ARPADA

PATIENT INFORMATION LEAFLET

ARPADA

TRADE NAME

Arpada

INTERNATIONAL NONPROPRIETARY NAME

Aripiprazole

PHARMACEUTICAL FORM

Tablets.

Description:

Arpada 5 mg: white round tablets with “5” embossed on one side.

COMPOSITION

Arpada 5 mg

Each tablet contains

Active ingredient: aripiprazole 5 mg.

Excipients: lactose monohydrate, hydrohypropylcellulose, sodium starch glycolate, microcrystalline cellulose, magnesium stearate.

ATC CODE OF THE DRUG N05AX12

PHARMACOTHERAPEUTIC GROUP

Antipsychotic agent. Neuroleptic.

PHARMACOLOGICAL PROPERTIES PHARMACODYNAMICS

Arpada demonstrates antagonism to subtype D2 dopamine receptors in mesolimbic pathway, typical for neuroleptics, at the same time having the property of partial agonism towards the

same receptors in mesocortical pathway. Aripiprazole is a partial agonist (mixed agonist- antagonist) of receptors 5HT1 and D2, i.e. it excites the receptor in deficiency of the neuromediator and blocks it in its excess. The drug has the least affinity among all atypical antipsychotic agents towards adrenergic (α1), histamine (H1) and muscarinic (m1) receptors. Such a pharmacodynamic spectrum explains high medical effectiveness of aripiprazole in schizophrenia and bipolar disorders and low incidence and severity of side effects, including body weight gain nad locomotor disorders. The latter is of extraordinary importance in long-term treatment of psychoses.

It is supposed that the therapeutic effect of aripiprazole in schizophrenia is determined by the combination of partial agonist activity towards dopaminee D2 and serotonin 5HT1a receptors and antagonist activity towards serotonin 5HT2 receptors.

Aripiprazole has high in vitro affinity towards dopaminee D2 and D3 receptors, serotonin 5HT1a and 5HT2a receptors and moderate affinity towards dopaminee D4, serotonin 5HT2c and 5HT7, alpha1-adrenoreceptors and histamine H1 receptors. Aripiprazole is also characterized by moderate affinity to serotonin reuptake sites and absence of affinity to muscarinic receptors.

PHARMACOKINETICS

Activity of Arpada is predominantly determined by the parent substance aripiprazole and its main metabolite dehydroaripiprazole which ensures affinity to dopaminee D2 receptors, similar to affinity of the parent substance aripiprazole, and is 40% of that of the parent substance recovered in plasma. Average elimination half-life of aripiprazole is about 75 hours. Steady-state concentration is reached in 14 days. Accumulation of the drug in repeated administration is predictable. Parameters of aripiprazole pharmacokinetics in steady state are dose-proportional. No diurnal variations of distribution of aripiprazole and its metabolite dehydroaripiprazole have been revealed.

Aripiprazole is rapidly absorbed after oral intake, and the peak plasma concentration is achieved within 3-5 hours. Absolute bioavailability of Arpada tablets is 87%. Food intake does not affect bioavailability of aripiprazole.

Aripiprazole is intensively distributed in tissues with apparent distribution volume of 4.9 l/kg. In the therapeutic concentration of over 99% aripiprazole binds with serum proteins, mainly with albumin. Aripiprazole does not influence pharmacokinetics and pharmacodynamics of warfarin,

i.e. does nor displace warfarin from the link with blood proteins.

Aripiprazole is subjected to presystemic metabolism only to a negligible degree. Aripiprazole is metabolized in liver by three pathways: dehydration, hydroxylation and N-dealkylation. In vitro experiments show that dehydration and hydrohylation of aripiprazole are performed under the influence of enzymes CYP3A4 and CYP2D6, while N-dealkylation is catalyzed by the enzyme CYP3A4. Aripiprazole is the main component of the drug in blood. In steady state the area under the curve “concentration of the drug – time” (AUC) of dehydroaripiprazole is about 39% of the AUC of aripiprazole in plasma.

