invega (paliperidone) Tablets

Active ingredient:
paliperidone
Sodium chloride

4.1. Therapeutic indications

INVEGA is indicated in the treatment of schizophrenia.
4.2. Posology and application form

Dosage:

Adults (> 18 years): Schizophrenia

The recommended dose of INVEGA for schizophrenia treatment is once a day, 6 mg in the morning. Initially dose titration is not necessary. Some patients may benefit from higher or lower doses in the 3-12 mg dose recommended daily. Where necessary, dose adjustment should only be performed after clinical reassessment. When dose escalation is required, an increase of 3 mg per day is recommended, usually over 5 days.

Schizoaffective Disorder

The recommended dose of INVEGA for treatment of schizoaffective disorder is once a day, 6 mg in the morning. Initially dose titration is not necessary. Some patients may benefit from higher or lower doses in the 3-12 mg dose recommended daily. At higher doses, a general trend towards stronger effects has been observed. Where necessary, dose adjustment should only be performed after clinical reassessment. When dose escalation is required, an increase of 3 mg per day is recommended, usually over 4 days.

Transition to other antipsychotic agents:

There is no systematic collection of special data regarding the transition of patients from INVEGA to other antipsychotic agents. Because of the different pharmacodynamic and pharmacokinetic profiles of antipsychotic agents, there is a medical need for counseling of a physician when switching to another antipsychotic product.

Application frequency and duration:

The recommended dose for INVEGA is 6 mg for morning treatment of schizophrenia once a day. Dose adjustments can be made where necessary.

Method of Application:

INVEGA is for oral use and can be administered on an empty or full stomach. INVEGA as a whole must not be swallowed, chewed, divided or crushed by any liquid.

Administration of INVEGA should be standardized according to nutrient intake (see Section 5.2 Pharmacokinetic Properties). Patients should always be informed that they should always take INVEGA with hunger or always with breakfast and not to make changes in practice on hunger or toughness conditions.

The drug is designed to release the active substance at a controlled rate within an unabsorbed shell. Tablet shell is discarded together with insoluble core components; they should not be worried when they see something resembling a tablet in a patient's stool.

Additional information on special populations:

Kidney / Liver failure:

• In patients with mild renal insufficiency (creatinine clearance> 50 to <80 mL / min) the recommended initial dose is 3 mg once daily. The dose may be increased to 6 mg per day depending on clinical response and tolerability.

• In patients with moderate to severe renal insufficiency (creatinine clearance> 10 to <50 mL / min) the recommended dose of INVEGA is 3 mg once daily. INVEGA

Since creatinine clearance is not studied in patients below 10 ml / min, use in these patients is not recommended.

• Dose adjustment is not required for patients with mild to moderate hepatic insufficiency. INVEGA has not been studied in patients with severe hepatic insufficiency.

Pediatric population:

INVEGA has not examined the safety and efficacy of patients under the age of 18 years.
Geriatric population:

In elderly patients with normal renal function (> 80 ml / min), the same recommended dose for adults with normal renal function is recommended. However, since renal function may be reduced in elderly patients, dose adjustment may be required depending on renal function status (see Section 4.2 Posology and Application, Kidney / Liver failure).

Other special populations:

PHARMACEUTICAL PROPERTIES 1 List of Subsidiary Materials

Polyethylene oxide 200K Sodium chloride Povidone (K29-32) Stearic acid

(Red) E172 Hydroxyethyl cellulose Polyethylene glycol 3350 Cellulose acetate Hypromellose Titanium dioxide E171 Polyethylene glycol 400

Carnauba wax Iron oxide (black) E172 Propylene glycol
6.2. Incompatibilities

It does not have any known incompatibilities.
6.3. Shelf life

24 months
6.4. Special precautions for storage

Store at room temperature below 30 ° C. We are protected from moisture.
6.5. The nature and content of the packaging

28 tablets blister packaging.

