Invega

Paliperidone (Invega) is an oral, atypical antipsychotic used to treat schizophrenia. It is a short acting form of Invega Sustenna and Invega Trinza. Other atypical antipsychotic drugs include

• olanzapine (Zyprexa),
• quetiapine (Seroquel),
• ziprasidone (Geodon), and
• aripiprazole (Abilify).

Atypical antipsychotics differ from typical antipsychotics because they cause a lesser degree of movement (extrapyramidal) side effects and constipation.

The exact mechanism of action of paliperidone is not known, but, like other anti-psychotics, it is believed that paliperidone affects the way the brain works by interfering with communication among the brain's nerves. Nerves communicate with each other by making and releasing chemicals called neurotransmitters. The neurotransmitters travel to other nearby nerves where they attach to receptors on the nerves. The attachment of the neurotransmitters either stimulates or inhibits the function of the nearby nerves. Paliperidone blocks several of the receptors on nerves including dopamine type 2, serotonin type 2, and alpha 2 adrenergic receptors. It is believed that many psychotic illnesses are caused by abnormal communication among nerves in the brain and that by altering communication through neurotransmitters, paliperidone can alter the psychotic state. The FDA approved paliperidone in December, 2006.

Paliperidone can cause low blood pressure especially when standing up from a sitting or lying position (orthostatic hypotension). Therefore, paliperidone should be used cautiously with other drugs also associated with orthostatic hypotension.

Paliperidone is metabolized (eliminated) by liver enzymes. Drugs that increase the action of these enzymes will decrease blood levels of paliperidone thereby decreasing its effect. Paliperidone should not be taken with carbamazepine (Tegretol), phenytoin (Dilantin), rifampin (Rifadin), St. John's Wort, and other drugs that may decrease its blood levels.

Paliperidone blocks the effect of dopamine in the brain while dopamine agonists such as levodopa (Sinemet) increase the levels of dopamine in the brain. Combining these agents is not recommended since the effect of both drugs will be reduced.

Divalproex sodium increases blood levels of paliperidone by 50%. The dose of paliperidone should be adjusted based on clinical judgment.

Unborn babies exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and withdrawal symptoms after birth. Symptoms reported included agitation, hypertonia, hypotonia, tremor, somnolence, depressed breathing, and feeding disorder. Currently there is no data on the use of paliperidone during pregnancy. Paliperidone should only be used during pregnancy if the potential benefit to the mother outweighs the potential for side effects in the fetus.

A pregnancy exposure registry has been established to monitor the use of atypical antipsychotics, including paliperidone, during pregnancy. All pregnant women treated with atypical antipsychotics are advised to enroll in this pregnancy registry and report any side effects.

Paliperidone is known to enter human milk but its effects on the breastfeeding infant or milk production is not yet known.

Tablets: 1.5, 3, 4, 6, and 9 mg

Paliperidone should be stored at room temperature, between 15 C and 30 C (59 F and 86 F).

Included as part of the PRECAUTIONS section.

Invega 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

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

Some medicines may interact with Invega 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.

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

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Invega there are no specific foods that you must exclude from your diet when receiving Invega.

If you take too much this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Overall Adverse Reaction Profile

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased mortality in elderly patients with dementia-related psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS]
• Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS]
• QT prolongation [see WARNINGS AND PRECAUTIONS]
• Tardive dyskinesia [see WARNINGS AND PRECAUTIONS]
• Metabolic changes [see WARNINGS AND PRECAUTIONS]
• Hyperprolactinemia [see WARNINGS AND PRECAUTIONS]
• Potential for gastrointestinal obstruction [see WARNINGS AND PRECAUTIONS]
• Orthostatic hypotension and syncope [see WARNINGS AND PRECAUTIONS]
• Falls [see WARNINGS AND PRECAUTIONS]
• Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS]
• Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Dysphagia [see WARNINGS AND PRECAUTIONS]
• Suicide [see WARNINGS AND PRECAUTIONS]
• Priapism [see WARNINGS AND PRECAUTIONS]
• Thrombotic thrombocytopenic purpura (TTP) [see WARNINGS AND PRECAUTIONS]
• Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS]
• Antiemetic effect [see WARNINGS AND PRECAUTIONS]
• Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see WARNINGS AND PRECAUTIONS]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see WARNINGS AND PRECAUTIONS]

The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with INVEGA® and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with INVEGA® and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis.

