Risperidone (Long-Acting Injection) (Risperdal Consta — Janssen Inc.)

• Indicated for the management of the manifestations of schizophrenia and related psychotic disorders in adults; it has been shown to improve both positive and negative symptoms.
• Adult schizophrenia efficacy is based in part on a 12-week, placebo-controlled trial, together with extrapolation from the established efficacy of oral Risperdal in this population; effectiveness beyond 12 weeks has not been systematically evaluated in controlled trials with the injection itself (though oral Risperdal has demonstrated maintenance of clinical improvement over 1 year).
• Indicated as monotherapy maintenance treatment for bipolar I disorder in patients who have previously responded to oral antipsychotics or other anti-manic treatment, to delay the occurrence of manic episodes; it is not indicated as adjunctive (add-on) treatment for bipolar disorder.
• For patients who have never taken oral risperidone, tolerability with oral risperidone (Risperdal/Risperdal M-TAB) should be established before starting Risperdal Consta.
• Not studied and use not recommended in patients under 18 years of age; no pediatric data are available.

• Safety during pregnancy has not been established; no clinical studies have been conducted with Risperdal Consta specifically.
• A retrospective observational cohort study using a US claims database found a statistically significant relative risk of congenital malformations of 1.26 (95% CI: 1.02–1.56) for first-trimester risperidone exposure versus no antipsychotic exposure; no biological mechanism has been identified, teratogenic effects were not seen in animal studies, and a causal relationship has not been established from this single study.
• There is one published case report of agenesis of the corpus callosum in an infant exposed to risperidone in utero; a causal link to risperidone was not established.
• Neonates exposed to antipsychotics (including Risperdal) during the third trimester are at risk of extrapyramidal and/or withdrawal symptoms after delivery — agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported, varying from self-limited to requiring intensive care and prolonged hospitalization.
• Risperdal Consta should not be used during pregnancy unless the expected benefit to the mother markedly outweighs the potential risk to the fetus.

• Risperidone and its active metabolite 9-hydroxyrisperidone are excreted into human breast milk (confirmed in humans; also demonstrated in lactating dogs, where risperidone concentration in milk approximated plasma and 9-hydroxyrisperidone concentration was higher in milk than plasma).
• Nursing should not be undertaken while a patient is receiving Risperdal Consta, and for at least 12 weeks after the last injection — this long window (versus a much shorter clearance interval for daily oral risperidone) reflects the injection's prolonged release profile.

• Boxed Serious Warning: elderly patients with dementia treated with atypical antipsychotics have an increased risk of death versus placebo — a pooled analysis of thirteen placebo-controlled trials (modal duration 10 weeks) across various atypical antipsychotics showed a mean 1.6-fold increase in death rate, with most deaths cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature; Risperdal Consta is not approved for dementia-related psychosis.
• Geriatric patients generally have decreased renal, hepatic, and cardiac function and an increased tendency toward orthostatic hypotension; because risperidone is substantially excreted by the kidneys, lower starting doses, slower dose titration, and lower maximal doses are recommended, and monitoring renal function may be useful.
• In an open-label trial, 57 clinically stable elderly patients (≥65 years) with schizophrenia received Risperdal Consta every 2 weeks for up to 12 months with no notable difference in tolerability versus non-elderly patients; standard dosing recommendations (25 mg IM every 2 weeks) apply to otherwise healthy elderly patients. Risperdal Consta has not been studied in elderly patients with bipolar disorder.
• Because elderly patients have a greater tendency toward orthostatic hypotension, they should be taught non-pharmacologic measures (e.g., sitting on the edge of the bed for several minutes before standing, rising slowly from sitting) and monitoring of orthostatic vital signs should be considered.

• Safety and efficacy in children and adolescents under 18 years of age have not been established, and use is not recommended; the monograph states no data are available.
• Weight gain has been observed with atypical antipsychotic use in pediatric/adolescent populations generally, and independent of drug-specific effects can be associated with adverse changes in glucose and lipid metabolism; long-term safety (including cardiometabolic effects and effects on growth, maturation, and behavioural development) in patients under 18 has not been systematically evaluated for this product.

