Project on CPMP Dossier Documentation for OLANZAPINE Drug

The CPMP (Committee of Proprietary Medicinal Products)Dossier Document provides a harmonized structure and format for new product applications & it contains the information to be presented in registration applications for new pharmaceuticals .
This CPMP Dossier Document is divided into five separate sections. The five sections address 1) Summary of Dossier 2) Description of product 3) Impurity profile 4) Clinical Documentation & 5) References.

DRUG DESCRIPTION
ADMINISTRATIVE DATA
PHARMACEUTICAL INFORMATION PHARMACEUTICAL DEVELOPMENT

VALIDATION
STABILITY OF THE DRUG
BIOAVAILABILITY PROFILE TOXICOLOGY
CLINICAL DOCUMENTATION
REFERENCES

DRUG DESCRIPTION . . .
Olanzapine ( Trade names Zyprexa, Zyprexa Zydis, Zalasta, Zolafren, Olzapin, Rexapin or in combination with fluoxetine Symbyax ) is a typical antipsycotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder. Olanzapine is thought to modify the actions of several chemicals in the brain. Olanzapine is available as 2.5-mg, 5-mg, 7.5-mg, 10-mg, 15-mg, and 20-mg tablets that can be swallowed (Zyprexa) and 5-mg, 10mg, 15-mg, and 20-mg tablets that disintegrate when placed under the tongue (Zyprexa Zydis). It is also available as a 10 mg vial for a rapid-acting intramuscular injection for short-term acute use. The development of solid dosage forms that disintegrate quickly in the mouth without requiring water has advantage for patients who have difficulty in swallowing, such as, infants, patients with mental problems and non- cooperative patients, as well as the population in general.

Dosage and administration . . .

Dose may be adjusted depending on the persons response to the drug. The dose also will depend on certain medical problems the person may have. It is generally recommended to be taken once daily before bed as it is highly sedating. However, sedation tends to diminish as treatment is pursued. The dosage of olanzapine varies depending upon the reason for its use. When used to treat schizophrenia, 510 mg is the typical starting dosage. If dosage adjustments are needed, increases are made in 5-mg increments once a week. When treating schizophrenia, a total daily dosage of 1015 mg is usually effective. Olanzapine is eliminated from the body more quickly in young people than in older (over age 60) individuals, in men than in women, and in smokers faster than in non-smokers. Dosage adjustments may be needed based upon individual patient characteristics.

 Olanzapine is chemically known as 2- methyl-4-(4-methyl- 1 -piperazinyl)10H-thieno[2,3-] [ 1 ,5] benzodiazepine. US 5,501,861 discloses a fast dissolving tablet composition containing water-soluble carbohydrate made by compression-molded method comprising active ingredient, diluent, binder, and volatile salt. US 5,464,632 discloses rapidly disintegratable multiparticulate tablet, which disintegrates in the mouth in less than sixty seconds, wherein the active agent is in the form of coated microcrystals or coated or uncoated micro granules. US 5,919,485 discloses solid oral formulation comprising olanzapine, wherein the formulation is coated with a polymer selected from hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, dimethylaminoethyl methacrylate, methyl acrylate acid ester copolymer, ethyl acrylate-methyl methacrylate copolymer.

 Olanzapine is available as a tablet in strengths of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg. It also comes as an orally disintegrating wafer (known as Zydis), which dissolves on the tongue, in strengths of 5 mg, 10 mg, 15 mg and 20 mg. It is also available as a 10 mg vial for a rapid-acting intramuscular injection for short-term acute use. Dose may be adjusted depending on the person' response to the drug. The dose also will depend on certain medical problems the person may have. It is generally recommended to be taken once daily before bed as it is highly sedating. However, sedation tends to diminish as treatment is pursued.

PHARMACOLOGICAL ASPECTS . . .
Pharmacokinetics
Pharmacokinetics is the determination of the fate of substances administered externally to a living organism. Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body (e.g. by enzymes) and the effects and routes of excretion of the metabolites of the drug

Pharmacodynamics Pharmacodynamics is the study of the physiological effects of drugs on the body and the mechanisms of drug action Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug.

PHARMACOKINETICS
Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours and apparent plasma clearance ranges from 12 to 47 L/hr. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age.

PHARMACODYNAMICS
Olanzapine binds with high affinity to the following receptors serotonin 5HT2A/2C, 5HT6, dopamine D1-4 , histamine H1 and adrenergic 1 receptors . Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 and muscarinic M1-5. Olanzapine binds weakly to GABAA, BZD, and adrenergic receptors. Antagonism at receptors other than dopamine and 5HT2 may explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of adrenergic 1 receptors may explain the orthostatic hypotension observed with this drug.

MANUFACTURING FORMULA
Sr. No. 1. 2. 3. 4. 5. 6. Ingredients Olanzapine Lactose Polyvinylpyrrolidone Isopropyl Alcohol Purified Talc Magnesium Stearate Quantity 25.750 kg. 2.575 kg. 0.640 kg. 12.000 lit. 0.260 kg. 0.130 kg. Overages 3% Diluent Exipient Binder Lubricant Lubricant

Manufacturing Process . . .

