Consumer medicine information

Invega

Paliperidone

BRAND INFORMATION

Brand name

Invega

Active ingredient

Paliperidone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Invega.

What is in this leaflet

This leaflet answers some of the common questions about Invega. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

If you have any concerns about using Invega, ask your doctor or pharmacist. Your doctor and pharmacist have more information.

Keep this leaflet with your medicine. You may need to read it again.

What Invega is used for

Invega belongs to a group of medicines called antipsychotic agents which improve the symptoms of certain types of mental illness.

It is used to treat symptoms of schizophrenia, a mental illness with disturbances in thinking, feelings and behaviour. It is also used to treat other types of related psychoses. Invega helps to correct a chemical imbalance in the brain associated with these conditions.

Invega tablets are formulated with a special shell that controls the release of the active ingredient gradually throughout the day. The tablet shell does not dissolve completely after all the drug has been released and sometimes the tablet shell may be seen in your stool. This is normal.

Your doctor, however, may prescribe this medicine for another use.

Ask your doctor if you have any questions about why it has been prescribed to you.

Invega is not addictive.

Before you take it

When you must not take it

Do not take Invega if you know you are allergic to any of its ingredients listed at the end of this leaflet or medicines containing risperidone (e.g. RISPERDAL). Signs of allergy may include skin rash, itching, shortness of breath, and/or swollen face or tongue.

Do not take it after the expiry date printed on the pack. If you take it after the expiry date has passed, it may not work as well.

Do not take it if the packaging is torn or shows signs of being tampered with.

Do not take it if the tablets appearance has changed.

Do not take it to treat any other complaints unless your doctor says it is safe to do so.

Before you start to take it

Invega should be used with caution in some people, particularly those who have been diagnosed with more than one medical condition.

  1. Before you start taking Invega, make sure you tell your doctor if you have, or have ever had, the following:
  • Neuroleptic Malignant Syndrome (a serious reaction to some medicines that causes a sudden increase in body temperature, very fast heartbeat, extremely high or low blood pressure and severe muscle stiffness or fits)
  • Tardive dyskinesia (a reaction to some medicines with involuntary movements of the tongue, face, mouth, jaws, arms, legs or trunk)
  • irregular heart rhythm, high or low blood pressure or you've had a heart attack or stroke in the past
  • you are prone to dizziness when standing up from a lying or sitting position
  • unusual, excessive sweating or diarrhoea, dehydration or problems with your body temperature regulation
  • epilepsy, fits, seizures
  • involuntary movements or unusual restlessness or difficulty sitting still
  • Parkinson's Disease (a progressive movement and thinking disorder that tends to affect older people)
  • suicidal thoughts or past suicide attempts
  • inflammation of the lungs due to aspiration (the inhalation of food particles or fluids into the lungs).
  • any problems with swallowing, or stomach or intestinal disorders that reduces your ability to keep food down and/or pass normal bowel movements
  • kidney or liver problems
  • any problems with confusion or unsteadiness
  • dementia or Lewy body dementia.
    Older people suffering dementia may be at an increased risk of stroke or death with Invega.
  • Sugar diabetes
  • unusual thirst, tiredness, blurred vision, upset stomach or need to urinate - common signs of high blood sugars
  • stroke or other brain blood vessel problems
  • continuous and/or painful erections (called 'priapism')
  • low white blood cell count
    If you have low numbers of some white blood cells, your risk of contracting an infection or developing a fever is increased with Invega.
  • blood clots
    Tell your doctor if you or someone else in your family has a history of blood clots. Blood clots in the lungs and legs can occur with Invega. Blood clots in the lungs can result in death.
  1. Tell your doctor if:
  • you have any eye surgery planned.
    Your doctor will need to assess whether you are at increased risk of a surgical complication (called 'Intraoperative Floppy Iris Syndrome'. You may be recommended to stop Invega temporarily leading up to your eye surgery
  • you are pregnant or are planning to become pregnant.
    Your doctor will advise you whether you should take Invega.
    Newborn babies of mothers taking Invega in their last trimester may be at risk of having difficulty feeding or breathing, shaking, muscle stiffness and/or weakness, sleepiness or agitation.
  • you are breast feeding.
    As Invega is excreted in breast milk. It is recommended that you do not breast-feed while taking it.
  1. Other medicines and alcohol

You should not drink alcohol while taking Invega.
Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.
In particular tell your doctor if you are taking:
  • sleeping tablets, tranquillisers, pain-killers, or some allergy medications called antihistamines
  • medicines to treat epilepsy
  • medicines to treat depression, panic disorder, anxiety or obsessive-compulsive disorder
  • medicines that increase the activity of the central nervous system (psychostimulants such as methylphenidate)
  • any medicines to treat irregular heart rhythms or heart failure
  • any medicines to treat high blood pressure, including water tablets (diuretics)
  • other medicines to treat mental illnesses or psychotic conditions
  • medicines to relieve nausea or vomiting, indigestion, reflux or other stomach problems
  • some medicines to treat malaria.
    Your doctor will need to consider whether any of the above medicines will affect your Invega.
  1. Older People

Your doctor may adjust your dose based on your kidney function.

Taking it for the first time

At the start of treatment you may have a fall in blood pressure making you feel dizzy on standing up, or your heart may beat faster. These should go away after a few days. Tell your doctor if these symptoms continue or worry you.

How to take it

Your doctor will decide the Invega strength and dose most suitable for you.

Invega should be taken once daily, in the morning, at about the same time each day.

You should decide whether you will always take Invega on an empty stomach before breakfast, or always with food at breakfast. You must not switch between taking Invega on an empty stomach and taking it with food.

The tablet should be swallowed whole with water or other liquid. Invega tablets must not be chewed, split or crushed.

Your doctor will decide the dose of Invega that is suitable for you, based on your condition and kidney function.

The usual dosage for Invega is between 3 mg and 12 mg once daily.

For people with severe kidney problems the starting dose may be as low as 3 mg every other day. Your doctor may later decide to increase the dose as required for best symptoms control.

Follow your doctor's instructions carefully and do not change or stop your dosage without consulting your doctor first.

Invega is not recommended for children under 18 years.

If you forget to take it

  • If you forget to take it, take the missed dose as soon as you remember. Then resume taking Invega as you normally would the following morning.
  • Do not take a double dose to make up for the one you missed.
  • If you forget to take it for a number of days or more, tell your doctor before starting your medicine again.

If you have problems remembering when to take your medicine, ask your pharmacist for some hints.

Overdose

If you think you or anybody else has taken too much Invega, contact your doctor, pharmacist or the Poisons Information Centre who will advise you what to do.

