3-Month paliperidone palmitate for preventing relapse in schizophrenia

A 3-month paliperidone palmitate (PPM-3) extended-release inject­able suspension was approved by the FDA in May 2015 for preventing relapse among patients with schizophre­nia, under the brand name Invega Trinza (Table 1). Administered 4 times a year, PPM-3 provides the longest interval of any approved long-acting injectable anti­psychotic (LAIA). PPM-3 can be adminis­tered to patients with schizophrenia who have been taking 1-month paliperidone palmitate (PPM-1) extended-release inject­able suspension (brand name, Invega Sustenna), once a month, for at least 4 months.

How it works
PPM-3 is a LAIA injection. Because of its low solubility in water, paliperidone palmitate dissolves slowly once injected before being hydrolyzed as paliperidone and absorbed into the bloodstream. From time of release on Day 1, PPM-3 remains active for as long 18 months.

PPM-3 reaches a maximum plasma con­centration between Day 30 and Day 33. In clinical trials, PPM-3 had a median half-life of 84 to 95 days when injected into the del­toid muscle and a median half-life of 118 to 139 days when injected into the gluteal muscle.

Paliperidone is not extensively metabo­lized in the liver. Although results of a study suggest that cytochrome P450 (CYP) 2D6 and CYP3A4 might play a role in metabolizing paliperidone, there is no evi­dence that it has a significant role.

Dosing and administration
PPM-3 is administered intramuscularly by a licensed health care professional, once every 3 months. The recommended dosage is based on the patient’s previous dosage of PPM-1 (Table 2).

See the prescribing information for administration instructions.

Efficacy
The efficacy of PPM-3 was assessed in a long-term double-blind, placebo-controlled, randomized-withdrawal trial in adult patients with acute symptoms (previously treated with an oral antipsy­chotic) or adequately treated with a LAIA, either PPM-1 or another agent; patients receiving PPM-1, 39 mg, injections were ineligible. All patients entering the study received PPM-1 in place of the next sched­uled injection.

The study comprised 3 treatment periods:
   • 17-Week flexible-dose open-label period with PPM-1 (ie, first part of a 29-week open-label stabilization phase): Patients (N = 506) received PPM-1 with a flexible dose based on symptom response, tolerabil­ity, and medication history. Patients had to achieve a Positive and Negative Syndrome Scale (PANSS) total score of <70 at Week 17 to enter the second phase.
   • 12-Week open-label with PPM-3 (ie, sec­ond part of the 29-week open-label stabili­zation phase): Patients (N = 379) received a single injection of PPM-3 that was 3.5 times the last dose of PPM-1. Patients had to achieve a PANSS total score of <70 and ≤4 for 7 specific PANSS items.
   • A variable length double-blind treat­ment period: Patients (N = 305) were ran­domized 1:1 to continue treatment with PPM-3 (273 mg, 410 mg, 546 mg, or 819 mg) or placebo (administered once every 12 weeks) until relapse, early with­drawal, or end of the study. The primary efficacy measure was time to first relapse, defined as psychiatric hospitalization, ≥25% increase or a 10-point increase in total PANSS score on 2 consecutive assessments, deliberate self-injury, violent behavior, sui­cidal or homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on 2 consecutive assessments of the specific PANSS items.

Among the patients in the third treat­ment period, 23% of those who received placebo and 7.4% of those who received PPM-3 experienced a relapse event. The time to relapse was significantly longer for patients who received PPM-3 than for those who received placebo.

See Table 3 for adverse reactions reported in patients who received PPM-3 and those taking placebo in the study.

Contraindications
Allergic reactions. Patients who have a hypersensitivity to paliperidone, ris­peridone, or their components should not receive PPM-3. Anaphylactic reac­tions have been reported in patients who previously tolerated risperidone or oral paliperidone, which could be significant because the drug is slowly released over 3 months. Other adverse reactions, includ­ing angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary reten­tion, were reported post-approval of paliperidone; however, these adverse effects were reported voluntarily from an unknown population size and, therefore, it is unknown whether there is a causal rela­tionship to the drug or its frequency.

Drug-drug interactions. Although pali­peridone is not expected to cause drug– drug interactions with medications that are metabolized by CYP isoenzymes, it is recommended to avoid using a strong inducer of CYP3A4 and/or P-glycoprotein.

