Dailymed – Clozapine Tablet, Orally Disintegrating

5.1 Severe Neutropenia

Background

ClozapTEVA ine ODT can reason neutropenia (a low absolute neutrophil be counted [ANC]), defined as a reduction underneath pretreatment normal tiers of blood neutrophils. The ANC is normally to be had as a factor of the complete blood count number (CBC), inclusive of differential, TEVA and is greater applicable to drug-triggered neutropenia than is the white blood cell (WBC) count number. The ANC will also be calculated using the following system: ANC equals the Total WBC count extended with the aid of the overall percent of neutrophils received from the differential (neutrophil “segs” plus neutrophil “bands”). Other granulocytes (basophils and eosinophils) make a contribution minimally to neutropenia and their measurement isn’t always vital [see Adverse Reactions (6.2)]. Neutropenia may be moderate, moderate, or extreme (see Tables 2 and three). To improve and standardize knowledge, “intense neutropenia” replaces the previous phrases intense leukopenia, intense granulocytopenia, or agranulocytosis.

Severe neutropenia, ANC less than (<) 500/µL, takes place in a small percentage of sufferers taking Clozapine ODT and is associated with an growth in the danger of great and doubtlessly fatal infections. Risk of neutropenia seems best at some point of the first 18 weeks on remedy after which declines. The mechanism by way of which Clozapine ODT reasons neutropenia is unknown and isn't dose-based.

Two separate control algorithms are supplied underneath, the primary for sufferers in the fashionable populace, and the second one for patients diagnosed to have baseline neutropenia.

Clozapine ODT Treatment and Monitoring within the General Patient Population (see Table 2)

Obtain a CBC, including the ANC value, previous to beginning treatment with Clozapine ODTto ensure the presence of a regular baseline neutrophil depend (identical to or greater than 1500/µL) and to permit later comparisons. Patients in the trendy populace with an ANC equal to or more than (≥) 1500/µL are considered inside regular range (Table 2) and are eligible to initiate treatment. Weekly ANC tracking is needed for all patients throughout the first 6 months of remedy. If a patient’s ANC remains equal to or greater than 1500/µL for the primary 6 months of remedy, monitoring frequency can be reduced to every 2 weeks for the following 6 months. If the ANC stays identical to or more than 1500/µL for the second one 6 months of non-stop therapy, ANC monitoring frequency can be reduced to once every 4 weeks thereafter.

Table 2: Clozapine ODT Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring for the General Patient Population

*  Confirm all preliminary reports of ANC much less than 1500/µL with a repeat ANC measurement inside 24 hours**  If clinically suitable

Clozapine ODT Treatment and Monitoring in Patients with Benign Ethnic Neutropenia (see Table 3)

Benign ethnic neutropenia (BEN) is a condition discovered in sure ethnic businesses whose average ANC values are lower than “preferred” laboratory tiers for neutrophils. It is maximum generally determined in people of African descent (approximate occurrence of 25-50%), some Middle Eastern ethnic agencies, and in different non-Caucasian ethnic corporations with darker pores and skin. BEN is extra common in men. Patients with BEN have ordinary hematopoietic stem-cell number and myeloid maturation, are wholesome, and do no longer suffer from repeated or excessive infections. They are TEVA not at multiplied danger for developing Clozapine ODT-precipitated neutropenia. Additional assessment can be had to decide if baseline neutropenia is because of BEN. Consider hematology session earlier than starting up or at some stage in Clozapine ODT treatment as essential.

Patients with BEN require a distinctive ANC set of rules for Clozapine ODT control due to their decrease baseline ANC levels. Table 3 presents tips for handling Clozapine ODT remedy and ANC tracking in patients with BEN.

Table 3: Patients with Benign Ethnic Neutropenia (BEN); Clozapine ODT Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring

*  Confirm all preliminary reviews ofANC much less than 1500/µL with a repeat ANC size within 24 hours

** If clinically suitable

General Guidelines for Management of All Patients with Fever or with Neutropenia

Fever: Interrupt Clozapine ODT as a precautionary measure in any patient who develops fever, defined as a temperature of 38.5ºC [one zero one.3ºF] or extra, and reap an ANC stage. Fever is regularly the primary sign of neutropenic contamination.

ANC much less than 1000/µL: If fever happens in any patient with a ANC much less than one thousand/µL, provoke appropriate workup and treatment for infection and check with Tables 2 or 3 for control.