You can contact the Poisons Information Centre by dialling:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

Signs of overdose may include drowsiness, dizziness, sleepiness, excessive trembling, nausea, excessive muscle stiffness, increased heart rate, shortness of breath, very low blood pressure causing fainting or unconsciousness.

While you are using it

Things you must do

Follow your doctor's instructions carefully.

Always seek your doctor's advice before changing or stopping treatment. Your doctor will be happy to discuss any questions you may have with your treatment.

Tell your doctor if you are pregnant or planning to become pregnant.

Tell your doctor immediately if you notice any involuntary movements of the tongue, mouth, cheeks or jaw. These may be symptoms of a condition called tardive dyskinesia, which can develop in people taking antipsychotic medicines, including Invega. This condition is more likely to occur during longer term treatment and in older women. In very rare cases, these symptoms may be permanent. However, if detected early, these symptoms are usually reversible.

If any doctors, dentists or pharmacists want to start you on any new medicines listed under point 3 of 'Before you start to take it' (above), tell them you are taking Invega. Your doctor, dentist or pharmacist will need to consider whether any new medicines will affect your Invega.

Things you must not do

Do not use Invega to treat any other complaint unless your doctor says so.

Do not give this medicine to anyone else, even if their symptoms seem similar.

Do not change your dose or stop taking Invega without first checking with your doctor.

Do not drink alcohol. Invega can increase the effects of alcohol.

Things to be careful of

Ask your doctor before taking any other medicines.

Invega can increase the effects of medicines which slow your reactions. Always ask your doctor or pharmacist before taking other medicines including herbal treatments and medicines that can be bought in a pharmacy or supermarket.

Avoid driving or operating machinery until you are sure that Invega does not affect your alertness. Invega may cause dizziness, drowsiness or light-headedness in some people, especially after the first dose. Make sure you know how you react to Invega before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy.

Avoid excessive eating. There is a possibility of weight gain when taking Invega. Your doctor may monitor your body weight or recommend strategies to assist with weight management.

Side Effects

All medicines may have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

All medicines can have side effects. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Invega.

It helps most people with symptoms of schizophrenia or other types of related psychoses, but it may have unwanted side effects in a few people.

Tell your doctor if you notice any of the following and they worry you:

  • difficulty thinking, working or carrying out your usual daily activities because of:
    - nausea
    - headache
    - trembling, muscle weakness, unsteadiness on your feet or lack of coordination
    - sleeplessness, drowsiness, tiredness, lack of energy or difficulty in concentrating
  • behavioural changes such as:
    - unexplained confusion or agitation
    - unusual anxiety or depression
    - elated mood
    - lack of emotion
  • joint or movement changes such as:
    - muscle tightness or stiffness, writhing movements, spasm or muscle pain
    - unusual restlessness, repetitive or involuntary movements
    - unusual facial movements or a sustained upwards stare
  • other changes such as:
    - unexplained increased appetite or weight gain
    - diarrhoea, indigestion, heartburn, abdominal pain, constipation
    - "flu-like" symptoms, cough, stuffy nose
    - inability to or pain when passing urine
    - dry mouth, distorted taste sensation, unexplained salivation or drooling
    - acne
    - dry skin
    - reddening or discolouration of skin
    - nose bleeds
    - unusual thirst, tiredness, upset stomach or need to urinate
    - unusual secretion of breast milk, breast swelling, missed or irregular menstrual periods
    - decreased libido
    - difficulty getting or maintaining an erection; or having continuous and/or painful erections

These are mild side effects of Invega but may require medical attention.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • Signs of heart or blood pressure problems including:
    - fainting, blurry vision, light-headedness or dizziness, particularly on standing, that persists despite sitting or lying down
    - very fast heart rate or heart rhythm irregularities
  • signs of high blood sugar or diabetes such as:
    - unusual thirst, tiredness, upset stomach or need to urinate more often than usual
  • body temperature changes such as:
    - fever
    - unexplained high body temperature, excessive sweating or rapid breathing
  • involuntary movement of the tongue, mouth, cheeks or jaw
  • severe or life-threatening rash with blisters and peeling skin that may start in and around the mouth, nose, eyes, and genitals and spread to other areas of the body (Stevens-Johnson syndrome or toxic epidermal necrolysis).

These may be serious side effects of Invega. You may need urgent medical attention.

Serious side effects are uncommon.

If any of the following happen, stop taking Invega and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • rash, itching or hives on the skin; shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body. If you have them, you may have had a serious allergic reaction to Invega
  • sudden weakness or numbness of the face, arms, or legs, especially on one side, or instances of slurred speech (these are called mini-strokes)

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some people.

Do not hesitate to report any other side effects to your doctor or pharmacist.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using it

Storage

Keep the tablets in a dry place where the temperature stays below 25°C.

Do not store it or any medicines in the bathroom or near a sink. Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Do not use it beyond the expiry date (month and year) printed on the pack. Medicines cannot be stored indefinitely, even if stored properly.

Disposal

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Product Description

What it looks like

You can identify Invega tablets by their colour and shape. This is important because each type of tablets, contains a different amount of the active paliperidone:

  • 3 mg: White, capsule shaped tablets imprinted with "PAL 3".
  • 6 mg: Beige, capsule shaped tablets imprinted with "PAL 6".
  • 9 mg: Pink, capsule shaped tablets imprinted with "PAL 9".

All tablets come in blister packs of 28 tablets.

Ingredients

The active ingredient in Invega is paliperidone.

The tablets contain either 3 mg, 6 mg or 9 mg of paliperidone.

Inactive ingredients are carnauba wax, cellulose acetate, hyetellose, macrogol, polyethylene oxide, povidone, sodium chloride, stearic acid, butylated hydroxytoluene, hypromellose, titanium dioxide, and iron oxides. The 3 mg tablets also contain lactose monohydrate and triacetin.

Sponsor

Janssen-Cilag Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113
Telephone: 1800 226 334

NZ Office: Auckland New Zealand
Telephone: 0800 800 806

Registration Numbers

3 mg prolonged release tablet blister pack - AUST R 130502

6 mg prolonged release tablet blister pack - AUST R 130714

9 mg prolonged release tablet blister pack - AUST R 130717

This leaflet was prepared in July 2020.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Invega

Active ingredient

Paliperidone

Schedule

S4

 

1 Name of Medicine

Paliperidone.

2 Qualitative and Quantitative Composition

Invega (paliperidone) is a novel antipsychotic agent belonging to the benzisoxazole derivatives class.
Invega is available as a modified release tablet containing 3, 6, 9 and 12 mg of paliperidone.

Excipient(s) with known effect.

Lactose monohydrate - 3 mg tablet only.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modified release tablets.

3 mg.

White, capsule shaped tablets imprinted with "PAL 3".

6 mg.

Beige, capsule shaped tablets imprinted with "PAL 6".

9 mg.