The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of INVEGA®-treated subjects) were nervous system disorders. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of INVEGA®-treated subjects. [See Discontinuations Due to Adverse Reactions].

The safety of INVEGA® was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received INVEGA® at fixed doses ranging from 3 mg to 12 mg once daily. The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received INVEGA® at daily doses within the range of 3 mg to 15 mg (n=104), is also included.

The safety of INVEGA® was evaluated in 150 adolescent subjects 12-17 years of age with schizophrenia who received INVEGA® in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

The safety of INVEGA® was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of INVEGA®: 6 mg with the option to reduce to 3 mg (n=108) or 12 mg with the option to reduce to 9 mg (n=98) once daily. In the other study, 214 subjects received flexible doses of INVEGA® (3-12 mg once daily). Both studies included subjects who received INVEGA® either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of INVEGA® (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for INVEGA® often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Commonly-Observed Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia In Adults And Adolescents

Table 4 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies in adults, listing those that occurred in 2% or more of subjects treated with INVEGA® in any of the dose groups, and for which the incidence in INVEGA®-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 4: Adverse Reactions Reported by ≥ 2% of INVEGA®-Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials*

Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 12-17 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with INVEGA® in any of the dose groups, and for which the incidence in INVEGA®-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 5: Adverse Reactions Reported by ≥ 2% of INVEGA®-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial*

Commonly-Observed Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials - Schizoaffective Disorder In Adults

Table 6 enumerates the pooled incidences of adverse reactions reported in the two placebo-controlled 6-week studies in adult subjects, listing those that occurred in 2% or more of subjects treated with INVEGA® and for which the incidence in INVEGA®-treated subjects was greater than the incidence in subjects treated with placebo.

Table 6: Adverse Drug Reactions Reported by ≥ 2% of INVEGA®-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials *

The designs of the two placebo-controlled, 6-week, double-blind trials in adult subjects with schizoaffective disorder included the option for subjects to receive antidepressants (except monoamine oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine). In the subject population evaluated for safety, 230 (55%) subjects received INVEGA® as monotherapy and 190 (45%) subjects received INVEGA® as an adjunct to mood stabilizers and/or antidepressants. When comparing these 2 subpopulations, only nausea occurred at a greater frequency (≥ 3% difference) in subjects receiving INVEGA® as monotherapy.

Discontinuations Due To Adverse Reactions

The percentages of subjects who discontinued due to adverse reactions in the three schizophrenia placebo-controlled, 6-week, fixed-dose studies in adults were 3% and 1% in INVEGA®-and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in INVEGA®-and placebo-treated subjects, respectively).

Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, only dystonia led to discontinuation (<1% of INVEGA®-treated subjects).

The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective disorder placebo-controlled 6-week studies in adults were 1% and <1% in INVEGA®-and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in INVEGA®-and placebo-treated subjects, respectively).

Dose-Related Adverse Reactions

Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with INVEGA®, the incidences of the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder, hypertonia, parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.

In the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the adverse reactions that occurred with >2% incidence in the subjects treated with INVEGA® , the incidences of the following adverse reactions increased with dose: tachycardia, akathisia, extrapyramidal symptoms, somnolence, and headache.

In a placebo-controlled, 6-week, high-and low-dose study in adult subjects with schizoaffective disorder, akathisia, dystonia, dysarthria, myalgia, nasopharyngitis, rhinitis, cough, and pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects who received higher doses of INVEGA® compared with subjects who received lower doses.

Demographic Differences

An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and in the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder did not reveal any evidence of clinically relevant differences in safety on the basis of gender or race alone; there was also no difference on the basis of age [see Use In Specific Populations].

Extrapyramidal Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS (Table 7), and (4) incidence of spontaneous reports of EPS (Table 8). For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and INVEGA® 3 mg and 6 mg doses for any of these EPS measures.