• Critical timing rule — oral overlap for the FIRST injection only: because a single IM injection produces only a small initial release of drug (<1% of the dose) followed by a lag time of 3 weeks before the main release phase begins (main release runs from about week 3 to weeks 4–6, and subsides by about week 7), the monograph states that oral Risperdal/Risperdal M-TAB (or another antipsychotic medication) should be given with the FIRST injection of Risperdal Consta and continued for 3 weeks, to maintain adequate therapeutic plasma concentrations until the main release phase begins. This oral supplementation requirement applies to the first injection of a course of treatment (and again if restarting after a gap in treatment, or if switching from another antipsychotic) — it is not required to be repeated with every subsequent biweekly injection once the depot has reached the main release phase.
• Route/site: administered every 2 weeks by deep intramuscular injection only, into the gluteal or deltoid muscle, by a health care professional using the enclosed safety needle — never intravenously, and care must be taken to avoid inadvertent injection into a blood vessel.
• Needle selection differs by site: gluteal administration uses the 20G thin-wall (TW) 2-inch needle, injected into the upper-outer quadrant, alternating between the two buttocks; deltoid administration uses the 21G ultra-thin-wall (UTW) 1-inch needle, alternating between the two arms. Gluteal and deltoid injection have demonstrated bioequivalence under these recommended parameters, but repeated deltoid injections for more than 8 weeks have not been systematically studied.
• Recommended dose for both schizophrenia and bipolar I maintenance is 25 mg IM every 2 weeks; some non-responders may benefit from 37.5 mg or 50 mg. Maximum dose is 50 mg every 2 weeks — no additional benefit was seen above 50 mg in clinical trials, only a higher rate of adverse effects. A lower starting dose of 12.5 mg may be appropriate for hepatic/renal impairment, certain drug interactions, or patients with a history of poor tolerability to psychotropic medications; the efficacy of the 12.5 mg dose has not itself been studied in clinical trials.
• Dose titration: upward dose adjustment should not be made more often than every 4 weeks, and the clinical effect of a dose increase should not be anticipated earlier than 3 weeks after the first injection at the higher dose — both restrictions stem directly from the delayed-release pharmacokinetics. Two different dose strengths must not be combined in a single administration.
• Reassessment: patients should be periodically reassessed to determine the continued need for treatment, and responding patients should be maintained on the lowest effective dose.
• Renal impairment: Risperdal Consta itself has not been studied in renally impaired patients. If treatment is required, start oral risperidone at 0.5 mg twice daily in week 1, increasing to 1 mg twice daily or 2 mg once daily in week 2; if at least 2 mg/day oral is well tolerated, 25 mg IM every 2 weeks may begin (or a 12.5 mg starting dose may be used instead). Oral supplementation must still be continued for 3 weeks after the first injection until the main release phase begins; slower titration may be medically appropriate in some patients.
• Hepatic impairment: Risperdal Consta itself has not been studied in hepatically impaired patients (patients with hepatic impairment have an increased free fraction of risperidone, about 35% higher, based on oral data). The same staged oral titration used for renal impairment (0.5 mg BID week 1 → 1 mg BID or 2 mg once daily week 2 → 25 mg IM, or a 12.5 mg IM starting dose) and the same 3-week post-first-injection oral supplementation requirement apply.
• Switching from other antipsychotics: there are no systematically collected switching data; the prior antipsychotic should be gradually discontinued to ensure therapeutic concentrations are maintained through the 3-week lag after the first Risperdal Consta injection.
• Reinitiation after a treatment gap: there are no specific data; when restarting a patient who has had an interval off Risperdal Consta, oral supplementation (Risperdal or another antipsychotic) should again be administered as with a first injection.
• Reconstitution: remove the dose pack from the refrigerator and let it sit at room temperature for at least 30 minutes before reconstituting (do not warm it any other way). Reconstitute only with the diluent supplied in that specific dose pack (2 mL, added to the vial) — never substitute any dose pack component. The entire vial contents must be administered to deliver the intended dose. The kit is single-use only and must not be reprocessed or reused.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Because Risperdal Consta is administered by a health care professional, the potential for patient self-overdose is low, and no cases of overdose were reported in premarketing studies of the injection itself.
• Reported oral risperidone overdoses (estimated doses of 20–360 mg) produced exaggerated pharmacological effects: drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms; QT prolongation, widened QRS complex, convulsions, hyponatremia, and hypokalemia have also been reported in overdose. Torsade de pointes has been reported with combined overdose of oral risperidone and paroxetine.
• There is no specific antidote. Management is supportive: establish and maintain an airway with adequate oxygenation/ventilation, and start continuous cardiovascular/ECG monitoring immediately to detect arrhythmias.
• Hypotension and circulatory collapse should be treated with IV fluids and/or sympathomimetic agents — epinephrine and dopamine should specifically be avoided, since beta-stimulation may worsen hypotension in the setting of risperidone-induced alpha-blockade. Severe extrapyramidal symptoms should be treated with anticholinergic medication.
• For management of a suspected overdose, contact the regional Poison Control Centre; close medical supervision and monitoring should continue until the patient recovers.

