Paliperidone Long Acting Injections (Sustenna / Trinza / Hafyera) – Psychopharmacology and Clinical Application

MECHANISMS OF ACTION OF PALIPERIDONE

Paliperidone’s mechanism of action is mediated through the antagonism of central dopamine D2 receptors and serotonin 5-HT2A receptors. [Yang and Plosker 2007]

Paliperidone also has antagonistic activity against α1 and α2 adrenergic and H1 histaminergic receptors. 

There is no first-pass metabolism as paliperidone palmitate is administered by intramuscular injection (either the deltoid muscle or the gluteal area). [Hough et al. 2009] 

PHARMACOKINETICS OF PALIPERIDONE

Invega Sustenna: [PI]

• Following a single intramuscular dose, the median Tmax of 13 days. The release of the drug starts as early as day 1 and lasts for as long as 126 days.
• The median half-life of paliperidone following Invega Sustenna single-dose administration over the dose range of 25 mg (39 mg of paliperidone palmitate) – 150 mg (234 mg of paliperidone palmitate) ranged from 25 days – 49 days.

Switching patients from Paliperidone tablets to Invega Sustenna – Equivalent dosages

Risperdal Consta and Invega Sustenna Dose Equivalence 

• Paliperidone is not extensively metabolised in the liver, with 59% excreted unchanged in the urine. 
• Less than 10% of the dose is metabolised with four metabolic pathways detected (dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission) in vivo. 
• Of note, an essential pharmacokinetic profile variable for paliperidone palmitate administration is needle length, whereby a 1-inch 23G needle is recommended for patients weighing <90 kg, and a 1½-inch 22G needle is recommended for patients weighing ≥90 kg. [Samtani et al. 2009]
• Other important predictors include BMI, creatinine clearance, injection site and volume. 

Invega Trinza: [PI]

• Following a single intramuscular dose of Invega Trinza, the median Tmax is 30-33 days.
• The median apparent half-life of paliperidone following Invega Trinza administration over the dose range of 175-525 mg ranged from 84-95 days following deltoid injections and 118-139 days following gluteal injections.

Invega Halfyera:

• Following gluteal injection(s) of Invega Hafyera at doses of 1092 or 1560 mg, the median Tmax is 29 to 32 days.
• The release of the drug starts as early as day 1 and is predicted to last longer than 18 months.
• The median half-life following 1092 or 1560 mg dose was 148 and 159 days, respectively.
• The mean peak concentration (Cmax) was higher (1.4 to 1.5-fold) for Invega Hafyera than corresponding doses of 3-month paliperidone palmitate.
• The concentration of paliperidone remaining in the circulation 18 months after 1560 mg 6-month Invega Hafyera is stopped is estimated to be 18% of the average steady-state levels.

Drug interactions

• Paliperidone is minimally metabolised in the liver by CYP2D6 and CYP3A4, with analyses showing no difference in the clearance of paliperidone by extensive or poor metabolisers. [Hoy et al. 2010]
• As there is no extensive metabolism in the liver, it seems unlikely that there would be any significant interactions with the cytochrome P450 isoenzyme system. 
• Paliperidone is also not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely.
• Interestingly, although CYP2D6 only plays a minor role, co-administration with the potent CYP2D6 inhibitor, paroxetine, has been shown to cause a 16% increase in paliperidone exposure. [Citrome 2010]  
• In addition, paliperidone palmitate is a weak inhibitor of P-glycoprotein (P-gp) at higher concentrations. 
• Avoid using strong CYP3A4 and/or P-gp inducers (carbamazepine, Rifampin, St John’s wort) during a dosing interval for LAIs. If administering a potent inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

DOSING OF PALIPERIDONE PALMITATE (INVEGA SUSTENNA / INVEGA TRINZA / INVEGA HAFYERA)

Invega Sustenna: (Once a month paliperidone palmitate extended-release injectable suspension – PP1M)

For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone before initiating treatment with Invega Sustenna.

Available doses: 

• Invega Sustenna (as palmitate) 25 mg modified release injection (39 mg paliperidone palmitate)
• 50 mg modified release injection pre-filled syringe: 78 mg paliperidone palmitate.
• 75 mg of paliperidone as 117 mg paliperidone palmitate.
• 150 mg of paliperidone as 234 mg paliperidone palmitate.

Recommended initiation of Invega Sustenna is with a dose of 150 mg on treatment day 1 and 100 mg one week later (day 8), both administered in the deltoid muscle.

The recommended monthly maintenance dose is 75 mg; some patients may benefit from lower or higher doses within the recommended range of 25 to 150 mg based on individual patient tolerability and/or efficacy.

