Xeplion Prolonged release suspension for intramuscular injection

XEPLION is indicated for the treatment of schizophrenia and for the prevention of recurrence of symptoms of schizophrenia.

For patients who have never taken oral paliperidone, or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with XEPLION.

Posology

The recommended initiation of XEPLION is with a dose of 150 mg on treatment Day 1 and 100 mg one week later, both administered in the deltoid muscle. 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. 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 should be considered (see section 5.2), as the full effect of the dose adjustment may not be evident for several months.

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 u00b1 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 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, initiate dosing as described for the initial recommended initiation of XEPLION above.

Method of administration

XEPLION is intended for deep intramuscular use only. Inject slowly, deep into the muscle. Care should be taken to avoid inadvertent injection into a blood vessel. Each injection should be administered by a health care professional. Administration should be in a single injection. Do not administer the dose in divided injections. Do not administer intravascularly or subcutaneously.

The recommended needle size for administration of XEPLION into the deltoid muscle is determined by the patientu2019s weight. For those u2265 90 kg (u2265 200 lb), the 1u00bd inch, 22-gauge needle is recommended. For those < 90 kg (< 200 lb), the 1-inch, 23 gauge needle is recommended. Deltoid injections should be alternated between the two deltoid muscles. The recommended needle size for administration of XEPLION into the gluteal muscle is the 1u00bd-inch, 22 gauge needle. Administration should be made into the upper-outer quadrant of the gluteal area. Gluteal injections should be alternated between the two gluteal muscles.

XEPLION is contraindicated in patients with a known hypersensitivity to paliperidone or to any of the components in the formulation.

XEPLION is contraindicated in patients with a known hypersensitivity or intolerance to risperidone as paliperidone is an active metabolite of risperidone.

Moderate to severe renal impairment.

Parkinsonu2019s disease and Dementia with Lewy Bodies.

Neuroleptic Malignant Syndrome

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

Tardive Dyskinesia/Extrapyramidal symptoms

Medicines with dopamine receptor antagonistic properties such as XEPLION have been associated with the induction of tardive dyskinesia characterized by rhythmical, involuntary movements, predominantly of the tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of XEPLION, should be considered.

Extrapyramidal symptoms and psychostimulants

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

Leukopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia, and agranulocytosis have been reported with XEPLION. Agranulocytosis has been reported during postmarketing 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 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 10 9 /L) should discontinue XEPLION and have their WBC followed until recovery.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with XEPLION. 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.

Elderly Patients with Dementia

XEPLION has not been studied in elderly patients with dementia. Since paliperidone is an active metabolite of risperidone, elderly patients with dementia should not be treated with XEPLION as there is an overall increase in mortality, cardiovascular and cerebrovascular adverse events. (see section 4.3).

Hyperglycaemia and Diabetes Mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with XEPLION. Patients with an established diagnosis of diabetes mellitus, who are started on XEPLION should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with XEPLION should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with XEPLION should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when XEPLION was discontinued; however, other patients required continuation of anti-diabetic treatment despite discontinuation of XEPLION.

Weight gain

Weight gain has been observed. Clinical monitoring of weight is recommended.

Parkinsonu2019s Disease and Dementia with Lewy Bodies

XEPLION, is contraindicated in patients with Parkinsonu2019s Disease or patients with Dementia with Lewy Bodies (DLB) (See section 4.3) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medications such as XEPLION. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms. In addition, in clinical trials, elderly risperidone treated patients had a higher mortality than placebo treated elderly patients.

Priapism

Medicines with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with paliperidone during postmarketing surveillance.

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, Reyeu2019s syndrome, and brain tumour.

Administration

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

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. IFIS may increase the risk of eye complications during and after the operation. Current or past use of XEPLION should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping XEPLION therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the XEPLION therapy.

QT Interval

Caution should be exercised when XEPLION is prescribed in patients with a history of cardiac dysrhythmias, in patients with congenital long QT syndrome, and in concomitant use with medicines known to prolong the QT interval.

Orthostatic Hypotension

Paliperidone may induce orthostatic hypotension in patients based on its alpha- blocking activity. 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 hypovolaemia, and treatment with antihypertensive medications).

