PBRS 2015-Regulatory Sciences6 May 2015

Pharmacokinetic propertiesPharmacokinetic properties Pharmacodynamic propertiesPharmacodynamic properties

Pharmacology of a Drug Approved by FDA in 2010Pharmacology of a Drug Approved by FDA in 2010

SILENOR (DOXEPIN)SILENOR (DOXEPIN)

Mirza Danish Hussain Barlas Assistant Manager Business Development and Regulatory Affairs

(Pharm-D , R.Ph, MBA-Mkt, MBA-SC, CRCP)

Disclaimer

The information withinthis presentation is based on the

References, the Presenter's Interest andRegulatory Experience.

The FDA Drug Approval Process

The FDA-CDER ensures that drugs marketed are safe and effective. It conducts limited research in the areas of drug quality, safety, and effectiveness.

1. Investigational New Drug (IND) Application 2. New Drug Application (NDA) 3. Abbreviated New Drug Application (ANDA): Generics 4. Therapeutic Biologic Applications (BLA) 5. Drug Applications for Over-the-Counter (OTC) Drugs

The Problem

Insomnia and Sleep Maintenance Difficulty. Types of Insomnia 1.Transient (short term) insomnia. 2.Chronic (long term) insomnia.

The Symptoms Not being able to fall asleep. Waking frequently during the night. Waking too early. Being unable to return to sleep.

The Psychology

The Complications

The Solution

Silenor (Doxepin) Tablets 3mg and 6mg

A low-dose oral tablet formulation of the H1 receptor Antagonist Doxepin.

The Generic

Doxepin

The Pharmacology

Silenor binds with high affinity to histamine (H1) receptors. This mechanism of action is different from that of any other prescription medication currently approved for the treatment of insomnia.

Pharmacodynamics

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1. The mechanism of action of doxepin is not definitely known. 2. It is not a central nervous system stimulant nor a monoamine oxidase

inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of nor-adrenaline by reuptake into the nerve terminals is prevented.

3. Silenor binds with high affinity to histamine (H1) receptors which makes it a H1 receptor Antagonist.

Pharmacokinetics

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AbsorptionDoxepin is well absorbed from the gastro-intestinal tract.

Approximately 55%-87% of orally administered doxepin undergoes first pass metabolism in the liver.

This forming the primary active metabolite desmethyldoxepin.

Peak plasma concentrations for doxepin ranging from 8.8-45.8 ng/ml

Peak levels were reached between 2 and 4 hours after administration.

Peak levels for the primary metabolite desmethyldoxepin ranged from 4.8-14.5 ng/ml (mean 9.7 ng/ml)

Peak levels were achieved between 2 and 10 hours after administration.

Pharmacokinetics

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DistributionThe mean apparent volume of distribution for doxepin is approximately 20 l/kg.

The protein binding for doxepin is approximately 76%.

The plasma elimination half-life of doxepin ranged from 8 to 24 hours.

The half-life of desmethyldoxepin ranged from 33-80 hours.

Mean plasma clearance for doxepin is approximately 0.84 1/kg/hr.

Pharmacokinetics

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MetabolismPaths of metabolism of doxepin include: 1.Demethylation2.N-oxidation 3.Hydroxylation4.Glucuronide formation

Pharmacokinetics

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Excretion Doxepin is excreted primarily in the urine, mainly as its metabolites, either free or in conjugate form.

The Side Effects

The Side Effects that are known to occur are 1. Somnolence2. Sedation3. Nausea4. Upper respiratory tract infection

The References

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/

https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/1090/silenor-doxepin

http://www.drugs.com/newdrugs/somaxon-announces-fda-approval-silenor-doxepin-insomnia-2070.html