Invega Sustenna

Keep all appointments with your doctor.

Ask your pharmacist any questions you have about paliperidone extended-release injection.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Invega Sustenna is part of the drug class:

• Other antipsychotics

Invega Sustenna may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• dizziness
• extreme tiredness
• weakness
• headache
• dry mouth
• increased saliva
• weight gain
• stomach pain
• injection site reactions

Some side effects can be serious. If you experience any of these, call your doctor immediately:

• fever
• muscle pain or stiffness
• confusion
• fast, pounding, or irregular heartbeat
• sweating
• unusual movements of your face or body that you cannot control
• slow or stiff movements
• restlessness
• painful erection of the penis that lasts for hours

Invega Sustenna may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

Some medicines may interact with Invega Sustenna which may increase side effects, and increase or decrease the action of either drug. Your doctor may need to change the doses of your medicines or carefully monitor for side effects if you are taking medicines that interact with Invega Sustenna.

Tell your doctor about the medicines you take including prescription and nonprescription medications, vitamins, nutritional supplements, and herbal supplements. Especially tell your doctor if you take:

• antidepressants
• certain antibiotics such as erythromycin (E.E.S., E-Mycin, Erythrocin), and moxifloxacin (Avelox)
• certain antipsychotics such as chlorpromazine (Thorazine), pimozide (Orap), risperidone (Risperdal) and thioridazine
• levodopa (in Sinemet, in Stalevo)
• medications for anxiety
• high blood pressure medicines 
• medications for seizures
• medications for irregular heartbeat such as amiodarone (Cordarone), disopyramide (Norpace), dofetilide (Tikosyn), procainamide (Procanbid, Pronestyl), quinidine (Quinidex), and sotalol (Betapace, Betapace AF)
• sedatives
• sleeping pills
• tranquilizers

Tell your doctor and pharmacist if you:

• are allergic to paliperidone, risperidone (Risperdal), or any other medications
• have inflammatory bowel disease (IBD)
• have kidney or liver disease
• have or have ever had a prolonged QT interval (a rare heart problem that may cause fainting or irregular heartbeat)
• have a slow or irregular heartbeat
• have had a heart attack
• have low levels of potassium or magnesium in your blood
• have had a seizure
• have had a stroke
• have had a head injury
• have a brain tumor
• have Parkinson's disease (a disorder of the nervous system that causes difficulties with movement, muscle control, and balance)
• have diabetes
• have breast cancer
• have had surgery involving the intestines
• have any condition that causes blockage or narrowing of the esophagus (tube that connects the mouth and stomach), stomach, or intestines such as cystic fibrosis (an inborn disease that causes problems with breathing, digestion, and reproduction), and inflammatory bowel disease (a group of conditions that cause swelling of the lining of the intestines)

Tell your doctor if you are pregnant, or if you plan to become pregnant or are breastfeeding. If you become pregnant while receiving Invega Sustenna, call your doctor. 

If you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving Invega Sustenna.

Tell your doctor if you plan to exercise or be exposed to extreme heat.

Tell your doctor about the medicines you take including prescription and nonprescription medications, vitamins, nutritional supplements, and herbal supplements. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.

Since this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Paliperidone injection is used to treat the symptoms of psychotic (mental) disorders, including schizophrenia. It may be used alone or in combination with other medicines to treat schizoaffective disorder. This medicine should not be used to treat behavioral problems in older adults who have dementia.

This medicine is to be given only by or under the direct supervision of your doctor.

• If you have an allergy to paliperidone, risperidone, or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have kidney disease.
• If you have ever had a long QT on ECG or other heartbeat that is not normal.
• If you are taking any drugs that can cause a certain type of heartbeat that is not normal (prolonged QT interval). There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
• If you are taking any of these drugs: Rifampin or St. John's wort.
• If you are taking carbamazepine.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with Invega Sustenna.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Invega Sustenna® (paliperidone palmitate) is indicated for the treatment of:

• Schizophrenia [see Clinical Studies (14.1)].
• Schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers or antidepressants [see Clinical Studies (14.2)].

Invega Sustenna® is available as a white to off-white aqueous extended-release injectable suspension for intramuscular injection in dose strengths of 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg paliperidone palmitate.

