Asenapine - Uses, Dosage, Contraindications, Warnings, and Precautions

Overview:

Asenapine is a medicine that functions in the brain to manage schizophrenia. It is also called a second-generation antipsychotic or atypical antipsychotic drug. Asenapine regulates dopamine and serotonin levels to enhance thought, mindset, and manners. Unfortunately, older patients with dementia-associated psychosis managed with antipsychotic medications are at higher risk of death.

Thus it is not approved for the management of patients with dementia-associated psychosis. The FDA approved Asenapine on 13 march 2015 for a pediatric patient with bipolar disorder. Asenapine is a sublingual tablet kept beneath the tongue and left to liquefy. The pill will melt in the saliva rapidly. Therefore, the patient is advised to fast ten minutes after administration.

How Does Asenapine Work?

The Asenapine mechanism of action in schizophrenia and bipolar I disorder is unidentified. It is recommended that the effectiveness of Asenapine in schizophrenia could be intervened via a blend of antagonist activity at D2 and 5-HT2A receptors. Asenapine displays increased affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7 receptors, dopamine D2A, D2B, D3, D4, and D1 receptors, α1A, α2A, α2B, and α2C -adrenergic receptors and histamine H1 receptors, and intermediate association for H2 receptors. In vitro assays revealed that Asenapine functions as an antagonist at receptors. Asenapine has no apparent affinity for muscarinic and cholinergic receptors.

Uses of Asenapine

Asenapine is indicated for the following:

• Schizophrenia in grown-up patients.

• Bipolar I disorder.

• Acute monotherapy of manic episodes or mixed episodes in adults and pediatric patients 10 to 17 years of age.

• Adjunctive therapy with lithium or Valproate in adults.

• Supervising the monotherapy treatment in grown-ups.

Dosage Forms and Strength

• Asenapine - 2.5 mg tablets, black cherry flavored, are rounded, white color to off-white color sublingual tablets, with a hexagon shape on its side.
• Asenapine - 5 mg tablets, black cherry flavored, are rounded, white color to off-white colored sublingual tablets, with five on its side inside a circle.
• 10 mg tablets are black cherry flavored, rounded, white color to off-white color sublingual tablets, with ten on its side inside a circle.

Limitations

High mortality has been noted in old-aged patients with dementia-associated psychosis. Senior patients with dementia-associated psychosis are managed with antipsychotic drugs and are at increased risk of death. Asenapine is not authorized for the management of cases with dementia-related psychosis.

Dosage and Administration

1. Route of Administration- The drug is administered sublingually. Patients should keep the tablet underneath the tongue and let it liquefy. Sublingual tablets should not be crushed, munched, or consumed. Patients are advised not to consume or drink for at least ten minutes after administration.

2. Bipolar Disorder

Acute Management of Manic or Mixed Episodes:

• Monotherapy in Adults- The advised initial and management dose of Asenapine is 5 mg to 10 mg two times every day. Clinical trials do not assess the safety of amounts exceeding 10 mg twice daily.

• Monotherapy in Pediatric Patients- The recommended dose of Asenapine is 2.5 mg to 10 mg twice daily in pediatric patients aged 10 to 17 years. The dosage may be modified for personal reaction and tolerability. The initial dosage of Asenapine is 2.5 mg two times daily. After three days, the dosage can be raised to 5 mg twice daily and from 5 milligrams to 10 milligrams. Pediatric patients aged 10 to 17 years seem to be additionally liable to dystonia after starting dosage with Asenapine when the suggested escalation plan is not obeyed. Clinical trials do not assess the safety of more than 10 mg doses twice daily.

• Adjunctive Therapy in Adults: The suggested initial dose of Asenapine is 5 mg twice daily when taken as an adjunctive treatment with lithium or Valproate. Based on the individual's clinical reaction and tolerability, the dose can be improved to 10 mg twice daily. Clinical trials do not assess the safety of doses beyond 10 mg two times daily as adjunctive treatment with lithium or Valproate.

