Saveril
Saveril Uses, Dosage, Side Effects, Food Interaction and all others data.
Saveril is classified as an \'atypical\' antipsychotic drug because of its profile of binding to dopamine receptors and its effects on various dopamine-mediated behaviors differ from those exhibited by other typical antipsychotic drug products. In particular, although Saveril does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor. This evidence, consistent with the view that Saveril is preferentially more active at limbic than at striatal dopamine receptors. This may explain the relative freedom of Saveril from extrapyramidal side effects. Saveril also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors.
Saveril is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. Saveril is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors. Saveril acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Saveril's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Saveril's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Saveril's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug.
Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use.Saveril induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection. Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils. Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs. Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program. These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC5 Monitor the patient's troponin, CRP, ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be re-challenged with clozapine.
| Trade Name | Saveril |
| Availability | Prescription only |
| Generic | Clozapine |
| Clozapine Other Names | Clozapin, Clozapina, Clozapine, Clozapinum |
| Related Drugs | quetiapine, Abilify, Seroquel, aripiprazole, olanzapine, risperidone |
| Weight | 25mg, 100mg |
| Type | Tablet |
| Formula | C18H19ClN4 |
| Weight | Average: 326.823 Monoisotopic: 326.129824335 |
| Protein binding | 97% (bound to serum proteins) |
| Groups | Approved |
| Therapeutic Class | Atypical neuroleptic drugs |
| Manufacturer | Genetics Pharmaceuticals |
| Available Country | Pakistan |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Schizophrenia in patients unresponsive to, or intolerant of, conventional antipsychotic drugs.Psychosis in Parkinson's disease.
Saveril is also used to associated treatment for these conditions: Suicidal Behaviour, Treatment-resistant Schizophrenia, Advanced dopaminomimetic psychosis
How Saveril works
Saveril's antipsychotic action is likely mediated through a combination of antogistic effects at D2 receptors in the mesolimbic pathway and 5-HT2A receptors in the frontal cortex. D2 antagonism relieves positive symptoms while 5-HT2A antagonism alleviates negative symptoms.
Dosage
Saveril dosage
Schizophrenia:
Adult over 16 years, 12.5 mg once or twice (elderly 12.5 mg once) on first day then 25-50 mg (elderly 25-37.5 mg) on second day then increased gradually (if well tolerated) in steps of 25-50 mg daily (elderly max. increment 25 mg daily) over 14-21 days up to 300 mg daily in divided doses (larger dose at night, up to 200 mg daily may be taken as a single dose at bedtime); if necessary may be further increased in steps of 50-100 mg once (preferably) or twice weekly; usual dose 200-450 mg daily (max. 900 mg daily)
Psychosis in Parkinson\'s disease:
Adult over 16 years, 12.5 mg at bedtime then increased according to response in steps of 12.5 mg up to twice weekly; usual dose range 25-37.5 mg at bedtime, usual maximum 50 mg daily; exceptionally, dose may be increased further in steps of 12.5 mg weekly to maximum 100 mg daily in 1-2 divided doses
Side Effects
Common side effects are constipation, dizziness or lightheadedness (mild), drowsiness, headache (mild), increased watering of mouth, nausea or vomiting, unusual weight gain. Less common side effects include abdominal discomfort or heartburn, dryness of mouth.
Toxicity
Saveril carries a black-box warning for agranulocytosis.
Precaution
Medication should not be stopped abruptly; should be tapered off over 1-2 weeks. If conditions warrant abrupt discontinuation (leukopenia, myocarditis, cardiomyopathy), monitor patient for psychosis and cholinergic rebound (headache, nausea, vomiting, diarrhea). Elderly patients are more susceptible to adverse effects (including agranulocytosis, cardiovascular, anticholinergic, and tardive dyskinesia). Significant risk of agranulocytosis, potentially life-threatening. WBC testing should occur weekly for the first 6 months of therapy; thereafter, if acceptable WBC counts are maintained (WBC 3000/mm3, ANC 1500/mm3) then WBC counts can be monitored every other week. WBCs must be monitored weekly for the first 4 weeks after therapy discontinuation. Use with caution in patients receiving other marrow suppressive agents. Eosinophilia has been reported to occur with Saveril and may require temporary or permanent interruption of therapy.
Cognitive and/or motor impairment (sedation) is common with Saveril, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Has been associated with benign, self-limiting fever (<100.4°F, usually within first 3 weeks). However, Saveril may also be associated with severe febrile reactions, including neuroleptic malignant syndrome (NMS). Saveril\'s potential for extrapyramidal symptoms appear to be extremely low.
May cause anticholinergic effects; should be used with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or history of bowel obstruction. May cause hyperglycemia; in some cases may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Use with caution in patients with hepatic disease or impairment; hepatitis has been reported as a consequence of therapy.