Pink, capsule shaped tablets imprinted with "PAL 9".

12 mg.

Dark yellow, capsule shaped tablets imprinted with "PAL 12".
Invega utilises osmotic drug release technology, whereby osmotic pressure delivers paliperidone from the dosage form at a controlled rate. The system, which resembles a capsule shaped tablet in appearance, comprises an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug layer dome of the tablet. Each strength is identified by a unique colour overcoat and print markings. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible colour overcoat erodes quickly. Water is then imbibed through the semipermeable, rate-controlling membrane. The membrane controls the rate at which water enters the tablet core, which, in turn, controls drug delivery. The hydrophilic polymers of the core hydrate and swell, creating a gel containing paliperidone that is then pushed out through the tablet orifices. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell, along with insoluble core components.

4 Clinical Particulars

4.1 Therapeutic Indications

Invega is indicated for the treatment of schizophrenia, including acute treatment and recurrence prevention.
Invega is indicated for the treatment of acute exacerbations of schizoaffective disorder as monotherapy and in combination with antidepressants and/or mood stabilisers (lithium and valproate).

4.2 Dose and Method of Administration

The administration of Invega should be standardised in relation to food intake (see Section 5.2 Pharmacokinetic Properties). The patient should be instructed to always take Invega in the fasting state or always take it together with breakfast and not to alternate between administration in the fasting state or in the fed state.
Invega must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

Schizophrenia.

The recommended dose of Invega for the treatment of schizophrenia is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the usual range of 3 to 9 mg once daily. Dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days. When dose increases are indicated, small increments of 3 mg/day are recommended. If required the dose may be increased to the maximum recommended dose of 12 mg once daily.

Acute exacerbation of schizoaffective disorder.

The recommended dose of Invega for the treatment of schizoaffective disorder is 6 mg once daily, administered in the morning. While initial dose titration is not required, the patients would require dosage adjustment to lower or higher doses within the dose range of 3 to 12 mg once daily. There was a trend towards significant improvement compared to placebo, from low dose (3 mg) to high dose (12 mg) paliperidone. This trend must be weighed against dose related increase in adverse reactions.
Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 4 days.
Concomitant use of Invega with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is coadministered with Invega. Concomitant use of Invega with oral risperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.

Dosing in special populations.

Hepatic impairment.

No dose adjustment is required in patients with mild to moderate hepatic impairment. As Invega has not been studied in patients with severe hepatic impairment, caution is recommended when using the medicine in such patients.

Renal impairment.

Dosing must be individualised according to the patient's renal function status. For patients with mild renal impairment (creatinine clearance ≥ 50 to < 80 mL/min), the recommended initial dose is 3 mg once daily. The dose may be increased based on clinical response and tolerability. For patients with moderate renal impairment (creatinine clearance ≥ 30 to < 50 mL/min), the recommended dose of Invega is 3 mg once daily. For patients with severe renal impairment (creatinine clearance ≥ 10 to < 30 mL/min), the recommended initial dose of Invega is 3 mg every other day, which may be increased to 3 mg once daily after clinical reassessment. As Invega has not been studied in patients with creatinine clearance below 10 mL/min, use is not recommended in such patients.

Elderly.

In general, the same dosing recommendations apply for elderly patients with normal renal function as for adult patients with normal renal function (creatinine clearance ≥ 80 mL/min). However, because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status (see Section 4.2 Dose and Method of Administration, Dosing in special populations, Renal impairment).

Paediatric use.

Invega has not been studied in this patient group and should not be used in this age group.

4.3 Contraindications

Invega (paliperidone) is contraindicated in patients with a known hypersensitivity to paliperidone, risperidone or to any components in the Invega formulation.

4.4 Special Warnings and Precautions for Use

QT prolongation.

Invega was not shown to result in any clinically significant increase in QTc intervals from baseline compared to placebo. However, as with other antipsychotics, caution should be exercised when Invega is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other drugs known to increase the QTc interval particularly in elderly patients.
The effects of paliperidone on the QT interval were evaluated in a double blind, active controlled (moxifloxacin 400 mg single dose), multicentre QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo and active controlled (olanzapine 10 mg), 6 week, fixed-dose efficacy trials in adults with schizophrenia. In the QT study (n = 141), a supratherapeutic dose of an immediate release oral formulation (8 mg) resulted in a mean steady-state peak plasma concentration greater than twice the exposure observed with the maximum recommended Invega dose of 12 mg (Cmax ss = 113 and 45 nanogram/mL, respectively). In the model adjusted day averaged linear derived QT correction (QTcLD), there was a mean increase of 5.5 msec (90% CI: 3.66; 7.25) in the Invega treatment group (n = 44). None of the subjects had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study. For the three fixed dose efficacy studies, extensive electrocardiography (ECG) measurements were taken at 15 time points on specified days (including the times of expected Cmax) using a standardised methodology. Mean QTcLD increase did not exceed 5 msec in any treatment group at any time point, based on pooled data from 836 subjects treated with Invega, 357 subjects treated with olanzapine and 350 subjects treated with placebo. One subject each in the Invega 12 mg and olanzapine groups had a change exceeding 60 msec at one time point during these studies (changes of 62 and 110 msec, respectively). No subject receiving Invega had a QTcLD exceeding 500 msec at any time in any of these three studies.
In the pooled double blind safety analysis set, the largest mean increase in QTcLD interval, observed 22 hours after dose administration on day 8, ranged between 1.6 to 4.4 msec across Invega treatment groups.
In the overall phase 3 safety database (n = 2,054), which included both the double blind and open label extension studies, there were two patients with QTcLD prolongation > 500 msec.

Tardive dyskinesia.

A syndrome of potentially irreversible, involuntary, dyskinetic, rhythmical movements, including those of the tongue and/or face, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.
There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.
Given these considerations, Invega should be prescribed in a manner that is most likely to minimise the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with Invega, drug discontinuation should be considered. However, some patients may require treatment with Invega despite the presence of the syndrome.

Extrapyramidal symptoms.

As with other antipsychotics, extrapyramidal symptoms (EPS) including akathisia have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). The presentation of akathisia may be variable and compromises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and risk of relapse.

Extrapyramidal symptoms and psychostimulants.

Caution is warranted in patients receiving both psychostimulants (e.g. methylphenidate) and paliperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications. Gradual withdrawal of one or both treatments should be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Neuroleptic malignant syndrome.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported.

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in postmarketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycaemia or diabetes in trial subjects treated with Invega. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment emergent hyperglycaemia related adverse events in patients treated with the atypical antipsychotics. Because Invega was not marketed at the time these studies were performed, it is not known if Invega is associated with this increased risk.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Leukopoenia, neutropoenia and agranulocytosis.