• Supportive Therapy of Bipolar I Disorder in Monotherapy in Adults: Resume the Asenapine dose that the patient obtained during stabilization which is 5 mg to 10 mg twice daily. Depending on the clinical reaction and tolerability in the patient, an amount of 10 mg two times daily can be reduced to 5 mg two times daily. Clinical tests do not assess the safety of doses exceeding 10 mg twice daily.

Contraindications

Asenapine is contraindicated in the following cases,

• In patients with intense hepatic impairment.

• A record of hypersensitivity responses to Asenapine. Responses have contained anaphylaxis reaction, angioedema, hypotension, tachycardia, inflamed tongue, dyspnea, wheezing, and rashes.

Warnings and Precautions

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis- Old-aged patients with dementia-associated psychosis managed with antipsychotic medications are at a high risk of death. The reasons for death vary. The death cases occurred due to cardiovascular conditions such as heart failure, sudden death, or infection like pneumonia. Asenapine is not authorized for the management of patients with dementia-associated psychosis.

Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related

1. Psychosis- In placebo-controlled tests in old aged cases with dementia, patients randomized to Risperidone, Aripiprazole, and Olanzapine had a more increased incidence of stroke and quick ischemic attack, involving fatal stroke. Asenapine is not authorized for the management of patients with dementia-related psychosis.

2. Neuroleptic Malignant Syndrome- A fatal symptom complex called neuroleptic malignant syndrome (NMS) is reported in relationship with the intake of antipsychotic medications. Clinical indications of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Also, there is increased creatine phosphokinase, myoglobinuria, and acute renal failure. If NMS is doubted, instantly stop Asenapine and give intensive symptomatic therapy and observation.

3. Tardive Dyskinesia- An irreversible, involuntary, and dyskinetic syndrome may evolve in patients taking antipsychotic medications, including Asenapine. The risk is higher in elderly women patients. The risk will become irreversible and advance with the therapy time and cumulative dosage. It may happen after stopping treatment. Asenapine is given in such a way as to decrease the chance of Tardive dyskinesia. Chronic antipsychotic therapy is typically secured for patients with a chronic illness comprehending to react to antipsychotic drugs. And for those options, adequate but potentially reduced harmful medicines are unknown. If manifestations of TD occur in the case of Asenapine, stoppage of the drug should be evaluated. Nevertheless, some patients may need treatment with Asenapine despite the syndrome's existence.

4. Metabolic Changes- The metabolic changes include hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. These changes have been described below:

• Hyperglycemia- In certain patients, hyperglycemia is associated with ketoacidosis or hyperosmolar coma. Death might occur if the patients are managed with atypical antipsychotics. Therefore, evaluate fasting plasma glucose before or shortly after initiation of antipsychotic medication and occasionally observe during long-term treatment.

• Dyslipidemia- Atypical antipsychotics induce adverse changes in lipids. Therefore, before or shortly after the beginning of antipsychotic medicine, acquire a fasting lipid profile at baseline and occasionally observe between the treatments.

• Weight Gain- It has been monitored in cases managed with atypical antipsychotics, including Asenapine. Observe weight at baseline and repeatedly after that.

5. Hypersensitivity Reactions: These reactions have been noted in patients treated with Asenapine. In some cases, these responses happened after the initial dose. These involve anaphylactic reactions, angioedema, hypotension, tachycardia, inflamed tongue, dyspnea, wheezing, and rashes.

6. Orthostatic Hypotension, Syncope, and Other Hemodynamic Consequences- Atypical antipsychotics generate orthostatic hypotension and syncope. This is most common with the initial dose titration and improving the dose. Orthostatic vital signs are monitored in patients at risk of hypotension and cases with cerebrovascular disorder. Asenapine is used with caution when managing patients who accept management with other medicines that can cause hypotension, bradycardia, and respiratory or central nervous system depression.