May cause orthostatic hypotension and tachycardia; should be used with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Concurrent use of psychotropics and benzodiazepines may increase the risk of severe cardiopulmonary reactions.
Myocarditis, pericarditis, pericardial effusion, cardiomyopathy, and CHF have also been associated with clozapine. Fatalities due to myocarditis have been reported; highest risk in the first month of therapy, however, later cases also reported. Myocarditis or cardiomyopathy should be considered in patients who present with signs/symptoms of heart failure (dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema), chest pain, palpitations, new electrocardiographic abnormalities (arrhythmias, ST-T wave abnormalities), or unexplained fever. Patients with tachycardia during the first month of therapy should be closely monitored for other signs of myocarditis. Discontinue clozapine if myocarditis is suspected; do not rechallenge in patients with clozapine-related myocarditis. The reported rate of cardiomyopathy in clozapine-treated patients is similar to that in the general population. The majority of patients were over 50 years of age and were taking clozapine for >6 months. Saveril should be discontinued in patients with confirmed cardiomyopathy unless benefit clearly outweighs risk. Rare cases of thromboembolism, including pulmonary embolism and stroke resulting in fatalities, have been associated with clozapine.
Interaction
Olanzapine may antagonize the effects of levodopa and dopamine agonists. Drugs that induce CYP1A2 or glucoronyl transferase enzymes e.g, Omeprazole and Rifampicin, may increase Olanzapine clearance. Inhibitors of CYP1A2 may potentially inhibit Olanzapine elimination. Carbamazepine may increase the clearance of Olanzapine. Concomitant administration of activated charcoal reduces the oral bioavailability of Olanzapine by 50-60%. Caution should be taken when Olanzapine is administered with centrally acting drugs and alcohol.
Food Interaction
- Avoid alcohol.
- Exercise caution with St. John's Wort. This herb induces both CYP3A4 and CYP1A2 metabolism and may reduce clozapine serum levels.
- Limit caffeine intake. Caffeine may reduce clozapine metabolism.
- Take with or without food. The absorption is unaffected by food.
[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.
Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.
Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.
Saveril Cholesterol interaction
[Moderate] Atypical antipsychotic drugs have been associated with undesirable alterations in lipid levels.
While all agents in the class have been shown to produce some changes, each drug has its own specific risk profile.
Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.
Saveril Drug Interaction
Major: aripiprazole, aripiprazole, lorazepam, lorazepam, escitalopram, escitalopram, lithium, lithium, quetiapine, quetiapine, sertraline, sertraline, olanzapine, olanzapineModerate: lamotrigine, lamotrigineMinor: divalproex sodium, divalproex sodiumUnknown: cholecalciferol, cholecalciferol
Saveril Disease Interaction
Major: dementia, agranulocytosis, anticholinergic effects, hepatitis, acute alcohol intoxication, CNS depression, NMS, tardive dyskinesiaModerate: aspiration, seizure, hyperglycemia/diabetes, hypotension, lipid alterations, weight gain, hyperglycemia, renal dysfunction, thromboembolic events, hyperprolactinemia, liver disease, parkinsonism
Elimination Route
Rapid and almost complete.
Half Life
8 hours (range 4-12 hours)
Elimination Route
Approximately 50% of the administered dose is excreted in the urine and 30% in the feces.
Pregnancy & Breastfeeding use
There are no adequate studies of Saveril in pregnant women. Studies in animals suggest no important effects on the fetus. Saveril can be used in pregnancy if the physician feels that it is necessary. Animal studies suggest that Saveril is secreted in breast milk. Therefore, women taking Saveril should not nurse their infants.
Contraindication
Severe cardiac disorders (e.g. myocarditis); renal impairment (avoid if creatinine clearance less than 10 ml/minute); history of neutropenia or agranulocytosis; bone-marrow disorders; paralytic ileus; alcoholic and toxic psychoses; history of circulatory collapse; drug intoxication; coma or severe CNS depression; uncontrolled epilepsy; breast-feeding.
Acute Overdose
The most commonly reported signs and symptoms associated with Saveril overdose are: altered states of consciousness, including drowsiness, delirium and coma; tachycardia; hypotension; respiratory depression or failure; hypersalivation. Aspiration pneumonia and cardiac arrhythmias have also been reported. Seizures have occurred in a minority of reported cases. Fatal overdoses have been reported with Saveril, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.
Management of Overdose:
Should be established and maintained an airway; should be ensured adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdosage. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine and derivatives when treating hypotension, and quinidine and procainamide when treating cardiac arrhythmia.
There are no specific antidotes for Saveril. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.In managing overdosage, the physician should consider the possibility of multiple drug involvement.