Consider hematology session.

See Neuroleptic Malignant Syndrome (NMS) and Fever under WARNINGS AND PRECAUTIONS (five) and Instructions for Patients, below PATIENT COUNSELING INFORMATION (17).

Rechallenge after an ANC less than 500/µL (severe neutropenia)

For a few patients who revel in extreme Clozapine ODT-related neutropenia, the hazard of serious psychiatric contamination from discontinuing Clozapine ODT treatment can be more than the risk of rechallenge (e.g., sufferers with extreme schizophrenic infection who have no remedy options aside from Clozapine ODT). A hematology session may be beneficial in figuring out to rechallenge a patient. In standard, but, do no longer rechallenge sufferers who increase extreme neutropenia with Clozapine ODT or a clozapine product.

If a patient might be rechallenged, the clinician must bear in mind thresholds provided in Tables 2 and three, the patient’s scientific and psychiatric records, a dialogue with thepatient and his/her caregiver approximately the blessings and risks of Clozapine ODT rechallenge, and the severity and traits of the neutropenic episode.

Using Clozapine ODT with Other Drugs Associated with Neutropenia

It is uncertain if concurrent use of other tablets acknowledged to purpose neutropenia will increase the hazard or severity of Clozapine ODT-caused neutropenia. There is not any sturdy scientific purpose to avoid Clozapine ODT remedy in sufferers concurrently handled with these drugs. If Clozapine ODT is used simultaneously with an agent regarded to cause neutropenia (e.g., some chemotherapeutic retailers), recall monitoring patients greater closely than the remedy hints furnished in Tables 2 and three. Consult with the treating oncologist in sufferers receiving concomitant chemotherapy.

five.2 Clozapine REMS Program

Clozapine ODT is best to be had through a constrained program underneath a REMS called the Clozapine REMS Program due to the chance of extreme neutropenia.

Notable requirements of the Clozapine REMS Program include:

Healthcare specialists who prescribe Clozapine ODT should be licensed with this system by enrolling and finishing training.

Patients who get hold of Clozapine ODT should sign up within the application and comply with the ANC testing and tracking necessities.•

Pharmacies dispensing Clozapine ODT need to be certified with this system by using enrolling and finishing education and have to handiest dispense to patients who are eligible to receive Clozapine ODT.

Further information is available at www.clozapinerems.com or 1-844-267-8678.

5.three Orthostatic Hypotension, Bradycardia, and Syncope

Hypotension, bradycardia, syncope, and cardiac arrest have happened with clozapine treatment. The threat is highest throughout the initial titration period, mainly with fast dose-escalation. These reactions can occur with the first dose, at doses as little as TEVA 12.five mg. These reactions may be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).

Treatment need to begin at a most dose of 12.five mg once daily or twice daily. The general daily dose may be accelerated in increments of 25 mg to 50 mg in keeping with day, if properly-tolerated, to a target dose of three hundred mg to 450 mg in line with day (administered in divided doses) through the stop of two weeks. Subsequently, the dose can be multiplied weekly or twice weekly, in increments of up to a hundred mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage agenda to reduce the hazard of serious cardiovascular reactions [see Dosage and Administration (2.three)]. Consider decreasing the dose if hypotension happens. When restarting patients who’ve had even a brief c program languageperiod off Clozapine ODT (i.e., 2 days or greater for the reason that remaining dose), re-provoke treatment at 12.five mg as soon as day by day or twice each day [see Dosage and Administration (2.6)].

Use Clozapine ODT cautiously in sufferers with cardiovascular disorder (history of myocardial infarction or ischemia, coronary heart failure, or conduction abnormalities), cerebrovascular disorder, and situations which would predispose sufferers to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia).

five.four Falls

Clozapine ODT may additionally cause somnolence, postural hypotension, and motor and sensory instability, which may additionally cause falls and, consequently, fractures or different injuries. For patients with diseases, situations, or medicines that could exacerbate these results, complete fall hazard tests when initiating antipsychotic treatment and commonly for patients on lengthy-term antipsychotic treatment.

5.five Seizures

Seizure has been estimated to arise in affiliation with clozapine use at a cumulative prevalence at 12 months of approximately five%, based on the incidence of 1 or greater seizures in 61 of 1743 sufferers exposed to clozapine all through its scientific testing prior to home advertising and marketing (i.e., a crude price of three.five%). The risk of seizure is dose-associated. Initiate remedy with a low dose (12.five mg), titrate slowly, and use divided dosing.

