Klonopin (Clonazepam) - Description and Clinical Pharmacology

DESCRIPTION

Klonopin, a benzodiazepine, is available as scoredtablets with a K-shaped perforation containing 0.5 mg of clonazepamand unscored tablets with a K-shaped perforation containing 1 mg or2 mg of clonazepam. Each tablet also contains lactose, magnesium stearate,microcrystalline cellulose and corn starch, with the following colorants:0.5 mg—FD&C Yellow No. 6 Lake; 1 mg—FD&C BlueNo. 1 Lake and FD&C Blue No. 2 Lake.

Klonopinis also available as an orally disintegrating tablet containing 0.125mg, 0.25 mg, 0.5 mg, 1 mg or 2 mg clonazepam. Each orally disintegratingtablet also contains gelatin, mannitol, methylparaben sodium, propylparabensodium and xanthan gum.

Chemically, clonazepamis 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2 H -1,4-benzodiazepin-2-one. It is a light yellow crystallinepowder. It has a molecular weight of 315.72 and the following structuralformula:

CLINICAL PHARMACOLOGY

Pharmacodynamics

The precise mechanism by which clonazepam exertsits antiseizure and antipanic effects is unknown, although it is believedto be related to its ability to enhance the activity of gamma aminobutyricacid (GABA), the major inhibitory neurotransmitter in the centralnervous system. Convulsions produced in rodents by pentylenetetrazolor, to a lesser extent, electrical stimulation are antagonized, asare convulsions produced by photic stimulation in susceptible baboons.A taming effect in aggressive primates, muscle weakness and hypnosisare also produced. In humans, clonazepam is capable of suppressingthe spike and wave discharge in absence seizures (petit mal) and decreasingthe frequency, amplitude, duration and spread of discharge in minormotor seizures.

Pharmacokinetics

Clonazepam is rapidly and completely absorbed afteroral administration. The absolute bioavailability of clonazepam isabout 90%. Maximum plasma concentrations of clonazepam are reachedwithin 1 to 4 hours after oral administration. Clonazepam is approximately85% bound to plasma proteins. Clonazepam is highly metabolized, withless than 2% unchanged clonazepam being excreted in the urine. Biotransformationoccurs mainly by reduction of the 7-nitro group to the 4-amino derivative.This derivative can be acetylated, hydroxylated and glucuronidated.Cytochrome P-450 including CYP3A, may play an important role in clonazepamreduction and oxidation. The elimination half-life of clonazepam istypically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independentthroughout the dosing range. There is no evidence that clonazepaminduces its own metabolism or that of other drugs in humans.

Pharmacokinetics in Demographic Subpopulationsand in Disease States

Controlled studies examining the influence of genderand age on clonazepam pharmacokinetics have not been conducted, norhave the effects of renal or liver disease on clonazepam pharmacokineticsbeen studied. Because clonazepam undergoes hepatic metabolism, itis possible that liver disease will impair clonazepam elimination.Thus, caution should be exercised when administering clonazepam tothese patients.

Clinical Trials

Panic Disorder

The effectiveness of Klonopin in the treatment ofpanic disorder was demonstrated in two double-blind, placebo-controlledstudies of adult outpatients who had a primary diagnosis of panicdisorder (DSM-IIIR) with or without agoraphobia. In these studies,Klonopin was shown to be significantly more effective than placeboin treating panic disorder on change from baseline in panic attackfrequency, the Clinician's Global Impression Severity of Illness Scoreand the Clinician's Global Impression Improvement Score.

Study 1 was a 9-week, fixed-dose study involving Klonopindoses of 0.5, 1, 2, 3 or 4 mg/day or placebo. This study was conductedin four phases: a 1-week placebo lead-in, a 3-week upward titration,a 6-week fixed dose and a 7-week discontinuance phase. A significantdifference from placebo was observed consistently only for the 1 mg/daygroup. The difference between the 1 mg dose group and placebo in reductionfrom baseline in the number of full panic attacks was approximately1 panic attack per week. At endpoint, 74% of patients receiving clonazepam1 mg/day were free of full panic attacks, compared to 56% of placebo-treatedpatients.

Study 2 was a 6-week, flexible-dosestudy involving Klonopin in a dose range of 0.5 to 4 mg/day or placebo.This study was conducted in three phases: a 1-week placebo lead-in,a 6-week optimal-dose and a 6-week discontinuance phase. The meanclonazepam dose during the optimal dosing period was 2.3 mg/day. Thedifference between Klonopin and placebo in reduction from baselinein the number of full panic attacks was approximately 1 panic attackper week. At endpoint, 62% of patients receiving clonazepam were freeof full panic attacks, compared to 37% of placebo-treated patients.

Subgroup analyses did not indicate that there were anydifferences in treatment outcomes as a function of race or gender.