Xeplion LP

Xeplion LP 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 LP may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment is needed.

Xeplion LP is indicated for the treatment of schizophrenia in adults and in adolescents 15 years and older.

Xeplion LP is indicated for the treatment of schizoaffective disorder in adults.

Posology

Recommended initiation of Xeplion LP 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. The third dose should be administered one month after the second initiation dose. 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. Following the second initiation 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 LP should be considered , as the full effect of maintenance doses may not be evident for several months.

Switching from oral prolonged release paliperidone or oral risperidone to Xeplion LP

Previous oral paliperidone or oral risperidone can be discontinued at the time of initiation of treatment with Xeplion LP. Some patients may benefit from gradual withdrawal. Some patients switching from higher paliperidone oral doses (e.g., 9-12 mg daily) to gluteal injections with Xeplion LP may have lower plasma exposure during the first 6 months after the switch. Therefore, alternatively, it could be considered to give deltoid injections for the first 6 months.

Switching from risperidone long acting injection to Xeplion LP

When switching patients from risperidone long acting injection, initiate Xeplion LP therapy in place of the next scheduled injection. Patients previously stabilised on different doses of risperidone long acting injection can attain similar paliperidone steady-state exposure during maintenance treatment with Xeplion LP monthly doses according to the following:

Discontinuation of antipsychotic medicinal products should be made in accordance with appropriate prescribing information. If Xeplion LP is discontinued, its prolonged release characteristics must be considered. 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 LP be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 4 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 LP injection (day 8 ± 4 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 LP 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 LP, 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 LP, initiate dosing as described for the initial recommended initiation of Xeplion LP above.

Missed monthly maintenance dose (1 month to 6 weeks)

After initiation, the recommended injection cycle of Xeplion LP 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 LP, the recommendation is as follows:

For patients stabilised with doses of 25 to 100 mg

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 150 mg

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 LP, initiate dosing as described for the initial recommended initiation of Xeplion LP above.

Special populations

Elderly

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

In general, recommended dosing of Xeplion LP 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 LP has not been systematically studied in patients with renal impairment. For patients with mild renal impairment (creatinine clearance > 50 to < 80 ml/min), recommended initiation of Xeplion LP is with a dose of 100 mg on treatment day 1 and 75 mg one week later, both administered in the deltoid muscle. The recommended monthly maintenance dose is 50 mg with a range of 25 to 100 mg based on patient tolerability and/or efficacy.

Xeplion LP is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min).

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.

Paediatric population

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

Method of administration

Xeplion LP is intended for intramuscular use only. It must not be administered by any other route. It should be injected slowly, deep into the deltoid or gluteal 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 day 1 and day 8 initiation doses must each be administered in the deltoid muscle in order to attain therapeutic concentrations rapidly. Following the second initiation 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. It is also recommended to alternate between left and right sides (see below).

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

Deltoid muscle administration

The recommended needle size for initial and maintenance administration of Xeplion LP into the deltoid muscle is determined by the patient's weight. For those > 90 kg, the 1½ inch, 22 gauge needle (38.1 mm x 0.72 mm) is recommended. For those < 90 kg, the 1-inch, 23 gauge needle (25.4 mm x 0.64 mm) is recommended. Deltoid injections should be alternated between the two deltoid muscles.

Gluteal muscle administration

The recommended needle size for maintenance administration of Xeplion LP into the gluteal muscle is the 1½-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.

Posology

Schizophrenia (adults)

The recommended dose of Xeplion LP for the treatment of schizophrenia in adults 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 recommended range of 3 mg to 12 mg once daily. 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 5 days.

Schizoaffective disorder (adults)

The recommended dose of Xeplion LP for the treatment of schizoaffective disorder in adults is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from higher doses within the recommended range of 6 mg to 12 mg once daily. 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.

Switching to other antipsychotic medicinal products

There are no systematically collected data to specifically address switching patients from Xeplion LP to other antipsychotic medicinal products. Due to different pharmacodynamic and pharmacokinetic profiles among antipsychotic medicinal products, supervision by a clinician is needed when switching to another antipsychotic product is considered medically appropriate.

Elderly

Dosing recommendations for elderly patients with normal renal function (> 80 ml/min) are the same as for adults with normal renal function. However, because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status (see Renal impairment below). Xeplion LP should be used with caution in elderly patients with dementia with risk factors for stroke. Safety and efficacy of Xeplion LP in patients > 65 years of age with schizoaffective disorder have not been studied.

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. As Xeplion LP has not been studied in patients with severe hepatic impairment, caution is recommended in such patients.

Renal impairment

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 to 6 mg once daily based on clinical response and tolerability.

For patients with moderate to severe renal impairment (creatinine clearance > 10 to < 50 ml/min), the recommended initial dose of Xeplion LP is 3 mg every other day, which may be increased to 3 mg once daily after clinical reassessment. As Xeplion LP has not been studied in patients with creatinine clearance below 10 ml/min, use is not recommended in such patients.

Paediatric population

Schizophrenia: The recommended starting dose of Xeplion LP for the treatment of schizophrenia in adolescents 15 years and older is 3 mg once daily, administered in the morning.

Adolescents weighing < 51 kg: the maximum recommended daily dose of Xeplion LP is 6 mg.

Adolescents weighing > 51 kg: the maximum recommended daily dose of Xeplion LP is 12 mg.

Dosage adjustment, if indicated, should occur only after clinical reassessment based on the individual need of the patient.1 but no recommendation on a posology can be made. There is no relevant use of Xeplion LP in children aged less than 12 years.

Schizoaffective disorder: The safety and efficacy of Xeplion LP in the treatment of schizoaffective disorder in patients aged 12 to 17 years has not been studied or established. There is no relevant use of Xeplion LP in children aged less than 12 years.

Other special populations

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

Method of administration

Xeplion LP is for oral administration. It must be swallowed whole with liquid, and must not be chewed, divided, or crushed. The active substance is contained within a non-absorbable shell designed to release the active substance 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.

The administration of Xeplion LP should be standardised in relation to food intake. The patient should be instructed to always take Xeplion LP 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.

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

Xeplion LP 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, 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.

Leucopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia, and agranulocytosis have been reported with Xeplion LP. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leucopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of Xeplion LP 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 neutropenia 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 neutropenia (absolute neutrophil count < 1 X 10⁹/L) should discontinue Xeplion LP and have their WBC followed until recovery.

Hypersensitivity reactions

Anaphylactic reactions in patients who have previously tolerated oral risperidone or oral paliperidone have been rarely reported during post-marketing experience.

If hypersensitivity reactions occur, discontinue use of Xeplion LP; initiate general supportive measures as clinically appropriate and monitor the patient until signs and symptoms resolve.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes including diabetic coma and ketoacidosis, have been reported during treatment with paliperidone. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with Xeplion LP should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucose control.

Weight gain

Significant weight gain has been reported with Xeplion LP use. Weight should be monitored regularly.

Use in patients with prolactin-dependent tumours

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 a pre-existing tumour that may be prolactin-dependent.

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

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 LP has not been studied in elderly patients with dementia. Xeplion LP 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 LP 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 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 LP 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 LP 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.

Administration

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

Intraoperative Floppy Iris Syndrome

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicinal products with alpha 1a-adrenergic antagonist effect, such as Xeplion LP.

IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicinal products with alpha 1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha 1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially sodium-free.

Patients with schizoaffective disorder treated with paliperidone should be carefully monitored for a potential switch from manic to depressive symptoms.

QT interval

Caution should be exercised when Xeplion LP is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicines 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 Xeplion LP, should be discontinued.

Tardive dyskinesia

Medicines 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 Xeplion LP, should be considered.

Leukopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia, and agranulocytosis have been reported with antipsychotic agents, including Xeplion LP. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of Xeplion LP 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 neutropenia 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 neutropenia (absolute neutrophil count < 1 X 10⁹/L) should discontinue Xeplion LP and have their WBC followed until recovery.

Hyperglycemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reported during treatment with paliperidone. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Association with ketoacidosis has been reported very rarely and rarely with diabetic coma. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any atypical antipsychotic, including Xeplion LP, should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucose control.

Weight gain

Significant weight gain has been reported with Xeplion LP use. Weight should be monitored regularly.

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 Xeplion LP (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with Xeplion LP compared with 0.8% of subjects treated with placebo. Xeplion LP 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 LP should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Potential for gastrointestinal obstruction

Because the Xeplion LP tablet is non-deformable and does not appreciably change shape in the gastrointestinal tract, Xeplion LP should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic) or in patients with dysphagia or significant difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of medicines in non-deformable controlled-release formulations. Due to the controlled-release design of the dosage form, Xeplion LP should only be used in patients who are able to swallow the tablet whole.

Conditions with decreased gastro-intestinal transit time

Conditions leading to shorter gastrointestinal transit time, e.g., diseases associated with chronic severe diarrhoea, may result in a reduced absorption of paliperidone.

Renal impairment

The plasma concentrations of paliperidone are increased in patients with renal impairment and, therefore, dosage adjustment may be required in some patients. 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.

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 LP has not been studied in elderly patients with dementia. The experience from risperidone 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 have 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. Xeplion LP should be used with caution in elderly patients with dementia who have risk factors for stroke.

Parkinson's disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing Xeplion LP 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 α-adrenergic blocking effects have been reported to induce priapism. During postmarketing surveillance priapism has also been reported with 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 LP 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.

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 LP and preventive 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 medicines or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumour.

Paediatric population

The sedative effect of Xeplion LP should be closely monitored in this population. A change in the time of administration of Xeplion LP may improve the impact of sedation on the patient.

Because of the potential effects of prolonged hyperprolactinemia on growth and sexual maturation in adolescents, regular clinical evaluation of endocrinological status should be considered, including measurements of height, weight, sexual maturation, monitoring of menstrual functioning, and other potential prolactin-related effects.

During treatment with Xeplion LP regular examination for extrapyramidal symptoms and other movement disorders should also be conducted.

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, such as Xeplion LP.

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.

Lactose content (pertains only to the 3 mg tablets)

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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. Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to Xeplion LP is known.

Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects. Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to Xeplion LP is known.

Summary of the safety profile

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

Tabulated list of adverse reactions

The following are all ADRs that were reported with paliperidone by frequency category estimated from paliperidone palmitate clinical trials. The following terms and frequencies are applied: 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); and not known (cannot be estimated from the available data).

Undesirable effects noted with risperidone formulations

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.

Description of selected adverse reactions

Anaphylactic reaction

Rarely, cases of anaphylactic reaction after injection with Xeplion LP have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.

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 with Xeplion LP. 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).

Extrapyramidal symptoms (EPS)

EPS included a pooled analysis of the following terms: parkinsonism (includes salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, glabellar reflex abnormal, and parkinsonian rest tremor), akathisia (includes akathisia, restlessness, hyperkinesia, and restless leg syndrome), dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus), and tremor. It should be noted that a broader spectrum of symptoms are included that do not necessarily have an extrapyramidal origin.

Weight gain

In the 13-week study involving the 150 mg initiation dosing, the proportion of subjects with an abnormal weight increase > 7% showed a dose-related trend, with a 5% incidence rate in the placebo group compared with rates of 6%, 8% and 13% in the Xeplion LP 25 mg, 100 mg, and 150 mg groups, respectively.

During the 33-week open-label transition/maintenance period of the long-term recurrence prevention trial, 12% of Xeplion LP-treated subjects met this criterion (weight gain of > 7% from double-blind phase to endpoint); the mean (SD) weight change from open-label baseline was + 0.7 (4.79) kg.

Hyperprolactinaemia

In clinical trials, median increases in serum prolactin were observed in subjects of both genders who received Xeplion LP. Adverse reactions that may suggest increase in prolactin levels (e.g. amenorrhoea, galactorrhoea, menstrual disturbances, 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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medical 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 via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: [email protected]

Adults

Summary of the safety profile

The adverse drug reactions (ADRs) most frequently reported in clinical trials with adults were headache, insomnia, sedation/somnolence, parkinsonism, akathisia, tachycardia, tremor, dystonia, upper respiratory tract infection, anxiety, dizziness, weight increased, nausea, agitation, constipation, vomiting, fatigue, depression, dyspepsia, diarrhoea, dry mouth, toothache, musculoskeletal pain, hypertension, asthenia, back pain, electrocardiogram QT prolonged, and cough.

The ADRs that appeared to be dose-related included headache, sedation/somnolence, parkinsonism, akathisia, tachycardia, dystonia, dizziness, tremor, upper respiratory tract infection, dyspepsia, and musculoskeletal pain.

In the schizoaffective disorder studies, a greater proportion of subjects in the total Xeplion LP dose group who were receiving concomitant therapy with an antidepressant or mood stabiliser experienced adverse events as compared to those subjects treated with Xeplion LP monotherapy.

Tabulated list of adverse reactions

The following are all the ADRs that were reported in clinical trials and postmarketing experience with paliperidone by frequency category estimated from Xeplion LP clinical trials in adults. The following terms and frequencies are applied: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Undesirable effects noted with risperidone formulations

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. In addition to the above adverse reactions, the following adverse reactions have been noted with the use of risperdone products and can be expected to occur with Xeplion LP.

Nervous system disorders: cerebrovascular disorder

Eye disorders: floppy iris syndrome (intraoperative)

Respiratory, thoracic and mediastinal disorders: rales

Description of selected adverse reactions

Extrapyramidal symptoms (EPS)

In schizophrenia clinical trials, there was no difference observed between placebo and the 3 and 6 mg doses of Xeplion LP. Dose dependence for EPS was seen with the two higher doses of Xeplion LP (9 and 12 mg). In the schizoaffective disorder studies, the incidence of EPS was observed at a higher rate than placebo in all dose groups without a clear relationship to dose.

EPS included a pooled analysis of the following terms: Parkinsonism (includes salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex abnormal, parkinsonian rest tremor), akathisia (includes akathisia, restlessness, hyperkinesia, and restless leg syndrome), dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus), and tremor. It should be noted that a broader spectrum of symptoms are included that do not necessarily have an extrapyramidal origin.

Weight gain

In schizophrenia clinical trials, the proportions of subjects meeting a weight gain criterion of > 7% of body weight were compared, revealing a similar incidence of weight gain for Xeplion LP 3 mg and 6 mg compared with placebo, and a higher incidence of weight gain for Xeplion LP 9 mg and 12 mg compared with placebo.

In schizoaffective disorder clinical trials, a higher percentage of Xeplion LP-treated subjects (5%) had an increase in body weight of > 7% compared with placebo-treated subjects (1%). In the study that examined two dose groups , the increase in body weight of > 7% was 3% in the lower-dose (3-6 mg) group, 7% in the higher-dose (9-12 mg) group, and 1% in the placebo group.

Hyperprolactinaemia

In schizophrenia clinical trials, increases in serum prolactin were observed with Xeplion LP in 67% of subjects. Adverse reactions that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, menstrual disturbances, gynaecomastia) were reported overall in 2% of subjects. Maximum mean increases of serum prolactin concentrations were generally observed on Day 15 of treatment, but remained above baseline levels at study endpoint.

Class effects

QT prolongation, ventricular arrythmias (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 drugs - Frequency unknown.

Paliperidone is the active metabolite of risperidone. The safety profile of risperidone may be pertinent.

Elderly

In a study conducted in elderly subjects with schizophrenia, the safety profile was similar to that seen in non-elderly subjects. Xeplion LP has not been studied in elderly patients with dementia. In clinical trials with some other atypical antipsychotics, increased risks of death and cerebrovascular accidents have been reported.

Paediatric population

Summary of the safety profile

In one short-term and two longer-term studies with paliperidone prolonged-release tablets conducted in adolescents 12 years and older with schizophrenia, the overall safety profile was similar to that seen in adults. In the pooled adolescent schizophrenia population (12 years and older, N = 545) exposed to Xeplion LP, the frequency and type of undesirable effects were similar to those in adults except for the following ADRs that were reported more frequently in adolescents receiving Xeplion LP than adults receiving Xeplion LP (and more frequently than placebo): sedation/somnolence, parkinsonism, weight increase, upper respiratory tract infection, akathisia, and tremor were reported very commonly (> 1/10) in adolescents; abdominal pain, galactorrhoea, gynaecomastia, acne, dysarthria, gastroenteritis, epistaxis, ear infection, blood triglyceride increased, and vertigo were reported commonly (> 1/100, < 1/10) in adolescents.

Extrapyramidal Symptoms (EPS)

In the short-term, placebo-controlled, fixed-dose adolescent study, the incidence of EPS was higher than placebo for all doses of Xeplion LP with an increased frequency of EPS at higher doses. Across all adolescent studies, EPS was more common in adolescents than in adults for each Xeplion LP dose.

Weight gain

In the short-term, placebo-controlled, fixed-dose adolescent study, a higher percentage of Xeplion LP-treated subjects (6-19% depending on dose) had an increase in body weight of >7% compared to placebo-treated subjects (2%). There was no clear dose relationship. In the long-term 2-year study, the subjects who were exposed to Xeplion LP during both the double-blind and open-label studies reported a modest weight gain (4.9 kg).

In adolescents, weight gain should be assessed against that expected with normal growth.

Prolactin

In the up to 2-year, open-label treatment study of Xeplion LP in adolescents with schizophrenia, incidence of elevated serum prolactin levels occurred in 48% of females and 60% of males. Adverse reactions that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, menstrual disturbances, gynaecomastia) were reported overall in 9.3% of subjects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medical 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 via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

Symptoms

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.

Management

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.

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 association with overdose. In the case of acute overdosage, the possibility of multiple medicinal product involvement should be considered.

Consideration should be given to the prolonged-release nature of the product 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. Administration of activated charcoal together with a laxative should be considered. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered. Close supervision and monitoring should continue until the patient recovers.

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

Xeplion LP 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 LP 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 LP 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 LP. 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 LP (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 LP 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 LP groups by day 8.

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

Maintaining symptom control and delaying relapse of schizophrenia

The efficacy of Xeplion LP in maintaining symptomatic control and delaying relapse of schizophrenia was established in a longer-term double-blind, placebo-controlled, flexible-dose study involving 849 non-elderly adult subjects who met DSM-IV criteria for schizophrenia. This study included a 33-week open-label acute treatment and stabilisation phase, a randomised, double-blind placebo-controlled phase to observe for relapse, and a 52-week open-label extension period. In this study, doses of Xeplion LP included 25, 50, 75, and 100 mg administered monthly; the 75 mg dose was allowed only in the 52-week open-label extension. Subjects initially received flexible doses (25-100 mg) of Xeplion LP during a 9-week transition period, followed by a 24-week maintenance period, where subjects were required to have a PANSS score of ≤ 75. Dosing adjustments were only allowed in the first 12 weeks of the maintenance period. A total of 410 stabilised patients were randomised to either Xeplion LP (median duration 171 days [range 1 day to 407 days]) or to placebo (median duration 105 days [range 8 days to 441 days]) until they experienced a relapse of schizophrenia symptoms in the variable length double-blind phase. The trial was stopped early for efficacy reasons as a significantly longer time to relapse (p < 0.0001, Figure 1) was seen in patients treated with Xeplion LP compared to placebo (hazard ratio = 4.32; 95% CI: 2.4-7.7).

Figure 1: Kaplan-Meier Plot of Time to Relapse - Interim Analysis (Intent-to-Treat Interim Analysis Set)

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Xeplion LP in all subsets of the paediatric population in schizophrenia.

Pharmacologic group: Psycholeptics, other antipsychotics ATC code: N05AX13

Xeplion LP 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 alfa1-adrenergic receptors and blocks, to a lesser extent, H1-histaminergic and alfa2-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 to a lesser extent than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects.

Clinical efficacy

Schizophrenia

The efficacy of Xeplion LP in the treatment of schizophrenia was established in three multi-centre, placebo-controlled, double-blind, 6-week trials in subjects who met DSM-IV criteria for schizophrenia. Xeplion LP doses, which varied across the three studies, ranged from 3 to 15 mg once daily. The primary efficacy endpoint was defined as a decrease in total Positive and Negative Syndrome Scale (PANSS) scores as shown in the following table. 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. All tested doses of Xeplion LP separated from placebo on day 4 (p<0.05). Predefined secondary endpoints included the Personal and Social Performance (PSP) scale and the Clinical Global Impression - Severity (CGI-S) scale. In all three studies, Xeplion LP was superior to placebo on PSP and CGI-S. Efficacy was also evaluated by calculation of treatment response (defined as decrease in PANSS Total Score > 30%) as a secondary endpoint.

In a long-term trial designed to assess the maintenance of effect, Xeplion LP was significantly more effective than placebo in maintaining symptom control and delaying relapse of schizophrenia. After having been treated for an acute episode for 6 weeks and stabilised for an additional 8 weeks with Xeplion LP (doses ranging from 3 to 15 mg once daily) patients were then randomised in a double-blind manner to either continue on Xeplion LP or on placebo until they experienced a relapse in schizophrenia symptoms. The trial was stopped early for efficacy reasons by showing a significantly longer time to relapse in patients treated with Xeplion LP compared to placebo (p=0.0053).

Schizoaffective disorder

The efficacy of Xeplion LP in the acute treatment of psychotic or manic symptoms of schizoaffective disorder was established in two placebo-controlled, 6-week trials in non-elderly 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 (YMRS) and/or Hamilton Rating Scale 21 for Depression (HAM-D 21). The population included subjects with schizoaffective bipolar and depressive types. In one of these trials, efficacy was assessed in 211 subjects who received flexible doses of Xeplion LP (3-12 mg once daily). In the other study, efficacy was assessed in 203 subjects who were assigned to one of two dose levels of Xeplion LP: 6 mg with the option to reduce to 3 mg (n = 105) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. Both studies included subjects who received Xeplion LP either as monotherapy or in combination with mood stabilisers and/or antidepressants. Dosing was in the morning without regard to meals. Efficacy was evaluated using the PANSS.

The Xeplion LP group in the flexible-dose study (dosed between 3 and 12 mg/day, mean modal dose of 8.6 mg/day) and the higher dose group of Xeplion LP in the 2 dose-level study (12 mg/day with option to reduce to 9 mg/day) were each superior to placebo in the PANSS at 6 weeks. In the lower dose group of the 2 dose-level study (6 mg/day with option to reduce to 3 mg/day), Xeplion LP was not significantly different from placebo as measured by the PANSS. Only few subjects received the 3 mg dose in both studies and efficacy of this dose could not be established. Statistically superior improvements in manic symptoms as measured by YMRS (secondary efficacy scale) were observed in patients from the flexible-dose study and the Xeplion LP higher dose in the second study.

Taking the results of both studies together (pooled study-data), Xeplion LP improved the psychotic and manic symptoms of schizoaffective disorder at endpoint relative to placebo when administered either as monotherapy or in combination with mood stabilisers and/or antidepressants. However, overall the magnitude of effect in regard to PANSS and YMRS observed on monotherapy was larger than that observed with concomitant antidepressants and/or mood stabilisers. Moreover, in the pooled population, Xeplion LP was not efficacious in patients concomitantly receiving mood stabiliser and antidepressants in regard to the psychotic symptoms, but this population was small (30 responders in the paliperidone group and 20 responders in the placebo group). Additionally, in study SCA-3001 in the ITT population the effect on psychotic symptoms measured by PANSS was clearly less pronounced and not reaching statistical significance for patients receiving concomitantly mood stabilisers and/or antidepressants. An effect of Xeplion LP on depressive symptoms was not demonstrated in these studies, but has been demonstrated in a long-term study with the long-acting injectable formulation of paliperidone (described further down in this section).

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. Efficacy was also evaluated by calculation of treatment response (defined as decrease in PANSS Total Score > 30% and CGI-C Score ≤ 2) as a secondary endpoint.

In a long-term trial designed to assess the maintenance of effect, the long-acting injectable formulation of paliperidone was significantly more effective than placebo in maintaining symptom control and delaying relapse of psychotic, manic, and depressive symptoms of schizoaffective disorder. After having been successfully treated for an acute psychotic or mood episode for 13 weeks and stabilised for an additional 12 weeks with the long-acting injectable formulation of paliperidone (doses ranging from 50 to 150 mg) patients were then randomised to a 15-month double-blind relapse prevention period of the study to either continue on the long-acting injectable formulation of paliperidone or on placebo until they experienced a relapse of schizoaffective symptoms. The study showed a significantly longer time to relapse in patients treated with the long-acting injectable formulation of paliperidone compared to placebo (p<0.001).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Xeplion LP in all subsets of the paediatric population in the treatment of schizoaffective disorders.

The efficacy of Xeplion LP in the treatment of schizophrenia in adolescents between 12 and 14 years old has not been established.

The efficacy of Xeplion LP in adolescent subjects with schizophrenia (Xeplion LP N = 149, placebo N = 51) was studied in a randomised, double-blind, placebo-controlled, 6-week study using a fixed-dose weight-based treatment group design over the dose range of 1.5 mg/day to 12 mg/day. Subjects were 12-17 years of age and met DSM-IV criteria for schizophrenia. Efficacy was evaluated using PANSS. This study demonstrated the efficacy of Xeplion LP of the medium dose group in adolescent subjects with schizophrenia. Secondary by dose analysis demonstrated the efficacy of 3 mg, 6 mg, and 12 mg dose given once daily.

Efficacy of Xeplion LP over a flexible dose range of 3 mg/day to 9 mg/day in adolescent subjects (12 years and older) with schizophrenia (Xeplion LP N = 112, aripiprazole N = 114) was also evaluated in a randomised, double-blind, active-controlled study that included an 8-week, double-blind acute phase and an 18-week, double-blind maintenance phase. The changes in PANSS total scores from baseline to Week 8 and Week 26 were numerically similar between the Xeplion LP and aripiprazole treatment groups. In addition, the difference in the percentage of patients demonstrating > 20% improvement in PANSS total score at Week 26 between the two treatment groups was numerically similar.

Absorption and distribution

Paliperidone palmitate is the palmitate ester prodrug of paliperidone. Due to its extremely low water solubility, paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolysed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median T_max of 13 days. The release of the active substance starts as early as day 1 and lasts for at least 4 months.

Following intramuscular injection of single doses (25-150 mg) in the deltoid muscle, on average, a 28% higher C_max was observed compared with injection in the gluteal muscle. The two initial deltoid intramuscular injections of 150 mg on day 1 and 100 mg on day 8 help attain therapeutic concentrations rapidly. The release profile and dosing regimen of Xeplion LP results in sustained therapeutic concentrations. The total exposure of paliperidone following Xeplion LP administration was dose-proportional over a 25-150 mg dose range, and less than dose-proportional for C_max for doses exceeding 50 mg. The mean steady-state peak:trough ratio for a Xeplion LP dose of 100 mg was 1.8 following gluteal administration and 2.2 following deltoid administration. The median apparent half-life of paliperidone following Xeplion LP administration over the dose range of 25-150 mg ranged from 25-49 days.

The absolute bioavailability of paliperidone palmitate following Xeplion LP administration is 100%.

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

The plasma protein binding of racemic paliperidone is 74%.

Biotransformation and elimination

One week following administration of a single oral dose of 1 mg immediate-release ¹⁴C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolised in the liver. 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. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolisers and poor metabolisers of CYP2D6 substrates. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of medicinal products metabolised by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.

In vitro studies have shown that paliperidone is a P-gp substrate and a weak inhibitor of P-gp at high concentrations. No in vivo data are available and the clinical relevance is unknown.

Long acting paliperidone palmitate injection versus oral prolonged release paliperidone

Xeplion LP is designed to deliver paliperidone over a monthly period while prolonged release oral paliperidone is administered on a daily basis. The initiation regimen for Xeplion LP (150 mg/100 mg in the deltoid muscle on day 1/day 8) was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation.

In general, overall initiation plasma levels with Xeplion LP were within the exposure range observed with 6-12 mg prolonged release oral paliperidone. The use of the Xeplion LP initiation regimen allowed patients to stay in this exposure window of 6-12 mg prolonged release oral paliperidone even on trough pre-dose days (day 8 and day 36). Because of the difference in median pharmacokinetic profiles between the two medicinal products, caution should be exercised when making a direct comparison of their pharmacokinetic properties.

Hepatic impairment

Paliperidone is not extensively metabolised in the liver. Although Xeplion LP was not studied on patients with hepatic impairment, no dose adjustment is required in patients with mild or moderate hepatic impairment. In a study with oral paliperidone in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects. Paliperidone has not been studied in patients with severe hepatic impairment.

Renal impairment

The disposition of a single oral dose paliperidone 3 mg prolonged 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 (AUC_inf) of 1.5, 2.6, and 4.8 fold, respectively, compared to healthy subjects. Based on a limited number of observations with Xeplion LP in subjects with mild renal impairment and pharmacokinetic simulations, a reduced dose is recommended.

Elderly

Population pharmacokinetics analysis showed no evidence of age related pharmacokinetics differences.

Body mass index (BMI)/body weight

Pharmacokinetic studies with paliperidone palmitate have shown somewhat lower (10-20%) plasma concentrations of paliperidone in patients who are overweight or obese in comparison with normal weight patients.

Race

Population pharmacokinetics analysis of data from studies with oral paliperidone revealed no evidence of race-related differences in the pharmacokinetics of paliperidone following Xeplion LP administration.

Gender

No clinically significant differences were observed between men and women.

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. Effect of smoking on the pharmacokinetics of paliperidone was not studied with Xeplion LP. A population pharmacokinetic analysis based on data with oral paliperidone prolonged release tablets showed a slightly lower exposure to paliperidone in smokers compared with non-smokers. The difference is unlikely to be of clinical relevance.

The pharmacokinetics of paliperidone following Xeplion LP administration are dose proportional within the available dose range.

Absorption

Following a single dose, Xeplion LP exhibits a gradual ascending release rate, allowing the plasma concentrations of paliperidone to steadily rise to reach peak plasma concentration (Cmax) approximately 24 hours after dosing. With once-daily dosing of Xeplion LP, steady-state concentrations of paliperidone are attained within 4-5 days of dosing in most subjects.

Paliperidone is the active metabolite of risperidone. The release characteristics of Xeplion LP result in minimal peak-trough fluctuations as compared to those observed with immediate-release risperidone (fluctuation index 38% versus 125%).

The absolute oral bioavailability of paliperidone following Xeplion LP administration is 28% (90% CI of 23%-33%).

Administration of paliperidone prolonged-release tablets with a standard high-fat/high-caloric meal increases C_max and AUC of paliperidone by up to 50-60% compared with administration in the fasting state.

Distribution

Paliperidone is rapidly distributed. The apparent volume of distribution is 487 l. The plasma protein binding of paliperidone is 74%. It binds primarily to α1-acid glycoprotein and albumin.

Biotransformation and elimination

One week following administration of a single oral dose of 1 mg immediate-release ¹⁴C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolised by the liver. 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. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of Xeplion LP between extensive metabolisers and poor metabolisers of CYP2D6 substrates. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of medicines metabolised by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. The terminal elimination half-life of paliperidone is about 23 hours.

In vitro studies have shown that paliperidone is a P-gp substrate and a weak inhibitor of P-gp at high concentrations. No in vivo data are available and the clinical relevance is unknown.

Hepatic impairment

Paliperidone is not extensively metabolised in the liver. 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. No data are available in patients with severe hepatic impairment (Child-Pugh class C).

Renal impairment

Elimination of paliperidone decreased with decreasing renal function. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% in mild (Creatinine Clearance [Cr Cl] = 50 to < 80 ml/min), 64% in moderate (CrCl = 30 to < 50 ml/min), and 71% in severe (CrCl = < 30 ml/min) renal impairment. 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).

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 Xeplion LP 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.

Adolescents

Paliperidone systemic exposure in adolescent subjects (15 years and older) was comparable to that in adults. In adolescents weighing < 51 kg, a 23% higher exposure was observed than in adolescents weighing > 51 kg. Age alone did not influence the paliperidone exposure.

Race

Population pharmacokinetics analysis revealed no evidence of race-related differences in the pharmacokinetics of paliperidone following Xeplion LP administration.

Gender

The apparent clearance of paliperidone following Xeplion LP 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.

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 non-smokers. The difference is unlikely to be of clinical relevance, though.

Repeat-dose toxicity studies of intramuscularly injected paliperidone palmitate (the 1-month formulation) and orally administered paliperidone in rat and dog showed mainly pharmacological effects, such as sedation and prolactin-mediated effects on mammary glands and genitals. In animals treated with paliperidone palmitate an inflammatory reaction was seen at the intramuscular injection site. Occasionally abscess formation occurred.

In rat reproduction studies with oral risperidone, which is extensively converted to paliperidone in rats and humans, adverse effects were seen on the birth weight and survival of the offspring. No embryotoxicity or malformations were observed following intramuscular administration of paliperidone palmitate to pregnant rats up to the highest dose (160 mg/kg/day) corresponding to 4.1 times the exposure level in humans at the maximum recommended dose of 150 mg. Other dopamine antagonists, when administered to pregnant animals, have caused negative effects on learning and motor development in the offspring.

Paliperidone palmitate and paliperidone were not genotoxic. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (both species) were seen. The carcinogenic potential of intramuscularly injected paliperidone palmitate was assessed in rats. There was a statistically significant increase in mammary gland adenocarcinomas in female rats at 10, 30 and 60 mg/kg/month. Male rats showed a statistically significant increase in mammary gland adenomas and carcinomas at 30 and 60 mg/kg/month which is 1.2 and 2.2 times the exposure level at the maximum recommended human 150 mg dose. These tumours can be related to prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumour findings in rodents in terms of human risk is unknown.

Repeat-dose toxicity studies of paliperidone in rat and dog showed mainly pharmacological effects, such as sedation and prolactin-mediated effects on mammary glands and genitals. Paliperidone was not teratogenic in rat and rabbit. In rat reproduction studies using risperidone, which is extensively converted to paliperidone in rats and humans, a reduction was observed in the birth weight and survival of the offspring. Other dopamine antagonists, when administered to pregnant animals, have caused negative effects on learning and motor development in the offspring. Paliperidone was not genotoxic in a battery of tests. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (both species) were seen. These tumours can be related to prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumour findings in rodents in terms of human risk is unknown.

In a 7-week juvenile toxicity study in rats administered oral doses of paliperidone up to 2.5 mg/kg/day, corresponding to an exposure approximately equal to the clinical exposure based on AUC, no effects on growth, sexual maturation and reproductive performance were observed. Paliperidone did not impair the neurobehavioural development in males at doses up to 2.5 mg/kg/day. At 2.5 mg/kg/day in females, an effect on learning and memory was observed. This effect was not observed after discontinuation of treatment. In a 40-week juvenile toxicity study in dogs with oral doses of risperidone (which is extensively converted to paliperidone) up to 5 mg/kg/day, effects on sexual maturation, long bone growth and femur mineral density were observed from 3 times the clinical exposure based on AUC.

This medicinal product must not be mixed with other medicinal products.

Not applicable

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