• Insomnia (13–16% across the 25 mg/50 mg dose groups in the 12-week placebo-controlled trial, versus 14% placebo).
• Headache (15–22% across dose groups versus 12% placebo) and dizziness (8–11% versus 6% placebo).
• Somnolence/drowsiness (5–6% versus 3% placebo) and hallucination (6–7% versus 5% placebo, reflecting the underlying illness in some patients).
• Extrapyramidal symptoms: akathisia (2–9%) and parkinsonism (bradykinesia, extrapyramidal disorder, hypokinesia combined; 4–10% versus 3% placebo).
• Gastrointestinal effects: dyspepsia, constipation, and dry mouth (each reported up to 7% at the 50 mg dose, versus 1–2% placebo).
• Weight increase (4–5% versus 2% placebo) — with continued long-term treatment, mean weight gain of 2.6 kg has been observed.
• Mild local injection-site reactions (redness, swelling, or induration); at Week 10 (after the sixth gluteal injection), about 1% of patients had investigator-rated redness, swelling, or induration at the site, and injection pain scores decreased over successive injections in both gluteal and deltoid studies.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Neuroleptic malignant syndrome (NMS): a potentially fatal symptom complex — hyperthermia, muscle rigidity, altered mental status (including catatonic signs), and autonomic instability (irregular blood pressure, tachycardia, arrhythmias, diaphoresis), sometimes with elevated creatine phosphokinase, myoglobinuria/rhabdomyolysis, and acute renal failure. Management requires immediate discontinuation of all antipsychotics and intensive supportive treatment; because risperidone plasma levels persist for a minimum of about 6 weeks after the last Consta injection, NMS management and monitoring must account for this prolonged exposure.
• Tardive dyskinesia (TD): potentially irreversible, involuntary dyskinetic movements that can develop after even relatively brief treatment, though risk rises with cumulative dose and duration; most prevalent in the elderly. If signs develop, withdrawal of the drug should be considered.
• Increased mortality and cerebrovascular adverse events in elderly patients with dementia (see Geriatrics) — Risperdal Consta is not approved for this population.
• Hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes, in some cases serious and associated with ketoacidosis, hyperosmolar coma, or death; diabetic ketoacidosis has occurred even without a prior history of hyperglycemia.
• Venous thromboembolism (VTE), including fatal pulmonary embolism, reported in case reports and observational studies; all potential VTE risk factors should be identified before prescribing.
• Leukopenia, neutropenia, and agranulocytosis (a class effect of antipsychotics); patients with a history of clinically significant low WBC or drug-induced leukopenia/neutropenia require monitoring, especially in the first few months, and severe neutropenia (ANC < 1 × 10⁹/L) requires discontinuation and WBC follow-up until recovery.
• Severe hypersensitivity reactions (anaphylaxis, angioedema, anaphylactic shock) have occurred very rarely after injection — including in patients who had previously tolerated oral risperidone or paliperidone without any reaction; further treatment should be discontinued if this occurs.
• Serious injection-site reactions: abscess, cellulitis, cyst, hematoma, necrosis, nodule, and ulcer have been reported; isolated cases required surgical intervention.
• Retinal artery occlusion after injection has been reported very rarely in post-marketing surveillance, underscoring the need to avoid inadvertent intravascular injection.
• Orthostatic hypotension with dizziness, tachycardia, and syncope (syncope reported in 0.8% of patients, 12/1499, in repeated-dose studies); seizures occurred in 0.3% of patients (5/1499) in premarketing testing.
• QT prolongation, torsades de pointes, ventricular tachycardia, arrhythmia, cardiopulmonary arrest, and sudden death have been reported, mostly in patients with pre-existing cardiovascular disease, on other QT-prolonging drugs, or who had overdosed; very rarely QT prolongation has occurred without these confounding factors.
• Intraoperative Floppy Iris Syndrome (IFIS) during cataract surgery in patients on alpha1a-adrenergic-antagonist medicines including Risperdal Consta — surgeons should be informed of current or past use before cataract surgery.
• Priapism (prolonged, painful erection) has been reported post-marketing, not clearly dose- or duration-dependent.