Use warning when administering Clozapine ODT to sufferers with a records of seizures or different predisposing threat factors for seizure (e.g., head trauma or other CNS pathology, use of medicines that lower the seizure threshold or alcohol abuse). Because of the widespread danger of seizure related to Clozapine ODT use, caution sufferers approximately carrying out any hobby wherein surprising loss of cognizance may want to motive extreme threat to themselves or others (e.g., riding an car, working complicated machinery, swimming, mountaineering).

5.6 Myocarditis and Cardiomyopathy

Myocarditis and cardiomyopathy have came about with the use of clozapine. These reactions may be fatal. Discontinue Clozapine ODT and gain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy. Generally, patients with a history of clozapine-related myocarditis or cardiomyopathy should no longer be rechallenged with Clozapine ODT. However, if the advantage of Clozapine ODT remedy is judged to outweigh the capacity risks of recurrent myocarditis or cardiomyopathy, the clinician may additionally recollect rechallenge with Clozapine ODT in consultation with a cardiologist, after a entire cardiac evaluation, and underneath close tracking.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving Clozapine ODT who present with chest pain, dyspnea, chronic tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, different signs and symptoms or signs of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, proper axis deviation, and negative R wave development). Myocarditis most regularly provides inside the first two months of clozapine remedy. Symptoms of cardiomyopathy normally occur later than clozapine-associated myocarditis and generally after eight weeks of treatment. However, myocarditis and cardiomyopathy can occur at any period for the duration of remedy with Clozapine ODT. It is not unusual for nonspecific flu-like symptoms which includes malaise, myalgia, pleuritic chest pain, and occasional-grade fevers to precede greater overt signs of coronary heart failure. Typical laboratory findings encompass increased troponin I or T, improved creatinine kinase-MB, peripheral eosinophilia, and accelerated C-reactive protein (CRP). Chest roentgenogram may reveal cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide research, or cardiac catheterization) may reveal proof of left ventricular disorder.

five.7 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis handled with antipsychotic tablets are at an extended chance of death. Analyses of 17 placebo-managed trials (modal length of 10 weeks), largely in patients taking bizarre antipsychotic tablets, found out a danger of demise in drug-handled patients of between 1.6 to at least one.7 instances the chance of demise in placebo-handled patients. Over the course of an ordinary 10-week controlled trial, the charge of loss of life in drug-dealt with patients changed into approximately four.5%, in comparison to a rate of about 2.6% within the placebo group. Although the causes of demise had been varied, most of the deaths seemed to be both cardiovascular (e.g., heart failure, unexpected dying) or infectious (e.g., pneumonia) in nature. Observational research propose that, similar to strange antipsychotic drugs, remedy with conventional antipsychotic tablets may additionally growth mortality in this population. The extent to which the findings of improved mortality in observational studies can be attributed to the antipsychotic drug in place of some feature(s) of the sufferers is not clear. Clozapine ODT isn’t always accepted for the remedy of patients with dementia-related psychosis [see Boxed Warning].

5.8 Eosinophilia

Eosinophilia, described as a blood eosinophil count of greater than seven-hundred/µL, has took place with clozapine remedy. In scientific trials, about 1% of sufferers developed eosinophilia. Clozapine-associated eosinophilia usually takes place all through the primary month of remedy. In some patients, it’s been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement will be steady with a drug response with eosinophilia and systemic signs syndrome (DRESS), additionally referred to as drug precipitated hypersensitive reaction syndrome (DIHS). If eosinophilia develops for the duration of Clozapine ODT treatment, examine directly for signs and symptoms and symptoms of systemic reactions, inclusive of rash or other allergic signs and symptoms, myocarditis, or other organ-unique sickness associated with eosinophilia. If clozapine-related systemic ailment is suspected, discontinue Clozapine ODT at once.

If a reason of eosinophilia unrelated to clozapine is recognized (e.g., allergies, allergic reactions, collagen vascular disease, parasitic infections, and specific neoplasms), deal with the underlying purpose and hold Clozapine ODT.

