• Pharmacotherapeutic Group
  Other antipsychotics.
• Mechanism of Action
  Aripiprazole's efficacy in schizophrenia and Bipolar I disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypo activity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5HT1a and 5HT2a receptors and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors.
  • Pharmacokinetic Properties
  • Absorption
    Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of Aripiprazole. Distribution: Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, Aripiprazole and Dehydro-Aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin. Biotransformation: Aripiprazole is extensively metabolized by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of Aripiprazole, and N-dealkylation is catalyzed by CYP3A4. At steady state, Dehydro-Aripiprazole, the active metabolite, represents about 40% of Aripiprazole AUC in plasma. Elimination: The mean elimination half-lives for Aripiprazole are approximately 75 hours in extensive metabolizers of CYP2D6 and approximately 146 hours in poor metabolizers of CYP2D6. The total body clearance of Aripiprazole is 0.7 ml/min/kg, which is primarily hepatic. Following a single oral dose of labelled Aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchanged Aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the feces.

Due to its α1-adrenergic receptor antagonism, Schizopra has the potential to enhance the effect of certain antihypertensive agents. Given the primary CNS effects of Aripiprazole, caution should be used when Schizopra is taken in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation. If Schizopra is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. A gastric acid blocker, the H2 antagonist Famotidine, reduces Schizopra rate of absorption but this effect is deemed not clinically relevant. Schizopra is metabolized by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers. Quinidine and other CYP2D6 inhibitors: A potent inhibitor of CYP2D6 (quinidine) increased Schizopra AUC by 107%, while Cmax was unchanged. The AUC and Cmax of dehydro-Aripiprazole, the active metabolite, decreased by 32% and 47% respectively. Ketoconazole and other CYP3A4 inhibitors: A potent inhibitor of CYP3A4 (ketoconazole) increased Schizopra AUC and Cmax by 63% and 37%, respectively. The AUC and Cmax of dehydro- Aripiprazole increased by 77% and 43%, respectively. In CYP2D6 poor metabolizers, concomitant use of potent inhibitors of CYP3A4 may result in higher plasma concentrations of Aripiprazole compared to that in CYP2D6 extensive metabolizers. Carbamazepine and other CYP3A4 inducers: Concomitant administration of Carbamazepine, a potent inducer of CYP3A4, the geometric means of Cmax and AUC for Aripiprazole were 68% and 73% lower, respectively, compared to when Schizopra (30 mg) was administered alone. Similarly, for dehydro-Aripiprazole the geometric means of Cmax and AUC after Carbamazepine co-administration were 69% and 71% lower, respectively, than those following treatment with Schizopra alone.

• Schizopra is indicated for the treatment of schizophrenia in adults and in adolescents aged 15 years and older.
• Schizopra is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder.
• For the prevention of a new manic episode in adults who experienced predominantly manic episodes and whose manic episodes responded to Aripiprazole treatment.
• Schizopra is indicated for the treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older.

• Adults
• Schizophrenia
  The recommended starting dose for Schizopra is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals. Schizopra is effective in a dose range of 10 to 30 mg/day. The maximum daily dose should not exceed 30 mg. Manic episodes in Bipolar I Disorder: the recommended starting dose for Schizopra is 15 mg administered on a once-a-day schedule without regard to meals. Recurrence prevention of manic episodes in Bipolar I Disorder: Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status.
• Special populations
• Paediatrics population
  Other pharmaceutical formulations containing Schizopra are available and may be more suitable to perform any initial titration in paediatrics population. Schizophrenia in adolescents aged 15 years and older: the recommended dose for Schizopra is 10 mg/day administered on a once-a-day schedule without regard to meals. Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for Schizopra is 10 mg/day administered on a once-a-day schedule without regard to meals. Hepatic impairment: No dosage adjustment is required for patients with mild to moderate hepatic impairment. The maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment. Renal impairment: No dosage adjustment is required in patients with renal impairment.
• Elderly
  The effectiveness of Schizopra in the treatment of schizophrenia and Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant
• Gender
  No dosage adjustment is required for female patients as compared to male patients.
• Dose adjustments due to interactions
  When concomitant administration of potent CYP3A4 or CYP2D6 inhibitors with Aripiprazole occurs, the Schizopra dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, Schizopra dose should then be increased. When concomitant administration of potent CYP3A4 inducers with Aripiprazole occurs, the Schizopra dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the Schizopra dose should then be reduced to the recommended dose.

Occurring in at least 1/100 patients; uncommon adverse reactions are those occurring in at least 1/1,000 but less than 1/100 patients; rare adverse reactions are those occurring in less than 1/1,000 patients.