• Cardiovascular disease — heart failure, history of myocardial infarction or ischemia, cerebrovascular disease, or conduction abnormalities — because of the drug's alpha-adrenergic antagonism and orthostatic hypotension risk; Risperdal Consta has not been evaluated to any appreciable extent in patients with recent MI or unstable heart disease.
• Renal or hepatic impairment (see Dosage & Administration for the required staged oral titration and possible 12.5 mg starting dose in these patients).
• History of seizures, Parkinson's disease, or Dementia with Lewy Bodies — the latter two groups have increased sensitivity to antipsychotics and increased NMS risk, which can present as confusion, obtundation, or postural instability with frequent falls in addition to extrapyramidal symptoms.
• Patients with risk factors for diabetes mellitus (e.g., obesity, family history) should have fasting blood glucose checked at baseline and periodically; patients with an established diabetes diagnosis need regular monitoring for worsening glucose control.
• Conditions affecting body temperature regulation (e.g., strenuous exercise, extreme heat/cold exposure, dehydration, or concomitant anticholinergic medications), since antipsychotics can impair the body's ability to regulate core temperature.
• Previously detected breast cancer or pituitary tumours, because risperidone elevates prolactin and roughly a third of human breast cancers are prolactin-dependent in vitro.
• Predisposition to hypotension, or conditions/medications where a hypotensive reaction would pose particular risk (including the elderly — see Geriatrics).

• Hypersensitivity to risperidone, to paliperidone, or to any other ingredient in the formulation or component of the container/delivery device — this is the only contraindication specified in the monograph. Very rare cases of severe hypersensitivity after injection have occurred even in patients who had previously tolerated oral risperidone or paliperidone without incident.

• Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine): may raise risperidone plasma levels (fluoxetine raised risperidone peak/AUC about 2- to 3-fold, with about a 50% rise in the combined active fraction; paroxetine raised the combined active fraction by about 45% after 4 weeks of co-treatment). When either drug is started in a patient on the recommended 25 mg dose, continue 25 mg unless clinical judgment supports lowering to 12.5 mg or interrupting treatment; when starting Risperdal Consta in a patient already on one of these, a 12.5 mg starting dose can be considered.
• Strong CYP3A4 and/or P-glycoprotein inhibitors (e.g., itraconazole): may substantially raise plasma concentrations of the active antipsychotic fraction — re-evaluate the Consta dose whenever such an inhibitor is started or stopped.
• Strong CYP3A4/P-gp inducers (e.g., carbamazepine, rifampicin): substantially lower risperidone and active-fraction plasma levels. Monitor closely for the first 4–8 weeks after starting an inducer (a Consta dose increase or added oral supplementation may be needed); when the inducer is stopped, re-evaluate and likely decrease the Consta dose — patients may be shifted to a lower Consta dose 2–4 weeks before the inducer is discontinued to pre-empt the expected rise in levels.
• Topiramate: reduces risperidone systemic exposure modestly (in a healthy-volunteer study, AUC about 11% lower and Cmax about 18% lower; in bipolar patients, AUC reduced 16–33% and Cmax 13–34% depending on topiramate dose); 9-hydroxyrisperidone pharmacokinetics were largely unaffected.
• Levodopa and dopamine agonists: Risperdal Consta may antagonize their effects (used to treat Parkinson's disease), and conversely antiparkinsonian benefit may be reduced.
• Antihypertensive agents: additive hypotensive effect; clinically significant hypotension has been reported post-marketing with concomitant antihypertensive use.
• Drugs known to prolong the QT interval: use with caution, per general antipsychotic-class precaution.
• Centrally acting drugs and alcohol: caution advised due to additive CNS depressant effects.
• Furosemide, specifically in elderly patients with dementia: this combination (as with oral Risperdal) has been associated with an increased mortality rate in that population — see the boxed Serious Warning under Geriatrics.
• Highly protein-bound drugs: no clinically relevant displacement of either drug from plasma proteins occurs when co-administered with Risperdal Consta.

