Cariprazine Hydrochloride

Registered South African indications:

• Acute relapses and maintenance therapy of schizophrenia

Registered South African contraindications

• Hypersensitivity to the active substance or to any of the excipients
• Concomitant administration of strong or moderate CYP3A4 inhibitors (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole, verapamil)
• Concomitant administration of strong or moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbitone, phenytoin, rifampicin, St. John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin)
• Pregnancy
• Lactation

Contraindications registered in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients
• Concomitant administration of strong or moderate CYP3A4 inhibitors (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole, verapamil)
• Concomitant administration of strong or moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin)

Recommendations in South Africa & other jurisdictions

Caution in the following patient groups

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Severe renal impairment (CrCl <30ml/min)
• Severe hepatic impairment (Child-Pugh score between 10 and 15)
• Elderly

Suicidal ideation and behaviour

• Risk of suicidality is inherent in psychotic illnesses, often manifesting early after initiation or change of antipsychotic therapy
• High-risk patients should be closely supervised during antipsychotic therapy

Akathisia and restlessness

• Common adverse reactions to antipsychotics include akathisia, characterized by a need for constant motion and actions like rocking or foot lifting
• Cariprazine should be used cautiously in patients prone to akathisia, with close monitoring especially early in treatment

Tardive dyskinesia

• Involuntary, potentially irreversible movements, particularly of the tongue or face, may occur, prompting consideration of treatment discontinuation

Parkinson's disease

• Antipsychotics like cariprazine may exacerbate symptoms in Parkinson's disease patients

Ocular symptoms/cataracts

• Lens opacity and cataracts observed in animal studies; human correlation not established but monitoring advised

Neuroleptic malignant syndrome (NMS)

• Potentially fatal, characterized by symptoms like hyperpyrexia and muscle rigidity; immediate discontinuation of cariprazine required on symptoms appearance

Seizures and convulsions

• Caution advised in patients with a history of seizures or conditions lowering seizure threshold

Elderly patients with dementia

• Not recommended for dementia in the elderly due to increased mortality risk

Risk of cerebrovascular accidents (CVA)

• Increased CVA risk noted in dementia patients, caution advised in patients with stroke risk factors

Cardiovascular disorders

• Blood pressure changes
  • Cariprazine may cause blood pressure changes; careful monitoring required in patients with known cardiovascular disease
• ECG changes
  • QT prolongation can develop in patients treated with antipsychotics. No significant QT prolongation observed; however, use cautiously in patients with a family history of QT prolongation and in patients treated with medicines that might cause QT prolongation
• Venous thromboembolism (VTE)

  • VTE cases reported; risk factors should be assessed and preventive measures taken

Hyperglycaemia and diabetes mellitus

• Patients with an established diagnosis of diabetes mellitus or patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should be monitored for serum glucose levels

Weight change

• Significant weight gain observed; regular monitoring advised

Excipients

• Contains Allura red AC, which may cause allergic reactions

Effects on ability to drive and use machines

• Cariprazine hydrochloride has an influence on the ability to drive and use machines, e.g. somnolence, fatigue, vertigo, dyskinesia. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with cariprazine hydrochloride does not affect them adversely

Forms avail. in SA and covered in this monograph: cap

South African registered indications and dosages

Acute relapses and maintenance therapy of schizophrenia

• Oral (cap): Initial: 1.5mg, once dly; Titration: Increase slowly in 1.5mg increments to a max of 6mg/day, as needed; Maintenance: Maintain the lowest effective dose as per clinical judgement

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Due to the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks, monitor for adverse reactions and treatment responses for several weeks after starting cariprazine and after each dosage change

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Switching from other antipsychotics to cariprazine: Gradual cross-titration should be considered, with gradual discontinuation of the previous treatment while initiating cariprazine

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Switching from cariprazine to another antipsychotic: No gradual cross-titration needed; initiate the new antipsychotic at its lowest dose while discontinuing cariprazine. Plasma concentration of cariprazine and its active metabolites declines by 50% in approximately 1 week

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Cariprazine is for oral use, to be taken once daily at the same time of the day. With or without food