Events of leukopoenia, neutropoenia and agranulocytosis have been reported with antipsychotic agents, including Invega. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during postmarketing surveillance.
Patients with a history of a clinically significant low white blood cell count (WBC) or a drug induced leukopoenia/ neutropoenia should be monitored during the first few months of therapy and discontinuation of Invega should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropoenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropoenia (absolute neutrophil count < 1 X 109/L) should discontinue Invega and have their WBC followed until recover.

Venous thromboembolism.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Invega and preventative measures undertaken.

Orthostatic hypotension.

Paliperidone may induce orthostatic hypotension in some patients based on its α-blocking activity. In pooled results of the three placebo controlled, six week, fixed dose trials in subjects with schizophrenia, syncope was reported in 0.8% (7/850) of subjects treated with Invega (3, 6, 9, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo. Invega should be used with caution in patients with known cardiovascular disease (e.g. heart failure, history of myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease or conditions that predispose the patient to hypotension (dehydration, hypovolaemia, and treatment with antihypertensive medications).
As expected based on its pharmacologic profile, treatment with Invega is associated with modest mean increases in heart rate at therapeutic doses.
Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Seizures.

During premarketing clinical trials in subjects with schizophrenia (the three placebo controlled, six week, fixed dose studies and a study conducted in elderly schizophrenic subjects), seizures occurred in 0.22% of subjects treated with Invega (3, 6, 9, 12 mg) and 0.25% of subjects treated with placebo.
As with other antipsychotic drugs, Invega should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Hyperprolactinaemia.

As with other drugs that antagonise dopamine D2-receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia and impotence have been reported with prolactin elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumourigenesis in humans; the available evidence is considered too limited to be conclusive at this time (see Section 5.3 Preclinical Safety Data).

Dysphagia.

Oesophageal dysmotility and aspiration have been associated with antipsychotic drug use. Invega and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Weight gain.

As with other atypical antipsychotics, weight gain has been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Clinical monitoring of weight is recommended.

Suicide.

The possibility of suicide attempt is inherent in psychotic illnesses, and close supervision of high risk patients should accompany drug therapy. Prescriptions for Invega should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

Potential for cognitive and motor impairment.

Somnolence and sedation were reported in subjects treated with Invega (see Section 4.8 Adverse Effects (Undesirable Effects)). Antipsychotics, including Invega, have the potential to impair judgment, thinking or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.

Priapism.

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Severe priapism may require surgical intervention. Priapism has been reported with paliperidone during postmarketing surveillance (see Section 4.8 Adverse Effects (Undesirable Effects)).

Body temperature regulation.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Invega to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity or being subject to dehydration.

Gastrointestinal.

Because the Invega tablet is nondeformable and does not appreciably change in shape in the gastrointestinal tract, Invega should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic, for example: oesophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled release formulations. Because of the controlled release design of the tablet, Invega should only be used in patients who are able to swallow the tablet whole.
A decrease in transit time, e.g. as seen with diarrhea, would be expected to decrease bioavailability and an increase in transit time, e.g. as seen with gastrointestinal neuropathy, diabetic gastroparesis, or other causes, would be expected to increase bioavailability. These changes in bioavailability are more likely when the changes in transit time occur in the upper GI tract.

Antiemetic effect.

An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdose with certain drugs or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumour.

Intraoperative floppy iris syndrome.

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including Invega (see Section 4.8 Adverse Effects (Undesirable Effects)). IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

Use in renal impairment.

The plasma concentrations of paliperidone are increased in patients with renal impairment and, therefore, dosage adjustment may be required in patients with mild (creatinine clearance ≥ 50 to < 80 mL/min) and moderate to severe (creatinine clearance 10 to < 50 mL/min) renal impairment (see Section 4.2 Dose and Method of Administration; Section 5 Pharmacological Properties). No data are available in patients with a creatinine clearance below 10 mL/min. Paliperidone should not be used in patients with creatinine clearance below 10 mL/min.

Use in hepatic impairment.

No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if Invega is used in such patients. In a study in subjects with moderate hepatic impairment (Child-Pugh class B), 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 (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

The safety, tolerability, and efficacy of Invega were evaluated in a 6 week placebo controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom 21 were 75 years of age and older). In this study, 76 subjects received flexible doses of Invega (3 to 12 mg once daily). In addition, a small number of subjects 65 years of age and older were included in the 6 week placebo controlled studies in which adult schizophrenic subjects received fixed doses of Invega (3 to 15 mg once daily) (see Section 5 Pharmacological Properties).
Overall, of the total number of subjects in clinical studies of Invega (n = 1,796), including those who received Invega or placebo, 125 (7.0%) were 65 years of age and older, of whom 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (also see Orthostatic hypotension in this section).
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Section 4.2 Dose and Method of Administration).

Use in elderly patients with dementia.

Invega has not been studied in elderly patients with dementia.

Overall mortality.

Elderly patients with dementia related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of 17 placebo controlled trials (modal duration of 10 weeks) in these subjects revealed a risk of death in the drug treated subjects of between 1.6 to 1.7 times that seen in placebo treated subjects. Over the course of a typical ten week controlled trial, the rate of death in drug treated subjects was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature. Invega is not approved for the treatment of patients with dementia related psychosis.

Cerebrovascular adverse events.

In placebo controlled trials in elderly patients with dementia treated with some atypical antipsychotic drugs, including risperidone, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities, compared to placebo.
In placebo controlled trials in elderly patients with dementia there was a significantly higher incidence of cerebrovascular adverse events, such as stroke (including fatalities) and transient ischaemic attacks, in patients (mean age 85 years, range 73-97) treated with risperidone compared to patients treated with placebo. The pooled data from six placebo controlled trials in mainly elderly patients (> 65 years of age) with dementia showed that cerebrovascular adverse events (serious and nonserious combined) occurred in 3.3% (33/989) of patients treated with risperidone and 1.2% (8/693) of patients treated with placebo. The odds ratio (95% exact confidence interval) was 2.96 (1.33, 7.45).

Use in children and adolescents younger than 18 years.

Safety and effectiveness of Invega in patients < 18 years of age have not been studied.

Use in patients with concomitant illness.

Clinical experience with Invega in patients with certain concomitant illnesses is limited.
Patients with Parkinson's disease or dementia with Lewy bodies who receive antipsychotics, including Invega, may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medication. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
The safety of use of Invega has not been evaluated in patients with relevant history of a significant or unstable cardiovascular or neurologic (including cerebrovascular) disease, a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension with Invega, caution should be observed in patients with known cardiovascular disease (see Section 4.4 Special Warnings and Precautions for Use).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The risks of using Invega in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of Invega, it should be used with caution in combination with other centrally acting drugs.

Use with medicines known to cause QT prolongation.