Interaction with other Medicine
Olanzapine may antagonize the effects of levodopa and dopamine agonists. Drugs that induce CYP1A2 or glucoronyl transferase enzymes e.g, Omeprazole and Rifampicin, may increase Olanzapine clearance. Inhibitors of CYP1A2 may potentially inhibit Olanzapine elimination. Carbamazepine may increase the clearance of Olanzapine. Concomitant administration of activated charcoal reduces the oral bioavailability of Olanzapine by 50-60%. Caution should be taken when Olanzapine is administered with centrally acting drugs and alcohol.
Storage Condition
Store between 15-30°C.
Innovators Monograph
You find simplified version here Saveril
Saveril contains Clozapine see full prescribing information from innovator Saveril Monograph, Saveril MSDS, Saveril FDA label
FAQ
What is Saveril used for?
Saveril is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. Saveril is also used to reduce the risk of suicidal behavior in people with schizophrenia or similar disorders.
How safe is Saveril ?
Saveril may be associated with the occurrence of severe cardiovascular side effects, including dilated cardiomyopathy, myocarditis and pericarditis, which may be fatal when not timely recognized and managed.
How does Saveril work?
Saveril is an antipsychotic medicine that helps to adjust the levels of dopamine and other chemicals available in your brain.
What are the common side effects of Saveril?
Common side effects of Saveril are include:
- drowsiness.
- dizziness, feeling unsteady, or having trouble keeping your balance.
- increased salivation.
- dry mouth.
- restlessness.
- headache.
Is Saveril safe during pregnancy?
No specific risks for the mother and children can be attributed to the use of Saveril during pregnancy.
Is Saveril safe during breastfeeding?
In a consensus guideline on the use of psychotropic medication in pregnancy and the postpartum period, the British Association for Psychopharmacology considers breastfeeding a contraindication for Saveril due to the risk of agranulocytosis and seizures.
Can I drink alcohol with Saveril?
Avoid alcohol while you are taking Saveril, especially when you first start treatment. Drinking alcohol while taking Saveril can cause drowsiness and affect concentration, putting you at risk of falls and other accidents.
Can I drive after taking Saveril?
Do not drive a car, operate machinery, swim, or climb while taking clozapine, because if you suddenly lose consciousness, you could harm yourself or others.
When should be taken of Saveril?
Saveril is usually taken 1 or 2 times per day with or without food. Typically patients begin at a low dose of medicine and the dose is increased slowly over several weeks.
How many time can I take Saveril daily?
Saveril is usually taken 1 or 2 times per day.
How long does Saveril take to work?
It usually takes 3 to 6 weeks or longer before the benefits of Saveril are noticeable. The full effects of Saveril may not be seen until after 6 to 12 months.
How long does Saveril stay in my system?
It has a long half-life and can remain in a person's system for weeks. In studies, Saveril was detectable on a urine test for up to a month, on a hair test for up to 28 days, and on a saliva test for up to 5 or 6 days.
Can I take Saveril for a long time?
long-term use of Saveril can cause a serious movement disorder that may not be reversible. The longer you use Saveril, the more likely you are to develop this disorder, especially if you are a woman or an older adult.
How long can I take Saveril for?
Saveril treatment should be continued for at least six months, unless you develop a side effect that means you have to stop the medicine.
Who should not take Saveril?
You should not take Saveril if you are allergic to it. Saveril is not approved for use by anyone younger than 18 years old.
What happens if I miss a dose?
Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.
What happens if I overdose?
Seek emergency medical attention. Overdose symptoms may include drowsiness, confusion, fast heartbeats, feeling light-headed, weak or shallow breathing, drooling, choking, or seizure.
What happens if I suddenly stop Saveril?
Rapid discontinuation of Saveril has been reported to cause rebound psychosis and worsening of symptoms within 24 to 48 hours of drug cessation.
Will Saveril affect my fertility?
Animal models given doses of 0.4 to 0.9 times the maximum recommended human dose, have revealed no evidence of impaired fertility or harm to the fetus.
Can Saveril affect my heart?
Saveril causes tachycardia, and 25% of patients with schizophrenia can experience 10-15 beats per minute increase in heart rate, which is usually benign. In normal volunteers, Saveril can also cause bradycardia, of which clinicians should be aware.
Can Saveril affect my kidneys?
Saveril has been shown, on rare occasions, to cause acute renal failure due to acute interstitial nephritis.
Can Saveril affects my liver?
Though elevations in liver function tests are often transient and asymptomatic, there are many reported cases of Saveril-induced hepatotoxicity, with damage to the liver, involvement of multiple organs, and even fulminant liver failure arising with moderate Saveril doses.