Not established for use in children below 18 years

Pregnancy

Recommendations below are applicable to South Africa and other jurisdictions

• Contraindicated (South African recommendations)
• Caution; not recommended (Recommendations in other jurisdictions)
• There are no or limited amount of data from the use of cariprazine in pregnant women. Studies in animals have shown reproductive toxicity including developmental malformations in rats
• Cariprazine is not recommended during pregnancy and in women of childbearing potential not using effective contraception. After discontinuation of cariprazine treatment contraception should be used for at least 10 weeks due to the slow elimination of active moieties
• Neonates exposed to antipsychotics (including cariprazine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress or feeding disorder. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases, neonates have required intensive care unit support and prolonged hospitalization. Consequently, newborns should be monitored carefully
• Women of childbearing potential must be advised to avoid pregnancy while on cariprazine. Female patients of child-bearing potential must use highly effective contraceptive methods during treatment and for at least 10 weeks following the last dose of cariprazine

Breastfeeding

Recommendations below are applicable to South Africa and other jurisdictions

• Contraindicated (South African recommendations)
• Caution; not recommended (Recommendations in other jurisdictions)
• It is unknown whether cariprazine or its major active metabolites are excreted in human milk. Cariprazine and its metabolites are excreted in milk of rats during lactation. A risk to the newborns/infants cannot be excluded
• Breastfeeding should be discontinued during treatment with cariprazine

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• The effect of cariprazine on human fertility has not been evaluated. In rat studies lower female fertility and conception indices were observed

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate (CrCl 30-89ml/min): No dose adjustment recommended
• Severe (CrCl <30ml/min): Caution; not recommended

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate (Child Pugh score between 5-9): No dose adjustment recommended
• Severe (Child-Pugh score between 10 and 15): Caution; not recommended

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended
  Available data in elderly patients aged ≥ 65 years treated with cariprazine are not sufficient to determine whether or not they respond differently from younger patients. Dose selection for an elderly patient should be more cautious

Blood and Lymphatic System Disorders

Uncommon

• Anaemia
• Eosinophilia

Rare

• Neutropenia

Immune System Disorders

Rare

• Hypersensitivity

Endocrine Disorders

Uncommon

• Decreased blood thyroid stimulating hormone

Rare

• Hypothyroidism

Metabolism and Nutrition Disorders

Common

• Dyslipidaemia
• Increased weight
• Decreased appetite
• Increased appetite

Uncommon

• Abnormal blood sodium
• Diabetes mellitus
• Increased blood glucose

Psychiatric Disorders

Common

• Sleep disorders
• Insomnia
• Abnormal dreams/nightmare
• Circadian rhythm sleep disorder
• Dyssomnia
• Hypersomnia
• Initial insomnia
• Middle insomnia
• Nightmare
• Somnambulism
• Terminal insomnia
• Anxiety

Uncommon

• Suicidal behaviour
• Delirium
• Depression
• Decreased libido
• Increased libido
• Erectile dysfunction

Nervous System Disorders

Very common

• Akathisia
• Psychomotor hyperactivity
• Restlessness
• Parkinsonism
• Akinesia
• Bradykinesia
• Bradyphrenia
• Cogwheel rigidity
• Extrapyramidal disorder
• Gait disturbance
• Hypokinesia
• Joint stiffness
• Tremor
• Masked facies
• Muscle rigidity
• Musculoskeletal stiffness
• Nuchal rigidity

Common

• Sedation
• Dizziness
• Dystonia
• Blepharospasm
• Muscle tightness
• Oromandibular dystonia
• Torticollis
• Trismus
• Other extrapyramidal diseases and abnormal movement disorders
• Balance disorder
• Bruxism
• Drooling
• Dysarthria
• Gait deviation
• Glabellar reflex abnormal
• Hyporeflexia
• Movement disorder
• Restless legs syndrome
• Salivary hypersecretion
• Tongue movement disturbance

Uncommon

• Tardive dyskinesia
• Dyskinesia
• Choreoathetosis
• Grimacing
• Oculogyric crisis
• Protrusion tongue
• Dysaesthesia
• Lethargy

