Summary

• Prior to initiating INVEGA TRINZA in adults for the treatment of schizophrenia, it is important to establish adequate treatment with INVEGA SUSTENNA for at least 4 months. In order to establish a consistent maintenance dose, it is recommended that the last 2 doses of INVEGA SUSTENNA be the same dosage strength prior to initiating INVEGA TRINZA.¹
• INVEGA HAFYERA is indicated for the treatment of schizophrenia in adults after they have been adequately treated with either INVEGA SUSTENNA for at least 4 months or INVEGA TRINZA following at least one 3-month injection cycle.²
• There is no systematically collected data for the management of breakthrough psychotic symptoms for patients treated with INVEGA SUSTENNA, INVEGA TRINZA, or INVEGA HAFYERA. Clinicians should exercise their clinical judgment. Specifically, a thorough assessment regarding the impact of residual or recurring symptoms on the patient’s functioning and quality of life should be conducted to weigh the potential benefits and risks of dose escalation or oral supplementation.^3-5
• A review article by Correll et al (2018)⁶ provides practical considerations for the management of breakthrough psychotic symptoms in patients with schizophrenia receiving long-acting injectable (LAI) antipsychoticsbased on clinical, pharmacokinetic and dosing considerations. A decision tree provided by the authors is provided in Figure: Management of Breakthrough Psychotic Symptoms in a Patient Receiving a Long-Acting Injectable at Optimized Doses.
• If residual symptoms of schizophrenia occur with administration of a second-generation LAI antipsychotic, a clinical reassessment is justified as per guidelines.Subsequently:
  • First-line strategy: treatment of the LAI antipsychotic should be optimized by increasing the dose while monitoring for tolerance, or
  • Second-line strategy: through a combination of an oral antipsychotic with the current LAI antipsychotic, OR by changing the current LAI antipsychotic for another LAI antipsychotic per clinical judgment
• When considering coadministration of paliperidone palmitate with risperidone or oral paliperidone, caution should be exercised since paliperidone is the major active metabolite of risperidone and has a similar pharmacological profile as risperidone.⁷
• To avoid a missed dose:
  • For patients on INVEGA SUSTENNA, injections may be given up to 7 days before or after the monthly time point.⁸
  • For patients on INVEGA TRINZA, injections may be given the injection up to 2 weeks before or after the next scheduled time point.⁹
  • For patients on INVEGA HAFYERA, injections up to 2 weeks before or 3 weeks after the scheduled 6-month timepoint.²
• Use of the flexible dosing windows represents an allowance under certain circumstances and does not imply that the dosing interval can be consistently shortened or extended on a regular basis.⁹

clinical data

Practical Considerations for Management of Breakthrough Psychotic Symptoms

Correll et al (2018)⁶ provided practical recommendations for the management of breakthrough symptoms in patients with schizophrenia receiving LAI antipsychotics based on clinical, pharmacokinetic and dosing considerations.

General Factors

Breakthrough symptoms are not always indicative of treatment failure. Psychotic relapse, concurrent medical illness, substance abuse/misuse, other psychiatric comorbidities, psychosocial stressors, suboptimal drug administration, incorrect dosage, ineffective medication, use of other drugs leading to pharmacodynamic (PD) or pharmacokinetic (PK) interactions, poor adherence, adverse events leading to refusal or discontinuation of treatment and low plasma therapeutic levels may contribute to breakthrough psychosis and/or symptom worsening. In addition, despite continued antipsychotic treatment, idiopathic symptomatic worsening and exacerbation of the illness for unknown, disease-related reasons may occur. Therefore, identification of all potential factors that could contribute to specific symptoms or symptom clusters will help in devising a patient-specific mitigation strategy to optimize outcomes (refer to Table 4: Key Questions Asked by Health-Care Providers to Ascertain the Etiology of Breakthrough Symptoms within the Correll et al [2018] publication).

Relevance of PK and PD of Long-Acting Injectable Antipsychotics

In order to establish effective plasma concentrations, proper preparation and administration of LAI antipsychotics is essential.

• For INVEGA SUSTENNA, this includes vigorous shaking of the prefilled syringe for a minimum of 10 seconds to ensure a homogenous suspension, choosing the appropriate needle size, selecting the appropriate administration site (deltoid or gluteal), and ensuring INVEGA SUSTENNA is NOT administered in subcutaneous tissue.⁸
• For INVEGA TRINZA, this includes proper preparation for injection (with the syringe tip pointing up, SHAKE the INVEGA TRINZA prefilled syringe VIGOROUSLY with a loose wrist for at least 15 seconds within 5 minutes prior to administration to ensure a homogenous suspension). If more than 5 minutes pass before injection, shake vigorously with the tip cap pointing up again for at least 15 seconds. Ensure selection of the appropriate needle size as determined by injection area and patient weight. See the approved local labeling of INVEGA TRINZA for complete instructions.⁹
• For INVEGA HAFYERA, this includes shaking with the syringe tip cap pointing up VERY FAST for at least 15 seconds, resting briefly, and shaking again for 15 seconds within 5 minutes prior to administration. If more than 5 minutes pass before injection, shake the syringe very fast with the tip cap pointing up again for at least 30 seconds. See the approved local labeling of INVEGA HAFYERA for complete instructions.²

In addition, missed LAI doses and their effect on blood concentrations should be considered.

• Missing doses of INVEGA SUSTENNA, INVEGA TRINZA, and INVEGA HAFYERA should be avoided. For a missed maintenance dose, the reinitiation regimen should be determined by the duration of time since the previous dose of INVEGA SUSTENNA, INVEGA TRINZA, and INVEGA HAFYERA.^2,8-10

Drug-drug interactions should be taken into consideration as a potential cause of symptom breakthrough or psychotic symptom worsening.

• Concomitant use of paliperidone palmitate and a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) may decrease exposure to paliperidone.^10,11

Please refer to the local product labeling for additional information on complete administration instructions, management of missed doses, and drug-drug interactions.

Practical Considerations

Patients experiencing an acute exacerbation while receiving an LAI antipsychotic may present at a psychiatrist’s office or emergency room. Based upon the above factors, a decision tree to guide treatment considerations for the management of breakthrough psychotic symptoms was developed. Please see Figure: Management of Breakthrough Psychotic Symptoms in a Patient Receiving a Long-Acting Injectable at Optimized Doses.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 25 April 2024.