Clozapine-associated eosinophilia has also occurred in the absence of organ involvement and can clear up without intervention. There are reviews of successful rechallenge after discontinuation of clozapine, with out recurrence of eosinophilia. In the absence of organ involvement, preserve Clozapine ODT under cautious monitoring. If the full eosinophil remember keeps to boom over several weeks in the absence of systemic ailment, the choice to break Clozapine ODT therapy and rechallenge after the eosinophil remember decreases must be based totally on the general scientific assessment, in consultation with an internist or hematologist.

5.9 QT Interval Prolongation

QT prolongation, Torsades de Pointes and different life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine remedy. When prescribing Clozapine ODT, remember the presence of extra danger factors for QT prolongation and serious cardiovascular reactions. Conditions that growth these dangers encompass the subsequent: records of QT prolongation, lengthy QT syndrome, circle of relatives history of lengthy QT syndrome or surprising cardiac loss of life, widespread cardiac arrhythmia, latest myocardial infarction, uncompensated heart failure, treatment with other medicines that cause QT prolongation, treatment with medicinal drugs that inhibit the metabolism of Clozapine ODT, and electrolyte abnormalities.

Prior to initiating treatment with Clozapine ODT, carry out a careful physical examination, scientific records, and concomitant medicinal drug records. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue Clozapine ODT if the QTc c language exceeds 500 msec. If patients revel in symptoms consistent with Torsades de Pointes or different arrhythmias (e.g., syncope, presyncope, dizziness, or palpitations), attain a cardiac evaluation and stop Clozapine ODT.

Use warning while administering concomitant medicines that lengthen the QT c programming language or inhibit the metabolism of Clozapine ODT. Drugs that purpose QT prolongation encompass: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), unique antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medicinal drugs (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Clozapine ODT is normally metabolized by way of CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of those enzymes can growth the attention of Clozapine ODT [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Hypokalemia and hypomagnesemia boom the hazard of QT prolongation. Hypokalemia can end result from diuretic therapy, diarrhea, and other reasons. Use caution while treating sufferers at risk for significant electrolyte disturbance, mainly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically display electrolytes. Correct electrolyte abnormalities earlier than starting up treatment with Clozapine ODT.

5.10 Metabolic Changes

Atypical antipsychotic drugs, which includes Clozapine ODT have been associated with metabolic modifications which could growth cardiovascular and cerebrovascular chance. These metabolic modifications encompass hyperglycemia, dyslipidemia, and body weight advantage. While ordinary antipsychotic pills may also produce some metabolic changes, every drug inside the elegance has its very own precise chance profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in a few instances extreme and associated with ketoacidosis or hyperosmolar coma or dying, has been reported in sufferers handled with bizarre antipsychotics which includes Clozapine ODT. Assessment of the relationship between extraordinary antipsychotic use and glucose abnormalities is complicated by using the opportunity of an expanded history hazard of diabetes mellitus in sufferers with schizophrenia and the increasing prevalence of diabetes mellitus inside the general population. Given these confounders, the connection among bizarre antipsychotic use and hyperglycemia-related negative reactions is not completely understood. However, epidemiological studies advocate an accelerated chance of remedy-emergent, hyperglycemia-associated unfavourable reactions in sufferers dealt with with the extraordinary antipsychotics. Precise hazard estimates for hyperglycemia-associated adverse reactions in patients dealt with with bizarre antipsychotics aren’t available.

Patients with a longtime prognosis of diabetes mellitus who’re began on Clozapine ODT ought to be monitored regularly for worsening of glucose manage. Patients with threat elements for diabetes mellitus (e.g., obesity, circle of relatives history of diabetes) who are beginning remedy with unusual antipsychotics must undergo fasting blood glucose testing at the start of remedy and periodically at some stage in remedy. Any patient dealt with with odd antipsychotics should be monitored for signs and symptoms of hyperglycemia together with polydipsia, polyuria, polyphagia, and weakness. Patients who expand signs of hyperglycemia at some point of treatment with bizarre antipsychotics must go through fasting blood glucose checking out. In a few cases, hyperglycemia has resolved while the strange antipsychotic changed into discontinued; but, a few patients required continuation of anti-diabetic remedy no matter discontinuation of the suspect drug.