BLENDING, GRANULATION . . .
TABLETTING . . . COATING AND PACKAGING . . .

 The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose. Results from method validation can be used to judge the quality, reliability and consistency of the product. Validation or revalidation is needed before the introduction of Analytical methods into routine use; whenever the conditions change for which the method has been validated (e.g., an instrument with different characteristics or samples with a different matrix); and whenever the method is changed and the change is outside the original scope of the method.

TYPES OF ANALYTICAL PROCEDURES TO BE VALIDATED . .

Identification tests. Quantitative tests for impurities content. Limit tests for the control of impurities. Quantitative tests of the active moiety in samples of drug substance or drug product or other selected component(s) in the drug product. Accuracy Precision Specificity Limit of detection Linearity and range

 CONTROL OF STARTING MATERIAL . Synthesis of the drug substance from the designated starting material has been adequately described and appropriate inprocess controls and intermediate specifications are applied. CONTROL OF EXCIPIENTS . All excipients used in the manufacture of the tablets are routinely tested for compliance with current relevant international standards.

PACKING MATERIAL . Specification of packing material, Aluminum sheets, boxes, carton are also checked and recorded in the dossier.

STABILITY . . .
Olanzapine is a yellow or off-white crystalline solid which is not hygroscopic. Olanzapine is prepared by synthesis and subsequent crystallization processes. Four batches of olanzapine synthesized according to the defined synthetic process were placed under ICH storage conditions (2-8 C up to 18 months and 25C/60%RH up to 6 months) in double aluminium laminated bags in HPDE containers. The parameters tested are description, identification (HPLC), polymorphic form (XRD), water, related substances, and assay. Stress testing was also performed on one batch and included acid, base, oxidative, heat and light stress conditions. The proposed re-test period is justified based on the stability results when the active substance is stored in the original packing material.

 Bioequivalence studies :- Olanzapine

capsules were used in the clinical studies, whereas coated tablet formulations are now marketed. The following formulations were found to be bioequivalent in the marketing authorisation application for Zyprexa coated tablets: 2.5 mg and 5 mg coated tablets, 1 mg and 5 mg coated tablets and capsules, 5 mg tablets and 10 mg coated tablets and capsules, and 15 mg capsules and 5 and 7.5 mg coated tablets.

 Three additional bioequivalence studies were performed with the orodispersible tablet formulation. In the first study, the bioequivalence of olanzapine orodispersible tablets 5 mg and olanzapine coated tablets (5 mg) was assessed. The second bioequivalence study single doses of 20 mg (four 5 mg tablets) of olanzapine-coated tablets were compared to 20 mg (one tablet) of olanzapine orodispersible tablets. In the third study the bioequivalence of olanzapine orodispersible tablets containing olanzapine manufactured in different ways (5 mg and 10 mg tablets) was investigated. The aim of the study was to determine whether the processing of olanzapine affects the bioavailability.

 Toxicology is the study of the adverse effects of chemicals on living organisms. It is the study of symptoms, mechanisms, treatments and detection of poisioning, especially the poisoning of people. The therapeutic dose of olanzapine used in humans is approximately 0.33 mg/kg. Olanzapine overdose is associated with acute muscle toxicity.

 Single dose toxicity studies Repeated dose toxicity studies

Mutagenic potential Carcinogenic potential Reproduction studies

Immunotoxicity studies

o The clinical documentation includes an extensive clinical program of clinical pharmacological studies. o Detailed description of studies, trial results & conclusion for Olanzapine drugs are provided in the Dossier.

PRECAUTIONS . . .
Caution should be used in patients with heart disease because the drug may cause blood pressure to fall too low resulting in dizziness, rapid heartbeats, or fainting. Olanzapine should be used carefully in people with known seizure disorders since olanzapine may alter properties of the brain making seizures occur more easily. People with liver disease should have their liver function monitored regularly while taking olanzapine. Women who are pregnant or breast-feeding should not take olanzapine.

SIDE EFFECTS
Side effects that occur in more than 5% of patients taking olanzapine include involuntary movements, weakness, dizziness, extreme drowsiness, constipation, weight gain, dry mouth, low blood pressure, cold or fever. Other side effects that are possible include rash, body aches and pains, elevated liver enzymes, vision abnormalities, chest pain, or rapid heartbeats. Olanzapine has the potential to produce a serious side effect called Tar dive dyskinesia . This syndrome consists of involuntary, uncoordinated movements that may appear late in therapy and not disappear even after the drug is stopped.The incidence increases with increasing age and dosage of olanzapine. Women are at greater risk than There is no known effective treatment for tardive dyskinesia.

ACKNOWLEDGEMENT . . .
Dr. Naresh .R. Tongay (Research Scientist Haffkine Institute- Mumbai) for his guidance.

Mrs Sheetal Rai ( Junior faculty ) Mr Maulik Chauhan ( junior Faculty )

www.minddisorders.com/Ob-Ps/Olanzapine.html www.wikipedia.org/wiki/Olanzapine British Pharmacopoeia US Pharmacopoeia http://www.rxlist.com/zyprexa-drug.htm www.google.com