ receptors were blocked.

Ziprasidone also interacts with serotonin 5HT_2C, 5HT_1D, and 5HT_1A receptors, with affinity for these receptors comparable to or exceeding affinity for D₂ receptors.

Ziprasidone has moderate affinity for neuronal serotonin and norepinephrine transporters, exhibits moderate affinity for histamine H₁ and alpha₁-adrenergic receptors.

The affinity of ziprasidone for muscarinic M₁ receptors is negligible.

Ziprasidone is an antagonist of both serotonin 2A and dopamine D₂ receptors.

Ziprasidone is also a potent antagonist of 5HT_2C and 5HT_1D receptors and an agonist of 5HT_1A receptors.

It inhibits the neuronal reuptake of norepinephrine and serotonin.

Pharmacokinetics

Absorption. After oral administration of ziprasidone with food, C_max in plasma is usually reached in 6-8 hours.

The absolute bioavailability of a 20 mg dose is 60%.

Pharmacokinetic studies have shown that the bioavailability of ziprasidone increases to 100% when taken with food, so the drug is recommended to be taken with meals.

Distribution. V_d is approximately 1.1 L/kg.

Ziprasidone is more than 99% bound to blood proteins.

Biotransformation and excretion. T_1/2 of ziprasidone after oral administration is 6.6 hours.

Steady state is reached within 1-3 days.

The average clearance of intravenously administered ziprasidone is 5 ml/min/kg.

Approximately 20% of the dose is excreted by the kidneys and 66% is excreted in the bile through the intestines.

When taking therapeutic doses from 40 to 80 mg twice daily, the pharmacokinetic profile of ziprasidone is linear.

Ziprasidone is metabolized mainly by three pathways to form four main circulating metabolites: benzisothiazolepiperazine (BITP) sulfoxide, BITP sulfone, ziprasidone sulfoxide, and S-methyldihydroziprasidone.

Unchanged Ziprasidone accounts for approximately 44% of the total drug substance circulating in serum.

In vivo studies have established that conversion to S-methyldihydroziprasidone is the main metabolic pathway of the drug.

In vitro studies indicate that this metabolite is formed by aldehyde oxidase-catalyzed reduction followed by S-methylation.

Oxidative metabolism also occurs, mainly involving the CYP3A4 isoenzyme and potentially involving the CYP1A2 isoenzyme.

In vitro experiments, S-methyldihydroziprasidone and ziprasidone sulfoxide exhibited properties that may cause QTc interval prolongation.

S-methyldihydroziprasidone is predominantly eliminated from the body through the intestine via biliary excretion with minimal involvement of the CYP3A4 isoenzyme.

Ziprasidone sulfoxide is eliminated by renal excretion and secondary metabolism catalyzed by the CYP3A4 isoenzyme.

Special patient groups. Pharmacokinetic screening of patients did not reveal significant pharmacokinetic differences between smoking and non-smoking patients.

Given that renal clearance does not affect the total clearance of ziprasidone, no increase in its blood levels was observed when used in patients with varying renal function.

Exposure to 20 mg of ziprasidone twice daily for several days in patients with mild (creatinine clearance (CrCl) greater than 60 ml/min), moderate (CrCl 30-60 ml/min), and severe renal failure (requiring dialysis) was 146%, 87%, and 75% of the drug exposure in healthy volunteers (CrCl greater than 70 ml/min), respectively.

In mild or moderate hepatic impairment (Child-Pugh class A/B) caused by cirrhosis, serum concentrations of ziprasidone after oral administration were 30% higher, and T_1/2 increased by approximately 2 hours compared to healthy volunteers.

The effect of hepatic impairment on serum metabolite concentrations is unknown.

Indications

Schizophrenia and other psychotic states (treatment and prevention).

ICD codes

Dosage Regimen

Orally, with meals.

Treatment of schizophrenia

The recommended dose is 40 mg twice daily.

Subsequently, the daily dose can be adjusted according to the clinical picture and course of the disease and increased to the maximum – 160 mg/day (80 mg twice daily).

If necessary, the daily dose can be increased to the maximum within 3 days.

Prevention of schizophrenia

The minimum initial dose is recommended – 20 mg twice daily.

Elderly patients (over 65 years)

Dose adjustment is required for concomitant diseases and/or conditions limiting the use of ziprasidone (the minimum initial dose is recommended).

Renal impairment: no dose adjustment is required.

Hepatic impairment the dose of the drug should be reduced.

Adverse Reactions

Classification of the frequency of side effects (World Health Organization): very common > 1/10; common > 1/100, < 1/10; uncommon > 1/1000, < 1/100; rare >1/10000,< 1/1000; very rare < 1/10000, including isolated reports.

