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Can cariprazine be used in pediatric patients?

No. Cariprazine has been approved for the treatment of schizophrenia in adults.1
However, a Paediatric Investigation Plan (PIP), a development plan aimed at ensuring that the necessary data are obtained through studies in children, has been submitted and approved by the European Medicines Agency’s Paediatric Committee (PDCO) to support the authorization of cariprazine for use in adolescent patients.2
Once the pediatric development has been completed, cariprazine will potentially be approved for the treatment of schizophrenia in adolescent patients. Preliminary data on the safety and dosing of cariprazine in adolescents has been published.3

References

  1. Reagila Summary of Product Characteristics (SmPC).
  2. Reagila Pediatric Plan. https://www.ema.europa.eu/en/documents/pip-decision/p/0105/2021-ema-decision-17-march-2021-refusal-modification-agreed-paediatric-investigation-plan_en.pdf
  3. Szatmári B, Barabássy Á, Harsányi J, et al. Cariprazine Safety in Adolescents and the Elderly: Analyses of Clinical Study Data. Front Psychiatry. 2020;11:61.
    https://pubmed.ncbi.nlm.nih.gov/32194443/

Can cariprazine be used in the elderly (over 65 years old)?

Adults over 65 years of age were not included in the cariprazine clinical studies1 due to safety considerations associated with antipsychotic use in the elderly, including increased risk of cardiovascular2 and cerebrovascular diseases,3 increased risk of mortality especially in dementia,2,3 increased risk of hepatic and renal impairment, and polypharmacy.4,5

Only 17 patients over 65 years of age were included in a Japanese study in the cariprazine group. No patients over 65 years of age were included in the other schizophrenia studies. No conclusions can be made due to the small number of patients.1

Cariprazine has not been studied in elderly patients with dementia and is not recommended for the treatment of elderly patients with dementia due to increased risk of overall mortality.3

Due to various comorbidities, use of all antipsychotics in the elderly is challenging.2,4 Although studies are not planned, the manufacturer is committed to gathering data on the elderly (risk management plan): data on elderly patients who experience side effects when treated with cariprazine is gathered and followed up. Preliminary data on the safety and dosing of cariprazine in elderly patients has been published.5

References

  1. Reagila European public assessment report (EPAR).
  2. Kheirbek RE, Fokar A, Little JT, et al. Association Between Antipsychotics and All-Cause Mortality Among Community-Dwelling Older Adults. J Gerontol A Biol Sci Med Sci, 2019, Vol. 74, No. 12, 1916–1921. doi: 10.1093/gerona/glz045
  3. Reagila Summary of Product Characteristics (SmPC).
  4. Maixner SM, Mellow AM, Tandon R. The efficacy, safety, and tolerability of antipsychotics in the elderly. J Clin Psychiatry. 1999;60 Suppl 8:29-41.
  5. Szatmári B, Barabássy Á, Harsányi J, et al. Cariprazine Safety in Adolescents and the Elderly: Analyses of Clinical Study Data. Front Psychiatry. 2020;11:61.
    https://pubmed.ncbi.nlm.nih.gov/32194443/

Are there plans for cariprazine approval in other indications in Europe, e.g. bipolar mania, bipolar depression, MDD?

The company is constantly evaluating important indications where cariprazine can be of benefit in the treatment of patients. At the moment, however, the only approved indication for cariprazine in the EU is treatment of schizophrenia.

Can cariprazine be used to treat Personality Disorders (e.g. Borderline)?

Cariprazine is not indicated for the treatment of personality disorders. Cariprazine has been used off label in Borderline Personality Disorder, as described in the published case report below.1

Reference

  1. Grant JE, Chamberlain SR. Cariprazine treatment of borderline personality disorder: A case report. Psychiatry Clin Neurosci. 2020;74(9):511-512.

Can cariprazine be used in autism spectrum disorder?

Cariprazine is not indicated for the use in autism spectrum disorder. Cariprazine has been used off label in autism spectrum disorder and intellectual disability disorder, as described in the published clinical report below.1

A clinical trial investigating the pharmacokinetics, safety, and tolerability of cariprazine in paediatric participants with autism spectrum disorder aged 5-17 years was completed in December 2021.2

Further US studies to examine the effects of cariprazine on irritability and social aspects of this indication are planned.