Table 7: Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication - Schizophrenia Studies in Adults

Table 8: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term - Schizophrenia Studies in Adults

Compared to data from the studies in adults subjects with schizophrenia, pooled data from the two placebo-controlled 6-week studies in adult subjects with schizoaffective disorder showed similar types and frequencies of EPS as measured by rating scales, anticholinergic medication use, and spontaneous reports of EPS-related adverse events. For subjects with schizoaffective disorder, there was no dose-related increase in EPS observed for parkinsonism with the Simpson-Angus scale or akathisia with the Barnes Akathisia Rating Scale. There was a dose-related increase observed with spontaneous EPS reports of hyperkinesia and dystonia and in the use of anticholinergic medications.

Table 9 shows the EPS data from the pooled schizoaffective disorder trials.

Table 9: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term - Schizoaffective Disorder Studies in �Adults

The incidences of EPS-related adverse events in the adolescent schizophrenia studies showed a similar dose-related pattern to those in the adult studies. There were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies (Table 10).

Table 10: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term - Schizophrenia Studies in Adolescent Subjects

Class Effect

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between INVEGA® and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between INVEGA® and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, INVEGA® was associated with increases in serum prolactin [see WARNINGS AND PRECAUTIONS].

Other Adverse Reactions Observed During Premarketing Evaluation Of INVEGA®

The following additional adverse reactions occurred in < 2% of INVEGA®-treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by INVEGA®-treated subjects who participated in other clinical studies.

Cardiac disorders: bradycardia, palpitations

Eye disorders: eye movement disorder

Gastrointestinal disorders: flatulence

General disorders: edema

Immune system disorders: anaphylactic reaction

Infections and infestations: urinary tract infection

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased

Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity

Nervous system disorders: opisthotonus

Psychiatric disorders: agitation, insomnia, nightmare

Reproductive system and breast disorders: breast discomfort, menstruation irregular, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: pruritus, rash

Vascular disorders: hypertension

The safety of INVEGA® was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGA® in adults with schizophrenia [see Clinical Studies]. In general, adverse reaction types, frequencies, and severities during the initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse reactions reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of INVEGA®; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, ileus, priapism, swollen tongue, tardive dyskinesia, urinary incontinence, urinary retention.

Adverse Reactions Reported With Risperidone

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.

Read the entire FDA prescribing information for Invega (Paliperidone)

Atypical or second-generation antipsychotic agent.1 2 3 4 5 6 7 8 12 39 41

Absorption

Bioavailability

Absolute oral bioavailability is 28%; single-dose peak plasma concentrations attained approximately 24 hours after dosing.1

Food

Food increases rate and extent of absorption, and possible increase in exposure.1

Special Populations

Decreased bioavailability in patients with decreased GI transit time (e.g., diarrhea); increased bioavailability in patients with increased GI transit time (e.g., GI neuropathy, diabetic gastroparesis).1 Changes in bioavailability more likely when transit time changes occur in the upper GI tract.1 (See GI Effects under Cautions.)

Distribution

Extent

Not known whether paliperidone crosses the placenta.1 Risperidone (the parent drug of paliperidone) crosses the placenta in rats.1 Paliperidone is distributed into human milk.a

Plasma Protein Binding

74%.1

Special Populations

In mild to moderate hepatic impairment (Child-Pugh class B); decreased total paliperidone exposure due to decreased protein binding.1 (See Hepatic Impairment under Dosage and Administration.)

Elimination

Metabolism

In vitro studies suggested a role for CYP2D6 and CYP3A4; however, in vivo results suggest a limited role.1 39

Elimination Route

Paliperidone and its metabolites excreted in urine (80%), mainly as unchanged drug, and in the feces (11%).1 39

Half-life

Terminal half-life is approximately 23 hours.1 39 41

Special Populations

In patients with renal impairment, mean plasma terminal half-life is 24, 40, and 51 hours in individuals with mild, moderate, and severe renal impairment, respectively.1 (See Renal Impairment under Dosage and Administration.)

No difference in exposure or clearance of paliperidone between extensive metabolizers and poor metabolizers of CYP2D6.1

Take this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

You may take this medicine with or without food.

Swallow the extended-release tablet whole with a liquid (water or juice). Do not crush, break, or chew it.