From the cardiovascular system: uncommon – palpitations, tachycardia, hypertensive crisis, increased blood pressure (BP), orthostatic hypotension, syncope; rare – isolated systolic or diastolic hypertension, labile BP.

From the senses: common – visual impairment; -uncommon: photophobia; rare – ear pain, amblyopia, conjunctival itching and dryness, eye discomfort.

From the digestive system: common – nausea, vomiting, constipation, dyspepsia, dry mouth, increased salivation; uncommon – diarrhea, dysphagia, gastritis, abdominal discomfort, tongue swelling, flatulence;

Metabolism and nutrition disorders: uncommon – increased appetite; rare – hypocalcemia.

From the musculoskeletal system: common – muscle rigidity; uncommon – muscle cramps, limb pain, joint stiffness; rare – trismus.

From the nervous system: very common – drowsiness, akathisia; common – dystonia, extrapyramidal disorders, tardive dyskinesia, parkinsonism (including cogwheel rigidity, bradykinesia, hypokinesia), tremor, dizziness, sedation, headache, restlessness, agitation, insomnia; -uncommon: generalized tonic-clonic seizures, ataxia, dysarthria, oculogyric crisis, attention impairment, hypertonia, tremor, sensory disturbances (hypoesthesia, paresthesia), lethargy, excitement, anxiety disorders, feeling of a lump in the throat, sleep disorder (nightmares), mania, hypomania; rare – serotonin syndrome, neuroleptic malignant syndrome, panic attacks, depressive syndrome, bradyphrenia, affective disorders; very rare – torticollis, facial nerve paresis, akinesia, hyperkinesia, restless legs syndrome;

From the genitourinary system: rare – urinary incontinence, dysuria, enuresis, erectile dysfunction, increased erection, galactorrhea, gynecomastia, anorgasmia, priapism.

From the respiratory system: uncommon – dyspnea.

From the skin: uncommon – angioedema, urticaria, skin rash, acne; rare – psoriasis, allergic dermatitis, alopecia, erythema, papular rash.

Laboratory parameters: uncommon – increased activity of “liver” enzymes in the blood; rare – prolongation of the QT interval on ECG, increased LDH activity, eosinophilia, lymphopenia.

General disorders: common – asthenia, weakness; -uncommon: gait disturbances.

Other thromboembolism, including pulmonary embolism, deep vein thrombosis, the frequency of which is not established.

Contraindications

• Hypersensitivity to ziprasidone or any component of the drug;
• Prolongation of the QT interval on the electrocardiogram (ECG), including congenital long QT syndrome;
• Myocardial infarction (acute, subacute stage);
• Decompensated chronic heart failure;
• Arrhythmia requiring the use of class IA and III antiarrhythmic drugs;
• Concomitant therapy with drugs that prolong the QT interval: arsenic trioxide, halofantrine, levacetylmethadol, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron, mefloquine, sertindole or cisapride;
• Pregnancy, lactation period;
• Age under 18 years;
• Congenital galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

With caution. Severe bradycardia, electrolyte disturbances (hypokalemia, hypomagnesemia), bipolar disorder, elderly age (over 65 years), history of seizures, severe hepatic impairment, risk of stroke, concomitant use of alcohol, thrombosis, due to the risk of thromboembolism.

Use in Pregnancy and Lactation

The drug Zipsila^® is not used during pregnancy and breastfeeding.

Use in Hepatic Impairment

Use with caution in severe hepatic impairment.

Use in Renal Impairment

Renal impairment: no dose adjustment is required.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Use with caution in elderly patients (over 65 years).

Special Precautions

QT interval. Ziprasidone causes mild to moderate, dose-dependent prolongation of the QT interval.

Therefore, the drug should not be used together with drugs that also prolong the QT interval.

Caution should be exercised when using the drug Zipsila^® in patients with severe bradycardia.

Electrolyte disturbances, such as hypokalemia or hypomagnesemia, increase the risk of malignant arrhythmia, so they must be identified before starting therapy with ziprasidone.

If the QT interval length is more than 500 msec, it is recommended to discontinue the use of the drug Zipsila^®.

Neuroleptic malignant syndrome (NMS). NMS is a rare, potentially dangerous condition associated with the use of antipsychotic drugs, including ziprasidone.

Symptoms of NMS: increased body temperature (hyperpyrexia), muscle rigidity, altered mental status, and autonomic nervous system instability (arrhythmia, BP fluctuations, tachycardia, profuse sweating, heart rhythm disturbance).