References

  1. Cohen LS, Pella C. Cariprazine in Autism Spectrum Disorder and Intellectual Disability Disorder. Global Journal of Intellectual & Developmental Disabilities 2019, 6(4), 71-75.
  2. ClinicalTrials.gov Identifier: NCT04382885. https://clinicaltrials.gov/ct2/show/NCT04382885

Does cariprazine cause prolactin increase?

No treatment-emergent adverse events related to elevation of prolactin levels were reported in cariprazine-treated patients in clinical studies. Mean decreases in prolactin levels from baseline were seen in all treatment groups, with the exception of the risperidone group. No adverse events of hyperprolactinemia were reported. Decreased prolactin levels were more pronounced in women than men in clinical short-term and open-label studies.1

It’s highly probable that the prolactin decreases observed were due to the previously taken antipsychotic causing hyperprolactinaemia that normalized once it was discontinued and cariprazine treatment was initiated.1

Antipsychotic-induced hyperprolactinaemia may be associated with inhibition of D2 receptors in the tuberoinfundibular system.2 Cariprazine is a partial agonist of the D2 receptor, which suggests that cariprazine is not expected to increase prolactin levels,3 and decreases in prolactin levels have been observed in clinical trials with cariprazine.1

There are no data on the time course of changes in prolactin levels for cariprazine. In licensed dose ranges, cariprazine has been shown to decrease prolactin mean levels from baseline to study endpoint in short-term and long-term studies in the range of -13.4 to -17.1 ng/ml.4

In long-term safety studies in patients with schizophrenia receiving cariprazine (1.9-9 mg/day), mean prolactin levels fell by 18.3 ng/ml at 48 weeks versus baseline. While part of this reduction may be related to some of the patients coming off a prolactin-increasing antipsychotic, the reduction is consistent with the activation of D2 receptors at/near the natural tonic level of dopamine by the partial agonist effect of the drug.3

Reported time to recovery when the D2 partial agonist aripiprazole was given as an adjunct for risperidone-induced hyperprolactinaemia ranges from within the first 2 weeks to 24 weeks.5-7
When a switching strategy for antipsychotic-induced hyperprolactinaemia employing aripiprazole was used, normalization was seen about 4 weeks after complete discontinuation of the previously taken antipsychotic.8,9 These different time frames for recovery are possibly due to differences in study populations and the speed of titration of aripiprazole.5

References

  1. Reagila European public assessment report (EPAR).
  2. Molitch ME. Dopamine agonists and antipsychotics. European Journal of Endocrinology 2020, 183, C11-C13.
  3. Roberts RJ, et al. Update on schizophrenia and bipolar disorder: focus on cariprazine. Neuropsychiatr Dis Treat. 2016 Jul 25;12:1837-42.
  4. Ivkovic J, et al. Effect of Brexpiprazole on Prolactin: An Analysis of Short- and Long-Term Studies in Schizophrenia. J Clin Psychopharmacol. 2019; 39 (1):13-19.
  5. Ranjbar F, et al. Adjunctive treatment with aripiprazole for risperidone-induced hyperprolactinemia. Neuropsychiatr Dis Treat. 2015;11:549-555. https://www.ncbi.nlm.nih.gov/pubmed/25784810
  6. Shores LE. Normalization of risperidone-induced hyperprolactinemia with the addition of aripiprazole. Psychiatry (Edgmont). 2005;2(3):42-45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004714/
  7. Lee BJ, et al. Effect of aripiprazole on cognitive function and hyperprolactinemia in patients with schizophrenia treated with risperidone. Clin Psychopharmacol Neurosci. 2013;11:60-66.
  8. Chen CY, Lin TY, Wang CC, Shuai HA. Improvement of serum prolactin and sexual function after switching to aripiprazole from risperidone in schizophrenia: a case series. Psychiatry Clin Neurosci. 2011;65:99-97.
  9. Lu ML, Shen WW, Chen CH. Time course of the changes in antipsychotic-induced hyperprolactinemia following the switch to aripiprazole. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1978-1981. https://www.sciencedirect.com/science/article/pii/S027858460800300X?via%3Dihub

Does cariprazine cause metabolic changes/metabolic syndrome?