Overdose. When assessing treatment options and recovery, consider the half-life of PPM-3 and its long-lasting effects.

Because PPM-3 is administered by a licensed health care provider, the potential for overdose is low. However, if overdose occurs, general treatment and manage­ment measures should be employed as with overdose of any drug and the pos­sibility of multiple drug overdose should be considered. There is no specific antidote to paliperidone. Contact a certified poi­son control center for guidance on man­aging paliperidone and PPM-3 overdose. Generally, management consists of sup­portive care.

Black-box warning in dementia. As with all atypical antipsychotics, the black-box warning for PPM-3 states that it is not approved for, and should not be used in, patients with dementia-related psychosis. An analysis of placebo-controlled studies revealed that patients taking an antipsy­chotic had (1) 1.6 to 1.7 times the risk of death than those who received placebo and (2) a higher incidence of cerebrovas­cular adverse reactions.

Adverse reactions
The safety profile of PPM-3 is similar to that of PPM-1. The most common adverse reactions are:
   • reaction at the injection site
   • weight gain
   • headache
   • upper respiratory tract infection
   • akathisia
   • parkinsonism.

See the full prescribing information for a complete list of adverse effects.

Related Resources
• Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone pal­mitate: once monthly treatment option for schizophrenia. Current Psychiatry. 2010;9(3):48-49.
• Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clini­cal trial [published online March 29, 2015]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2015.0241.

Drug Brand Names
Paliperidone palmitate • Invega Sustenna, Invega Trinza
Risperidone • Risperdal

A 3-month paliperidone palmitate (PPM-3) extended-release inject­able suspension was approved by the FDA in May 2015 for preventing relapse among patients with schizophre­nia, under the brand name Invega Trinza (Table 1). Administered 4 times a year, PPM-3 provides the longest interval of any approved long-acting injectable anti­psychotic (LAIA). PPM-3 can be adminis­tered to patients with schizophrenia who have been taking 1-month paliperidone palmitate (PPM-1) extended-release inject­able suspension (brand name, Invega Sustenna), once a month, for at least 4 months.

How it works
PPM-3 is a LAIA injection. Because of its low solubility in water, paliperidone palmitate dissolves slowly once injected before being hydrolyzed as paliperidone and absorbed into the bloodstream. From time of release on Day 1, PPM-3 remains active for as long 18 months.

PPM-3 reaches a maximum plasma con­centration between Day 30 and Day 33. In clinical trials, PPM-3 had a median half-life of 84 to 95 days when injected into the del­toid muscle and a median half-life of 118 to 139 days when injected into the gluteal muscle.

Paliperidone is not extensively metabo­lized in the liver. Although results of a study suggest that cytochrome P450 (CYP) 2D6 and CYP3A4 might play a role in metabolizing paliperidone, there is no evi­dence that it has a significant role.

Dosing and administration
PPM-3 is administered intramuscularly by a licensed health care professional, once every 3 months. The recommended dosage is based on the patient’s previous dosage of PPM-1 (Table 2).

See the prescribing information for administration instructions.

Efficacy
The efficacy of PPM-3 was assessed in a long-term double-blind, placebo-controlled, randomized-withdrawal trial in adult patients with acute symptoms (previously treated with an oral antipsy­chotic) or adequately treated with a LAIA, either PPM-1 or another agent; patients receiving PPM-1, 39 mg, injections were ineligible. All patients entering the study received PPM-1 in place of the next sched­uled injection.

The study comprised 3 treatment periods:
   • 17-Week flexible-dose open-label period with PPM-1 (ie, first part of a 29-week open-label stabilization phase): Patients (N = 506) received PPM-1 with a flexible dose based on symptom response, tolerabil­ity, and medication history. Patients had to achieve a Positive and Negative Syndrome Scale (PANSS) total score of <70 at Week 17 to enter the second phase.
   • 12-Week open-label with PPM-3 (ie, sec­ond part of the 29-week open-label stabili­zation phase): Patients (N = 379) received a single injection of PPM-3 that was 3.5 times the last dose of PPM-1. Patients had to achieve a PANSS total score of <70 and ≤4 for 7 specific PANSS items.
   • A variable length double-blind treat­ment period: Patients (N = 305) were ran­domized 1:1 to continue treatment with PPM-3 (273 mg, 410 mg, 546 mg, or 819 mg) or placebo (administered once every 12 weeks) until relapse, early with­drawal, or end of the study. The primary efficacy measure was time to first relapse, defined as psychiatric hospitalization, ≥25% increase or a 10-point increase in total PANSS score on 2 consecutive assessments, deliberate self-injury, violent behavior, sui­cidal or homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on 2 consecutive assessments of the specific PANSS items.