Caution is advised when Invega is used in combination with medicines known to cause QT prolongation, e.g. class IA antiarrhythmics (e.g. quinidine, disopyramide) and class III antiarrhythmics (e.g. amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g. mefloquine).

Use with medicines containing risperidone.

Concomitant use of Invega with oral risperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.

Use with psychostimulants.

The combined use of psychostimulants (e.g. methylphenidate) with paliperidone can lead to the emergence of extrapyramidal symptoms upon change of either or both treatments (see Section 4.4 Special Warnings and Precautions for Use).

Potential for Invega to affect other medicines.

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolised by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolised 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 metabolised by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.
Given the primary CNS effects of paliperidone (see Section 4.8 Adverse Effects (Undesirable Effects)), Invega should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonise the effect of levodopa and other dopamine agonists. Caution is advised when paliperidone is combined with medicines known to lower the seizure threshold (e.g. phenothiazines or butyrophenones, tricyclics or SSRIs, tramadol, mefloquine, etc.)
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 Section 4.4 Special Warnings and Precautions for Use).
Pharmacokinetic interaction between Invega and lithium is unlikely.
Coadministration of Invega at steady state (12 mg once daily) with divalproex sodium extended release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.

Potential for other medicines to affect Invega.

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP3A5. This suggests 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, there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone.
In vitro studies have shown that paliperidone is a P-gp substrate.
Paliperidone is metabolised to a limited extent by CYP2D6 (see Section 5 Pharmacological Properties). In an interaction study in healthy males who were CYP2D6 extensive metabolisers, single doses of Invega 3 mg were administered alone or after treatment with the potent CYP2D6 inhibitor paroxetine, 20 mg daily for 13 days. The mean peak plasma concentration and systemic exposure of unbound paliperidone were increased by 12% and 19%, respectively. This effect is unlikely to be clinically significant.
Coadministration of Invega once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. The decrease may be greater with higher carbamazepine doses. On initiation of carbamazepine or when increasing the dose of carbamazepine, the dose of Invega should be re-evaluated and increased if necessary. Conversely, on discontinuation or dose reduction of carbamazepine, the dose of Invega should be re-evaluated and decreased if necessary.
Paliperidone, a cation under physiological pH, is primarily excreted unchanged by the kidneys, approximately half via filtration and half via active secretion. Concomitant administration of trimethoprim, a drug known to inhibit active renal cation drug transport, did not influence the pharmacokinetics of paliperidone.
Medicinal products affecting gastrointestinal transit time may affect the absorption of paliperidone, e.g. metoclopramide.
Coadministration 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 coadministered with valproate after clinical assessment.
Pharmacokinetic interaction between lithium and Invega is unlikely.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Mating and fertility of male and female rats were not affected at oral paliperidone doses up to 2.5 mg/kg/day (twice the maximum recommended clinical dose based on body surface area (mg/m2)). The 2.5 mg/kg/day dose produced slight maternal toxicity, increased preimplantation loss and slightly reduced the number of live embryos; the no effect dose was 0.63 mg/kg/day.
In rat fertility studies with risperidone, which is extensively converted to paliperidone in rats and humans, mating (but not fertility) was impaired at doses 0.2 to 5 times the maximum human dose on a mg/m2 basis, by an effect on females. In repeat dose toxicity studies in beagle dogs, risperidone at doses of 1 to 17 times the maximum human dose on a mg/m2 basis was associated with adverse effects on the male reproductive system (inhibited ejaculation, incomplete spermatogenesis, reduced sperm motility and concentration, reduced gonadal and prostatic weight, prostatic immaturity, decreased serum testosterone). Serum testosterone and sperm parameters partially recovered but remained decreased after treatment was discontinued. No effect doses were not determined in either rat or dog.
(Category C)
The safety of Invega during human pregnancy has not been established.
A retrospective observational cohort study based on a US claims database compared the risk of congenital malformations for live births among women with and without antipsychotic use during the first trimester of pregnancy. Paliperidone, the active metabolite of risperidone, was not specifically evaluated in this study. The risk of congenital malformations with risperidone, after adjusting for confounder variables available in the database, was elevated compared to no antipsychotic exposure (relative risk = 1.26, 95% CI: 1.02-1.56). No biological mechanism has been identified to explain these findings and teratogenic effects have not been observed in non-clinical studies.

Nonteratogenic class effect.

Neonates exposed to antipsychotic drugs (including Invega) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been postmarket reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeling disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited; in other cases neonates have required additional medical treatment or monitoring.
Invega should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.
 In animal studies with paliperidone and human studies with risperidone, paliperidone is excreted in milk. Women receiving Invega should not breastfeed.
Oral administration of paliperidone to rats from early gestation to lactation was associated with adverse effects in pups (clinical signs, reduced bodyweight gain and survival, impaired righting reflex) during lactation at doses similar to the maximal recommended clinical dose on mg/m2 basis; the no effect dose was less than the clinical dose. In risperidone studies in rats, oral administration of risperidone during late gestation and lactation was associated with increased pup deaths during early lactation at doses 0.2 to 5 times the maximum human dose on a mg/m2 basis (a no effect dose was not determined) and with reduced pup weight gain at doses fivefold or greater than the maximal recommended human dose on a mg/m2 basis. There were also increases in stillborn rat pups at an oral risperidone dose 2.5 to 5 times the maximum human dose on a mg/m2 basis. It is not known whether these effects of risperidone and paliperidone resulted from a direct effect on the fetuses and pups and/or to an effect on the dams.

4.7 Effects on Ability to Drive and Use Machines

Invega may interfere with activities requiring mental alertness and may have visual effects (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety of Invega in the treatment of schizophrenia was evaluated in 1205 adult subjects with schizophrenia who participated in 3 double blind, placebo controlled 6 week trials, of whom 850 subjects received Invega at fixed doses ranging from 3 mg to 12 mg once daily.
The safety of Invega was also evaluated in 622 subjects with schizoaffective disorder who participated in two double blind, placebo controlled, 6 week 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 doses of Invega adjusted in the range of 3-12 mg once daily during the first 2 weeks (mean dose = 8.9 mg/day), with doses fixed thereafter. Both studies included subjects who received Invega either as monotherapy or in combination with antidepressants and/or mood stabilisers.
The information in this section was derived from pooled data.
The majority of adverse drug reactions (ADRs) were mild to moderate in severity.

Double blind, placebo controlled data: schizophrenia.

Adverse drug reactions reported by ≥ 2% of Invega treated subjects in the three 6 week double blind, placebo controlled, fixed dose schizophrenia trials are shown in Table 1.

Double blind, placebo controlled data: schizoaffective disorder.

ADRs reported by ≥ 2% of Invega treated subjects in the two placebo controlled schizoaffective disorder trials are shown in Table 2.