Seizures

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

Body Temperature Regulation

Disruption of the bodyu2019s ability to reduce core body temperature may occur. 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 medication with anticholinergic activity, or being subject to dehydration.

Hypersensitivity reactions

Although tolerability with oral paliperidone or risperidone should be established prior to initiating treatment with XEPLION, very rare cases of anaphylactic reactions have been reported during postmarketing experience with patients who have previously tolerated oral risperidone or oral paliperidone. (See section 4.2 and section 4.8). If hypersensitivity reactions occur, discontinue use of XEPLION; initiate general supportive measures as clinically appropriate and monitor the patient until signs and symptoms resolve. (See section 4.3 and section 4.8).

Caution is advised when prescribing XEPLION with medicines known to prolong the QT interval. Since XEPLION is hydrolysed to paliperidone (see section 5.2), results from studies with oral paliperidone should be taken into consideration when assessing interaction potential.

Potential for XEPLION to Affect Other Medicines

XEPLION is not expected to cause clinically important pharmacokinetic interactions with medicines that are metabolised by cytochrome P-450 isozymes. 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. Therefore, XEPLION is not expected to inhibit clearance of medicines that are metabolised by these metabolic pathways in a clinically relevant manner. XEPLION is also not expected to have enzyme inducing properties. XEPLION is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown. Given the primary CNS effects of paliperidone (see section 4.8) XEPLION should be used with caution in combination with other centrally acting medicines and alcohol. XEPLION may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension (see section 4.4: Orthostatic Hypotension), an additive effect may be observed when XEPLION is administered with other therapeutic agents that have this potential. Pharmacokinetic interaction between XEPLION and lithium is unlikely.

Potential for Other Medicines to Affect XEPLION

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP3A5. This suggests that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, there are no indications in vitro or in vivo that these isozymes play a significant role in the metabolism of paliperidone. In vitro studies have shown that paliperidone is a P-gp substrate. Paliperidone is metabolised to a limited extent by CYP2D6 (see section 5.2: Metabolism and Elimination). In an interaction study in healthy subjects in which oral paliperidone was administered concomitantly with paroxetine, a potent CYP2D6 inhibitor, no clinically relevant effects on the pharmacokinetics of paliperidone were observed. Co-administration of oral paliperidone extended 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 medicine excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of 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. Paliperidone, a cation under physiological pH, is primarily excreted unchanged by the kidneys, approximately half via filtration and half via active secretion. Concomitant administration of trimethoprim, a medicine known to inhibit active renal cation medicine transport, did not influence the pharmacokinetics of paliperidone.

Concomitant Use of XEPLION with risperidone or with oral paliperidone

Since paliperidone is the major active metabolite of risperidone, caution should be exercised when XEPLION is coadministered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of XEPLION with other antipsychotics is limited.

Concomitant use of XEPLION with psychostimulants

The combined use of psychostimulants (e.g methylphenidate) with paliperidone can lead to the emergence of extrapyramidal symptoms upon change of either or both treatments (see section 4.4).

Pregnancy

The safety of intramuscularly-injected XEPLION or orally-dosed paliperidone for use during human pregnancy has not been established. Neonates exposed to XEPLION during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms that may be severe. These symptoms in the neonates may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder.

Breastfeeding

In animal studies with paliperidone and in human studies with risperidone, paliperidone was excreted in the milk. Therefore, women receiving XEPLION should not breast-feed infants.

XEPLION can have an influence on the ability to drive and use machines due to potential nervous system effects (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to XEPLION is known.

Clinical Trial Data

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

Tabulated list of adverse reactions in Clinical Studies

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 (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1,000 to < 1/100); rare (u2265 1/10,000 to < 1/1,000); 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

Not Known

Infections and Infestations

Upper respiratory tract infection, urinary tract infection, influenza.

Pneumonia, bronchitis, respiratory tract infection, sinusitis, cystitis, ear infection, eye infection, tonsillitis, cellulitis, acarodermatitis, subcutaneous abscess.

Onychomycosis

Blood and lymphatic system disorders

White blood cell count decreased, anaemia, haematocrit decreased, eosinophil count increased.

Neutropenia, thrombocytopenia.

Immune System Disorder

Hypersensitivity.

Endocrine Disorder

Hyperprolactinaemia

Inappropriate antidiuretic hormone secretion.

