Paliperidone (Invega)

Pharmacokinetics of Paliperidone

Metabolism Paliperidone does not undergo extensive metabolism (since it is already the active metabolite of risperidone).
Elimination A significant portion of its metabolism occurs in the kidneys, secondary to renal clearance and elimination.

Paliperidone: Cytochrome P450 Metabolism

Substrate of (Metabolized by)
  • Paliperidone's mechanism of action is through dopamine (D2) and serotonin (5HT2A) receptor antagonism in the brain. Paliperidone is also active as an antagonist at alpha-1 and alpha-2 adrenergic receptors and H1 histaminergic receptors, which explains side effects such as tachycardia, hypertension, and sedation.
  • Since paliperidone is the active metabolite of risperidone, they both act via similar pathways. However, since paliperidone is an active metabolite, it undergoes limited hepatic metabolism, thereby minimizing the risks of hepatic drug–drug and drug–disease interactions.

Dosing for Paliperidone

Starting 3 mg PO daily
Titration Increase by 3 mg every 7 days
Maximum 12 mg PO daily
  • Paliperidone comes in oral and intramuscular formulations (1 month, and 3 month)
  • Invega Sustenna Intramuscular (1-month Long-Acting Injectable) initiation doses need to be given in the deltoid (not gluteal) to achieve higher plasma doses
  • Since allergic and hypersensitivity reactions are often not observed after the first dose, it is recommended to provide two daily oral doses of paliperidone ER (3 mg) or risperidone (1 mg) before initiating treatment in previously paliperidone niave patients.[1]
  • Paliperidone is delivered as a standard loading dose for all patients. 150mg IM of paliperidone is given on Day 1, with 100mg IM on Day 8
  • The loading dose of contains 150 mg of paliperidone (delivered as 234 mg of paliperidone palmitate)
  • The dose equivalents between paliperidone:paliperidone palmitate are as follows:
    • 150mg eq. (234mg)
    • 100mg eq. (156mg)
    • 75mg eq. (117mg)
    • 50mg eq. (78mg)
    • 25mg eq. (39mg)
  • The 1st monthly maintenance dose should be administered 5 weeks after the very first injection (regardless of the timing of the second injection)

Invega Trinza is a 3-month injectable form of paliperidone for the treatment of adult schizophrenia. It can only be used after Invega Sustenna (1-month paliperidone palmitate prolonged-release injectable suspension) has been established as an adequate treatment for at least 4 months

The product monograph for paliperidone IM formulations does not recommend PO bridging (in fact, it says “Once treatment with IM paliperidone has been initiated, additional coverage with oral antipsychotics is not required and these medications can be discontinued”). However, this is because the pivotal studies included patients who were already at steady-state/therapeutic levels on PO dosing prior to starting an LAI. Thus, in an acute care setting where patients may be antipsychotic naive, or not adherent to medications, it makes clinical sense to actually continue an oral bridge for 2 loading doses (i.e. - 7 days), as long as there are no concern about side effects.

Paliperidone IM (Invega) has some benefits over a Risperidone IM (Consta):

  • Smaller IM needle
  • Monthly injection (vs. every 2 weeks)
  • Can be stored at room temperature (vs. refrigeration needed for risperidone Consta)
  • The incidence of parkinsonism and akathisia increases in a dose-related manner.[2]
  • Paliperidone does not immediately reach steady state even after the loading dose! In some cases, it can take several months for it to reach steady state. In these cases, patients may need oral supplementation of paliperidone if there are breakthrough symptoms.[3]
  • IM Paliperidone can cause tachycardia
  • There is thought to be a dose-responsive relationship between paliperidone plasma concentration and prolactin levels.[4]
  • Elevation of prolactin levels can occur as soon as 6 days after initiation of treatment.[5]
  • Paliperidone should be avoided in individuals with severe renal impairment, and dose should be reduced in those with mild-moderate impairment.
For Providers