After a single dose administration of labeled [14C] aripiprazole about 27% and 60% of radioactivity are recovered in urine and in faeces, respectively. Less than 1% of unchanged aripiprazole is recovered in urine and about 18% of the administered dose is excreted in the unchanged form with faeces. Total clearance of aripiprazole is 0.7 ml/min/kg, mainly due to hepatic excretion.

THERAPEUTIC INDICATIONS

schizophrenia: acute attacks and supportive therapy;

type I bipolar disorder: manic episodes and supportive therapy in order to prevent recurrent attacks in patients with type I bipolar disorder with a recent manic or mixed episode;

addition to antidepressant therapy in a heavy depressive disorder.

DOSAGE AND ADMINISTRATION

Tablets should be administered orally.

Schizophrenia: the recommended initial dose is 10 or 15 mg once daily regardless the timing of meals, the supportive dose is 15 mg once daily. Clinical studies demonstrated efficiency of the drug in doses of 10-30 mg daily. The maximum daily dose should not exceed 30 mg.

Manic episodes in type I bipolar disorder: the recommended initial dose is 15 mg once daily regardless the timing of meals as monotherapy or combination therapy. The maximum daily dose should not exceed 30 mg.

Prevention of recurrent manic episodes in type I bipolar disorder: patients receiving aripiprazole as monotherapy or combination therapy continue treatment with the same dose. Daily dose adjustment, including dose reduction, should be considered according to the clinical status.

As addition to antidepressant therapy in a heavy depressive disorder Arpada should be prescribed in an initial dose of 5 mg daily. If necessary and well tolerated, the daily dose can be increased weekly by 5 mg to the maximum of NMT 15 mg daily.

Duration of treatment should be the minimum one required for control of symptoms and should not exceed 12 weeks. Administration of the daily dose of 30 mg is associated with a significant increase in incidence of side effects, therefore the daily dose of 10 mg should be exceeded only in exceptional cases and under close monitoring of the clinical picture.

Patients with renal failure

No dose adjustment in administration of the drug to patients with renal failure is required.

Patients with hepatic failure

No dose adjustment in administration of the drug to patients with hepatic failure is required.

Elderly patients (over 65 years)

No dose adjustment is required.

Influence of the gender of the patient on dosage regimen Dosage regimen is the same for patients of both genders. Influence of smoking on dosage regimen

Dosage regimen is the same for smoking and non-smoking patients.

Dosage in concomitant therapy

In concomitant administration of Arpada and potent inhibitors of isoenzyme CYP3A4 (ketoconazole, clarythromycin) the dose of Arpada should be reduced by half. In withdrawal of isoenzyme CYP3A4 inhibitors the dose of Arpada should be increased.

In concomitant administration of Arpada and potent inhibitors of isoenzyme CYP2D6 (quinidine, fluoxetine, paroxetine) the dose of Arpada should be reduced at least by half. In withdrawal of isoenzyme CYP2D6 inhibitors the dose of Arpada should be increased.

Arpada should be administered without alteration of the dosage regimen if it is prescribed as additional therapy in patients with a heavy depressive disorder.

In concomitant administration of Arpada and potent inhibitors of isoenzymes CYP2D6 (quinidine, fluoxetine, paroxetine) and CYP3A4 (ketoconazole, clarythromycin) the dose of Arpada should be reduced by ¾ (i.e. to 25% of the usual dose). In withdrawal of inhibitors of isoenzyme CYP2D6 and/or CYP3A4 the dose of Arpada should be increased.

In concomitant administration of Arpada and potent, moderate or weak inhibitors of isoenzymes CYP2D6 and CYP3A4 the dose of Arpada can be initially reduced by ¾ (i.e. to 25% of the usual dose) and then increased in order to achieve the optimal clinical result.

When Arpada is prescribed to patients with low activity of isoenzyme CYP2D6, the dose of Arpada should be initially reduced by half and then increased in order to achieve the optimal clinical result. In concomitant administration of Arpada and a potent inhibitor of isoenzyme CYP3A4 in patients with low activity of isoenzyme CYP2D6 the dose of Arpada should be reduced by ¾ (i.e. to 25% of the usual dose).

In concomitant administration of Arpada and potential inducers of isoenzyme CYP3A4 (carbamazepine) the dose of the drug should be increased twofold. In withdrawal of inducers of isoenzyme CYP3A4 the dose of Arpada should be reduced to 10-15 mg.