• Blood and Lymphatic System Disorders
  • Uncommon
    leukopenia, neutropenia, thrombocytopenia.
  • Rare
    eosinophilia, lymphadenopathy
• Cardiac Disorders
  • Uncommon
    bradycardia, palpitations; cardiopulmonary failure, myocardial infarction, cardiorespiratory arrest, atrioventricular block, extrasystoles, sinus tachycardia, atrial fibrillation, angina pectoris, myocardial ischemia.
  • Rare
    atrial flutter, supraventricular tachycardia, ventricular tachycardia.
• Ear and Labyrinth Disorders
  • Rare
    ear canal erythema, hyperacusis, vertigo positional, tinnitus.
• Endocrine Disorders
  • Rare
    early menarche.
• Eye Disorders
  • Uncommon
    dry eye; photophobia, diplopia, eyelid oedema, photopsia.
  • Rare
    eye redness, chromotopsia, conjunctivitis, eye disorder, eye movement disorder, gaze palsy, lacrimation increased.
• Gastrointestinal Disorders
  • Uncommon
    diarrhea, gastritis, dysphagia, gastro esophageal reflux disease, swollen tongue, esophagitis, hypo aesthesia oral.
  • Rare
    abdominal distension, abnormal faeces, eructation, faeces discolored, constipation, Gastrointestinal disorder, gastrointestinal pain, glossitis, lip dry, parotid gland enlargement, pruritus tongue discoloration, pancreatitis.
• Hepatobiliary Disorders
  • Rare
• Immune System Disorders
  • Rare
    decreased immune responsiveness, hypersensitivity.
• Infections and Infestations
  • Rare
    sinusitis, urinary tract infection, body tinea, gastroenteritis viral, herpes simplex, localized infection, lower respiratory tract infection, oral candidiasis, parotitis, gastroenteritis.
• Injury, Poisoning and Procedural Complications
  • Common Fall
  • Uncommon self-mutilation
  • Rare
    heat stroke, injury, muscle strain, clavicle fracture, femoral neck fracture, hip fracture, humorous fracture, mouth injury, open wound.
• Investigations
  • Common
    weight decreased, creatinine phosphokinase increased.
  • Uncommon
    Weight increased, blood creatine increased, heart rate increased, blood glucose increased, pyrexia, blood prolactin increased, blood urea increased, electrocardiogram QT prolonged, blood bilirubin increased, hepatic enzyme increased.
  • Rare
    electrocardiogram abnormal, urine output increased, blood creatine phosphokinase abnormal, orthostatic hypotension, blood urine present, electrocardiogram PR prolongation, electrocardiogram T wave inversion, eosinophil count increased, head lag abnormal, heart rate irregular, physical examination, urine ketone body present, white blood cell count increased, blood lactate dehydrogenase increased, glycosylated hemoglobin increased, gamma-glutamyl transferase increased.
• Metabolism and Nutrition Disorders
  • Uncommon
    Weight increased, blood creatine increased, heart rate increased, blood glucose increased, pyrexia, blood prolactin increased, blood urea increased, electrocardiogram QT prolonged, blood bilirubin increased, hepatic enzyme increased.
  • Rare
    hyperlipidemia, anorexia, diabetes mellitus (including blood insulin increased, carbohydrate tolerance decreased, diabetes mellitus non-insulin-dependent, glucose tolerance impaired, glycosuria, glucose urine, glucose urine present), hyperglycemia, hypokalemia, hypoglycemia, polydipsia; increased appetite, dehydration, hyponatraemia.
  • Rare
    diabetic ketoacidosis, hyperuricaemia.
• Immune System Disorders
  • Rare
    decreased immune responsiveness, hypersensitivity.
• Musculoskeletal and Connective Tissue Disorders
  • Uncommon
    muscle rigidity, musculoskeletal rigidity, muscle tightness, muscle spasms, muscular weakness, mobility decreased.
  • Rare
    bone pain, nuchal rigidity, sensation of heaviness, flank pain, jaw disorder, kyphosis, osteoarthritis, and rhabdomyolysis.
• Neoplasms Benign, Malignant and Unspecified (including Cysts and Polyps)
  • Rare
    oral neoplasm, skin papilloma.
• Nervous System Disorders
  • Common: co-ordination abnormal.
  • Uncommon
    memory impairment, cerebrovascular accident, hypokinesia, hypotonia, myoclonus, hypertonia, akinesia, bradykinesia, drooling, cogwheel rigidity, dystonia, disturbance in attention, dizziness postural, dysarthria, paraesthesia, Parkinsonism, psychomotor hyperactivity, hypoaesthesia, speech disorder, tardive dyskinesia.
  • Rare
    burning sensation, convulsion, depressed level of consciousness, dysgeusia, akinaesthesia, ataxia, bradykinesia, coma, dysphasia, facial palsy, judgment impaired, and loss of consciousness, migraine,neuroleptic malignant syndrome, paraesthesia circumoral, sleep phase rhythm disturbance, Grand Malconvulsion, and choreoathetosis, unresponsive to verbal stimuli.
• Psychiatric Disorders
  • Common
    suicidal ideation.
  • Uncommon
    aggression, loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self-injury, completed suicide, tic, homicidal ideation, depression, confusional state, nightmare, mania, abnormal dreams, hallucination auditory, nervousness, hallucination, apathy, thinking abnormal, and bruxism.
  • Rare
    catatonia, sleep walking, bradyphrenia, delirium, depressed mood, disorientation, euphoric mood, logorrhea, mental status changes, mood altered, panic attack, sleep disorder, blunted affect, cognitive deterioration, delusional perception, insomnia, eating disorder, emotional distress, impulsive behavior, asthenia, mood swings, psychomotor retardation, somatoform disorder.
• Renal and Urinary Disorders
  • Uncommon
    nocturia, polyuria, incontinence, urinary retention.
  • Rare
    proteinuria, bladder discomfort, chromaturia, enuresis, micturition urgency, oliguria, urethral discharge, urinary hesitation.
• Reproductive System and Breast Disorders
  • Uncommon
    erectile dysfunction, amenorrhea, breast pain, irregularmenstruation
  • Rare
    genital pruritus female, vulvovaginal discomfort, pelvic pain, breast discharge, sexual dysfunction, gynaecomastia, priapism.
• Respiratory, Thoracic and Mediastinal Disorders
  • Common
    nasal congestion, dyspnea, pneumonia aspiration.
  • Uncommon
    hiccups, epistaxis.
  • Rare
    dry throat, rhinorrhoea, sinus congestion, hoarseness, nasal dryness, painful respiration, paranasal sinus hyper secretion.
• Skin and Subcutaneous Tissue Disorders
  • Common
    rash (including erythematous, exfoliative, generalized, macular, maculopapular, popular rash, acneiform, allergic contact, exfoliative seborrheic dermatitis, neurodermatitis, and drug eruption),hyperhidrosis.
  • Uncommon
    pruritus, photosensitivity reaction, alopecia, urticarial.
  • Rare
    decubitus ulcer, face oedema, pemphigus, psoriasis, dry skin.
• Social Circumstances
  • Rare
    Smoker
• Vascular Disorders
  • Common
    hypertension
  • Uncommon
    hypotension, hot flush
  • Rare
    flushing, hyperaemia.
• Post-marketing Experience
  • Rare
    occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritis/ urticarial, or oropharyngea; spasm), and blood glucose fluctuation. Very rare occurrences of increased AST and increased ALT have been reported.
• Psychiatric Disorders
  • Uncommon
    Hyper sexuality
  • Unknown
    Pathological gambling, impulse-control disorders, obsessive-compulsive disorders, eating disorders.