In a pooled statistics analysis of eight studies in person topics with schizophrenia, the mean modifications in fasting glucose concentration within the clozapine and chlorpromazine corporations have been +eleven mg/dL and +four mg/dL respectively. A better percentage of the clozapine institution demonstrated specific increases from baseline in fasting glucose concentrations, in comparison to the chlorpromazine institution (Table four). The clozapine doses were one hundred-900 mg in step with day (imply modal dose: 512 mg in line with day). The most chlorpromazine dose changed into 1800 mg according to day (imply modal dose: 1029 mg according to day). The median length of publicity changed into forty two days for clozapine and chlorpromazine.

Table 4: Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia

Dyslipidemia

Undesirable alterations in lipids have passed off in sufferers dealt with with extraordinary antipsychotics, which include Clozapine ODT. Clinical tracking, such as baseline and periodic comply with-up lipid reviews in sufferers using Clozapine ODT, is suggested.

In a pooled statistics analysis of 10 studies in person topics with schizophrenia, clozapine treatment was associated with increases in serum overall ldl cholesterol. No statistics have been accumulated on LDL and HDL cholesterol. The mean increase in total ldl cholesterol changed into 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled information analysis of 2 research in grownup subjects with schizophrenia, clozapine treatment became associated with increases in fasting serum triglyceride. The mean growth in fasting triglyceride changed into seventy one mg/dL (fifty four%) inside the clozapine group and 39 mg/dL (35%) in the chlorpromazine organization (Table 5). In addition, clozapine remedy turned into associated with categorical increases in serum overall ldl cholesterol and triglyceride, as illustrated in Table 6. The share of patients with express will increase in overall ldl cholesterol or fasting triglyceride accelerated with the duration of publicity. The median period of clozapine and chlorpromazine publicity changed into forty five days and 38 days, respectively. The clozapine dose range become a hundred mg to 900 mg day by day; the maximum chlorpromazine dose became 1800 mg daily.

Table 5: Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia

Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia

Weight Gain

Weight benefit has befell with the usage of antipsychotics, such as Clozapine ODT. Monitor weight at some stage in treatment with Clozapine ODT. Table 7 summarizes the data on weight benefit via the duration of publicity pooled from 11 research with clozapine and lively comparators. The median length of publicity became 609, 728, and forty two days, inside the clozapine, olanzapine, and chlorpromazine institution, respectively.

Table 7: Mean Change in Body Weight (kg) by duration of exposure from studies in person subjects with schizophrenia

Table eight summarizes pooled information from 11 research in person topics with schizophrenia demonstrating weight gain ≥7% of frame weight relative to baseline. The median duration of publicity turned into 609, 728, and 42 days, within the clozapine, olanzapine, and chlorpromazine organization, respectively.

Table eight: Proportion of adult topics in schizophrenia research with weight benefit ≥7% relative to baseline frame weight

five.eleven Neuroleptic Malignant Syndrome

Antipsychotic capsules which include Clozapine ODT can purpose a potentially deadly symptom complicated called Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS encompass hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood stress, tachycardia, diaphoresis, and cardiac dysrhythmias). Associated findings can include expanded creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. It is crucial to don’t forget the presence of other critical clinical situations (e.g., excessive neutropenia, infection, heat stroke, primary CNS pathology, vital anticholinergic toxicity, extrapyramidal signs, and drug fever).

The management of NMS should encompass (1) instantaneous discontinuation of antipsychotic drugs and other drugs now not crucial to concurrent therapy, (2) intensive symptomatic treatment and medical tracking, and (3) treatment of co-morbid scientific conditions. There is not any preferred agreement approximately particular pharmacological treatments for NMS.

If a patient requires antipsychotic drug treatment after restoration from NMS, the capacity reintroduction of drug therapy must be carefully taken into consideration. NMS can recur. Monitor carefully if restarting treatment with antipsychotics.

NMS has took place with clozapine monotherapy and with concomitant CNS-lively medicines, inclusive of lithium.

five.12 Hepatotoxicity

Severe, lifestyles threatening, and in some cases fatal hepatotoxicity such as hepatic failure, hepatic necrosis, and hepatitis have been stated in sufferers treated with clozapine [see Adverse Reactions (6.2)]. Monitor for the appearance of signs and signs and symptoms of hepatotoxicity consisting of fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Perform serum checks for liver harm and don’t forget permanently discontinuing remedy if hepatitis or transaminase elevations blended with different systemic signs are because of clozapine.

five.13 Fever

During clozapine therapy, patients have experienced transient, clozapine-associated fever. The top prevalence is in the first three weeks of remedy. While this fever is usually benign and self-restricted, it is able to necessitate discontinuing treatment. The fever may be associated with an increase or lower in WBC be counted. Carefully compare patients with fever to rule out intense neutropenia or contamination. Consider the possibility of NMS [see Warnings and Precautions (5.11)].