Part of the tablet may pass into your stool after your body has absorbed the medicine. This is normal and is nothing to worry about.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (extended-release tablets):
  • For schizophrenia:
    • Adults—At first, 6 milligrams (mg) once a day, every morning. Some patients may need 3 mg per day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 12 mg per day.
    • Children 12 to 17 years of age and weighs 51 kg (112 lbs) or more—At first, 3 mg once a day, every morning. Your doctor may increase your dose if needed. However, the dose is usually not more than 12 mg per day.
    • Children 12 to 17 years of age and weighs less than 51 kg (112 lbs)—At first, 3 mg once a day, every morning. Your doctor may increase your dose if needed. However, the dose is usually not more than 6 mg per day.
    • Children younger than 12 years of age—Use and dose must be determined by your doctor.
  • For schizoaffective disorder:
    • Adults—At first, 6 milligrams (mg) once a day, every morning. Some patients may need 3 mg per day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 12 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Potential for Invega® to Affect Other Drugs

Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)], Invega® should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.

Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when Invega® is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.9)].

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed 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-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown.

Pharmacokinetic interaction between lithium and Invega® is unlikely.

In a drug interaction study, co-administration of Invega® (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when Invega® 3–15 mg/day was added to their existing valproate treatment.

Potential for Other Drugs to Affect Invega®

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate.

Co-administration of Invega® 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of Invega® should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of Invega® should be re-evaluated and decreased if necessary.

Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3)]. In an interaction study in healthy subjects in which a single 3 mg dose of Invega® was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.

Co-administration of a single dose of Invega® 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for Invega® should be considered when Invega® is co-administered with valproate after clinical assessment.

Pharmacokinetic interaction between lithium and Invega® is unlikely.

NDC 50458-550-01

Invega®
PALIPERIDONE
Extended-Release Tablets

3mg

Tablets should be swallowed whole.
Do not divide, crush, or chew.
Invega should be taken once daily.

Rx only

30 Tablets

janssen

You should not use Invega if you are allergic to paliperidone or risperidone (Risperdal).

Invega can cause a serious movement disorder that may not be reversible. Symptoms of this disorder include uncontrollable muscle movements of your lips, tongue, eyes, face, arms, or legs. The longer you use paliperidone, the more likely you are to develop a serious movement disorder. The risk of this side effect is higher in women and older adults.

To make sure Invega is safe for you, tell your doctor if you have ever had:

• heart disease, heart attack, heart rhythm disorder, long QT syndrome;

• high or low blood pressure, or fainting spells;

• low white blood cell (WBC) counts;

• a stomach or intestinal disorder;

• liver or kidney disease;

• seizures or epilepsy;

• breast cancer;

• suicidal thoughts;

• an electrolyte imbalance (such as low potassium or magnesium levels in your blood);

• diabetes (paliperidone may raise your blood sugar); or

• a serious neurologic disorder caused by taking an antipsychotic medicine.

Tell your doctor if you are pregnant or plan to become pregnant while using Invega.

Taking antipsychotic medication during the last 3 months of pregnancy may cause problems in the newborn, such as withdrawal symptoms, breathing problems, feeding problems, fussiness, tremors, and limp or stiff muscles. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you become pregnant while taking Invega, do not stop taking it without your doctor's advice.

Paliperidone can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

Older adults may be more sensitive to the effects of this medicine.

Get emergency medical help if you have signs of an allergic reaction to Invega: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking Invega and call your doctor at once if you have any of these signs of a serious movement disorder:

• tremors or shaking in your arms or legs;

• uncontrolled muscle movements in your face (chewing, lip smacking, frowning, tongue movement, blinking or eye movement); or

• any new or unusual muscle movements you cannot control.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;

• thoughts about suicide or hurting yourself;

• breast swelling (in women or men), nipple discharge;

• changes in menstrual periods;

• impotence, penis erection that is painful or lasts 4 hours or longer;

• weight gain;

• low white blood cell counts - sudden weakness or ill feeling, fever, chills, sore throat, mouth sores, swollen gums, pain when swallowing, skin sores, cough, trouble breathing;

• high blood sugar - increased thirst, increased urination, hunger, fruity breath odor; or

• severe nervous system reaction - very stiff (rigid) muscles, high fever, fast or pounding heartbeats, fainting.