CONTRAINDICATIONS

hypersensitivity to aripiprazole or another component of the drug;

children and adolescents aged under 18.

SIDE EFFECTS

The parameters of incidence of side effects used below are determined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000).

Cardiovascular disorders: common – orthostatic hypotension, tachycardia; uncommon – bradycardia, palpitations, myocardial infarction, prolonged QT interval, cardiac arrest, hemorrhages, atrial fibrillation, heart failure, AV block, myocardial ischaemia, deep vein thrombosis, phlebitis, extrasystole; rare – vasovagal syndrome, atrial flutter, thrombophlebitis, intracranial hemorrhage, brain ischaemia; very rare – syncope, increased arterial pressure.

Gastrointestinal tract disorders: very common – nausea, loss of appetite; common – increased appetite (in treatment of depression in combination with antidepressants), dyspepsia, vomiting, constipation, hypersecretion of saliva, mouth dryness, heaviness in abdomen, diarrhea; uncommon – gastroenteritis, difficult swallowing, flatulence, gastritis, tooth decay, gingivitis, hemorrhoid, gastroesophageal reflux, gastrointestinal hemorrhages, periodontal abscess, tongue edema, fecal incontinence, colitis, rectal hemorrhages, stomatitis, oral mucosa ulcers, cholecystitis, faecal impaction, oral mucosa candidiasis, belching, gastric ulcer; rare – esophagitis, bleeding gums, tongue inflammation, hematemesis, intestinal hemorrhages, duodenal ulcer, cheilitis, liver enlargement, intestinal perforation; very rare – increased activity of alanine aminotransferase (ALT) and aspartat aminotransferase (AST), hepatitis, jaundice, pancreeatitis, dysphagia.

Immune system disorders: very rare – allergic reactions (anaphylaxia, angioneurotic edema, itching and urticaria), laryngospasm.

Locomotor system disorders: common – arthtralgia, muscle rigidity; uncommon – myasthenia, arthritis, arthrosis, muscle weakness, muscle spasms, bursitis; very rare – increased activity of creatine phosphokinase, rhabdomyolysis, tendinitis, tenobursitis, myalgia.

Nervous system disorders: very common – insomnia, somnolence, headache, akathisia; common

dizziness, tremor, extrapyramidal syndrome, psychomotor excitation, depression, nervousness, hostility, suicidal thoughts, maniac thoughts, mental confusion, resistance to performance of passive movements (tooth wheel syndrome), lethargy, decreased attention, sedation; uncommon

dystonia, muscle twitching, paresthesias, tremor of extremities, impotence, bradykinesia, increased/decreased libido, panic reactions, apathy, poor memory, stupor, amnesia, stroke, hyperactivity, depersonalization, dyskinesia, restless legs syndrome, myoclonus, depressed mood, increased reflexes, retarded intellectual function, hypersensitivity to irritants, eye-moving reaction disorder; rare – delirium, euphoria, bucoglossal syndrome, akinesia, depression of consciousness up to loss of consciousness, inhibited reflexes, compulsive thoughts, malignant neuroleptic syndrome; very rare – speech disorder, convulsions.

Respiratory system disorders: common – dyspnea, pneumonia; uncommon – epistaxis, hiccup, laryngitis; rare – blood spitting, increased expectoration, dry nasal mucosa, lung edema, pulmonary embolism, hypoxia, respiratory failure, apnoe; very rare – aspiration pneumonia.

Skin and subcutaneous tissue disorders: common – skin dryness, itching, skin ulcers; uncommon

acne, vesiculobullous (blistery) rash, eczema, alopecia (loss of hair), psoriasis, seborea; rare – maculopapular rash, exfoliative dermatitis, urticaria, hyperhydrosis.

Sensory organ disorders: common – blurred vision, photophobia, ear pain; uncommon – eye dryness, eye pain, tinnitus, otitis media, cataract, loss of taste, blepharitis; rare – increased lacrimation, frequent blinking, otitis externa, ambliopia, deafness, diplopia, intraocular hemorrhages.

