Pharmacology: Olanzapine is an antipsychotic agent that demonstrates a broad pharmacological profile across a number of receptor systems. It is a thienbenzodiazepine atypical antipsychotic. It has affinity for dopamine (D1, D2 and D4), histamine (H1), serotonin (5HT2A/2C) and adrenergic receptors.
Pharmacokinetics: Olanzapine is well-absorbed after oral administration, reaching peak plasma concentrations within 5-8 hrs. The absorption is not affected by food. Oral bioavailability relative to IV administration has not been determined. Olanzapine is metabolized in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which does not pass the blood-brain barrier. Cytochromes P-450-CYP1A2 and P-450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacological activity is from the parent olanzapine.
After oral administration, the mean terminal elimination half-life of Olan in healthy subjects varied on the basis of age and gender. In healthy elderly, mean t½ is 51.8 hrs. In non-elderly subjects, the mean t½ is 33.8 hrs. In female versus male subjects, the mean elimination t½ was 36.7 hrs versus 32.3 hrs. In renally impaired patients (creatinine clearance <10 mL/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4) or drug clearance (21.2 vs 25 L/hr). A mass balance study showed that approximately 57% of radiolabeled olanzapine appeared in urine principally as metabolites.
The plasma clearance of Olan is lower in the elderly versus young subjects, in females versus males, and in nonsmokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.
The plasma protein-binding of olanzapine is about 93% over the concentration range of about 7-1000 ng/mL. Olan is bound predominantly to albumin and α1-acid glycoprotein.
Treatment of schizophrenia in adults. Olan is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.
Olan should be administered on a once-daily schedule without regard to meals, generally beginning with 5-10 mg initially with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week. Daily dosage may subsequently be adjusted on the basis of individual clinical status within the range of 5-20 mg daily. An increase to a dose greater than the routine therapeutic dose of 10 mg/day ie, to a dose of ≥15 mg/day, is recommended only after appropriate clinical re-assessment.
Elderly: A lower starting dose (5 mg/day) is not routinely required but should be considered for those ≥65 years when clinical factors warrant so.
Patients with Hepatic or Renal Impairment: A lower starting dose (5 mg) may be considered for such patients.
Female Compared with Male Patients: The starting dose and dose range need not be routinely altered for female patients relative to male patients.
Nonsmoking Patients Compared with Smoking Patients: The starting dose and dose range need not be routinely altered for nonsmoking patients relative to smoking patients.
When >1 factor is present which might result in slower metabolism (female gender, geriatric age, nonsmoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients.
Experience with Olan in overdosage is limited.
Symptoms: In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech. In the limited number of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or ECG. Vital signs were usually within normal limits following overdoses.
Based on animal data, the predicted symptoms would reflect an exaggeration of the drug's known pharmacological actions. Symptoms may include somnolence, mydriasis, blurred vision, respiratory depression, hypotension and possible extrapyramidal disturbances.
Treatment: There is no specific antidote to Olan; therefore, appropriate supportive measures should be initiated. The possibility of multiple drug involvement should be considered.
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. The use of activated charcoal for overdose should be considered because the concomitant administration of activated charcoal was shown to reduce the oral bioavailability of Olan by 50-60%.
Hypotension and circulatory collapse should be treated with appropriate measures eg, IV fluids and/or sympathomimetic agents eg, norepinephrine (do not use epinephrine, dopamine or other sympathomimetic agents with β-agonist activity since β-stimulation may worsen hypotension in the setting of α-blockade induced by olanzapine). Cardiovascular monitoring should be considered to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.
Patients with a known hypersensitivity to any ingredient of Olan.
Patients with known risk for narrow-angle glaucoma.
Concomitant Illness: Olan has showed a low incidence of anticholinergic in clinical trials. Caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions since clinical experience with Olan in patients with concomitant illness is limited.
Transient, asymptomatic elevations of hepatic transaminases, ALT, AST have been seen occasionally especially in early treatment. Caution should be exercised in patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients with preexisting conditions associated with limited hepatic functional reserve and in patients who are being treated with potentially hepatotoxic drugs. In the event of elevated ALT and/or AST during treatment, follow up should be organized and dose reduction should be considered.
As with other neuroleptic drugs, caution should be exercised in patients with low leucocyte and/or neutrophil counts for any reason, in patients with a history of drug-induced bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with myeloproliferative disease. Thirty-two patients with clozapine-related neutropenia or agranulocytosis histories received Olan without decreases in baseline neutrophil counts.
Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with other antipsychotic drugs. In clinical trials, there were no reported cases of NMS in patients receiving Olan.
NMS is associated with hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. In such an event or with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic drugs, including Olan, must be discontinued.
Olan should be cautiously used in patients who have a history of seizures or have conditions associated with seizures.
Tardive Dyskinesia: Olan was associated with a statistically significant lower incidence of treatment-emergent dyskinesia in comparative studies of ≤1 year. However, the risk of tardive dyskinesia increases with long-term exposure, and therefore, if signs or symptoms of tardive dyskinesia appear in a patient on Olan, a dose reduction or drug discontinuation should be considered. These symptoms can temporarily deteriorate or even arise after discontinuation of treatment.
Caution should be used when Olan is taken in combination with other centrally acting drugs and alcohol (given the primary CNS effect of Olan).
As it exhibits in vitro dopamine antagonism, Olan may antagonize the effects of direct and indirect dopamine agonists.
Postural hypotension was infrequently observed in the elderly in the Olan clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients >65 years.
In clinical trials, Olan was not associated with a persistent increase in absolute QT intervals. However, as with other antipsychotics, caution should be exercised when Olan is prescribed with drugs known to increase QTc interval, especially in the elderly.
Effects on the Ability to Drive or Operate Machinery: There are chances that Olan may cause somnolence, patients should be cautioned about operating hazardous machinery, including motor vehicles.
Use in pregnancy & lactation: There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with Olan. Nevertheless, because human experience is limited, this drug should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Olan was excreted in milk of treated rats during lactation. It is not known if Olan is excreted in human milk. Patients should be advised not to breastfeed an infant if they are taking Olan.
Use in children: Olan has not been studied in subjects <18 years.
There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with Olan. Nevertheless, because human experience is limited, this drug should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Olan was excreted in milk of treated rats during lactation. It is not known if Olan is excreted in human milk. Patients should be advised not to breastfeed an infant if they are taking Olan.
Frequent (>10%): Somnolence and weight gain are the only frequent undesirable effects associated with the use of Olan. Weight gain is related to a lower pre-treatment body mass index (BMI) and initial starting dose of ≥15 mg.
Occasional (1-10%): Dizziness, increased appetite, peripheral oedema, orthostatic hypotension, and mild, transient anticholinergic effects including constipation and dry mouth are the occasional undesirable effects associated with the use of Olan.
Transient, asymptomatic elevations of hepatic transaminases, ALT, AST have been seen occasionally, especially in early treatments.
Although in various studies, Olan-treated patients had a lower incidence of parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the preexisting history of individual acute and tardive extrapyramidal movement disorders, it can not be concluded at present that Olan produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.
Rare (<1%): Rarely, photosensitivity reaction has been reported.
Other Findings: Plasma prolactin levels were sometimes elevated, but associated clinical manifestations (eg, gynaecomastia, galactorrhoea and breast enlargement) were rare. In most patients, levels returned to normal ranges without cessation of treatment.
High creatine phosphokinase levels have been observed in rare cases.
As with other neuroleptic drugs, asymptomatic haematologic variations were occasionally seen.
Potential for Other Drugs to Affect Olan: Single dose of antacid (aluminum, magnesium) or cimetidine does not affect the oral bioavailability of Olanzapine. The concomitant administration of activated charcoal reduces the oral bioavailability of Olan by 50-60%. The metabolism of Olan may be induced by concomitant smoking (the clearance of Olan is 33% lower and the terminal elimination half-life is 21% longer in nonsmokers compared to smokers) or carbamazepine therapy (clearance is increased by 44% and the terminal elimination half-life is reduced by 20% when administered with carbamazepine). Smoking and carbamazepine therapy induce P-450-1A2 activity.
The pharmacokinetics of theophylline, which is metabolized by P-450-1A2, is not altered by Olan. The effect of potent inhibitors of P-450-1A2 activity on Olan pharmacokinetics has not been studied.
Potential for Olan to Affect Other Drugs: Olan does not cause inhibition of the metabolism of imipramine/desipramine (P-450-2D6 or P-450-3A1/A2), warfarin (P-450-2C9), theophylline (P-450-1A2) or diazepam (P-450-3A4 and P-450-2C19). Olan shows no interaction when co-administered with lithium or biperiden.
N05AH03 - olanzapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics
FC tab 5 mg x 10 x 10's. 10 mg x 10 x 10's.
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