7. Leukopenia, Neutropenia, and Agranulocytosis are temporarily related to antipsychotic drugs. Probable risk factors for leukopenia or neutropenia are pre-existing reduced white blood cell count (WBC), absolute neutrophil count (ANC), and drug-induced leukopenia or neutropenia.

8. QT Prolongation- Asenapine is avoided in cases with a history of cardiac arrhythmias, as the drug might increase the hazard of sudden death and lengthen the QTc interval. As a result, the patient experiences bradycardia, hypokalemia, or hypomagnesemia, and the existence of congenital prolongation of the QT interval.

9. Hyperprolactinemia- Asenapine can advance prolactin levels, and the increase can continue during chronic administration of the drugs.

10. Seizures- Asenapine is used cautiously in patients with a seizure history or situations that reduce the seizure threshold. Circumstances that reduce the seizure threshold may be more predominant in patients of old age.

11. Potential for Cognitive and Motor Impairment- Patients should be precautioned about working with hazardous machinery involving motor vehicles till they are well certain that Asenapine treatment does not affect them adversely.

12. Body Temperature Regulation- Atypical antipsychotics alter the ability to decrease core body temperature.

13. Dysphagia- Esophageal dysmotility and aspiration are connected with antipsychotic drug usage.

For Patients:

Why Is Asenapine Medication Prescribed?

Asenapine is given for managing the manifestation of schizophrenia, a mental illness that generates troubled or uncommon thinking, losing interest in life, and powerful or inappropriate emotions. Asenapine is utilized solitary or in other medicines to manage mania involving frenzied, abnormally enthusiastic mood and manifestations of depression in grown-ups and kids ten years of age and older with bipolar I disorder. Asenapine is a group of medications called atypical antipsychotics. It functions by altering the action of natural things in the brain.

What Is Mood Disorder?

Mood disorder is a condition in which the general emotional condition or mood is distorted and interrupts the capacity to function. Anxiety disorders affect mood and occur along with depression. The types of bipolar disorder include:

• Bipolar I Disorder: In this extreme erratic nature, this lasts for weeks.

• Bipolar II Disorder: In this erratic behavior, highs and lows are there but not extreme as type I.

• Cyclothymic Disorder: It includes a period of mania and depression that lasts for years. This is not as intense as bipolar I and II.

How Should Asenapine Be Used?

Asenapine is available as a sublingual tablet to liquefy under the tongue. It is typically given two times a day. Take Asenapine at the same time daily. Observe the guidance on the prescription slip, and discuss it with the doctor or pharmacist. Take Asenapine precisely as required. The patient must not open Asenapine sublingual tablets from the packet until he is prepared to consume them. The patient's hands should be dry when holding the tablets.

Follow the packet orders to remove the tablet from the cover without forcing the tablet via the tablet packet or damaging the tablet. After that, place the tablet under the tongue and let it liquefy, do not ingest, separate, munch, or crush it. Do not consume or drink anything for ten minutes after the tablet liquefies.

The doctor may need to alter the dose based on how the medication functions for the patient and the side effects he experiences. Discuss with the doctor how you feel during your treatment. Asenapine may support controlling the disease manifestations but will not cure the condition. Resume taking Asenapine even if you sense better. Do not cease the intake of Asenapine without discussing it with your doctor.

What Special Precautions Should Be Taken Before Taking Asenapine?

• Discuss with your doctor if you have an allergy to any medication or are allergic to any content in Asenapine tablets.

• Discuss with your doctor what other prescription and nonprescription medicines, vitamins, and herbal by-products you are consuming or intend to take. Be sure to say any of the following:

• Antibiotics including Gatifloxacin and Moxifloxacin.

• Antidepressants include Clomipramine, Duloxetine, Fluvoxamine, and Paroxetine.

• Antihistamines include Dextromethorphan; Ipratropium.

• Medicines for anxiety and high blood pressure.