Urogenital system disorders: uncommon – cystitis, frequent urination, leukorea, hematuria, disuria, amenorea, premature ejaculation, vaginal hemorrhage, vaginal candidiasis, renal failure, uterine hemorrhage, menorrhagia, albuminuria, renal calculi, nicturia, polyuria, uriesthesia; rare – pain in the mammary gland, cervicitis, galactorea, anorgasmia, burning sensation in urethra and genitals, glucosuria, hynecomastia (breast augmentation in males), painful erection; very rare – urinary incontinence, urine retention, priapism.

Other: common – asthenia, fatigue, flu-like syndrome, body shivering; uncommon – peripheral edema, facial edema, malaise, photophobia, mandibular pain, chill, mandibular rigidity, abdomen distension, chest strain; rare – throat pain, back rigidity, heaviness in the head, candidiasis, throat rigidity, Mendelson’s syndrome, heat stroke; very rare – temperature regulation disorder, pyrexia, chest and neck pain.

Metabolic and nutrition disorders: common – body weight loss; uncommon – dehydration, edema, hypercholesterolemia, hypokalemia, hyperlipidemia, hypoglycemia, thirst, increased blood urea, increased alkaline phosphatase level, iron-deficiency anemia, increased lactate dehydrogenase level, obesity; rare – hyperkalemia, gout, hypernatremia, cyanosis, urine acidification; vary rare – hyponatremia, increased ALT activity, increased AST activity, increased activity of creatine phosphokinase, anorexia, hyperglycemia, diabetic ketoacidosis, diabetic hyperosmolar coma.

SPECIAL INDICATIONS

Suicide attempts

Inclination to suicidal thoughts and attempts in characteristic of patients with psychosis, bipolar disorder and a heavy depressive disorder, therefore drug therapy should be combined with close medical control. Arpada should be prescribed in the minimum amount sufficient for treatment; this reduces the risk of overdose. Administration of antidepressants, according to the data of clinical studies, increases the risk of suicidal thoughts and attempts in children, adolescents and young adults with depression and other psychotic disorders. Therefore extreme caution should be exercised in administration of antidepressants, including in the form of combination therapy with antidepressants and Arpada, for treatment of children, adolescents and young adults. Increase in suicidal thoughts and behavior has not been observed in patients aged over 24; patients over 65 years old demonstrated reduction in incidence of this side effect.

Late dyskinesia

Risk of development of late dyskinesia increases with prolongation of neuroleptic therapy, therefore if symptoms of late dyskinesia appear in the condition of Arpada administration the dose of the drug should be reduced or it should be withdrawn. After termination of therapy these symptoms can temporarily increase or appear for the first time.

Malignant neuroleptic syndrome

A life-threatening complex of symptoms has been described during treatment with neuroleptics, including aripiprazole; this complex is known as malignant neuroleptic syndrome (MNS). The syndrome is manifested with hyperhyrexia, muscle rigidity, psychic disorders and unstable vegetative nervous system (irregular pulse and arterial pressure, tachycardia, sweating and heart arrhythmias). Moreover, increased activity of creatine phosphatase, myoglobinuria (rhabdomyolysis) and acute renal failure are sometimes observed. In case if MNS symptoms or unexplainable fever occur all nauroleptics, including Arpada, should be withdrawn.

Convulsions

As well as other neuroleptics, aripiprazole shoud be administered with caution in patients with history of convulsions and risk of development of these.

Psychoses associated with senile dementia and Alzheimer’s disease

Risk of lethal outcome increases in patients with psychoses associated with senile dementia in treatment with atypical neuroleptics. Psychoses in patients over 65 years old with Alzheimer’s disease were accompanied with cardiovascular system disorders: infarction, transient ischaemic disorder of cerebral circulation, including with lethal outcome. Administration of Arpada in

psychoses associated with senile dementia and in elderly patients with Alzheimer’s disease is not recommended.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in isolated cases pronounced and accompanied with ketoacidosis or hyperosmolar coma with lethal outcome, was observed in patients administering atypical neuroleptics. Though relation between administration of atypical neuroleptics and hyperglycemic disorders remains unclear, patients with diagnosed diabetes mellitus should regularly measure blood glucose during treatment with atypical neuroleptics. Patients with risk factors of diabetes mellitus (obesity, family history of diabetes mellitus) should measure blood glucose in the beginning of treatment with atypical neuroleptics and regularly during therapy. Patients administering atypical neuroleptics require constant monitoring of hyperglycemia symptoms, including increased thirst, frequent urination, polyphagia, weakness; special attention should be paid to patients with diabetes mellitus and risk factors of its development.