Switching strategies (These images are from the company website – (https://www.invegasustennahcp.com/dosing/transitioning)

Transitioning from Paliperidone Extended-Release Tablets to Invega Sustenna: 

Transitioning from Risperidone Tablet to Invega Sustenna: 

Transitioning from Risperdal LAI to Invega Sustenna: 

Transitioning from other LAIs to Invega Sustenna

Invega Trinza: Every-three-month paliperidone palmitate extended-release injectable suspension (PP3M)

• Invega Trinza should be used only after Invega Sustenna has been established as an adequate treatment for at least four months.
• The last two doses of Invega Sustenna should be the same dosage strength before starting Invega Trinza.
• Invega Trinza may be administered up to 7 days before or after the monthly time point of the next scheduled Invega sustenna injection.
• Conversion from the Last Invega Sustenna (PP1M) Dose to the Invega Trinza (PP3M) Dose Using 3.5 as a Multiplier.

• Following the initial Invega Trinza (PP3M) dose, Invega Trinza (PP3M) should be administered every 3 months.
• If needed, dose adjustment can be made every 3 months in increments within the range of 175 mg to 525 mg based on individual patient tolerability and/or efficacy.
• For switching from Invega Trinza to oral paliperidone extended-release tablets, the daily dosing of the paliperidone extended-release tablets should be started 3 months after the last Invega Trinza dose and transitioned over the next several months following the last Invega Trinza dose.

Invega Hafyera: 

Initiate Invega Hafyera only after adequate treatment has been established with either:

Invega sustenna (PP1M) for at least 4 months

OR

Invega Trinza (PP3M) for at least one three-month injection cycle.

Transition from Invega sustenna (PP1M)

• Initiate Invega Hafyera when the next PP1M dose is scheduled.
• Invega Hafyera may be administered up to 1 week before or 1 week after the next scheduled PP1M dose.
• When switching from PP1M to Invega Hafyera, the two injection cycles immediately preceding the switch should be the same dosage strength before starting Invega Hafyera.

Transition from Trinza (PPM3): 

Initiate Invega Hafyera when the next PP3M dose is scheduled.

• Invega Hafyera may be administered up to 2 weeks before or 2 weeks after the next scheduled PP3M dose.
• Following the initial dose, administer Invega Hafyera once every 6 months.
• If needed, dosage adjustment can be made every 6 months between 1,092 mg to 1,560 mg based on individual response and tolerability.

MANAGEMENT OF MISSED DOSES

Invega Sustenna 

• To avoid a missed dose during the initiation phase, patients may be given the second dose 4 days before or after the one-week (day 8) timepoint.
• To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly timepoint.

If the target date for the second Invega Sustenna injection (1wk ± 4 days) is missed, the recommended reinitiation depends on the length of time which has elapsed since the patient’s first injection.

Missed second initiation dose (< 4 weeks from the first injection): 

• Administer the second injection of 100 mg in the deltoid muscle as soon as possible.
• Administer the third Invega Sustenna injection of 75 mg in either the deltoid or gluteal muscles 5 weeks after the first injection (regardless of the timing of the second injection).
• Continue regular monthly injections in the usual dose range after that.

Missed second initiation dose (4-7 weeks from the first injection): 

• Administer deltoid injection of 100 mg as soon as possible
• Administer another deltoid injection of 100 mg 1 week later.
• Continue regular monthly injections in the usual dose range after that.

Missed second initiation dose (> 7 weeks from the first injection): 

• Initiate dosing at starting Invega Sustenna doses as described earlier.

Missed Maintenance Dose (1 Month to 6 Weeks)

• Administer the previously stabilised dose as soon as possible
• Continue monthly injections

Missed Maintenance Dose (> 6 Weeks to 6 Months)

For patients stabilised with doses of 25 to 100 mg:

• A deltoid injection as soon as possible at the same dose the patient was previously stabilised on.
• Another deltoid injection (same dose) one week later (day 8).
• Resumption of the regular monthly cycle of injections

For patients stabilised with 150 mg:

• A deltoid injection of 100 mg as soon as possible at the 100 mg dose.
• Another deltoid injection of 100 mg one week later (day 8)
• Resumption of the regular monthly cycle of injections

Missed Maintenance Dose (> 6 Months): 

• Initiate dosing as initial dosing for sustenna.

Invega Trinza 

However, patients may be given the injection up to 2 weeks before or after the 3-month time point on exceptional occasions.

Missed dose> 3½ Months up to 4 Months

• Administer the Invega Trinza dose as soon as possible
• Continue with the 3-month injections after that.

Missed dose> 4 Months up to 9 Months

• Do NOT administer the next dose of Invega Trinza.
• Reinitate Trinza

Missed dose> 9 Months

• Re-initiate treatment PP1M
• Resume treatment with Invega Trinza after the patient has been adequately treated with PP1M for at least 4 months.