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

• Suicidality
  Results of an epidemiological study suggested that there was no increased risk of Suicidality with Schizopra compared to other antipsychotics among adult patients with schizophrenia or bipolar disorder.
• Cardiovascular disorders
  Schizopra should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant.
• QT prolongation
  Schizopra should be used with caution in patients with a family history of QT prolongation.
• Neuroleptic Malignant Syndrome (NMS)
  If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic active substances, including Schizopra, must be discontinued.
• Seizure
  Schizopra should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.
• Dysphagia
  Schizopra and other antipsychotic active substances should be used cautiously in patients at risk for aspiration pneumonia.
• Effects on Fertility
  Disturbances of spermatogenesis were seen at 60 mg/kg/day and prostatic atrophy was seen at 40 and 60 mg/kg/day.
• Use in Pregnancy
  Treatment caused increased foetal mortality (100 mg/kg), decreased foetal weight (30 mg and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 100 mg/kg) and minor skeletal variations (100 mg/kg).At 30 mg/kg, maternal toxicity, slightly prolonged gestation, an increase in stillbirths, poor postnatal care/nursing, and decreases in pup weight (persisting into adulthood) and survival were seen.
• Non-Teratogenic Class Effect
  Neonates exposed to antipsychotic drugs (including Aripiprazole) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery.
• Use in Lactation
  Aripiprazole is excreted in breast milk. Patients should be advised not to breast-feed if they are taking Schizopra.
• Effects on Ability to Drive and Use Machines
  As with other antipsychotics, patients should be cautioned about operating hazardous machinery, including motor vehicles.

Hypersensitivity to the active substance