Leucopenia, neutropenia, agranulocytosis

It is known that neuroleptics, including aripiprazole, can induce temporary alterations of blood picture – leukopenia, neutropenia and agranulocytosis. Risk factors include low concentration of white blood cells in the patient before treatment and leukapenia and neutropenia induced with other drugs. Blood picture in such patients should be regularly controlled, especially during the first months of treatment with Arpada. In a clinically significant reduction in white blood cell concentration of unclear etiology withdrawal of Arpada should be considered.

Close control is required for patients with clinically significant neutropenia in order to reveal fever or other signs of infection for immediate beginning of proper treatment. In severe neutropenia (neutrophil count below 1000/mm3) treatment with Arpada is interrupted until blood picture is normalized.

Cardiovascular diseases

Due to risk of development of orthostatic hypotension aripiprazole should be administered with caution in patients with cardiovascular diseases (myocardial infarction, ischaemic heart disease; heart failure, history of heart conductivity disorders), cerebral circulation disorders or conditions predisposing to arterial hypotension (dehydration, hypovolemia, therapy with antihypertensive agents).

Cognitive and locomotor disorders

As well as other neuroleptics, Arpada can induce cognitive and locomotor disorders. Particularly, clinical studies of Arpada revealed cases of somnolence and retardation. During treatment patients should abstain from driving and operating dangerous mechanisms.

Thermoregulation disorder

It is known that neuroleptics can induce thermoregulation disorder. This should be borne in mind when prescribing Arpada to patients with increased risk of overheating due to intensive physical exercise, high environmental temperature, administration of drugs with m-cholinoblocking activity, dehydration.

Dysphagia

Cases of esophageal peristalsis disorders and the resulting aspiration pneumonia have been observed during treatment with neuroleptics.

Exercise caution prescribing the drug to patients with risk factors of development of aspiration pneumonia.

Risk of development of venous thromboembolism

Administration of neuroleptics, including Arpada, can be associated with risk of development of venous thromboembolism. Due to this risk factors of this complication should be revealed before prescription of Arpada and during treatment with the drug. If necessary, measures should be taken in order to prevent development of venous thromboembolism.

INFLUENCE ON ABILITY TO DRIVE AND OPERATE OTHER MECHANISMS

As well as in case with other neuroleptics, in prescription of aripiprazole the patient should be warned of the danger of operating with moving mechanisms and driving.

PREGNANCY AND LACTATION

No adequate and strictly controlled studies in pregnant women have been performed. The drug can be administered during pregnancy only if potential benefit for the mother outweighs potential risk for the fetus.

Aripiprazole penetrates in breast milk, therefore breast feeding during treatment with the drug is not recommended.

PEDIATRIC USE

The drug is contraindicated to children and adolescents aged under 18 years.

DRUG INTERACTIONS

The mechanism of action of aripiprazole is related to influence on the central nervous system, which should be borne in mind in concomitant administration with other drugs with central action.

Due to antagonistic action towards α1-adrenoreceptors, aripiprazole can increase the effect of antihypertensive drugs.

Exercise caution in concomitant administration of aripiprazole and drugs prolonging the QT interval or causing electrolyte imbalance.

Aripiprazole does not influence pharmacokinetics and pharmacodynamic of warfarin and does not displace warfarin from the link with blood proteins.

The Н2-histamine receptor blocker famotidine, strongly inhibiting secretion of hydrochloric acid in the stomach, reduces the speed of aripiprazole absorption, but this does not influence the clinical effect of aripiprazole.