If NMS is detected, the drug Zipsila^® should be immediately discontinued.

Tardive dyskinesia. Long-term use of ziprasidone may cause the development of tardive dyskinesia and other extrapyramidal disorders.

Patients with bipolar disorders are especially predisposed to the development of these complications.

The frequency of these conditions increases with age and also depends on the duration of treatment with ziprasidone.

If signs and symptoms of tardive dyskinesia appear, it is necessary to either reduce the dose or discontinue the use of the drug Zipsila^®.

Seizures. Treatment with the drug Zipsila^® should be carried out with caution in patients with a history of seizures.

Liver function disorders. Experience with the use of ziprasidone in patients with severe hepatic impairment is limited, so the drug should be used with caution in this group of patients.

Increased risk of cerebrovascular events in persons with dementia. There may be an increased risk of cerebrovascular events in patients with dementia.

The drug Zipsila^® should be used with caution in patients with risk factors for stroke.

When using ziprasidone, thromboembolism may develop, including pulmonary embolism and deep vein thrombosis, the frequency of which is not established.

Effect on the ability to drive vehicles and operate machinery. The drug Zipsila^® may cause drowsiness, dizziness, tremor, sedation, restlessness, and other side effects, therefore, during the use of the drug, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require concentration and speed of psychomotor reactions.

Overdose

The maximum confirmed single use of ziprasidone was 12800 mg.

In this case, extrapyramidal disorders and prolongation of the QT interval to 446 msec (without identified complications or negative impact on the cardiovascular system) were noted.

In general, the most common symptoms of overdose are extrapyramidal disorders, drowsiness, and anxiety.

Reduced pain sensitivity, seizures, or dystonic reactions in the head and neck area, due to overdose, may create a risk of aspiration during induced vomiting.

Treatment there is no specific antidote.

In case of acute overdose, airway patency, adequate ventilation, and lung oxygenation should be ensured.

Gastric lavage (after intubation, if the patient is unconscious) and the use of activated charcoal in combination with laxatives are possible.

Monitoring of cardiovascular functions, including continuous ECG recording to detect possible arrhythmias, is necessary.

Hemodialysis is not very effective.

Drug Interactions

Pharmacokinetic and pharmacodynamic studies with ziprasidone and drugs that prolong the QT interval have not been conducted.

An additive effect of ziprasidone and these drugs cannot be ruled out.

In this regard, Ziprasidone should not be used simultaneously with drugs that prolong the QT interval (class IA and III antiarrhythmic drugs, arsenic trioxide, halofantrine, levacetylmethadol, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron, mefloquine, sertindole or cisapride).

An in vivo study with dextromethorphan showed that Ziprasidone does not have a mediated effect via the CYP2D6 isoenzyme on the metabolism of dextromethorphan and its main metabolite dextrorphan.

The CYP3A4 isoenzyme inhibitor ketoconazole (400 mg/day) increases the serum concentration of ziprasidone by less than 40%.

At the expected T_max of ziprasidone, the serum concentration of S-methyldihydroziprasidone increases by approximately 55%, and that of Ziprasidone sulfoxide by 8%.

No additional QT interval prolongation was observed.

No changes in pharmacokinetics were detected with the simultaneous use of potent CYP3A4 isoenzyme inhibitors, so dose adjustment of the drugs is not required.

When using ziprasidone with serotonergic drugs, serotonin syndrome may develop.

Signs of serotonin syndrome: confusion, agitation, increased body temperature, sweating, ataxia, hyperreflexia, myoclonus, and diarrhea.

Cimetidine, a non-specific inhibitor of CYP isoenzymes, does not have a significant effect on the pharmacokinetics of ziprasidone.

The use of antacids containing aluminum and magnesium does not affect the pharmacokinetics of ziprasidone.

Benztropine, propranolol, and lorazepam do not affect the pharmacokinetic parameters of ziprasidone serum concentration.

It does not affect the pharmacokinetics of lithium.

Concomitant use of ziprasidone and carbamazepine at a dose of 200 mg twice daily for 21 days led to an approximately 35% decrease in ziprasidone concentration.

Given the targeted effect of ziprasidone on the CNS, caution should be exercised when using it in combination with other drugs that depress CNS activity, including alcohol.

The use of ziprasidone does not cause significant changes in the pharmacokinetics of estrogens (ethinyl estradiol, a CYP3A4 substrate) or progesterone.

Storage Conditions

At a temperature not exceeding 30°C (86°F), in the original packaging. Keep out of reach of children.

Shelf Life

3 years. Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.