Among the patients in the third treat­ment period, 23% of those who received placebo and 7.4% of those who received PPM-3 experienced a relapse event. The time to relapse was significantly longer for patients who received PPM-3 than for those who received placebo.

See Table 3 for adverse reactions reported in patients who received PPM-3 and those taking placebo in the study.

Contraindications
Allergic reactions. Patients who have a hypersensitivity to paliperidone, ris­peridone, or their components should not receive PPM-3. Anaphylactic reac­tions have been reported in patients who previously tolerated risperidone or oral paliperidone, which could be significant because the drug is slowly released over 3 months. Other adverse reactions, includ­ing angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary reten­tion, were reported post-approval of paliperidone; however, these adverse effects were reported voluntarily from an unknown population size and, therefore, it is unknown whether there is a causal rela­tionship to the drug or its frequency.

Drug-drug interactions. Although pali­peridone is not expected to cause drug– drug interactions with medications that are metabolized by CYP isoenzymes, it is recommended to avoid using a strong inducer of CYP3A4 and/or P-glycoprotein.

Overdose. When assessing treatment options and recovery, consider the half-life of PPM-3 and its long-lasting effects.

Because PPM-3 is administered by a licensed health care provider, the potential for overdose is low. However, if overdose occurs, general treatment and manage­ment measures should be employed as with overdose of any drug and the pos­sibility of multiple drug overdose should be considered. There is no specific antidote to paliperidone. Contact a certified poi­son control center for guidance on man­aging paliperidone and PPM-3 overdose. Generally, management consists of sup­portive care.

Black-box warning in dementia. As with all atypical antipsychotics, the black-box warning for PPM-3 states that it is not approved for, and should not be used in, patients with dementia-related psychosis. An analysis of placebo-controlled studies revealed that patients taking an antipsy­chotic had (1) 1.6 to 1.7 times the risk of death than those who received placebo and (2) a higher incidence of cerebrovas­cular adverse reactions.

Adverse reactions
The safety profile of PPM-3 is similar to that of PPM-1. The most common adverse reactions are:
   • reaction at the injection site
   • weight gain
   • headache
   • upper respiratory tract infection
   • akathisia
   • parkinsonism.

See the full prescribing information for a complete list of adverse effects.

Related Resources
• Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone pal­mitate: once monthly treatment option for schizophrenia. Current Psychiatry. 2010;9(3):48-49.
• Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clini­cal trial [published online March 29, 2015]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2015.0241.

Drug Brand Names
Paliperidone palmitate • Invega Sustenna, Invega Trinza
Risperidone • Risperdal

A 3-month paliperidone palmitate (PPM-3) extended-release inject­able suspension was approved by the FDA in May 2015 for preventing relapse among patients with schizophre­nia, under the brand name Invega Trinza (Table 1). Administered 4 times a year, PPM-3 provides the longest interval of any approved long-acting injectable anti­psychotic (LAIA). PPM-3 can be adminis­tered to patients with schizophrenia who have been taking 1-month paliperidone palmitate (PPM-1) extended-release inject­able suspension (brand name, Invega Sustenna), once a month, for at least 4 months.

How it works
PPM-3 is a LAIA injection. Because of its low solubility in water, paliperidone palmitate dissolves slowly once injected before being hydrolyzed as paliperidone and absorbed into the bloodstream. From time of release on Day 1, PPM-3 remains active for as long 18 months.

PPM-3 reaches a maximum plasma con­centration between Day 30 and Day 33. In clinical trials, PPM-3 had a median half-life of 84 to 95 days when injected into the del­toid muscle and a median half-life of 118 to 139 days when injected into the gluteal muscle.

Paliperidone is not extensively metabo­lized in the liver. Although results of a study suggest that cytochrome P450 (CYP) 2D6 and CYP3A4 might play a role in metabolizing paliperidone, there is no evi­dence that it has a significant role.

Dosing and administration
PPM-3 is administered intramuscularly by a licensed health care professional, once every 3 months. The recommended dosage is based on the patient’s previous dosage of PPM-1 (Table 2).