Other clinical trial data.

Paliperidone is the active metabolite of risperidone, therefore the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. This subsection includes additional ADRs reported with paliperidone and/or risperidone in clinical trials.
ADRs reported with paliperidone and/or risperidone by ≥ 2% of Invega treated subjects in a pooled dataset of the 9 double blind, placebo controlled schizophrenia, schizoaffective disorder, and other unapproved indication trials are shown in Table 3.
ADRs reported with paliperidone and/or risperidone by < 2% of Invega-treated subjects in a pooled dataset of the 9 double blind, placebo controlled schizophrenia, schizoaffective disorder, and other unapproved indication trials are shown in Table 4.
ADRs reported with paliperidone and/or risperidone in other clinical trials but not reported by Invega (3-12 mg) treated subjects in a pooled dataset of the 9 double blind, placebo controlled schizophrenia, schizoaffective disorder, and other unapproved indication trials are shown in Table 5.

Monotherapy versus combination therapy.

The designs of the two placebo controlled, 6 week, double blind trials in subjects with schizoaffective disorder included the option for subjects to receive antidepressants (except monoamine oxidase inhibitors) and/or mood stabilisers (lithium, valproate, or lamotrigine). In the subject population evaluated for safety, 230 (55%) subjects received Invega as monotherapy and 190 (45%) subjects received Invega in combination with antidepressants and/or mood stabilisers. 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.

Schizophrenia trials.

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

Schizoaffective disorder trials.

In a placebo controlled, 6 week high and low dose study in subjects with schizoaffective disorder, dystonia, dysarthria, and nasopharyngitis occurred more frequently (i.e. a difference of at least 3%) in subjects who received higher doses of Invega compared with subjects who received lower doses. Hypertonia occurred more frequently in subjects who received lower doses of Invega compared with subjects who received higher doses.

Dose related adverse events.

Based on the pooled data from the three placebo controlled, six week, fixed dose schizophrenia studies, adverse events that occurred with 2% or more incidence in the subjects treated with Invega, the incidences of the following adverse events increased with dose: somnolence, orthostatic hypotension, salivary hypersecretion, akathisia, dystonia, extrapyramidal disorder, hypertonia and parkinsonism. For most of these, the increased incidence was seen primarily at the 12 mg and, in some cases, the 9 mg dose.
In the placebo controlled, 6 week high and low dose study in subjects with schizoaffective disorder, dystonia, dysarthria, and nasopharyngitis occurred more frequently (i.e. a difference of at least 3%) in subjects who received higher doses of Invega compared with subjects who received lower doses. Hypertonia occurred more frequently in subjects who received lower doses of Invega compared with subjects who received higher doses.

Extrapyramidal symptoms (EPS).

Pooled data from the three placebo controlled, six week, fixed dose studies in subjects with schizophrenia provided information regarding treatment emergent EPS and dose relatedness for EPS with the two higher doses of Invega (9 and 12 mg once daily). Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates EPS related symptoms, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale total score (mean change from baseline) which evaluates dyskinesia, (4) incidence of spontaneous reports of EPS, and (5) use of anticholinergic medications to treat emergent EPS. For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose related increase observed for the 9 and 12 mg doses. There was no difference observed between placebo and Invega 3 and 6 mg doses for any of these EPS measures. See Tables 6 and 7.
Table 8 shows the EPS data from the pooled schizoaffective disorder trials.
Compared to data from the studies in schizophrenia, pooled data from the two placebo controlled 6 week studies in 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.

Laboratory test abnormalities.

In the pooled data from the three placebo controlled, six week, fixed dose schizophrenia studies, a between group comparison revealed no medically important differences between Invega and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, haematology or urinalysis parameters. Similarly, there were no differences between Invega and placebo in the incidence of discontinuations due to changes in haematology, 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 Section 4.4 Special Warnings and Precautions for Use).

Weight gain.

In the pooled data from the three placebo controlled and active controlled (olanzapine), six week, fixed-dose schizophrenia studies, the proportions of subjects meeting a weight gain criterion of ≥ 7% of bodyweight were compared. Weight gain incidence for Invega 3 mg, 6 mg, 9 mg and 12 mg was 7%, 6%, 9% and 9% respectively. In comparison the incidence for placebo was 5%.
In the pooled data from the two placebo controlled, 6 week studies in subjects with schizoaffective disorder, a higher percentage of Invega treated subjects (5%) had an increase in bodyweight of ≥ 7% compared with placebo treated subjects (1%). In the study that examined high and low dose groups, the increase in bodyweight of ≥ 7% was 3% in the low dose group, 7% in the high dose group, and 1% in the placebo group.

Other findings observed during clinical studies.

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 Section 5.1 Pharmacodynamic Properties). 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 data.

Adverse events first identified as ADRs during postmarketing experience with paliperidone and/or risperidone are included in Table 9.
Very common: ≥ 1/10; Common: ≥ 1/100 to < 1/10; Uncommon ≥ 1/1,000 to < 1/100; Rare: ≥ 1/10,000 to < 1/1,000; Very Rare: < 1/10,000, including isolated reports; Unknown: cannot be estimated from the available clinical trial data.

Adverse events reported with risperidone.

Paliperidone is the major active metabolite of risperidone. Adverse events reported with risperidone can be found in the Adverse Effects (Undesirable Effects) section of the risperidone Product Information.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials, the highest estimated ingestion of Invega was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e. drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in the setting of overdose with oral paliperidone.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

Management of overdose.

There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the prolonged release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered.
In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered.
The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyride, procainamide, and quinidine carry a theoretical hazard of additive QT prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly, the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension.
Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (adrenaline and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Paliperidone is a centrally active dopamine D2-antagonist with predominant serotonergic 5HT2A antagonistic activity. Paliperidone is also active as an antagonist at α1 and α2-adrenergic receptors and H1-histaminergic receptors. 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. Paliperidone is the major active metabolite of risperidone.
The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2A) receptor antagonism. Antagonism at receptors other than D2 and 5HT2A may explain some of the other effects of paliperidone.

Polysomnography.

Centrally acting medications through their mechanism of action, drug release profile, and/or time of dose administration may affect sleep. To evaluate the impact of morning dosing of Invega on sleep architecture and continuity, a placebo controlled study was conducted in 36 subjects with schizophrenia in which Invega 9 mg or placebo was administered once daily for 14 days. The following observations were made (mean data compared with placebo): reduced latency to persistent sleep by 41.0 (SE 18.70) minutes, decreased sleep onset latency by 35.2 (SE 14.99) minutes, decreased number of awakenings after sleep onset by 7.0 (SE 3.88) events, increased total sleep time by 52.8 (SE 24.01) minutes, increased sleep period time by 41.7 (SE 18.75) minutes, and increased sleep efficiency index by 11.0% (SE 5.00). There was also a statistically significant decrease (relative to placebo) in stage 1 sleep of 11.9 (SE 4.44) minutes and increase in stage 2 sleep of 50.7 (SE 17.67) minutes. No clinically relevant effect on REM sleep was observed.

