Zukaria5 mg

Zukaria is an atypical (second-generation) antipsychotic indicated for:

• Schizophrenia — treatment in adults and adolescents (10-17 years); this is an FDA-approved, well-established indication.
• Bipolar I disorder, acute manic or mixed episodes — as monotherapy or as adjunct to lithium or valproate, in adults and adolescents (10-17 years); FDA-approved.
• Bipolar I disorder maintenance therapy — as monotherapy in adults, based on continuation-of-response trial data (guideline-supported/adjunct use).

Zukaria is not approved for the treatment of psychosis associated with dementia (see Precautions and Warnings, boxed warning).

Each sublingual tablet contains Asenapine Maleate as the active ingredient, equivalent to the labelled strength of asenapine base. Tablets are formulated as a fast-dissolving sublingual preparation and also contain standard excipients for sublingual delivery (e.g., gelatin, mannitol) and colorants, which vary by strength.

Zukaria is an atypical antipsychotic agent belonging to the dibenzo-oxepino pyrrole class, structurally distinct from other antipsychotics. It is formulated exclusively as a fast-dissolving sublingual tablet because it undergoes extensive first-pass metabolism and has very low oral bioavailability if swallowed intact.

It is used in the management of schizophrenia and bipolar I disorder and works by modulating multiple neurotransmitter receptor systems in the brain, in particular dopamine and serotonin receptors.

Atypical (second-generation) antipsychotic agent — Zukaria belongs to this therapeutic class.

The precise mechanism of action of Asenapine Maleate in schizophrenia and bipolar I disorder is not fully understood, but is believed to be mediated through combined antagonist activity at central dopamine D2 and serotonin 5-HT2A receptors.

Asenapine Maleate also displays high affinity for several other serotonin, dopamine, alpha-adrenergic, and histamine receptors, but has negligible affinity for muscarinic cholinergic receptors. Antagonism at receptors other than dopamine and serotonin may explain some other effects of the drug, including orthostatic hypotension (alpha-1 adrenergic antagonism) and sedation (histamine H1 antagonism).

Asenapine Maleate is rapidly absorbed after sublingual administration, with peak plasma concentration reached in about 30-90 minutes. Oral bioavailability if swallowed is very low (under 2%) due to extensive first-pass glucuronidation and CYP1A2-mediated metabolism, which is why sublingual administration is essential. It is highly protein bound (~95%) and is metabolized mainly via direct glucuronidation (UGT1A4) and oxidative metabolism (CYP1A2), with a plasma elimination half-life of approximately 24 hours.

Zukaria must be administered sublingually only. Correct technique is essential for effectiveness:

• Peel back the foil packaging of the blister and gently remove the tablet — do not push the tablet through the foil, as this can damage it.
• Place the tablet under the tongue and allow it to dissolve completely; this typically occurs within seconds. Do NOT swallow, chew, or crush the tablet.
• Avoid eating or drinking for at least 10 minutes after taking the tablet, since food and liquids can reduce absorption.

Swallowing the tablet whole or crushing it significantly reduces the bioavailability of Zukaria and will make treatment less effective.

• Fluvoxamine (strong CYP1A2 inhibitor): Co-administration significantly increases plasma concentrations of Zukaria; concurrent use should be approached with caution and, if used together, a lower dose of Zukaria may be needed.
• Paroxetine (CYP2D6 substrate): Zukaria is a moderate inhibitor of CYP2D6 and increases paroxetine plasma levels approximately two-fold; dose reduction of paroxetine or other CYP2D6 substrates with a narrow therapeutic index may be needed.
• Other QT-interval-prolonging drugs: Concomitant use with other drugs known to prolong the QT interval (e.g., certain antiarrhythmics, some antipsychotics, some antibiotics) should be avoided due to additive risk of QT prolongation.
• Antihypertensive agents: Zukaria may enhance the hypotensive effect of antihypertensive medications due to its alpha-adrenergic antagonism, increasing risk of orthostatic hypotension.
• CNS depressants (alcohol, benzodiazepines, opioids): Additive sedation and CNS depression may occur when used together with Zukaria.
• Dopamine agonists (e.g., levodopa): Zukaria may antagonize the effects of dopamine agonists due to its dopamine-receptor-blocking activity.

Common side effects of Zukaria include:

• Somnolence (drowsiness) and sedation
• Oral hypoesthesia (numbness or reduced sensation of the mouth/tongue) — a distinctive and characteristic side effect of sublingual Zukaria, usually transient
• Akathisia (restlessness) and other extrapyramidal symptoms
• Dizziness
• Weight gain
• Increased appetite
• Fatigue
• Dysgeusia (altered taste)

Less common but serious effects include neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension/syncope, QT prolongation, seizures, leukopenia/neutropenia, hyperprolactinemia, and metabolic changes (dyslipidemia, hyperglycemia) — see Precautions and Warnings for details.

Pregnancy: There are no adequate and well-controlled studies of Zukaria in pregnant women. Neonates exposed to antipsychotic drugs, including Zukaria, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Zukaria should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus; use only if clearly needed and under close medical supervision. Consult a physician before use during pregnancy.