Patients with schizophrenia are known to have an increased risk for cerebro- and cardiovascular disorders. This is further aggravated by an increased cardiovascular risk from antipsychotic treatment.1 Atypical antipsychotic drugs, including cariprazine, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile.2

In the cariprazine studies, the proportion of patients who experienced shifts from normal values at baseline to high values during treatment were:3

Cholesterol   cariprazine 8.4%placebo 9.3%
Triglyceridescariprazine 9.4%placebo 9.7%
Fasting plasma glucosecariprazine 3.4%placebo 2.0%

In clinical trials, glucose-related adverse reactions have been reported with cariprazine.4 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.4

Both increased and decreased body weight has been observed with cariprazine treatment.1 The mean increase in body weight from baseline to end of treatment in the short-term studies was 0.9 kg, while in the long term studies it was -0.3 kg at 26 weeks, 1.8 kg at 48 weeks and 0.6 kg up to 92 weeks. Overall, taking all studies into account, a slight weight increase of 0.9 kg with cariprazine was observed.1

In the long-term maintenance of effect study, there was no clinically relevant difference in change of body weight from baseline to end of treatment (1.1 kg for cariprazine and 0.9 kg for placebo).3 In the open-label phase of the study, during 20 weeks’ cariprazine treatment 9.0% of patients developed potentially clinically significant (PCS) weight gain (defined as an increase ≥ 7%) while during the double-blind phase, 9.8% of patients who continued with cariprazine treatment had PCS weight gain versus 7.1% of patients randomized to placebo after the 20-week open-label cariprazine treatment.3  In the negative symptom study, the mean change of body weight was -0.4 kg for cariprazine and +0.6 kg for risperidone5 and PCS weight gain was observed in 6.0% of the cariprazine group versus 7.4% of the risperidone group.3

There is a published report on a patient with metabolic syndrome that was reversed following a switch from olanzapine to cariprazine.6

References

  1. Reagila European public assessment report (EPAR).
  2. Vraylar prescribing information (USA). https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204370s006lbl.pdf
  3. Barabássy Á, et al. Safety and Tolerability of Cariprazine in Patients with Schizophrenia: A Pooled Analysis of Eight Phase II/III Studies. Neuropsychiatr Dis Treat. 2021;17:957-970.
  4. Reagila Summary of Product Characteristics (SmPC).
  5. Németh G, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet, 2017; 389 (10074):1103-1113.
  6. Halaris A, Wuest J. Metabolic Syndrome Reversal With Cariprazine. J Clin Psychopharmacol. 2019;39(4):413-416. https://www.ncbi.nlm.nih.gov/pubmed/31188240

Can cariprazine be co-administered with benzodiazepines, sedatives and other antipsychotics?

Clinical study protocols allowed co-administration of benzodiazepines and some other sedatives.
In one clinical study co-administration of another antipsychotic for up to 4 weeks with cariprazine was also allowed. No unexpected safety concern was detected while co-administering cariprazine with sedatives, benzodiazepines and antipsychotics.1

Cariprazine should be used with caution in combination with other centrally acting medicinal products and alcohol.2

Co-administration of cariprazine with 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) is contraindicated. Co-administration of cariprazine and strong or moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated.2

References

  1. Rancans E, Dombi ZB, Barabássy Á. Dosing Cariprazine Within and Beyond Clinical Trials: Recommendations for the Treatment of Schizophrenia. Front Psychiatry. 2022;12:770234.
  2. Reagila Summary of Product Characteristics (SmPC).

Is cariprazine effective in hostile/aggressive patients?

Aggressive behaviour and agitation can be seen in patients with schizophrenia. In a pooled post‐hoc analysis of the three 6‐week pivotal trials, significant improvement in hostility was seen in cariprazine- versus placebo-treated patients with schizophrenia.1

These effects were partially independent of PANSS positive symptom items and independent of sedation. The greatest effect of cariprazine was seen in patients with the highest level of baseline hostility. Results of this post-hoc analysis suggest that cariprazine may be an effective treatment for hostility in patients with schizophrenia.1

Reference

  1. Citrome L, Durgam S, Lu K, Ferguson P, Laszlovszky I. The effect of cariprazine on hostility associated with schizophrenia: post hoc analyses from 3 randomized controlled trials. J Clin Psychiatry. 2016;77(1):109-115. https://pubmed.ncbi.nlm.nih.gov/26845266/

How long does it take for cariprazine to have an effect on acute symptoms of schizophrenia?

In the short-term studies, cariprazine was already effective after 1 week of treatment at higher doses (3; 4,5 or 6 mg/day)1,2, and after 2 weeks at the lowest dose (1.5 mg/day).1

References

  1. Durgam S, Starace A, Li D, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014;152(2-3):450-457. https://pubmed.ncbi.nlm.nih.gov/24412468/
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