Mechanism of Action

Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)]. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unknown. The efficacy of paliperidone in schizophrenia could be mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

Pharmacodynamics

Paliperidone is a centrally active dopamine Type 2 (D2) receptor antagonist and a serotonin Type 2 (5HT2A) receptor antagonist. Paliperidone is also active as an antagonist at α1 and α2 adrenergic receptors and H1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro.

Pharmacokinetics

Absorption and Distribution

Due to its extremely low water solubility, the 1-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median Tmax of 13 days. The release of the drug starts as early as day 1 and lasts for as long as 126 days.

Following intramuscular injection of single doses (39 mg – 234 mg) in the deltoid muscle, on average, a 28% higher Cmax was observed compared with injection in the gluteal muscle. The two initial deltoid intramuscular injections of 234 mg on day 1 and 156 mg on day 8 help attain therapeutic concentrations rapidly. The release profile and dosing regimen of Invega Sustenna® results in sustained therapeutic concentrations. The AUC of paliperidone following Invega Sustenna® administration was dose-proportional over a 39 mg-234 mg dose range, and less than dose-proportional for Cmax for doses exceeding 78 mg. The mean steady-state peak:trough ratio for an Invega Sustenna® dose of 156 mg was 1.8 following gluteal administration and 2.2 following deltoid administration.

Following administration of paliperidone palmitate the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6–1.8.

Based on a population analysis, the apparent volume of distribution of paliperidone is 391 L. The plasma protein binding of racemic paliperidone is 74%.

Metabolism and Elimination

In a study with oral immediate-release 14C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.

The median apparent half-life of paliperidone following Invega Sustenna® single-dose administration over the dose range of 39 mg – 234 mg ranged from 25 days – 49 days.

Long-Acting Paliperidone Palmitate Injection versus Oral Extended-Release Paliperidone

Invega Sustenna® is designed to deliver paliperidone over a monthly period while extended-release oral paliperidone is administered on a daily basis. The initiation regimen for Invega Sustenna® (234 mg/156 mg in the deltoid muscle on Day 1/Day 8) was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation.

In general, overall initiation plasma levels with Invega Sustenna® were within the exposure range observed with 6–12 mg extended-release oral paliperidone. The use of the Invega Sustenna® initiation regimen allowed patients to stay in this exposure window of 6–12 mg extended-release oral paliperidone even on trough pre-dose days (Day 8 and Day 36). The intersubject variability for paliperidone pharmacokinetics following delivery from Invega Sustenna® was lower relative to the variability determined from extended-release oral paliperidone tablets. Because of the difference in median pharmacokinetic profiles between the two products, caution should be exercised when making a direct comparison of their pharmacokinetic properties.

Drug Interaction Studies

No specific drug interaction studies have been performed with Invega Sustenna®. The information below is obtained from studies with oral paliperidone.

Effects of other drugs on the exposures of paliperidone are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean Cmax and AUC values at steady-state was observed (see Figure 1). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration, a decrease in mean Cmax and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1)]. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone.

Figure 1: The effects of other drugs on paliperidone pharmacokinetics.

Clinically meaningful pharmacokinetic interaction between Invega Sustenna® and valproate (including valproic acid and divalproex sodium) is not expected. Oral administration of divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) with oral paliperidone extended-release tablets resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone.

After oral administration of paliperidone, the steady-state Cmax and AUC of divalproex sodium extended-release tablets were not affected in 13 patients stabilized on divalproex sodium extended-release tablets. In a clinical study, subjects on stable doses of divalproex sodium extended-release tablets had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3–15 mg/day was added to their existing divalproex sodium extended-release tablets treatment [see Drug Interactions (7.2)].

In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2)].

In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.

Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown.

Studies in Specific Populations

No specific pharmacokinetic studies have been performed with Invega Sustenna® in specific populations. All the information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modelling of oral paliperidone and Invega Sustenna®. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 2 [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].

After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

After oral administration of paliperidone in elderly subjects, the Cmax and AUC increased 1.2-fold compared to young subjects. However, there may be age-related decreases in creatinine clearance [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)].

Figure 2: Effects of intrinsic factors on paliperidone pharmacokinetics.

Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with Invega Sustenna®, the trough concentrations were similar between males and females.

Lower Cmax was observed in overweight and obese subjects. At apparent steady-state with Invega Sustenna®, the trough concentrations were similar among normal, overweight, and obese subjects.