Lactation: It is not known whether Zukaria is excreted in human breast milk. Because many drugs are excreted in breast milk and the potential for serious adverse reactions in nursing infants is unknown, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Consult a physician before use while breastfeeding.

Boxed Warning: Increased Mortality in Elderly Patients with Dementia-Related Psychosis

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

Administration Technique

Correct sublingual administration is critical to efficacy. The tablet must be allowed to dissolve completely under the tongue; swallowing it whole or crushing it significantly reduces bioavailability. Patients should avoid eating or drinking for at least 10 minutes after administration (see Administration).

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with Zukaria. Discontinue immediately if a hypersensitivity reaction occurs.

Neuroleptic Malignant Syndrome (NMS)

NMS is a rare but potentially fatal reaction associated with antipsychotic drugs, characterized by hyperthermia, muscle rigidity, altered mental status, and autonomic instability. If signs and symptoms of NMS appear, or unexplained high fever occurs without other clinical signs of NMS, Zukaria must be discontinued immediately.

Metabolic Changes

Atypical antipsychotics, including Zukaria, have been associated with weight gain, dyslipidemia, and hyperglycemia (including rare cases of diabetic ketoacidosis). Monitor weight, fasting glucose, and lipid profile at baseline and periodically during treatment.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop with long-term use of Zukaria. The risk increases with duration of treatment and total cumulative dose.

Orthostatic Hypotension

Zukaria may cause orthostatic hypotension and syncope, particularly during the initial dose-titration period, due to its alpha-1 adrenergic antagonist activity. Use with caution in patients with cardiovascular disease, cerebrovascular disease, or conditions predisposing to hypotension.

QT Prolongation

Use Zukaria with caution in patients with a history of QT prolongation, cardiac arrhythmias, or in combination with other QT-prolonging drugs, and in patients with relevant risk factors (e.g., electrolyte imbalance, bradycardia).

Other Precautions

Use with caution in patients with a history of seizures, in those at risk of aspiration pneumonia, and in patients with conditions affecting metabolism or hemodynamic responses. Zukaria may impair judgment, thinking, or motor skills; caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain the drug does not affect them adversely.

Reported signs of Zukaria overdose include somnolence, agitation, and extrapyramidal symptoms. There is no specific antidote to Zukaria. In case of suspected overdose, seek immediate medical attention or contact emergency services/poison control. Management should include general supportive measures, ensuring an adequate airway, oxygenation and ventilation, and cardiovascular monitoring (including continuous ECG monitoring for possible arrhythmias) in a facility equipped to provide such care until the patient recovers.

Store at room temperature (below 30°C), away from light and moisture. Keep the tablet in the blister pack until immediately before use. Keep out of reach of children.

Pediatric Use

Zukaria is approved for schizophrenia and for acute treatment of manic or mixed episodes of bipolar I disorder in adolescents aged 10-17 years, at reduced starting doses compared with adults (see Dosage and Administration). Safety and efficacy in children under 10 years have not been established.

Geriatric Use

Zukaria is not approved for the treatment of dementia-related psychosis due to increased risk of death in this population (see boxed warning). Use in elderly patients for approved indications should be undertaken with caution, considering the greater frequency of hepatic, renal, or cardiac impairment and concomitant disease/drug therapy in this population.

Renal Impairment

No dose adjustment of Zukaria is required.

Hepatic Impairment

No adjustment needed in mild-to-moderate impairment; contraindicated in severe hepatic impairment (see Contraindications).

The duration of treatment with Zukaria should be individualized based on clinical response and physician judgment. In schizophrenia and bipolar I disorder, treatment is often continued long-term for maintenance and relapse prevention; the need for continued treatment should be periodically reassessed by the prescribing physician. Do not stop or change the dose of Zukaria without consulting a physician, as abrupt discontinuation of antipsychotic medication may lead to relapse or withdrawal symptoms.

Atypical antipsychotics; dibenzo-oxepino pyrroles.

Asenapine Maleate exerts its therapeutic effects primarily through antagonism of central dopamine D2 receptors and serotonin 5-HT2A receptors, a combination believed to underlie its antipsychotic and mood-stabilizing effects while reducing the risk of extrapyramidal side effects compared with typical antipsychotics. It additionally has high affinity for numerous other serotonergic (5-HT1A, 5-HT2C, 5-HT6, 5-HT7), dopaminergic (D1, D3, D4), alpha-adrenergic (alpha-1, alpha-2), and histaminergic (H1) receptors, but has negligible affinity for muscarinic cholinergic receptors, which likely explains its low incidence of anticholinergic side effects.

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Zukaria is approved in adolescents 10-17 years of age for the treatment of schizophrenia (starting dose 2.5 mg sublingually twice daily) and for acute treatment of manic or mixed episodes associated with bipolar I disorder (starting dose 2.5 mg sublingually twice daily, titrated as needed). Safety and efficacy have not been established in children below 10 years of age. Adolescents should be monitored closely for weight gain, metabolic changes, and neuropsychiatric side effects during treatment with Zukaria.