Invega Hafyera:

To avoid a missed dose, patients may be given the injection up to 2 weeks before or 3 weeks after the scheduled 6-month dose.

Missed dose more than 6 Months and 3 Weeks, up to but Less than 8 Months Since Last Dose: 

• Do not administer the next dose of Invega Hayfera

Missed Dose 8 Months Up to and including 11 Months Since Last Dose: 

• Do not administer the next dose of Invega Hafyera.

Missed dose more than 11 Months Since Last Dose: 

• Re-initiate treatment with a PP1M product Resume Invega Hafyera after the patient has been adequately treated with a PP1M product for at least 4 months

SAFETY PROFILE OF PALIPERIDONE PALMITATE

The most common side effects of paliperidone palmitate were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder (incidence ≥5%).

Dose-related adverse reactions reported in patients with schizophrenia include akathisia and hyperprolactinemia. [Kramer et al 2010]; [Pandina et al 2010]; [Li et al 2015]; [Zhang et al 2015]  

Other notable adverse reactions reported in clinical trials include: 

• Extrapyramidal Symptoms: In placebo-controlled trials, the incidence of parkinsonism and akathisia were higher in the 78 mg and 156 mg paliperidone palmitate groups compared with placebo. Furthermore, in a long-term study of patients with schizoaffective disorder, hyperkinesia, parkinsonism, tremor, dyskinesia, and dystonia were reported with an incidence of ≥2%. 
• Dystonia: In males and younger patients, there is an increased risk of dystonia, usually occurring when therapy is first initiated in susceptible patients. Symptoms include spasming of the neck muscles, which can progress to tightening of the throat, and difficulty in breathing. 
• Orthostatic hypotension: Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity.

Paliperidone palmitate also comes with a black box warning of increased mortality in elderly patients with dementia-related psychosis due to an increased risk for cerebrovascular adverse reactions (including stroke and transient ischemic attack). As such, paliperidone palmitate is not approved for use in patients with dementia-related psychosis. 

CLINICAL EVIDENCE

Overall, both 1-month and 3-month formulations of PDP are safe and effective in treating schizophrenia and schizoaffective disorder. They may be most effective in patients with prior failed treatment of oral antipsychotics or other LAIAs, patients with a history of medication noncompliance, or patients with an individual preference for less frequent dosing. [Morris et al., 2017]

PP3M was better at preventing relapse compared to oral paliperidone. 50% of patients withdrawn from oral paliperidone, PP1M, or PP3M remained relapse-free for approximately 2, 6, and 13 months, respectively.

Compared to PP1M, PP3M is just as safe and effective and has the added advantage of increased adherence to a longer dose interval, decreasing the risk of relapse. [Edinoff et al., 2021]

Add-on or monotherapy paliperidone palmitate in Schizoaffective patients protected from psychotic, depressive, and manic symptoms. [Pacchiarotti et al., 2019]

Starting paliperidone LAI significantly improved clinical and functional outcomes in patients with schizophrenia, especially those with a shorter duration of illness. [Kim et al., 2021]

Invega Hafyera was recently approved after being studied in a randomised, double-blind, non-inferiority global Phase 3 study of 702 adults (ages 18–70) with schizophrenia, designed to demonstrate that injection cycles consisting of a single administration of Invega Hafyera (PP6M) (700 or 1000 mg) are not less effective than two sequentially administered injections of PP3M (350 or 525 mg) for the prevention of relapse in subjects with schizophrenia previously stabilised on corresponding doses of PP1M (100 or 150 mg) or PP3M (350 or 525 mg). [The Route 6 Study].

The results showed non-inferiority of PP6M compared with PP3M at the primary endpoint of time to first relapse at the end of the 12 months. Results found that 92.5 % of patients treated with PP6M and 95.1 % treated with PP3M were relapse-free at 12 months. [Hafyera PI]

SUMMARY

Paliperidone is the pharmacologically active metabolite of risperidone, and the intramuscular LAI formulation provides several advantages over oral therapy.

They are indicated in the prior failed treatment of oral antipsychotics or other LAIAs, in patients with a history of medication noncompliance, in patients with an individual preference for less frequent dosing and have shown to improve clinical and functional outcomes in patients with schizophrenia, especially those with a shorter duration of illness; thus also indicated early in the course of schizophrenia.

In addition, paliperidone undergoes limited hepatic metabolism and is also less susceptible to pharmacokinetic drug interactions.

At present, there are 1-, 3-, and 6-month formulations approved to treat schizophrenia and schizoaffective disorder in adults. 

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