Glucose urine present

Metabolism and nutrition disorders

Hyperglycaemia, weight increased, weight decreased, blood triglycerides increased

Diabetes mellitus

hyperinsulinaemia, increased appetite, anorexia, decreased appetite, increased blood cholesterol.

Hypoglycaemia

Polydipsia.

Psychiatric disorders

Insomnia

Agitation, depression, anxiety.

Sleep disorder, mania, confusional state, libido decreased, nervousness, nightmare.

Anorgasmia.

Nervous system disorders

Headache

Dystonia, parkinsonism, akathisia, dyskinesia, tremor, dizziness.

Tardive dyskinesia, convulsions, syncope, psychomotor hyperactivity, Neuroleptic malignant syndrome, cerebral ischaemia, unresponsive to stimuli, loss of consciousness, depressed level of consciousness, balance disorder.

Eye Disorder

Blurred vision, conjunctivitis, dry eye.

Eye movement disorder, eye rolling, photophobia, lacrimation increased, ocular hyperaemia.

Ear and labyrinth disorders

Vertigo, tinnitus, ear pain.

Cardiac disorders

Bradycardia, tachycardia.

Atrial fibrillation, atrioventricular block, electrocardiogram QT prolonged, postural orthostatic tachycardia syndrome, palpitations, abnormal sinus dysrhythmias.

Vascular disorders

Hypertension

Hypotension, orthostatic hypotension.

Deep vein thrombosis, flushing.

Respiratory thoracic and mediastinal disorders

Cough, nasal congestion.

Dyspnoea, pulmonary congestion, wheezing, pharyngolaryngeal pain, epistaxis.

Respiratory tract congestion.

Gastrointestinal disorders

Vomiting, abdominal pain, diarrhoea, nausea, constipation, toothache, dyspepsia.

Abdominal discomfort, gastroenteritis, dry mouth, flatulence.

Pancreatitis, swollen tongue, faecal incontinence, faecaloma, dysphagia.

Hepatobiliary disorders

Transaminases increased.

Gammaglutamyltransferase increased, hepatic enzyme increased.

Skin and Subcutaneous tissue disorders

Rash.

Urticaria, pruritus, alopecia, eczema, dry skin, erythema, acne.

Drug eruption, hyperkeratosis, dandruff.

Musculoskeletal and connective tissue disorders

Musculoskeletal pain, back pain.

Muscle spasms, joint stiffness, neck pain, arthralgia.

Blood creatine phosphokinase increased, joint swelling, muscular weakness.

Renal and urinary disorders

Urinary incontinence, pollakiuria, dysuria.

Urinary retention.

Reproductive system and breast disorders

Gynaecomastia, erectile dysfunction, ejaculation disorder, sexual dysfunction, galactorrhoea, amenorrhoea, menstruation delayed, menstrual disorder, vaginal discharge.

Breast pain, breast engorgement, breast enlargement, breast discharge, breast discomfort.

General disorders and Administration site conditions

Pyrexia, asthenia, fatigue, injection site reaction.

Face oedema, oedema, gait abnormal, chest discomfort, chest pain.

Malaise, induration.

Hypothermia, chills, body temperature increased, thirst, injection site abscess, injection site cellulitis, injection site haematoma.

Injury, poisoning and procedural complications

Fall.

Hyperprolactinaemia can in some cases lead to gynaecomastia, menstrual disturbances, amenorrhoea, and galactorrhoea.

In placebo-controlled trials, diabetes mellitus was reported in 0.32% in XEPLION-treated subjects compared to a rate of 0.39% in placebo group. Overall incidence from all clinical trials was 0.47% in all XEPLION-treated subjects.

Insomnia includes: initial insomnia, middle insomnia; 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. Convulsion includes: grand mal convulsion; Oedema includes: generalised oedema, oedema peripheral, pitting oedema. Menstrual disorder includes: menstruation irregular, oligomenorrhoea.

Symptoms

In general, expected signs and symptoms are those resulting from an exaggeration of paliperidoneu2019s 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 the setting of overdose with oral paliperidone.

In the case of acute overdosage, the possibility of multiple drug involvement should be considered.

Treatment

Consideration should be given to the extended-release nature of XEPLION and the long apparent 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.