Clinical trials.

Schizophrenia.

The efficacy of Invega (3 to 15 mg once daily) in the treatment of schizophrenia was established in three placebo controlled and active controlled (olanzapine), six week, fixed dose trials in subjects who met DSM-IV-TR criteria for schizophrenia. The active control was included for assay sensitivity purposes. Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganised thoughts, uncontrolled hostility/ excitement, and anxiety/ depression. Efficacy was also evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician rated scale that measures personal and social functioning in four domains of behaviour (socially useful activities including work and study, personal and social relationships, self care, and disturbing and aggressive behaviours).
In the first placebo controlled six week trial (n = 605) comparing fixed doses of paliperidone (3, 9 and 15 mg/day) with placebo, all doses were superior to placebo on the PANSS, all PANSS factors and the PSP scale.
In the second placebo controlled six week trial (n = 628) comparing fixed doses of paliperidone (6, 9 and 12 mg/day) with placebo, all doses were superior to placebo on the PANSS, all PANSS factors and the PSP scale.
In the third placebo controlled six week trial (n = 432) comparing fixed doses of paliperidone (6 and 12 mg/day) with placebo, both doses were superior to placebo on the PANSS, with the 6 mg/day dose of paliperidone superior to placebo on the PSP scale.
Additionally, in a pooled analysis of the three trials, the superiority of Invega versus placebo at each dose (3 to 15 mg once daily) was established on total PANSS (including all PANSS factors) and in the response measure of ≥ 30% reduction in PANSS total score. Each dose of Invega also showed superiority to placebo on the PSP scale demonstrating an improvement in social functioning. An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of age, race, or gender. See Table 10.
In a long-term trial designed to assess the maintenance of effect, Invega was significantly more effective than placebo in maintaining symptom control and preventing recurrence of schizophrenia symptoms. After having been treated for an acute episode for six weeks and stabilised for an additional eight weeks with Invega (doses ranging from 3 to 15 mg, flexible dosage regimen), patients were then randomised in a double blind manner to either continue on Invega or placebo until they experienced a recurrence of schizophrenia symptoms. Relapse was predefined as significant increase in PANSS (or predefined PANSS subscales), hospitalisation, clinically significant suicidal or homicidal ideation, or deliberate injury to self or others. The trial was stopped early for efficacy reasons by showing a significantly longer time to recurrence in patients treated with Invega compared to placebo (p < 0.001) (see Figure 1). Invega was also significantly more effective than placebo in maintaining personal and social performance.

Schizoaffective disorder.

Efficacy of Invega in the treatment of acute exacerbation of schizoaffective disorder was established in two placebo controlled, 6 week trials conducted in adult subjects. Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders, 2) had a Positive and Negative Syndrome Scale (PANSS) total score of at least 60, and 3) had prominent mood symptoms as confirmed by a score of at least 16 on the Young Mania Rating Scale and/or Hamilton Rating Scale for Depression. The population included subjects with schizoaffective bipolar and depressive types.
Both studies included subjects who received Invega either as monotherapy [no mood stabilisers and/or antidepressants (55%)] or in combination with mood stabilisers and/or antidepressants (45%). The most commonly used mood stabilisers were valproate and lithium. The most commonly used antidepressants were SSRIs and SNRIs. Invega was taken in the morning without regard to meals.
Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganised thoughts, uncontrolled hostility/ excitement, and anxiety/ depression. The primary efficacy endpoint was the change in the PANSS total score from baseline to week 6 last observation carried forward (LOCF) endpoint. Efficacy analyses were performed using the ITT analysis sets, which included subjects who received at least 1 dose of study medication, and both baseline and at least 1 postbaseline PANSS assessment.
The safety and efficacy of Invega in the prevention of relapse or recurrence of acute exacerbation of schizoaffective disorder has not been assessed.
In one of these trials subjects were permitted to have doses of Invega adjusted in the range of 3-12 mg once daily during the first 2 weeks, with doses fixed thereafter. The intent to treat (ITT) analysis set included 304 subjects (mean age: 37.6 years; range: 19-61 years), 186 subjects completed the double blind treatment. Efficacy was assessed in 211 subjects who were assigned to at least 1 dose of active study medication, and had both baseline and at least 1 postbaseline PANSS assessment.
In the other trial subjects received one of two dose levels of Invega: 6 mg with the option to reduce to 3 mg or 12 mg with the option to reduce to 9 mg, once daily. The intent to treat (ITT) analysis set included 310 subjects (mean age: 37.3 years; range:18-61 years), 212 subjects completed the double blind treatment. Efficacy was assessed in 203 subjects who were assigned to at least 1 dose of study medication, and had both baseline and at least 1 postbaseline PANSS assessment (n = 105 Invega 6 mg, with option to reduce to 3 mg daily and n = 98 Invega 12 mg, with option to reduce to 9 mg daily). See Table 11.
The Invega group in the study permitting dose adjustment for the first two weeks, followed by fixed dosing (in a range of 3-12 mg/day; mean modal dose of 8.6 mg/day) and the higher dose group of Invega in the 2 dose level study (12 mg with option to reduce to 9 mg daily), were each superior to placebo in the PANSS. In the lower dose group of the 2 dose level study (6 mg with option to reduce to 3 mg daily), Invega was not significantly different from placebo as measured by the PANSS.
Taking the results of both studies together, Invega improved the symptoms of schizoaffective disorder at endpoint relative to placebo when administered either as monotherapy or in combination with antidepressants and/or mood stabilisers. An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age, or geographic region. There were insufficient data to explore differential effects based on race.

5.2 Pharmacokinetic Properties

Following a single dose, the plasma concentrations of paliperidone steadily rise to reach peak plasma concentration (Cmax) in approximately 24 hours after dosing. The pharmacokinetics of paliperidone following Invega administration are dose proportional within the recommended clinical dose range (3 to 12 mg). The terminal elimination half-life of paliperidone is approximately 23 hours.
Steady-state concentrations of paliperidone are attained within 4-5 days of dosing in most subjects. In a study comparing the steady-state pharmacokinetics following once daily administration of 12 mg paliperidone(administered as prolonged release tablets) with 4 mg immediate release risperidone in schizophrenic subjects, the fluctuation indexes were 38% for paliperidone prolonged release compared to 125% for risperidone immediate release (see Figure 2).
Following administration of Invega, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.

Absorption.