• Medicines for uneven heartbeat like Amiodarone, Procainamide, Quinidine, and Sotalol

• Drugs for glaucoma, inflammatory bowel disease, motion sickness, myasthenia gravis, Parkinson's disease, ulcers, or urinary problems;

• Medicines for mental illness, such as Chlorpromazine, Thioridazine, and Ziprasidone

• Medications for seizures; include sedatives, sleeping pills, and Tranquilizers.

• Based on it, they alter the dosage of medicines or observe you for side effects.

• A detailed medical history and family history should be taken and discussed with your doctor if any family member has diabetes or if you have any previous medical history. Tell your doctor that if you ever had thoughts about hurting or killing yourself.

• Inform your doctor if you are pregnant, specifically if you are in the final months of your pregnancy or if you are preparing to become pregnant or are breastfeeding.

• If you have a surgical procedure involving dental surgery, inform the doctor or dentist that you are consuming Asenapine.

• You should understand that Asenapine makes you tired. So do not drive a car or function machinery until you know how this medication influences you.

• While taking Asenapine, alcohol can create side effects of Asenapine.

What Special Dietary Instructions Follow While Taking Asenapine?

Unless your doctor suggests otherwise, resume your regular diet.

What Should the Patient do if he misses the dose of Asenapine?

Consume the skipped dose as soon as you recall it. Nevertheless, if it is nearly time for the subsequent dosage, skip the missed dose and resume your regular dosing schedule. Do not take a double dosage to make up for a missed one.

What Side Effects Can Asenapine Cause?

• Dry mouth.

• Stomach aches.

• Constipation, heartburn, and vomiting. Advanced appetite increases saliva in the mouth.

• Weight gain.

• Dizziness and feeling unsteady or having a problem maintaining your balance.

• Excessive tiredness.

• Restlessness or steady desire to keep moving.

• Anxiety and depression.

• A problem in falling asleep or remaining asleep.

• An ache in the joints, arms, or legs.

Severe Complication Includes

• Rashes and itching.

• Difficulty breathing or ingestion.

• Inflammation of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs.

• Hoarseness and wheezing, muscle immobility or ache.

• Confusion and irregular heartbeat.

• Unmanageable motions of the arms, legs, face, mouth, tongue, jaw, lips, or cheeks.

• Seizures.

• Blood-colored urine.

What Should the Patient Know About the Storage and Disposal of Asenapine?

Keep the medication in its container, tightly sealed, and out of reach of kids. Keep it at room temperature and out from overheating and moisture. Needless drugs are disposed of in ways to confirm that pets, and kids, cannot swallow them. The best way to dispose of your medicine is via a medicine take-back program. It is mandatory to keep all medicine out of view and reach of kids as many tins are not child-resistant, and kids can unlock them smoothly. To protect kids from poisoning, constantly lock safety caps and instantly put the medication in a safe place. You should not wash this drug down the toilet.

What Should Be Done in Case of Emergency or Overdose of Asenapine?

In case of overdose contact, emergency care and the patient may experience difficulty in breathing and may have seizures. Contact the emergency service immediately. Symptoms of overdose involve confusion and agitation.

For Doctors:

Adverse Reactions

• Use in old aged patients with dementia-associated psychosis.

• Neuroleptic malignant syndrome.

• Tardive dyskinesia.

• Metabolic transformations.

• Hypersensitivity responses.

• Orthostatic hypotension, syncope, and additional hemodynamic consequences.

• Leukopenia, neutropenia, and agranulocytosis disorders.

• QT interval prolongation.

• Hyperprolactinemia and seizure.

• Potential for cognitive and motor impairment.

• Dysphagia.

Drug Interactions

• Antihypertensive Drugs- Due to its α1-adrenergic antagonism with the ability to cause hypotension, it improves the outcomes of particular antihypertensive agents. Thus there is a need to observe blood pressure and modify the dosage of antihypertensive drugs.