Rare

• Seizures/Convulsion
• Amnesia
• Aphasia

Frequency not known

• Neuroleptic malignant syndrome

Eye Disorders

Common

• Vision blurred

Uncommon

• Increased intraocular pressure
• Accommodation disorder
• Visual acuity reduced
• Eye irritation

Rare

• Cataract
• Photophobia

Ear and Labyrinth Disorders

Uncommon

• Vertigo

Cardiac Disorders

Common

• Tachyarrhythmia

Uncommon

• Cardiac conduction disorders
• Bradyarrhythmia
• Electrocardiogram QT prolonged
• Electrocardiogram T wave abnormal

Vascular Disorders

Common

• Hypertension

Uncommon

• Hypotension

Respiratory, Thoracic and Mediastinal Disorders

Uncommon

• Hiccups

Gastrointestinal Disorders

Common

• Vomiting
• Nausea
• Constipation

Uncommon

• Gastroesophageal reflux disease

Rare

• Dysphagia

Hepatobiliary Disorders

Common

• Hepatic enzymes increased

Uncommon

• Increased blood bilirubin

Frequency not known

• Toxic hepatitis

Skin and Subcutaneous Tissue Disorders

Uncommon

• Pruritus
• Rash

Musculoskeletal and Connective Tissue Disorders

Common

• Increased blood creatine phosphokinase

Rare

• Rhabdomyolysis

Renal and Urinary Disorders

Uncommon

• Dysuria
• Pollakisuria

Pregnancy, Puerperium and Perinatal Conditions

Frequency not known

• Neonatal drug withdrawal syndrome

General Disorders and Administration Site Conditions

Common

• Fatigue

Uncommon

• Thirst

• Strong or moderate inhibitors of CYP3A4
• Ketoconazole
• Boceprevir
• Clarithromycin
• Cobicistat
• Indinavir
• Itraconazole
• Nefazodone
• Nelfinavir
• Posaconazole
• Ritonavir
• Saquinavir
• Telaprevir
• Telithromycin
• Voriconazole
• Diltiazem
• Erythromycin
• Fluconazole
• Verapamil
• Strong and moderate inducers of CYP3A4
• Carbamazepine
• Phenobarbital
• Phenytoin
• Rifampicin
• Bosentan
• Efavirenz
• Etravirine
• Modafinil
• Nafcillin
• P-glycoprotein (P-gp) substrates
• Dabigatran
• Digoxin
• Centrally acting medicinal products

Other interactions

• Grapefruit juice
• Alcohol
• St. John's Wort

• Vital signs
  - Blood pressure
  - Orthostatics
  - Temperature
  - Pulse
  - Signs of infection
• Weight
• Height
• Body mass index (BMI)
• Fasting plasma glucose/HbA_1c
• Lipid panel
• Blood chemistries
  - Electrolytes
  - Renal function
  - Liver function
  - Thyroid stimulating hormone levels
• Prolactin

Specific cases may require

• Complete blood count

Additional observations

• Fall risk
• Tardive dyskinesia
• Mental status and alertness
• Adherence
• Metabolic syndrome history
• Monitor for adverse reactions and treatment response for several weeks

The mechanism of action of cariprazine hydrochloride is not fully known. However the therapeutic effect of cariprazine may be mediated through a combination of partial agonist activity at dopamine D_3, D₂ (Ki values of 0.085-0.3 nM versus 0.49-0.71 nM respectively) and serotonin 5-HT_1A receptors (Ki values of 1.4-2.6 nM), and antagonist activity at serotonin 5-HT_2B, 5-HT_2A and histamine H₁ receptors (Ki values of 0.58-1.1 nM, 18.8 nM and 23.3 nM, respectively). Cariprazine has low affinity for serotonin 5-HT_2C and adrenergic α 1 receptors (Ki values of 134 nM and 155 nM, respectively). Cariprazine has no appreciable affinity for cholinergic muscarinic receptors (IC₅₀ > 1000 nM). The two major active metabolites, desmethyl cariprazine and didesmethyl cariprazine have a similar in vitro receptor binding and functional activity profile as the parent active substance.