• The Product Monograph states plainly, under Drug-Food Interactions: "Interactions with food have not been established." No food-based precaution is described for this product in the source document.
• As this is an intramuscular injection administered by a health care professional rather than an oral medicine, there is no meal-timing requirement around the injection itself; any oral antipsychotic used for supplementation during the first 3 weeks carries its own separate food guidance that is not addressed by this monograph.

• There is no time-of-day restriction specified in the monograph — the clinically critical timing factor is the fixed 14-day (every-2-week) interval between injections, not the time of day the injection is given.
• The injection site is alternated with each administration (left/right buttock for gluteal dosing, or left/right arm for deltoid dosing) to reduce local irritation; the two available sites (gluteal vs. deltoid) should not be mixed with two different dose strengths in a single administration.
• Upward dose titration should occur no more often than every 4 weeks, and its clinical effect should not be expected until at least 3 weeks after the higher-dose injection, because of the delayed-release profile described under Dosage & Administration.
• If an injection appointment is missed or delayed, the monograph provides no systematic re-titration data; the prescriber should be contacted so they can determine timing of the next injection and whether interim oral antipsychotic supplementation is needed (the same logic as Reinitiation of Treatment, above).

• Store the entire kit refrigerated at 2°C–8°C, protected from light, in its original packaging, until ready to reconstitute and administer.
• If refrigeration is unavailable, the kit may be kept at room temperature not exceeding 25°C, protected from light, for no more than 7 days prior to administration; unrefrigerated product must never be exposed to temperatures above 25°C.
• Once reconstituted (suspended in the supplied diluent), it is recommended to use Risperdal Consta immediately; it must be used within 6 hours of suspension, and once in suspension it must not be exposed to temperatures above 25°C.
• Because the product is a suspension, settling occurs over time — the vial (kept upright) must be shaken vigorously for at least 10 seconds to resuspend the microspheres, and the syringe must be shaken vigorously again just before injection.
• Keep out of the reach of children; the expiry date is printed on the package and the product must not be used after that date.

• This medicine is given only by a health care professional, as a deep intramuscular injection into the buttock or upper arm, once every 2 weeks — it is not self-injected at home.
• After your very first injection only, keep taking your regular oral antipsychotic medicine at the dose your doctor prescribes for about 3 weeks, because this injection needs that long to start releasing its main dose into your body — stopping the pills too soon after the first shot can leave a gap in protection. Once the injection is fully established, this oral overlap is not repeated with every dose.
• Keep every injection appointment as close to the 2-week schedule as possible, and call your clinic right away if you have to miss or reschedule one, since there is no fixed rule for how to safely delay a dose.
• Because full effects of any dose change take a few weeks to appear, your doctor will not normally adjust your dose more often than every 4 weeks.
• Watch for and report right away: high fever with muscle stiffness and confusion, uncontrollable new movements of the face or body, a severe allergic reaction (swelling of the face/tongue/throat, difficulty breathing), sudden vision loss, signs of a blood clot, or a lump, ongoing pain, redness, warmth, or drainage at an injection site.
• Tell every doctor, dentist, and pharmacist that you are receiving Risperdal Consta, since it interacts with several common medicines and its effects last for weeks after the last dose.