Various pathways of aripiprazole metabolism are known, including those involving isoenzymes CYP2D6 and CYP3A4. Studies in normal adults showed that potent inhibitors of isoenzymes CYP2D6 (quinidine) and CYP3A4 (ketoconazole) influenced pharmacokinetics of aripiprazole, therefore doses of aripiprazole should be reduced if it is used in various combinations with inhibitors of isoenzymes CYP3A4 and CYP2D6. In concomitant administration of aripiprazole and weak inhibitors of isoenzymes CYP3A4 (diltiazem, escitalopram) or CYP2D6 a small increase in blood aripiprazole concentration can be expected.

Due to the fact that isoenzyme CYP1A is not involved in aripiprazole metabolism, smoking does not affect pharmacokinetics and the effect of aripiprazole.

In administration of aripiprazole concomitantly with carbamazepine, a potent inducer of isoenzyme CYP3A4, aripiprazole metabolism increases, therefore its dose should be adjusted. Similar effect of other potent inhibitors of isoenzymes CYP3A4 and CYP2D6 can be expected.

Aripiprazole metabolism in vitro does not involve isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1, due to which interaction of the drug with medicines and other factors (e.g., smoking) able to inhibit or activate these enzymes is unlikely. Concomitant administration of lithium or valproic acid preparations with 30 mg of aripiprazole had no clinically significant influence on pharmacokinetics of aripiprazole.

In clinical studies aripiprazole in the doses of 10-30 mg had no significant influence on metabolism of substrates of isoenzymes CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin) and CYP3A4 (dextromethorphan). Moreover, aripiprazole and its main metabolite dehydroaripiprazole did not alter metabolism with the use of isoenzyme CYP1A2 in vitro. Clinically significant influence of aripiprazole on drugs metabolized with these isoenzymes is unlikely.

No alterations of lamotrigine pharmacokinetics were observed in concomitant administration of aripiprazole (10-30 mg daily) and lamotrigine (100-400 mg daily) in patients with bipolar disorder, therefore adjustment of its dose is not required. Aripiprazole had no influence on

pharmacokinetics of escitalopram and venlafaxine in normal subjects, therefore no odse correction is required for these drugs in concomitant administration of aripiprazole.

During administration of aripiprazole in patients with a heavy depressive disorder concomitantly with fluoxetine (20-40 mg daily), paroxetine (37.5-50 mg daily) and sertraline (2-20 mg daily) no significant alterations of antidepressant concentrations in plasma were revealed.

Alcohol intake during treatment with aripiprazole can potentiate the sedative effect of the drug, therefore it should be avoided.

OVERDOSE

Clinical studies describe cases of accidental or deliberate overdose of aripiprazole with administration of a single dose up to 1260 mg, which were nor associated with lethal outcome. Symptoms of aripiprazole overdose included nausea, vomiting, asthenia, diarrhea and somnolence. Postmarketing experience of administration of a single dose up to 450 mg of aripiprazole indicates possible development of tachycardia. Moreover, cases of overdose of aripiprazole in children (administration of up to 195 mg) were described. Potentially dangerous symptoms of overdose include extrapyramidal disorders and transitory loss of consciousness.

Overdose requires supportive therapy, provision of adequate patency of airways, oxygenation, effective lung ventilation and symptomatic treatment. Drug reactions should be borne in mind. Monitoring of heart functioning with ECG registration for detection of arrhythmias should be started immediately. After proved or supposed overdose of aripiprazole close medical observation until complete disappearance of all symptoms is required.

Activated charcoal (50 g), administered 1 hour after administration of aripiprazole, reduced AUC and Cmax of aripiprazole by 51 and 41%, respectively, which allows to recommend its use in overdose.

Though there are no reliable data on the use of hemodialysis in overdose of aripiprazole, benefit from this method is unlikely, as aripiprazole is not excreted via idneys in the unchanged form and is to a large extent bound with plasma proteins.

PACKAGING

Tablets. 7 tablets in a blister.

4 blisters together with a leaflet in a carton box.

STORAGE CONDITIONS

Store in a dry place at temperature not exceeding 25°С.

Keep out of reach of children!

SHELF LIFE

3 years from the date of manufacture. Do not apply after the expiry date.

SALES TERMS

Sold under prescription.

MANUFACTURER

The holder of trade mark and marketing authorization is