Paliperidone palmitate injection for the acute and maintenance treatment of schizophrenia in adults

Figures & data

Figure 1 Timeline of availability of long-acting antipsychotic formulations that are Food and Drug Administration approved for use in the United States; other first-generation long-acting injectables are available in other countries.

Note: ^#No longer available: replaced by fluphenazine decanoate. *FDA approved for use in USA.
Abbreviation: LAI, long-acting injection.

Table 1 Receptor binding affinities (based on K_i values) of long-acting antipsychotic injections^19,45

Drug	Receptor
	5-HT2A	D2	5HT2A/D2	M1	α1	H1
Paliperidone (9-OH-risperidone)	High	High	High	Low	High	High
Olanzapine	High	Moderate	Low	Moderate	Moderate	High
Risperidone	High	High	High	Low	High	High
Haloperidol	Moderate	High	Moderate	Low	Moderate	Low
Fluphenazine	Moderate	High	Moderate	Low	High	Moderate

Notes: K_i determined by in vitro radioligand competition assays; K_i values: high (0–10 nm), moderate (11–100 nm), low (<100 nm); lower K_i values indicate higher receptor affinity.

Abbreviations: 5-HT_2A, serotonin type-2A; D₂, dopamine type-2; M₁, muscarinic type-1; α₁, α1 adrenergic; H₁, histamine type-1.

Table 2 Paliperidone palmitate clinical trials of treatment for acute schizophrenia

Authors	Study design	Treatment allocation	Efficacy findings	Comments
Gopal et al^Citation8	13 weeks, phase III N = 388 RCT, DB, PC Following a washout and tolerability period of ≤7 days, patients were randomized to receive one of three fixed doses of PP (78, 156, or 234 mg) or placebo administered by gluteal IM injection on days one, eight, 36, and 64	Placebo PP 78 mg PP 156 mg PP 234 mg	Mean PANSS change from baseline/statistics: Placebo −3.5 PP 78 mg −6.9 PP 156 mg* −6.9 (P < 0.05) PP 234 mg −5.5 CGI-S scale improvement: PP 156 mg* (P = 0.01) PSP score improvement: PP 78 mg* (P = 0.004) PP 156 mg* (P < 0.001)	PP treatment with 78 mg and 156 mg resulted in dose-related improvement in total PANSS score. Results associated with the 156 mg dose were statistically significant Limited results available with the 234 mg dose group
Kramer et al^Citation10	9 weeks N = 247 RCT, DB, PC Following a 5-day washout phase and a 7-day oral run-in period, patients were randomized to receive gluteal IM injections of PP doses (78 mg or 156 mg) or placebo on days one, eight, and 36	Placebo PP 78 mg PP 156 mg	Mean PANSS change from baseline/statistics: Placebo +6.2 PP 78 mg* −5.2 (P ≤ 0.001) PP 156 mg* −7.8 (P ≤ 0.001) CGI-S scale improvement: PP 78 mg* (P ≤ 0.004) PP 156 mg* (P ≤ 0.004)	PP was well tolerated in both 78 mg and 156 mg doses. Rapid onset of symptom response was seen by day eight compared to placebo. Both treatment groups’ response was maintained throughout the study
Nasrallah et al^Citation11	13 weeks, phase III N = 518 RCT, DB, parallel-group Following a ≤7-day screening, washout, and tolerability period, patients were randomized to one of three fixed PP doses (39, 78, or 156 mg) or placebo. Injections were administered by gluteal IM injection on days one, eight, 36, and 64	Placebo PP 39 mg PP 78 mg PP 156 mg	Mean PANSS change from baseline/statistics: Placebo −7.0 PP 39 mg* −13.6 (P < 0.05) PP 78 mg* −13.2 (P < 0.05) PP 156 mg* −16.1 (P ≤ 0.001) CGI-S scale improvement: PP 39 mg* (P = 0.003) PP 78 mg* (P = 0.006) PP 156 mg* (P = 0.002)	PP treatment groups resulted in statistically significant responses compared to placebo and improvement in total PANSS score
Pandina et al^Citation12	13 weeks, phase III N = 652 RCT, DB, PC Following a ≤7-day washout and tolerability period, patients were randomized to one of three PP doses or placebo: on day 1 (deltoid IM injection) 234 mg PP or placebo; on days eight, 36, and 64 (deltoid or gluteal IM injection) 234, 156, or 39 mg PP or placebo	Placebo PP 39 mg PP 156 mg PP 234 mg	Mean PANSS change from baseline/statistics: Placebo −2.9 PP 39 mg* −8.0 (P < 0.05) PP 156 mg* −11.6 (P < 0.05) PP 234 mg* −13.2 (P < 0.05) CGI-S scale improvement: PP 156 mg* (P = 0.005) PP 234 mg* (P < 0.001) PSP score improvement: PP 156 mg* (P = 0.007) PP 234 mg* (P < 0.001)	PP treatment group had significant dose-related improvement in total PANSS score when treatment was provided at an initial dose of 234 mg in the deltoid, followed by fixed-dose injections (39, 156, or 234 mg) into gluteal or deltoid muscle 1 week later and then once per month as maintenance treatment

Note:

* Statistically significant improvement.

Abbreviations: CGI-S, Clinical Global Impression of Severity; DB, double-blind; IM, intramuscular; PANSS, Positive and Negative Syndrome Scale; PC, parallel-controlled; PP, paliperidone palmitate; PSP, Personal and Social Performance Scale; RCT, randomized controlled trial.

Table 3 Doses of oral and injectable paliperidone needed to attain similar concentration at steady-state¹⁴

	Formulation
	Paliperidone extended-released tablet	Paliperidone palmitate long-acting injection
Dosing frequency	Once daily	Once every 4 weeks
Dose	3 mg	39–78 mg
	6 mg	117 mg
	12 mg	234 mg

Adapted from Invega^® Sustenna^™ product information.³

Table 4 Issues and barriers to long-acting injectable implementation and benefits of using paliperidone palmitate

Potential barriers	Paliperidone palmitate
Restricted pharmacologic options	Additional option from the newer antipsychotic category
Converting from short half-life oral to long half-life long-acting injectable	Initiation strategy seems to be effective for rapid conversion
Need to convert after the acute psychotic episode is already treated	Paliperidone palmitate is indicated for both acute and maintenance therapy
Lag-time before the benefits of long-acting route	Release of the drug starts as early as day one of administration/does not need oral supplementation during initiation

Table 5 Comparing the long-acting antipsychotic injections

	Dosing interval	Loading dose option	Oral dose overlap (if loading dose option is not selected)	Route of administration	Monitoring and safety
Paliperidone palmitate^Citation3	Every 4 weeks	Yes	Not required	Deltoid for loading then either gluteal/deltoid	Establishment of tolerance to the medication by prior oral administration required
Olanzapine pamoate^Citation46	Every 2–4 weeks	Yes	Not required	Gluteal only	Post injection monitoring required for 3 hours. Patient care program required Establishment of tolerance to the medication by prior oral administration recommended
Risperidone long-acting injection^Citation47	Every 2 weeks	No	Required	Gluteal/deltoid	Establishment of tolerance to the medication by prior oral administration required
Haloperidol decannoate^Citation48	Every 4 weeks	Yes	Recommended	Gluteal/deltoid	Monitor for hypotension post injection
Fluphenazine decanoate^Citation49	Every 2–4 weeks	Not established	Recommended	Gluteal/deltoid	Monitor for hypotension post injection

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