Blister: Polyvinyl chloride (PVC) / aluminum push layer coated with polychloro-trifluoroethylene (PCTFE)

6.6. Removal of remaining substances from medical product and other special measures

Unused products or waste materials are classified as' 'Medical Waste Control Regulation' 'and' 'Packaging Waste Control'

4.3. contraindications
4.4. Special use warnings and precautions

QT interval:

As with other antipsychotics, INVEGA should be taken with caution when prescribing INVEGA in patients with known cardiovascular disease or in patients with QT prolongation and other medicines that are thought to prolong QT interval.

Neuroleptic malignant syndrome:

Hyperthermia, Neuroleptic Malign Syndrome (NMS), characterized by muscle rigidity, autonomic instability, altered consciousness and elevation of serum creatinine phosphokinase levels, has been reported to occur with antipsychotic drugs including paliperidone. Additional clinical manifestations may include myoglobulinuria (rhabdomyolysis) and acute renal failure. If signs and symptoms are pointing to a NMS in a patient, all antipsychotic drugs, including INVEGA, should be discontinued.

Tardive dyskinesia:

Drugs with dopamine receptor antagonism have been shown to induce tardive dyskinesia, characterized in particular by language and / or percentage, rhythmic, involuntary movements

They have been associated. If signs and symptoms of tardive dyskinesia occur, discontinuation of all antipsychotic medications, including INVEGA, should be considered.

Hyperglycemia:

Glucose-mediated adverse events rarely occur in clinical trials with INVEGA

It has been reported. Clinical monitoring of patients with diabetes or risk factors for the development of diabetes mellitus is recommended.

Orthostatic hypotension:

Paliperidone may cause orthostatic hypotension due to alpha-blocker activity. INVEGA should be used with caution in patients with known cardiovascular disease (eg heart failure, myocardial infarction or ischemia, transmission abnormalities), in patients with cerebrovascular disease or in situations that may cause hypotension (eg dehydration, hypovolemia and antihypertensive medications).

Seizures:

As with other antipsychotic medications, INVEGA should be used with caution in patients who have potentially reduced seizure threshold or have a history of seizures.

Gastrointestinal obstruction potential:

Since INVEGA is not deformed and does not change its shape in the gastrointestinal tract, patients who have previously had severe gastrointestinal constriction (pathological or iatrogenic) or dysphagia or who are suffering from difficulty swallowing tablets should not be randomly applied. In patients known to be constricted, there are infrequent reports of obstructive symptoms associated with ingestion of formulated, controlled release formulation formulations. Due to the controlled release design of the dosage form, INVEGA should only be used in patients who can ingest as a whole (see section 4.2).

Old demented patients:

Conventional and atypical antipsychotic drugs cause an increased risk of death when used in the treatment of elderly patients with dementia-related psychosis.

INVEGA has not been studied in demented elderly patients. Overall mortality

In a meta-analysis of 17 controlled clinical trials, the mortality risk for demented elderly patients using atypical antipsychotic medications including risperidone, aripiprazole, olanzapine, and quetiapine increased compared to placebo.

Cerebrovascular adverse events

In placebo-controlled, clinical trials, the risk of developing cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) increased, including placebo-related deaths, in demented elderly patients treated with some atypical antipsychotic drugs such as risperidone, aripiprazole and olanzapine.

Parkinson's Disease and Lewy Body Dementia:

Patients with Parkinson's Disease or Lewy Body Dementia are at increased risk of developing Neuroleptic Malign Syndrome and increased sensitivity to antipsychotic drugs. For this reason, there is a need for a benefit risk assessment when prescribing antipsychotic drugs, including INVEGA in both groups. Symptoms of this increased sensitivity are postural instability with confusion, obtundation, frequent falls in addition to extrapyramidal symptoms.

Priapism:

Drugs with alpha-adrenergic blocker activity have been reported to cause priapism. Priapism has been reported in postmarketing observations for INVEGA.

Body temperature regulation:

The deterioration of the body's ability to reduce internal body temperature is linked to antipsychotic medications. It is recommended to prescribe INVEGA with caution in patients who may be exposed to excessive exercise, unusual exposure to heat, use of medicines with anticholinergic effects or dehydration of the individual, which can lead to increased internal body heat.

Antiemetic effect:

Antiemetic effect was seen in preclinical studies with paliperidone. This effect, if occurring in humans, may overdose some medications or mask such conditions as bowel obstruction, Reye's syndrome, and brain tumors.

Venous thromboembolic event:

Venous thromboembolic events (VTE) have been reported with antipsychotic drugs. Most patients with antipsychotic medication

Interactions with other medicinal products and other forms of interaction

Care should be taken when prescribing INVEGA with medications that prolong QT interval. INVEGA has the potential to affect other medicines:

Paliperidone is not expected to cause clinically significant pharmacokinetic interactions with drugs metabolized by cytochrome P-450 isoenzymes. In vitro studies in human liver microsomes have shown that it does not significantly inhibit the metabolism of drugs metabolised by cytochrome P450 isoenzymes, including paliperidone, CYP1A2, CYP2A6, CYP2C8 / 9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Therefore, it is unlikely that paliperidone will significantly inhibit the clearance of drugs metabolized by these metabolic pathways. In vitro studies have shown that paliperidone is not a CYP1A2, 2C19 or 3A4 inducer.

Paliperidone is a weak P-glycoprotein (P-gp) inhibitor at high concentrations. in vivo data are not available and its clinical significance is unknown.

Due to the primer effects on the central nervous system of Paliperidone (see Section 4.8 Undesirable Effects), INVEGA should be used with caution with other centrally acting drugs and alcohol. Paliperidone may antagonize the effects of levodopa and other dopamine agonists.

Because of the potential for inducing orthostatic hypotension (see Section 4.4 Special Use Indications and Precautions, Orthostatic Hypotension), additional effects may be observed when INVEGA is administered in combination with other therapeutic agents having this potential.

Pharmacokinetic interaction between INVEGA and lithium is unlikely.

Simultaneous administration of steady-state INVEGA (12 mg once daily) with extended release divalproex sodium tablets (500 mg to 2000 mg once daily) did not affect valproate's steady-state pharmacokinetics.

Potential for other drugs to affect INVEGA:

Paliperidone is not the substrate of CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. This demonstrates that there is no interaction with inhibitors or inducers of these isoenzymes. Although in vitro studies show that CYP2D6 and CYP3A4 are minimally involved in the metabolism of paliperidone, there is no in vitro or in vivo evidence that these enzymes play a significant role in the metabolism of paliperidone. In vitro studies have shown that paliperidone is a P-gp substrate.

Paliperidone is metabolically limited by CYP2D6 (see Section 5.2). Clinically significant effects on the pharmacokinetics of paliperidone have not been observed in an interaction study with healthy volunteers, in which INVEGA was co-administered with paroxetine, a potent CYP2D6 inhibitor.

Coadministration of INVEGA twice daily with carbamazepine 200 mg per day resulted in a reduction of approximately 37% in the mean steady-state Cmax and EAA values ​​of paliperidone. This decline is due, in part, to a 35% increase in renal clearance of paliperidone as a result of induction of renal P-gp by carbamazepine. The low rate of decline in urinary excretion of unchanged drug suggests that CYP metabolism during coadministration with carbamazepine and the effect on the bioavailability of paliperidone are low. When carbamazepine is started, INVEGA should be reevaluated and increased if necessary. Conversely, when carbamazepine is discontinued, INVEGA should be reevaluated and, if necessary, reduced.

Paliperidone, a cation at physiological pH, is released unchanged mainly from the kidneys, about half by filtration, half by active secretion. Simultaneous administration with trimethoprim, a known drug that inhibits the active passage of cationic drugs from the kidneys, has not affected the pharmacokinetics of paliperidone.

Simultaneous administration of a single dose of 12 mg INVEGA with extended release divalproex sodium tablets (two 500 mg tablets once daily) resulted in an approximately 50% increase in Cmax and EAA of paliperidone. If INVEGA is administered concurrently with valproate after clinical evaluation, reduction of INVEGA dose should be considered.

Pharmacokinetic interaction between INVEGA and lithium is unlikely. Use of INVEGA with risperidone:

4.6. Pregnancy and lactation

General advice

Pregnancy Category: C

Women with childbearing potential / Contraception (Contraception)

Paliperidone has not been proven as reliable as human pregnancy.

No teratogenic effects have been reported in animal studies. A slight increase in fetal mortality was observed in laboratory animals treated with high-dose paliperidone. This is toxic for high-dose mothers. Newborns were not affected by 20 to 34 times the highest human dose. INVEGA should not be used during pregnancy unless the benefits are higher than the risks. The effect of INVEGA at birth in humans is unknown.

The use of antipsychotic medication in the last trimester of pregnancy has been associated with recurrent extrapyramidal symptoms in the newborn.

Pregnancy period

INVEGA should not be used during pregnancy unless absolutely necessary.

Lactation period

In human studies with paliperidone and human studies with risperidone, paliperidone was excreted in breast milk. Therefore, women who use INVEGA should not breastfeed.

Reproduction ability / Fertility
4.7. Effects on vehicle and machine use
8.4. Undesirable effects

INVEGA's reliability in the treatment of schizophrenia was evaluated in 1205 adult patients participating in 3 double-blind, placebo-controlled 6-week studies. 850 of these patients received a single daily dose of INVEGA at fixed doses of 3-12 mg.

INVEGA's reliability was assessed in 622 patients with schizoaffective disorder participating in two 6-week, double-blind, placebo-controlled studies. In one of these studies, 206 patients were given one of two dose levels of INVEGA: 6 mg (n = 108) with a single dose of 3 mg / day or 12 mg (n = 98) with a reduction to 9 mg. In another study, 214 patients received INVEGA (3-12 mg daily dose) at flexible doses. Both studies included patients who received INVEGA either in the form of monotherapy or in combination with antidepressants and / or mood stabilizers.

The information given in this section was obtained from the total data.

Most adverse drug reactions are mild to moderate.

Infections and infestations:

Common: Urinary tract infection, nasopharyngitis, upper respiratory tract infection Uncommon: Rhinitis

Immune system diseases: Uncommon: Angioedema Rare: Anaphylactic reaction, hypersensitivity
Endocrine disorders:

Rare: Hyperprolactinemia

Metabolism and nutritional diseases:

Common: Weight gain, appetite increase

Uncommon: hyperglycaemia, decreased appetite

Psychiatric diseases:

Common: Restlessness

Uncommon: Anus, Sleep disorders

Nervous system diseases:

Very common: Headache

Common: Dystonia, extrapyramidal disorders, akathisia, tremor, hypertonia, dizziness, increased salivation, sedation, somnolence

Uncommon: syncope, tardive dyskinesia, dysarthria, parkinsonism, dyskinesia, postural dizziness, lethargy

Rare: Transient ischemic attack, Grand mal convulsions, convulsions, Parkinson type walking, Parkinson type muscle stiffness

Unknown: Cerebrovascular event, neuroleptic malignant syndrome
Eye diseases:

Common: Blurred vision Uncommon: Oculojiric crisis
Cardiac diseases:

Common: sinus tachycardia, tachycardia, bundle branch block

Uncommon: first grade atrioventricular block, bradycardia, left bundle branch block, palpitations, abnormal ECG, sinus arrhythmia

Rare: QT extension in ECG

Vascular diseases:

Common: Orthostatic hypotension Uncommon: Hypotension Rare: Ischemia

Respiratory, thoracic disorders and mediastinal disorders:

Common: pharyngolaryngeal pain, nasal congestion, cough Unknown: Aspiration pneumonia

Gastrointestinal diseases:

Common: Vomiting, upper abdominal pain, stomach upset, nausea, dyspepsia, mouth instability, constipation

Uncommon: Excess salivary secretion, swelling Unknown: Small bowel obstruction, tongue swelling

Skin and subcutaneous tissue diseases:

Common: Prurit

Uncommon: Rash

Rare: Papillary rash

Musculoskeletal disorders, connective tissue and bone diseases:

Common: arthralgia, back pain, pain in extremities, myalgia

Uncommon: Muscle stiffness, muscle spasms, muscle soreness, musculoskeletal pain, jaw clenching

Rare: Neck retention

Kidney and urinary diseases:

Uncommon: Urinary retention Rare: Urinary incontinence

Reproductive system and breast diseases:

Uncommon: Erectile dysfunction, galactore, amenore, retrograde ejaculation

Rare: Gynecomastia, discharge in the bladder, irregular menstruation, breast tenderness, breast pain, breast engorgement (breast swelling in breast feeding cycle)

Unknown: Priapism

General disorders:

Common: Asthenia, fatigue

Uncommon: edema, peripheral edema

Combined Therapy Against Monotherapy

The design of two placebo-controlled, 6-week, double-blind studies in patients with schizoaffective disorder includes the option to use antidepressants (except monoamine oxidase inhibitor) and / or mood stabilizers (lithium, valproate or lamotrigine) for patients. In a patient population assessed for reliability, 230 (55%) patients received INVEGA as monotherapy, and 190 (45%) patients received INVEGA in combination with antidepressants and / or mood stabilizers. Comparing these two subpopulations, patients who received INVEGA in the form of monotherapy only had a higher frequency of nausea (> 3% difference).

Dose-Related Adverse Reactions

Dyspnea, dysarthria and nasopharyngitis at placebo-controlled, 6-week high- and low-dose studies in patients with schizoaffective disorder occurred more frequently (ie, at least 3% difference) when compared to patients receiving low doses of patients receiving high doses of INVEGA. Hypertension is more common when INVEGA is compared with patients receiving high doses in patients receiving low doses.

These class-specific events:

Extrapramidal Symptoms (EPS): Data from 6-week, double-blind, placebo-controlled, fixed-dose studies of schizophrenia (see Section 5.1), placebo (11%) and INVEGA 3 and 6 mg 13% and 10%). Dosage correlations were observed at higher doses of INVEGA (25 and 26% for 9 and 12 mg, respectively). EPS contains an aggregate analysis of the following terms: dyskinesia, dystonia, hyperkinesia, Parkinsonism and tremor. Data from two 6-week, double-blind, placebo-controlled studies in patients with schizoaffective disorder (see Section 5.1) showed similar results.

Weight gain: The percentage of patients who met the weight-gain criteria of 7% or more was compared in the total data from 6-week, double-blind, placebo-controlled, fixed-dose schizophrenic studies (see Section 5.1) and compared with placebo )

A similar frequency was observed for INVEGA 3 and 6 mg (7% and 6%, respectively) and a higher frequency (9% and 9%, respectively) for INVEGA 9 and 12 mg.

In patients with schizoaffective disorder, weight gain of 7% or more in patients treated with INVEGA (5%) in a 6-week, placebo-controlled, two-run non-parametric study (see Section 5.1) compared with placebo-treated patients high. In the study of high and low dose groups, weight gain of 7% or more was 3% in the low dose group, 7% in the high dose group and 1% in the placebo group.

Laboratory tests: Serum Prolaktin. Increase in serum prolactin levels was observed in patients with INVEGA in both sexes receiving 6-week, double-blind, placebo-controlled, fixed-dose schizophrenic studies (see Section 5.1). The maximum mean increase in serum prolactin concentrations was generally observed on the 15th day of treatment, but remained above the baseline level at the end of the study.

Clinical Studies: Long-term, placebo-controlled study of adverse drug reactions

INVEGA's reliability has also been explored by a long-run study designed to evaluate the efficacy of INVEGA in adult schizophrenia patients (See Section 5.1). In general, the type, frequency, and severity of adverse drug reactions reported during the initial 14-week open-ended phase of this study are comparable to 6-week, placebo-controlled, fixed-dose trials. Adverse drug reactions reported in the long-term, double-blind phase of the study were similar in type and severity to those observed at the initial 14-week open-ended phase; but usually occur less frequently.

Class effects

Venous thromboembolic events have been reported with antipsychotic medications, including cases of pulmonary embolism and deep venous thrombosis-The incidence is unknown.

Reliability information reported with risperidone

Paliperidone is the active metabolite of risperidone. The release profile and pharmacokinetic characteristics of INVEGA are quite different from those seen with oral rapid-release risperidone formulations (see Section 5.2). Clinical trials with risperidone and the reliability information reported in post-marketing experience can be obtained from Risperidone's product information.

Additional information on special populations:

Geriatric population:

4.9. Overdose and treatment

symptoms

Generally, the expected signs and symptoms are an increase in the known pharmacological effects of the drug. These include dizziness and sedation, hypotension with tachycardia, QT-prolongation, and extrapyramidal symptoms. Torsade de pointes and ventricular fibrillation have been reported in a patient with overdose. In cases of acute overdosage, multiple drug possibilities should be considered.

Treatment

The long-term release structure of the product should be considered when assessing treatment needs and recovery. Paliperidone does not have a specific antidote. General supportive measures should be implemented. The airway should be kept open and maintained, adequate oxygenation and ventilation should be provided. Cardiovascular monitoring should be started immediately and continuous electrocardiographic monitoring should be performed for possible arrhythmias. Hypotension and circulatory collapse, intravenous fluids and / or sympathomimetic agent should be treated with appropriate precautions. Gastric lavage (after intubation if the patient is conscious) and the use of activated charcoal with a laxative should be considered. Anticholinergic agents should be administered in cases of severe extrapyramidal symptoms. Strict supervision and observation should continue until the patient comes to himself.

PHARMACOLOGICAL PROPERTIES

- contains a racemic mixture of paliperidone. Mechanism of action:

Paliperidone is a centrally active dopamine D2 antagonist with predominant serotonergic 5-HT2A antagonist activity. Paliperidone is also active as an antagonist at the a1 and a2 adrenergic receptors and H1 histaminergic receptors. Paliperidone does not have affinity for cholinergic muscarinic or p1-adrenergic and p2-adrenergic receptors. (+)
- and (
-)
- the pharmacological activity of the paliperidone enantiomers is qualitatively and quantitatively similar.

The mechanism of action of paliperidone is not known as it is in other medicines with the effect of schizophrenia. However, it has been suggested 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 in receptors other than D2 and 5HT2A may explain some of the other effects of paliperidone.

polysomnography

Centrally effective drugs may affect sleep through time of action mechanisms, drug release profiles and / or dosing time. A placebo-controlled trial of INVEGA 9 mg or placebo for 14 days once a day was performed on 36 volunteers to assess the effect of INVEGA on the sleep structure and continuity of the morning dose. The following observations were recorded (average compared to placebo): The delay time to continuous sleep decreased by 41.0 (SE 18.70) minutes, the delay time to the beginning of sleep decreased by 35.2 (SE 14.99) minutes, the number of waking after the onset of sleep decreased by 7.0 (SE 3.88) the total sleep duration increased by 52.8 (SE 24.01) minutes, the sleep period duration increased by 41.7 (SE 18.75) minutes and the sleep efficiency index increased by 11.0% (SE 5.00). In addition, there was no statistically significant effect on REM sleep, in phase 1 sleep (a statistically significant shortening (11.9 (SE 4.44) minutes compared to placebo and 50.7 (SE 17.67) minutes in stage 2 sleep).

electrophysiology

The effects on Paliperidone's QT interval were assessed by randomized, double-blind, multicenter, two-phase 1 study in adults with schizophrenia and schizoaffective disorder and three 6-week, fixed-dose triple efficacy studies with placebo and active control in adults with schizophrenia.

Volunteers were randomized to receive fast-release oral paliperidone (titrated from 4 mg to 8 mg) or single dose moxifloxacin (400 mg) once daily for 7 days in the first phase 1 study (n = 141). The mean steady-state peak plasma concentration reached at 8 mg dose once daily (n = 44) with fast-release oral paliperidone was more than twice as high as the exposure observed at the maximum recommended INVEGA dose (Cmax ss = 113 and 45 ng / mL , respectively). <span title="Modele göre ayarlanmış, güne göre ortalaması alınmış do