• CYP1A2 solid inhibitors like Fluvoxamine- Asenapine are metabolized by CYP1A2. Borderline dosage reduction for Asenapine expansion on Asenapine exposure was seen. Based on clinical response, the dose may be adjusted.

• CYP2D6 substrates and inhibitors- Asenapine may increase the inhibitory effect of Paroxetine on its metabolism, thus reducing the dosage of Paroxetine when used with Asenapine.

Clinical Pharmacology

• Pharmacokinetics

1. Absorption-: After sublingual administration, Asenapine is absorbed with extreme plasma concentrations within half to 1.5 hours. The total bioavailability of sublingual Asenapine at 5 mg is 35 %. The absolute bioavailability of Asenapine when ingested is less. Water intake a few minutes after Asenapine administration causes reduced Asenapine exposure.

2. Distribution- Asenapine is quickly distributed and has a considerable volume of distribution, indicating vast extravascular distribution. Asenapine is highly bound to plasma proteins involving albumin and 1-acid glycoprotein.

3. Metabolism and Elimination- Direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes are the primary metabolic paths for Asenapine. Hepatic clearance is controlled mainly by transitions in liver blood flow, that is, by the metabolizing enzymatic action. After an initial high immediate distribution stage, the terminal half-life of Asenapine is about 24 hours. Constant-state concentrations of Asenapine are achieved within three days of twice-daily dosing.

Use in Specific Populations

• Pregnancy- Neonates at the time of the third trimester. If exposed to Asenapine, there is a chance of developing extrapyramidal or withdrawal symptoms. These extrapyramidal symptoms involve agitation, hyper and hypotonia, respiratory distress, and feeding disorder. The severity of these symptoms varies. Thus monitor them and treat them accordingly.

• Lactation- The benefits of breastfeeding and the mother's need for Asenapine should be considered for this case.

• Pediatric Use- Usage of Asenapine in patients below ten years is not assessed. Thus the safety and effectiveness are not yet confirmed in pediatric patients. The pharmacokinetics is the same as in adults.

• Geriatric Use- In old-aged patients with dementia-related psychosis, using Asenapine has increased the risk of death. Thus it is not approved in these cases.

• Renal Impairment- There is no need to alter the Asenapine dosage for renal impairment.

• Hepatic Impairment- Asenapine is contraindicated in cases of severe hepatic impairment as its exposure is sevenfold higher in these patients. There is no need for dose alteration in mild and moderate cases of hepatic impairment.

Drug Abuse and Dependence

• Controlled Substance- Asenapine is not a controlled substance.

• Abuse- Patients should be evaluated for a history of medical abuse and should be given special care.

Overdosage

Management of Overdosage

No particular antidote is available for Asenapine. An electrocardiogram should be taken to manage overdose and concentrate on supportive therapy, keeping the adequate airway, ventilation, oxygenation, and managing the symptoms. Contact a certified poison control center for management. Hypotension and vascular collapse are treated accordingly. In cases of extrapyramidal symptoms, anticholinergic drugs are given. Medical observation gave till the recovery of the patient.

Nonclinical Toxicology

• Carcinogenesis- In a carcinogenicity study on Sprague- Dawley rats, Asenapine did not generate tumor additions when taken subcutaneously at a dosage of those causing plasma levels calculated to be five times for humans accepting the MRHD.

• Mutagenesis- There is no genotoxic potential for Asenapine.

• Impairment of Fertility- Asenapine did not impair fertility in studies.

Instructions for Use

Mandatory Tips

• The sublingual tablets should be kept under the tongue only.

• At the time of intake, only the tablet should be opened.

• Handle the drugs with dry hands.

Directions for Taking Asenapine Tablets

• Gently hold and press the tablet button, do not push or tear the tablet pack.

• Peel the colored tab.

• Gently remove the tablet from the pack.

• Keep the tablet under the tongue and allow it to liquefy.

• Do not chew or swallow the tablet.

• Do not eat or drink for at least 10 minutes.