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XEPLION 50 mg, 75 mg, 100 mg and 150 mg prolonged release suspension for injection

1. Name Of The Medicinal Product

XEPLION

XEPLION

XEPLION

XEPLION

2. Qualitative And Quantitative Composition

Each pre-filled syringe contains 78 mg paliperidone palmitate equivalent to 50 mg paliperidone.

Each pre-filled syringe contains 117 mg paliperidone palmitate equivalent to 75 mg paliperidone.

Each pre-filled syringe contains 156 mg paliperidone palmitate equivalent to 100 mg paliperidone.

Each pre-filled syringe contains 234 mg paliperidone palmitate equivalent to 150 mg paliperidone.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged release suspension for injection.

The suspension is white to off-white. The suspension is pH neutral (approximately 7.0).

4. Clinical Particulars

4.1 Therapeutic Indications

XEPLION is indicated for maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone.

In selected adult patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, XEPLION may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment is needed.

4.2 Posology And Method Of Administration

Posology

Recommended initiation of XEPLION is with a dose of 150 mg on treatment day 1 and 100 mg one week later (day 8), both administered in the deltoid muscle in order to attain therapeutic concentrations rapidly (see section 5.2). The recommended monthly maintenance dose is 75 mg; some patients may benefit from lower or higher doses within the recommended range of 25 to 150 mg based on individual patient tolerability and/or efficacy. Patients who are overweight or obese may require doses in the upper range (see section 5.2). Following the second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.

Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged release characteristics of XEPLION should be considered (see section 5.2), as the full effect of maintenance doses may not be evident for several months.

Switching from oral paliperidone or oral risperidone

Previous oral paliperidone or oral risperidone can be discontinued at the time of initiation of treatment with XEPLION. XEPLION should be initiated as described at the beginning of section 4.2 above.

Switching from Risperidone long acting injection.

When switching patients from risperidone long acting injection, initiate XEPLION therapy in place of the next scheduled injection. XEPLION should then be continued at monthly intervals. The one-week initiation dosing regimen including the intramuscular injections (day 1 and 8, respectively) as described in section 4.2 above is not required.

Patients previously stabilised on different doses of risperidone long acting injection can attain similar paliperidone steady-state exposure during maintenance treatment with XEPLION monthly doses according to the following:

Doses of Risperidone long acting injection and XEPLION needed to attain similar paliperidone exposure at steady-state

Previous Risperidone long acting injection dose

XEPLION injection

25 mg every 2 weeks

50 mg monthly

37.5 mg every 2 weeks

75 mg monthly

50 mg every 2 weeks

100 mg monthly

Discontinuation of antipsychotic medicinal products should be made in accordance with appropriate prescribing information. If XEPLION is discontinued, its prolonged release characteristics must be considered. As recommended with other antipsychotic medicinal products, the need for continuing existing extrapyramidal symptoms (EPS) medicine should be re-evaluated periodically.

Missed doses

Avoiding missed doses

It is recommended that the second initiation dose of XEPLION be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 2 days before or after the one-week (day 8) time point. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point.

If the target date for the second XEPLION injection (day 8 2 days) is missed, the recommended reinitiation depends on the length of time which has elapsed since the patient's first injection.

Missed second initiation dose (< 4 weeks from first injection)

If less than 4 weeks have elapsed since the first injection, then the patient should be administered the second injection of 100 mg in the deltoid muscle as soon as possible. A third XEPLION injection of 75 mg in either the deltoid or gluteal muscles should be administered 5 weeks after the first injection (regardless of the timing of the second injection). The normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy should be followed thereafter.

Missed second initiation dose (4-7 weeks from first injection)

If 4 to 7 weeks have elapsed since the first injection of XEPLION, resume dosing with two injections of 100 mg in the following manner:

1. a deltoid injection as soon as possible,

2. another deltoid injection one week later,

3. resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy.

Missed second initiation dose (> 7 weeks from first injection)

If more than 7 weeks have elapsed since the first injection of XEPLION, initiate dosing as described for the initial recommended initiation of XEPLION above.

Missed monthly maintenance dose (1 month to 6 weeks)

After initiation, the recommended injection cycle of XEPLION is monthly. If less than 6 weeks have elapsed since the last injection, then the previously stabilised dose should be administered as soon as possible, followed by injections at monthly intervals.

Missed monthly maintenance dose (> 6 weeks to 6 months)

If more than 6 weeks have elapsed since the last injection of XEPLION, the recommendation is as follows:

For patients stabilised with doses of 25 to 100mg:

1. a deltoid injection as soon as possible at the same dose the patient was previously stabilised on

2. another deltoid injection (same dose) one week later (day 8)

3. resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy

For patients stabilised with 150mg:

1. a deltoid injection as soon as possible at the 100 mg dose

2. another deltoid injection one week later (day 8) at the 100 mg dose

3. resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy

Missed monthly maintenance dose (> 6 months). If more than 6 months have elapsed since the last injection of XEPLION, initiate dosing as described for the initial recommended initiation of XEPLION above.

Special populations

Elderly population

Efficacy and safety in elderly > 65 years have not been established.

In general, recommended dosing of XEPLION for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. However, because elderly patients may have diminished renal function, dose adjustment may be necessary (see Renal impairment below for dosing recommendations in patients with renal impairment).

Renal impairment

XEPLION has not been systematically studied in patients with renal impairment (see section 5.2). For patients with mild renal impairment (creatinine clearance

XEPLION is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min) (see section 4.4).

Hepatic impairment

Based on experience with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. As paliperidone has not been studied in patients with severe hepatic impairment, caution is recommended in such patients.

Other special populations

No dose adjustment for XEPLION is recommended based on gender, race, or smoking status.

Paediatric population

The safety and efficacy of XEPLION in children < 18 years of age have not been established. No data are available.

Method of administration

XEPLION is intended for intramuscular use only. It should be injected slowly, deep into the muscle. Each injection should be administered by a health care professional. Administration should be in a single injection. The dose should not be given in divided injections. The dose should not be administered intravascularly or subcutaneously.

The day 1 and day 8 initiation doses must each be administered in the deltoid muscle in order to attain therapeutic concentrations rapidly (see section 5.2). Following the second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle. A switch from gluteal to deltoid (and vice versa) should be considered in the event of injection site pain if the injection site discomfort is not well tolerated (see section 4.8). It is also recommended to alternate between left and right sides (see below).

For instructions for use and handling of XEPLION, see package leaflet (information intended for medical or healthcare professionals).

Deltoid muscle administration

The recommended needle size for initial and maintenance administration of XEPLION into the deltoid muscle is determined by the patient's weight. For those

Gluteal muscle administration

The recommended needle size for maintenance administration of XEPLION into the gluteal muscle is the 1?-inch, 22 gauge needle (38.1 mm x 0.72 mm). Administration should be made into the upper-outer quadrant of the gluteal area. Gluteal injections should be alternated between the two gluteal muscles.

4.3 Contraindications

Hypersensitivity to the active substance, to risperidone or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Use in patients who are in an acutely agitated or severely psychotic state

XEPLION should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

QT interval

Caution should be exercised when paliperidone is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QT interval.

Neuroleptic malignant syndrome

Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels has been reported to occur with paliperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, all antipsychotics, including paliperidone, should be discontinued.

Tardive dyskinesia

Medicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including paliperidone, should be considered.

Hyperglycaemia

Rare cases of glucose related adverse reactions, e.g. increase in blood glucose, have been reported in clinical trials with paliperidone. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.

Hyperprolactinaemia

Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics has so far been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Paliperidone should be used with caution in patients with possible prolactin-dependent tumours.

Orthostatic hypotension

Paliperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity.

Based on pooled data from the three placebo-controlled, 6-week, fixed-dose trials with oral paliperidone prolonged release tablets (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with oral paliperidone compared with 0.8% of subjects treated with placebo. XEPLION should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g. dehydration and hypovolemia).

Seizures

XEPLION should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Renal impairment

The plasma concentrations of paliperidone are increased in patients with renal impairment and therefore, dose adjustment is recommended in patients with mild renal impairment. XEPLION is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min) (see sections 4.2 and 5.2).

Hepatic impairment

No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if paliperidone is used in such patients.

Elderly patients with dementia

XEPLION has not been studied in elderly patients with dementia. XEPLION should be used with caution in elderly patients with dementia with risk factors for stroke.

The experience from risperidone cited below is considered valid also for paliperidone.

Overall mortality

In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine had an increased risk of mortality compared to placebo. Among those treated with risperidone, the mortality was 4% compared with 3.1% for placebo.

Cerebrovascular adverse reactions

An approximately 3-fold increased risk of cerebrovascular adverse reactions has been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including risperidone, aripiprazole, and olanzapine. The mechanism for this increased risk is not known.

Parkinson's disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing XEPLION to patients with Parkinson's Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Priapism

Antipsychotic medicinal products (including risperidone) with alpha-adrenergic blocking effects have been reported to induce priapism. During postmarketing surveillance, priapism has also been reported with oral paliperidone, which is the active metabolite of risperidone. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 3-4 hours.

Body temperature regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicinal products. Appropriate care is advised when prescribing XEPLION 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 medicinal products with anticholinergic activity or being subject to dehydration.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. 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 XEPLION and preventative measures undertaken.

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 overdosage with certain medicinal products or of conditions such as intestinal obstruction, Reye's syndrome and brain tumour.

Weight gain

Patients should be advised of the potential for weight gain. Weight should be measured regularly.

Administration

Care must be taken to avoid inadvertent injection of XEPLION into a blood vessel.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Caution is advised when prescribing XEPLION with medicinal products known to prolong the QT interval, 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). This list is indicative and not exhaustive.

Potential for XEPLION to affect other medicinal products

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicinal products that are metabolised by cytochrome P-450 isozymes.

Given the primary central nervous system (CNS) effects of paliperidone (see section 4.8), XEPLION should be used with caution in combination with other centrally acting medicinal products, e.g., anxiolytics, most antipsychotics, hypnotics, opiates, etc. or alcohol.

Paliperidone may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson's disease, the lowest effective dose of each treatment should be prescribed.

Because of its potential for inducing orthostatic hypotension (see section 4.4), an additive effect may be observed when XEPLION is administered with other therapeutic agents that have this potential, e.g., other antipsychotics, tricyclics.

Caution is advised if paliperidone is combined with other medicinal products known to lower the seizure threshold (i.e., phenothiazines or butyrophenones, tricyclics or SSRIs, tramadol, mefloquine, etc.).

Co-administration of oral paliperidone prolonged release tablets at steady-state (12 mg once daily) with divalproex sodium prolonged release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.

No interaction study between XEPLION and lithium has been performed, however, a pharmacokinetic interaction is not likely to occur.

Potential for other medicinal products to affect XEPLION

In vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, but there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone. Concomitant administration of oral paliperidone with paroxetine, a potent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone.

Co-administration of oral paliperidone prolonged release once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone likely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount of active substance excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. Larger decreases in plasma concentrations of paliperidone could occur with higher doses of carbamazepine. On initiation of carbamazepine, the dose of XEPLION should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of XEPLION should be re-evaluated and decreased if necessary.

Co-administration of a single dose of an oral paliperidone prolonged release tablet 12 mg with divalproex sodium prolonged release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone, likely as a result of increased oral absorption. Since no effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium prolonged release tablets and XEPLION intramuscular injection. This interaction has not been studied with XEPLION.

Concomitant use of XEPLION with risperidone

Risperidone administered orally or intramuscularly will be metabolised to a variable degree to paliperidone. Consideration should be given if risperidone or oral paliperidone is co-administered with XEPLION.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of paliperidone during pregnancy. Intramuscularly injected paliperidone palmitate and orally administered paliperidone were not teratogenic in animal studies, but other types of reproductive toxicity were seen (see section 5.3). Neonates exposed to antipsychotics (including paliperidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. XEPLION should not be used during pregnancy unless clearly necessary.

Breastfeeding

Paliperidone is excreted in the breast milk to such an extent that effects on the breastfed infant are likely if therapeutic doses are administered to breastfeeding women. XEPLION should not be used while breast feeding.

Fertility

There were no relevant effects observed in the non-clinical studies.

4.7 Effects On Ability To Drive And Use Machines

Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to XEPLION is known.

4.8 Undesirable Effects

The most frequently reported adverse drug reactions (ADRs) in clinical trials were insomnia, headache, weight increased, injection site reactions, agitation, somnolence, akathisia, nausea, constipation, dizziness, tremor, vomiting, upper respiratory tract infection, diarrhoea, and tachycardia. Of these, akathisia appeared to be dose-related.

The following are all ADRs that were reported in XEPLION-treated subjects in clinical trials. The following terms and frequencies are applied: very common (common (uncommon (rare (very rare (< 1/10,000), and not known (cannot be estimated from the available data).

System Organ Class

Adverse Drug Reaction

Frequency

Very common

Common

Uncommon

Rare

Infections and infestations

upper respiratory tract infection

Immune system disorders

hypersensitivity

Endocrine disorders

hyperprolactinaemia

Metabolism and nutrition disorders

weight increased, blood glucose increased, blood triglycerides increased

hyperglycaemia, hyperinsulinaemia, increased appetite, decreased appetite, blood cholesterol increased

Psychiatric disorders

insomnia

agitation

nightmare

Nervous system disorders

headache

dystonia, parkinsonism, akathisia, dyskinesia, extrapyramidal disorder, tremor, dizziness, somnolence

syncope, convulsion, tardive dyskinesia, dysarthria, psychomotor hyperactivity, dizziness postural, lethargy

neuroleptic malignant syndrome, cerebrovascular accident

Eye disorders

vision blurred

eye rolling, eye movement disorder

Ear and labyrinth disorders

vertigo

Cardiac disorders

tachycardia

sinus tachycardia, conduction disorder, atrioventricular block first degree, bradycardia, postural orthostatic tachycardia syndrome, palpitations, electrocardiogram QT prolonged, electrocardiogram abnormal

Vascular disorders

hypertension

orthostatic hypotension

Gastrointestinal disorders

vomiting, abdominal discomfort/abdominal pain upper, diarrhoea, nausea, constipation, toothache

dry mouth

Skin and subcutaneous tissue disorders

rash

urticaria, pruritus generalised, pruritus

drug eruption

Musculoskeletal and connective tissue disorders

back pain, pain in extremity

myalgia, joint stiffness

Reproductive system and breast disorders

gynaecomastia, erectile dysfunction, sexual dysfunction, galactorrhoea, amenorrhoea, menstruation irregular, menstrual disorder, menstruation delayed

breast discharge

General disorders and administration site conditions

asthenia, injection site induration, fatigue, injection site pain

injection site pruritus

administration site pain, administration site reaction, injection site nodule

The following is a list of additional ADRs that have been reported with oral paliperidone:

System Organ Class

Adverse Drug Reaction

Infections and infestations

Common: nasopharyngitis

Uncommon: urinary tract infection, rhinitis

Immune system disorders

Rare: anaphylactic reaction

Psychiatric disorders

Uncommon: sleep disorder

Nervous system disorders

Rare: transient ischaemic attack, grand mal convulsion

Cardiac disorders

Uncommon: sinus arrhythmia

Rare: bundle branch block left

Vascular disorders

Uncommon: hypotension

Rare: ischaemia

Respiratory, thoracic and mediastinal disorders

Common: cough, pharyngolaryngeal pain, nasal congestion

Not known: pneumonia aspiration

Gastrointestinal disorders

Common: dyspepsia

Uncommon: flatulence

Rare: small intestinal obstruction

Not known: swollen tongue

Skin and subcutaneous tissue disorders

Rare: angioedema, rash papular

Musculoskeletal and connective tissue disorders

Common: arthralgia

Uncommon: musculoskeletal pain

Renal and urinary disorders

Uncommon: urinary retention

Rare: urinary incontinence

Pregnancy, puerperium and perinatal conditions

Not known: drug withdrawal syndrome neonatal (see section 4.6)

Reproductive system and breast disorders

Rare: breast engorgement, breast pain, breast tenderness, retrograde ejaculation

Not known: priapism

General disorders and administration site conditions

Uncommon: oedema peripheral

Rare: oedema

Description of selected adverse reactions

Injection site reactions

The most commonly reported injection site related adverse reaction was pain. The majority of these reactions were reported to be of mild to moderate severity. Subject evaluations of injection site pain based on a visual analogue scale tended to lessen in frequency and intensity over time in all Phase 2 and 3 studies. Injections into the deltoid were perceived as slightly more painful than corresponding gluteal injections. Other injection site reactions were mostly mild in intensity and included induration (common), pruritus (uncommon) and nodules (rare).

Weight gain

In the 13-week study involving the 150 mg initiation dosing, the proportion of subjects with an abnormal weight increase

During the 33-week open-label transition/maintenance period of the long-term recurrence prevention trial, 12% of XEPLION-treated subjects met this criterion (weight gain of

Laboratory tests

Serum prolactin

In clinical trials, median increases in serum prolactin were observed in subjects of both genders who received XEPLION. Adverse reactions that may suggest increase in prolactin levels (e.g. amenorrhoea, galactorrhoea and gynaecomastia) were reported overall in <1% of subjects.

Class effects

QT prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and Torsade de pointes may occur with antipsychotics. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic medicinal products (frequency unknown).

4.9 Overdose

In general, expected signs and symptoms are those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, QT prolongation, and extrapyramidal symptoms. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone. In the case of acute overdose, the possibility of multiple drug involvement should be considered.

Consideration should be given to the prolonged release nature of the medicinal product and the long elimination half-life of paliperidone when assessing treatment needs and recovery. There is no specific antidote to paliperidone. General supportive measures should be employed. Establish and maintain a clear airway and ensure adequate oxygenation and ventilation.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring for possible arrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluid and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered. Close supervision and monitoring should continue until the patient recovers.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Psycholeptics, other antipsychotics. ATC code: N05AX13

XEPLION contains a racemic mixture of (+)- and (-)-paliperidone.

Mechanism of action

Paliperidone is a selective blocking agent of monoamine effects, whose pharmacological properties are different from that of traditional neuroleptics. Paliperidone binds strongly to serotonergic 5-HT2- and dopaminergic D2-receptors. Paliperidone also blocks alpha 1-adrenergic receptors and slightly less, H1-histaminergic and alpha 2-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers are qualitatively and quantitatively similar.

Paliperidone is not bound to cholinergic receptors. Even though paliperidone is a strong D2-antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes less catalepsy and decreases motor functions less than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects.

Clinical efficacy

Acute treatment of schizophrenia

The efficacy of XEPLION in the acute treatment of schizophrenia was established in four short-term (one 9-week and three 13-week) double-blind, randomised, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of XEPLION in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on day 64 of the 13-week studies. No additional oral antipsychotic supplementation was needed during the acute treatment of schizophrenia with XEPLION. The primary efficacy endpoint was defined as a decrease in Positive and Negative Syndrome Scale (PANSS) total scores as shown in the table below. The PANSS is a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganised thoughts, uncontrolled hostility/excitement and anxiety/depression. Functioning was 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: socially useful activities (work and study), personal and social relationships, self-care and disturbing and aggressive behaviours.

In a 13-week study (n=636) comparing three fixed doses of XEPLION (initial deltoid injection of 150 mg followed by 3 gluteal or deltoid doses of either 25 mg/4 weeks, 100 mg/4 weeks or 150 mg/4 weeks) to placebo, all three doses of XEPLION were superior to placebo in improving the PANSS total score. In this study, both the 100 mg/4 weeks and 150 mg /4 weeks, but not the 25 mg/4 weeks, treatment groups demonstrated statistical superiority to placebo for the PSP score. These results support efficacy across the entire duration of treatment and improvement in PANSS and was observed as early as day 4 with significant separation from placebo in the 25 mg and 150 mg XEPLION groups by day 8.

The results of the other studies yielded statistically significant results in favour of XEPLION, except for the 50 mg dose in one study (see table below).

Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From Baseline to End Point- LOCF for Studies R092670-SCH-201, R092670-PSY-3003, R092670-PSY-3004 and R092670-PSY-3007: Primary Efficacy Analysis Set

Placebo

25 mg

50 mg

100 mg

150 mg

R092670-PSY-3007*

Mean baseline (SD)

Mean change (SD)

P-value (vs. Placebo)

n = 160

86.8 (10.31)

-2.9 (19.26)

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