The absolute oral bioavailability of paliperidone following Invega administration is 28%. Following administration of a single 15 mg paliperidone prolonged release tablet to healthy subjects, confined to bed for 36 hours, with a standard high fat/ high caloric meal, the Cmax and AUC values increased by 42% and 46%, respectively, compared with administration under fasting conditions. (See Section 4.2 Dose and Method of Administration.)
In vitro studies have shown that paliperidone is a P-gp substrate and a weak inhibitor of P-gp at high concentrations (see Section 4.4 Special Warnings and Precautions for Use).

Distribution.

Paliperidone is rapidly distributed. Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L. The plasma protein binding of paliperidone is 74%. It binds primarily to α1-acid glycoprotein and albumin. In vitro, high therapeutic concentrations of diazepam (3 microgram/mL), sulfamethazine (100 microgram/mL), warfarin (10 microgram/mL) and carbamazepine (10 microgram/mL) caused a slight increase in the free fraction of paliperidone at 50 nanogram/mL. These changes are not expected to be of clinical significance.

Metabolism and excretion.

One week following administration of a single oral dose of 1 mg immediate release 14C-paliperidone, 59% (range 51% - 67%) of the dose was excreted unchanged into urine, 32% (26% - 41%) of the dose was recovered as metabolites, and 6% - 12% of the dose was not recovered. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the faeces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation and benzisoxazole scission. In vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, however, in vivo results indicate that these isozymes play a limited role in the metabolism of paliperidone. Despite the large variation in the general population with regard to the ability to metabolise CYP2D6 substrates, population pharmacokinetic analyses indicated no discernable difference on the exposure and apparent clearance of paliperidone after administration of Invega between extensive metabolisers and poor metabolisers of CYP2D6 substrates. In vitro studies using microsomal preparations of heterologous systems indicate that CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5 are not involved in the metabolism of paliperidone.

Hepatic impairment.

In a study in subjects with moderate hepatic impairment (Child-Pugh class B), 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. Consequently, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment. (See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.)

Renal impairment.

The dose of Invega should be reduced in patients with mild, moderate or severe renal impairment (see Section 4.2 Dose and Method of Administration). The disposition of a single dose paliperidone 3 mg extended release tablet was studied in subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% on average in mild (CrCl = 50 to < 80 mL/min), 64% in moderate (CrCl = 30 to < 50 mL/min) and 71% in severe (CrCl = 10 to < 30 mL/min) renal impairment, corresponding to an average increase in exposure (AUCinf) of 1.5, 2.6, and 4.8-fold, respectively, compared to healthy subjects. The mean terminal elimination half-life of paliperidone was 24, 40, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl ≥ 80 mL/min). (See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.)

Gender.

The apparent clearance of paliperidone following Invega administration is approximately 19% lower in women than men. This difference is largely explained by differences in lean body mass and creatinine clearance between men and women.

Elderly.

Data from a pharmacokinetic study in elderly subjects (≥ 65 years of age, n = 26) indicated that the apparent steady-state clearance of paliperidone following Invega administration was 20% lower compared to that of adult subjects (18-45 years of age, n = 28). However, there was no discernable effect of age in the population pharmacokinetic analysis involving schizophrenia subjects after correction of age related decreases in CrCl. (See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.)

Children and adolescents younger than 18 years of age.

No pharmacokinetics data on Invega in patients < 18 years of age has been established.

Smoking status.

Based on in vitro studies utilising human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. A population pharmacokinetic analysis showed a slightly lower exposure to paliperidone in smokers compared with nonsmokers. The difference is unlikely to be of clinical relevance, though.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of genotoxic potential for paliperidone was found in bacterial reverse mutation tests, forward mutation tests in mammalian cells (mouse lymphoma), or an in vivo chromosomal aberration assay (rat micronucleus test). Risperidone, which is metabolised to paliperidone in humans, was also negative in genotoxicity assays.

Carcinogenicity.

The carcinogenic potential of paliperidone has not been determined. Paliperidone is the major active metabolite of risperidone, which has been assessed for carcinogenic potential in rodents.
Risperidone was administered in the diet to Swiss albino mice for 18 months and to Wistar rats for 25 months at doses equivalent to 0.3, 1.3 and 5 times (in mice) or 0.6, 2.5 and 10 times (in rats) the maximum human dose on a mg/m2 basis.
There were statistically significant increases in pituitary gland adenomas in female mice and endocrine pancreas adenomas in male rats at the two highest dose levels, and in mammary gland adenocarcinomas at all dose levels in female mice and female rats and at the highest dose in male rats.
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the carcinogenicity studies but measurements during repeat dose toxicity studies showed that risperidone elevated serum prolactin levels by five to sixfold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary and endocrine pancreas neoplasms has been found in rodents after chronic administration of other dopamine receptor antagonists and is considered to be prolactin mediated.
The relevance for human risk of the findings of prolactin mediated endocrine tumours in rodents is unknown. In controlled clinical trials, Risperdal elevated serum prolactin levels more than haloperidol, although to date neither clinical studies nor epidemiological studies have shown an association between chronic administration of these drugs and mammary tumorigenesis. However, since tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, Risperdal and Invega should be used cautiously in patients with previously detected breast cancer or in patients with pituitary tumours. Possible manifestations associated with elevated prolactin levels are amenorrhoea, galactorrhoea and menorrhagia (see Section 4.8 Adverse Effects (Undesirable Effects)).

Alcohol.

Given the primary CNS effects of Invega, patients should be advised to avoid alcohol while taking this medicine.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain the inactive ingredients: butylated hydroxytoluene; carnauba wax; cellulose acetate; hyetellose; hypromellose; iron oxide black; iron oxide red; iron oxide yellow - 3, 6, 12 mg only; lactose monohydrate - 3 mg only; macrogol 3350; macrogol 400 - 6, 9 and 12 mg only; polyethylene oxide; povidone; sodium chloride; stearic acid; titanium dioxide; triacetin - 3 mg only.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

3 mg.

White, capsule shaped tablets imprinted with "PAL 3".

6 mg.

Beige, capsule shaped tablets imprinted with "PAL 6".

9 mg.

Pink, capsule shaped tablets imprinted with "PAL 9".

12 mg.

Dark yellow, capsule shaped tablets imprinted with "PAL 12".
All strengths are supplied in PVC/PCTFE (Aclar)/Al, PVC/PCTFE (Aclar)/Al or polyamide/Al/PVC/Al blister packs of 7, 28 or 56 tablets. Not all presentations may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


C23H27FN4O3. MW = 426.49.
The chemical name of paliperidone is (±)-3-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1- piperidinyl]ethyl]- 6,7,8,9- tetrahydro-9-hydroxy- 2-methyl-4H-pyrido[1,2-a] pyrimidin-4-one.

CAS number.

144598-75-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes