Invega Sustenna75 mg

Established (FDA-approved) indications

• Schizophrenia in adults, as a long-acting maintenance treatment given by intramuscular injection.
• Schizoaffective disorder in adults, as monotherapy or as an adjunct to mood stabilizers and/or antidepressants (established for the once-monthly formulation).

Formulation-specific use

• Extended dosing-interval formulations (three-monthly and six-monthly injections) of Invega Sustenna are approved only for the maintenance treatment of schizophrenia in adults who have already been adequately treated with the once-monthly formulation for a minimum period, per product-specific labelling.

Invega Sustenna is not approved for treatment of acute agitation, and is not approved for dementia-related psychosis in elderly patients (see Contraindications and Precautions).

Each pre-filled syringe or vial of Paliperidone Palmitate contains paliperidone palmitate, an ester prodrug of paliperidone (the major active metabolite of risperidone), as a sterile aqueous extended-release nanocrystal suspension for intramuscular injection. Strengths are expressed in mg of paliperidone equivalents and vary by product (once-monthly, three-monthly, and six-monthly formulations).

Invega Sustenna is a long-acting injectable (LAI, "depot") atypical (second-generation) antipsychotic. It is the palmitate ester prodrug of paliperidone, which is slowly hydrolyzed after intramuscular injection to release active paliperidone into the systemic circulation over an extended period, allowing dosing intervals of one, three, or six months depending on the specific product formulation.

Invega Sustenna is intended for use only under the supervision of a qualified healthcare professional in a clinical setting; it is not a self-administered oral medicine.

Invega Sustenna belongs to the atypical (second-generation, or "newer generation") antipsychotics, specifically the benzisoxazole/benzisothiazole-related class, formulated as a long-acting injectable depot preparation.

Mechanism of action

The precise mechanism of Paliperidone Palmitate in schizophrenia and schizoaffective disorder is not fully established, but its therapeutic effect is thought to be mediated through a combination of central dopamine type 2 (D2) receptor antagonism and serotonin type 2A (5-HT2A) receptor antagonism. Paliperidone Palmitate also has affinity for alpha-1 and alpha-2 adrenergic receptors and H1 histaminergic receptors, which may explain some adverse effects such as orthostatic hypotension and sedation. It has negligible affinity for cholinergic muscarinic receptors.

Pharmacokinetics

After intramuscular injection, Paliperidone Palmitate dissolves slowly and is hydrolyzed to paliperidone, which is then absorbed into the systemic circulation. Owing to the low water solubility of the ester, plasma concentrations rise gradually to a peak over roughly 2-4 weeks (monthly formulation) and are sustained over the dosing interval. Paliperidone is eliminated mainly unchanged in urine, with a smaller fraction undergoing hepatic metabolism; elimination half-life is dependent on the rate of absorption from the injection site and increases progressively with the longer-acting formulations.

Invega Sustenna is for intramuscular injection only, given by a healthcare professional into the deltoid or gluteal muscle using the needle length supplied with the specific product for that injection site and patient weight. The suspension must be shaken thoroughly immediately before use to ensure a uniform suspension, and injected immediately after resuspension. Invega Sustenna must never be administered intravenously or subcutaneously, and should not be self-injected by the patient.

Invega Sustenna is associated with the following well-established, clinically significant interactions:

• CNS depressants (opioids, sedatives, alcohol): Concomitant use may increase the risk of sedation and respiratory depression; use with caution and counsel patients to avoid alcohol.
• Drugs that prolong the QT interval (e.g., certain antiarrhythmics, some antibiotics): Additive risk of QT prolongation and arrhythmia; avoid combining where possible and monitor if unavoidable.
• Antihypertensive agents: Invega Sustenna may potentiate the hypotensive effect due to its alpha-adrenergic blocking activity, increasing the risk of orthostatic hypotension.
• Strong CYP3A4/P-glycoprotein inducers (e.g., carbamazepine, rifampicin): May significantly reduce paliperidone plasma concentrations, potentially reducing efficacy; dose adjustment or closer monitoring may be needed.
• Dopaminergic agonists (e.g., levodopa): Invega Sustenna may antagonize the effect of dopamine agonists due to its dopamine-receptor-blocking activity.

Because paliperidone is the major active metabolite of risperidone, Invega Sustenna should generally not be used concurrently with oral or long-acting injectable risperidone or paliperidone products unless specifically directed by the treating physician.

Common side effects

• Injection site reactions (pain, redness, induration)
• Weight gain
• Somnolence/sedation
• Akathisia and other extrapyramidal symptoms (tremor, rigidity, abnormal gait)
• Headache
• Anxiety and insomnia

Less common but serious side effects

• Neuroleptic malignant syndrome (rare, potentially fatal) — see Precautions and Warnings
• Tardive dyskinesia — see Precautions and Warnings
• Metabolic changes: hyperglycemia, new-onset diabetes, dyslipidemia — see Precautions and Warnings
• QT-interval prolongation and arrhythmia
• Orthostatic hypotension and syncope, particularly during initiation and dose titration
• Leukopenia, neutropenia, and agranulocytosis
• Hyperprolactinemia (may present as galactorrhea, gynecomastia, menstrual irregularities, sexual dysfunction)
• Seizures
• Priapism (rare)

Pregnancy: Invega Sustenna should be used during pregnancy only if the potential benefit to the mother clearly justifies the potential risk to the fetus, and only under close physician supervision. Neonates exposed to antipsychotic drugs, including Invega Sustenna, during the third trimester are at risk of extrapyramidal and/or withdrawal symptoms after delivery; monitor newborns accordingly. Always consult a physician before use in pregnancy.

Lactation: Paliperidone is excreted in human breast milk. Because of the potential for adverse effects on the breastfed infant, and given the long duration of exposure inherent to a depot injectable, breastfeeding is generally not recommended during treatment with Invega Sustenna unless a physician judges that the benefit outweighs the risk; consult a physician before breastfeeding.

Boxed warning

Elderly patients with dementia-related psychosis treated with antipsychotic drugs, including Invega Sustenna, are at increased risk of death compared to placebo. Invega Sustenna is not approved for the treatment of patients with dementia-related psychosis.

Other important precautions

• Neuroleptic malignant syndrome (NMS): A rare but potentially fatal reaction characterized by hyperthermia, muscle rigidity, altered mental status, and autonomic instability; discontinue immediately if suspected and provide supportive care.
• Tardive dyskinesia: Involuntary, repetitive movements that may become irreversible; risk increases with cumulative dose and duration of treatment. Discontinue if clinically appropriate.
• Metabolic changes: Hyperglycemia, diabetes mellitus, and dyslipidemia have been reported; monitor blood glucose and lipid profile periodically, especially in patients with or at risk of diabetes.
• Weight gain: Monitor weight regularly during treatment.
• Orthostatic hypotension and syncope: Particularly during treatment initiation and dose changes; use caution in patients with cardiovascular disease, cerebrovascular disease, or predisposition to hypotension.
• QT prolongation: Avoid in patients with known QT prolongation, certain cardiac conditions, or concomitant use of other QT-prolonging drugs.
• Leukopenia, neutropenia, and agranulocytosis: Monitor complete blood counts in patients with a history of clinically significant low white blood cell count or drug-induced leukopenia/neutropenia.
• Seizures: Use with caution in patients with a history of seizures or conditions that lower the seizure threshold.
• Cognitive and motor impairment: Invega Sustenna may impair judgment, thinking, or motor skills; caution patients about operating machinery or driving until effects are known.
• Administration requirement: As a long-acting injectable, once administered Invega Sustenna cannot be rapidly removed from the body; adverse events, if they occur, may take considerably longer to resolve than with oral antipsychotics. Tolerability to oral paliperidone or risperidone is generally established before starting therapy.

Reported signs of Invega Sustenna overdose are generally consistent with an exaggeration of known pharmacological effects, and may include drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms; QT prolongation and serious arrhythmia are possible. Because Invega Sustenna is a long-acting injectable, any toxicity may be prolonged compared with oral antipsychotics.

There is no specific antidote for Invega Sustenna. In case of suspected overdose, seek immediate medical attention or contact emergency services/poison control. Management is supportive, with continuous cardiac monitoring (particularly for QT prolongation and arrhythmia) and close observation until the patient recovers, under hospital supervision.

Store at room temperature (below 30°C), away from light and moisture, and do not freeze. Keep out of reach of children. This product must be stored and handled by a healthcare facility/pharmacy, not by patients at home, as it is administered only by a healthcare professional.

Elderly

Invega Sustenna is not approved for the treatment of dementia-related psychosis in elderly patients because of an increased risk of death (see Precautions and Warnings). In elderly patients treated for approved indications, dosing follows adult recommendations with attention to renal function and cardiovascular risk.

Pediatric

Safety and efficacy of Invega Sustenna have not been established in pediatric patients; use is not recommended in this population.

Renal impairment

Dose reduction and careful individualization are required in mild renal impairment; Invega Sustenna is generally not recommended in moderate to severe renal impairment.

Hepatic impairment

No dose adjustment is needed in mild to moderate hepatic impairment; caution is advised in severe hepatic impairment due to lack of study data.

Invega Sustenna is intended for long-term maintenance treatment of schizophrenia and schizoaffective disorder. Duration of therapy is individualized by the treating physician based on clinical response, relapse risk, and tolerability, and treatment is often continued for an extended period (commonly a year or longer) with periodic reassessment; it should not be stopped or the interval extended without medical advice, given its long-acting nature.

Atypical (second-generation) antipsychotic; long-acting injectable (depot) formulation; benzisoxazole derivative

Paliperidone Palmitate (via its active moiety paliperidone) acts primarily as a central antagonist of dopamine D2 receptors and serotonin 5-HT2A receptors, with additional antagonism at alpha-1/alpha-2 adrenergic and H1 histaminergic receptors, producing antipsychotic effects while contributing to certain adverse effects such as sedation and orthostatic hypotension.

C

Invega Sustenna injection has not been established as safe and effective in pediatric patients, and is not recommended for use in this population. (Oral paliperidone, the active moiety, is separately approved for schizophrenia in adolescents aged 12 to 17 years, but this does not extend to the long-acting injectable formulations of Invega Sustenna.) Any use in minors should occur only under specialist psychiatric supervision with careful risk-benefit assessment.