Common Invega side effects may include:

• drowsiness;

• anxiety, feeling restless;

• tremors or shaking;

• uncontrolled muscle movements, problems with balance or walking;

• neck stiffness;

• weight gain; or

• fast heart rate.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Summary of Use during Lactation

Although no data are available for the use of paliperidone during breastfeeding, it is the active metabolite of risperidone. Risperidone data indicate that the concentrations of paliperidone (9-hydroxyrisperidone) in breastmilk are low, and amounts ingested by the infant are small. Because there is no published experience with paliperidone during breastfeeding and little long-term follow-up data, other agents may be preferred, especially while nursing a newborn or preterm infant. Because paliperidone is available only as a sustained-release product, timing of nursing with respect to doses would not be useful.

Drug Levels

Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone. No studies have measured paliperidone in breastmilk after administration of paliperidone. However, 9-hydroxyrisperidone has been measured in milk and plasma after administration of risperidone.

Maternal Levels. The manufacturer reports that the average adult plasma concentration of paliperidone after the maximum dose of 12 mg daily is about 37 mcg/L.[1] Using the average milk-to-plasma ratio of 9-hydroxyrisperidone of 0.3 from 3 reports of risperidone use during breastfeeding,[2][3][4] the average milk concentration would be expected to be about 11 mcg/L or a dose of 1.7 mcg/kg daily. An exclusively breastfed infant would receive an average of less than 1% of the maternal weight-adjusted dosage with this maternal dosage.

Infant Levels. In 2 breastfed infants (6 weeks and 3.3 months old) whose mothers were taking 2 mg of risperidone twice daily and 1.5 mg daily in 2 divided doses, respectively, risperidone and 9-hydroxyrisperidone were both undetectable (<1 mcg/L) in the serums of the infants.[3]

An infant was breastfed 6 times daily during maternal therapy with risperidone 2 mg once daily. Fifteen hours after the mother's last dose, the infant's plasma levels of risperidone was undetectable and 9-hydroxyrisperidone was 0.1 mcg/L.[4]

Effects in Breastfed Infants

No published information on paliperidone was found as of the revision date. However, limited data from the use of its parent drug, risperidone, during nursing indicate no short- or long-term adverse effects on the infant.[3][4][5]

Effects on Lactation and Breastmilk

Paliperidone has caused elevated prolactin serum levels, gynecomastia, and galactorrhea in patients taking the drug.[6][7][8][9][10][11] The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

Alternate Drugs to Consider

Haloperidol, Olanzapine

References

1. Food and Drug Administration. Drug approval package. Invega (paliperidone) extended-release tablets. 2006;127. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021999s000_TOC.cfm

2. Hill RC, McIvor RJ, Wojnar-Horton RE et al. Risperidone distribution and excretion into human milk: case report and estimated infant exposure during breast-feeding. J Clin Psychopharmacol. 2000;20:285-6. Letter. PMID: 10770482

3. Ilett KF, Hackett LP, Kristensen JH et al. Transfer of risperidone and 9-hydroxyrisperidone into human milk. Ann Pharmacother. 2004;38:273-6. PMID: 14742766

4. Aichhorn W, Stuppaeck C, Whitworth AB. Risperidone and breast-feeding. J Psychopharmacol. 2005;19:211-3. PMID: 15728443

5. Ratnayake T, Libretto SE. No complications with risperidone treatment before and throughout pregnancy and during the nursing period. J Clin Psychiatry. 2002;63:76-7. PMID: 11838633

6. Davidson M, Emsley R, Kramer M et al. Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone er): results of a 6-week, randomized, placebo-controlled study. Schizophr Res. 2007;93:117-30. PMID: 17466492

7. Kane J, Canas F, Kramer M et al. Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophr Res. 2007;90:147-61. PMID: 17092691

8. Marder SR, Kramer M, Ford L et al. Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study. Biol Psychiatry. 2007;62:1363-70. PMID: 17601495

9. Macaluso M, Khan AY. A 19-year-old Black woman with psychotic and depressive symptoms. Psychiatr Ann. 2008;38:312-4.

10. Skopek M, Manoj P. Hyperprolactinaemia during treatment with paliperidone. Australas Psychiatry. 2010;18:261-3. PMID: 20429680

11. Einarson TR, Hemels ME, Nuamah I ete al. An analysis of potentially prolactin-related adverse events and abnormal prolactin values in randomized clinical trials with paliperidone palmitate. Ann Pharmacother. 2012;46:1322-30. PMID: 22947594