See the prescribing information for administration instructions.

Efficacy
The efficacy of PPM-3 was assessed in a long-term double-blind, placebo-controlled, randomized-withdrawal trial in adult patients with acute symptoms (previously treated with an oral antipsy­chotic) or adequately treated with a LAIA, either PPM-1 or another agent; patients receiving PPM-1, 39 mg, injections were ineligible. All patients entering the study received PPM-1 in place of the next sched­uled injection.

The study comprised 3 treatment periods:
   • 17-Week flexible-dose open-label period with PPM-1 (ie, first part of a 29-week open-label stabilization phase): Patients (N = 506) received PPM-1 with a flexible dose based on symptom response, tolerabil­ity, and medication history. Patients had to achieve a Positive and Negative Syndrome Scale (PANSS) total score of <70 at Week 17 to enter the second phase.
   • 12-Week open-label with PPM-3 (ie, sec­ond part of the 29-week open-label stabili­zation phase): Patients (N = 379) received a single injection of PPM-3 that was 3.5 times the last dose of PPM-1. Patients had to achieve a PANSS total score of <70 and ≤4 for 7 specific PANSS items.
   • A variable length double-blind treat­ment period: Patients (N = 305) were ran­domized 1:1 to continue treatment with PPM-3 (273 mg, 410 mg, 546 mg, or 819 mg) or placebo (administered once every 12 weeks) until relapse, early with­drawal, or end of the study. The primary efficacy measure was time to first relapse, defined as psychiatric hospitalization, ≥25% increase or a 10-point increase in total PANSS score on 2 consecutive assessments, deliberate self-injury, violent behavior, sui­cidal or homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on 2 consecutive assessments of the specific PANSS items.

Among the patients in the third treat­ment period, 23% of those who received placebo and 7.4% of those who received PPM-3 experienced a relapse event. The time to relapse was significantly longer for patients who received PPM-3 than for those who received placebo.

See Table 3 for adverse reactions reported in patients who received PPM-3 and those taking placebo in the study.

Contraindications
Allergic reactions. Patients who have a hypersensitivity to paliperidone, ris­peridone, or their components should not receive PPM-3. Anaphylactic reac­tions have been reported in patients who previously tolerated risperidone or oral paliperidone, which could be significant because the drug is slowly released over 3 months. Other adverse reactions, includ­ing angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary reten­tion, were reported post-approval of paliperidone; however, these adverse effects were reported voluntarily from an unknown population size and, therefore, it is unknown whether there is a causal rela­tionship to the drug or its frequency.

Drug-drug interactions. Although pali­peridone is not expected to cause drug– drug interactions with medications that are metabolized by CYP isoenzymes, it is recommended to avoid using a strong inducer of CYP3A4 and/or P-glycoprotein.

Overdose. When assessing treatment options and recovery, consider the half-life of PPM-3 and its long-lasting effects.

Because PPM-3 is administered by a licensed health care provider, the potential for overdose is low. However, if overdose occurs, general treatment and manage­ment measures should be employed as with overdose of any drug and the pos­sibility of multiple drug overdose should be considered. There is no specific antidote to paliperidone. Contact a certified poi­son control center for guidance on man­aging paliperidone and PPM-3 overdose. Generally, management consists of sup­portive care.

Black-box warning in dementia. As with all atypical antipsychotics, the black-box warning for PPM-3 states that it is not approved for, and should not be used in, patients with dementia-related psychosis. An analysis of placebo-controlled studies revealed that patients taking an antipsy­chotic had (1) 1.6 to 1.7 times the risk of death than those who received placebo and (2) a higher incidence of cerebrovas­cular adverse reactions.

Adverse reactions
The safety profile of PPM-3 is similar to that of PPM-1. The most common adverse reactions are:
   • reaction at the injection site
   • weight gain
   • headache
   • upper respiratory tract infection
   • akathisia
   • parkinsonism.

See the full prescribing information for a complete list of adverse effects.

Related Resources
• Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone pal­mitate: once monthly treatment option for schizophrenia. Current Psychiatry. 2010;9(3):48-49.
• Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clini­cal trial [published online March 29, 2015]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2015.0241.

Drug Brand Names
Paliperidone palmitate • Invega Sustenna, Invega Trinza
Risperidone • Risperdal