5.14 Pulmonary Embolism

Pulmonary embolism and deep-vein thrombosis have took place in patients treated with clozapine. Consider the opportunity of pulmonary embolism in patients who gift with deep-vein thrombosis, acute dyspnea, chest pain, or with different respiratory signs and symptoms and signs. Whether pulmonary embolus and deep-vein thrombosis may be attributed to clozapine or some function(s) of sufferers isn’t always clear.

five.15 Anticholinergic Toxicity

Clozapine ODT has mighty anticholinergic outcomes. Treatment with Clozapine ODT can result in CNS and peripheral anticholinergic toxicity. Use with caution inside the presence of narrow-attitude glaucoma, concomitant anticholinergic medicines, prostatic hypertrophy, or other situations in which anticholinergic results can cause considerable negative reactions.

Treatment with Clozapine ODT can bring about gastrointestinal adverse reactions, together with constipation, intestinal obstruction, fecal impaction, and paralytic ileus. Such reactions can be fatal. Constipation ought to be to start with handled with the aid of ensuring adequate hydration and use of ancillary therapy together with bulk laxatives. Consultation with a gastroenterologist is really helpful in greater serious instances.

5.16 Interference with Cognitive and Motor Performance

Clozapine ODT can cause sedation and impairment of cognitive and motor performance. Caution patients approximately working dangerous machinery, together with motors, until they are reasonably certain that Clozapine ODT does not affect them adversely. These reactions may be dose-associated. Consider decreasing the dose in the event that they arise.

five.17 Tardive Dyskinesia

Tardive dyskinesia (TD) has took place in sufferers treated with antipsychotic tablets, along with Clozapine ODT. The syndrome includes doubtlessly irreversible, involuntary, dyskinetic moves. The hazard of TD and the probability that it turns into irreversible are believed to boom with more intervals of remedy and higher total cumulative doses. However, the syndrome can increase after relatively short remedy periods at low doses. Prescribe Clozapine ODT in a manner this is maximum probable to decrease the hazard of growing TD. Use the lowest effective dose and the shortest duration vital to manipulate signs and symptoms. Periodically assess the need for persisted remedy. Consider discontinuing treatment if TD happens. However, a few patients might also require treatment with Clozapine ODT notwithstanding the presence of the syndrome.

There is not any recognized treatment for TD. However, the syndrome may also remit in part or completely if remedy is discontinued. Antipsychotic remedy, itself, may suppress (or partially suppress) the signs and symptoms and symptoms, and it has the capacity to masks the underlying procedure. The effect of symptom suppression on the long-term path of TD is unknown.

five.18 Patients with Phenylketonuria

Phenylketonuric sufferers have to be informed that Clozapine ODT incorporates phenylalanine (a element of aspartame). Each 12.five mg, orally disintegrating tablet contains zero.87 mg phenylalanine. Each 25 mg, orally disintegrating pill carries 1.74 mg phenylalanine. Each a hundred mg, orally disintegrating tablet contains 6.96 mg phenylalanine. Each 150 mg, orally disintegrating tablet carries 10.forty four mg phenylalanine. Each 200 mg, orally disintegrating tablet carries 13.92 mg phenylalanine.

five.19 Cerebrovascular Adverse Reactions

In controlled trials, elderly sufferers with dementia-related psychosis treated with a few peculiar antipsychotics had an extended danger TEVA (compared to placebo) of cerebrovascular damaging reactions (e.g., stroke, temporary ischemic attack), which includes fatalities. The mechanism for this extended hazard isn’t regarded. An increased hazard can’t be excluded for Clozapine ODT or different antipsychotics or other affected person populations. Clozapine ODT need to be used with caution in patients with danger factors for cerebrovascular adverse reactions.

five.20 Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of Clozapine ODT

If abrupt discontinuation of Clozapine ODT is important (because of excessive neutropenia or every other clinical circumstance, for instance) [see Dosage and Administration (2.4), Warnings and Precautions (5.1)], monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting, and diarrhea.

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