A closer look at new FDA actions

Pharmacy Times, Volume 0, 0

Clozapine

Clinical Update

Drug treatment for schizophrenia isconsidered essential in managing acute,violent psychotic episodes and reducingtheir recurrence, while providing longtermstabilization of the condition. Firstgeneration,or typical, antipsychoticdrugs for schizophrenia are limited bytheir predisposition to cause extrapyramidalsymptoms (EPSs).

The emergence of second-generation,or atypical, antipsychotic drugs, beginningwith clozapine, has provided relativelyrapid-acting treatment for schizophreniawith far less risk of inducingeffects associated with previous agents.

Pharmacology

Although the specific correlationremains unclear, current wisdom impliesthat interfering with dopamine at D2receptors, especially at times whenthese fluctuating sites are in a "high-affinity"mode, yields the best results.Interference with dopamine at thesesites also contributes to the side effectsassociated with earlier therapies.

The first-generation treatments forschizophrenia (ie, haloperidol, chlorpromazine)are tightly bound to the D2receptors, regardless of the amount ofunbound dopamine present. This bindingaffects dopamine transmission at thebasal ganglia, causing motor function disruption.This action gives rise to EPSs,including muscle stiffness and peripheraltremors that can evolve into tardivedyskinesia and uncontrolled, spasmodic,peripheral movements.

In general, a 65% binding capacity atthe D2 receptors treats schizophrenia,whereas an 80% binding results in thedevelopment of EPSs. Older agents notonly adhere more tightly to the D2 receptors,but they maintain their hold forlonger durations—at least 1 to 2 days followingan oral dose. The eventual accumulationof the drug almost ensures thedevelopment of EPSs, especially asdoses are titrated upward.

Atypical antipsychotic agents such asclozapine also bind to the D2 receptors.Their binding, however, is described as"loose"—meaning that they easilydetach from the receptor and allowperiodic, if reduced, transmission ofdopamine to take place. In addition,whereas the 65% binding capacity is stillnecessary for effective treatment, studiesindicate that this level is not requiredat all times. The net effect of this looserbinding is to provide effective treatmentwhile minimizing the EPSs.

Administration and Dosing

Clozapine is given orally. Food has noeffect on absorption or clinical effect.Dosing for schizophrenia begins with12.5 mg once or twice daily. If the drugis tolerated, the dosing is increased in25-to 50-mg increments daily over a 2-week period, until a daily dose between300 and 450 mg is reached. Gradualincreases in dosing are necessary toprevent the possibility of hypotension,generalized seizures or myoclonic jerking,and sedation.

Subsequent increases in dosing shouldnot be more often than once or twiceweekly. Most patients respond to dailyranges of 300 to 600 mg; some mayrequire daily dosing of 600 to 900 mg.

Because clozapine readily detachesfrom the D2 receptors, proper compliancewith therapy is essential. If a patient missesjust 1 or 2 daily doses, he or she canexperience a rapid decompensation, orreemergence, of psychiatric symptoms.Discontinuation should be over a 1-to 2-week period, with careful observation forrecurrence of psychotic symptoms.

Stress can poseanother challenge.With increased dopaminepresent, clozapinewill be morerapidly displaced,causing a drop fromthe minimal 65%binding needed foreffectiveness. Duringsuch stressful episodes,an agent withgreater D2 receptor affinity can be addedonly for the duration of the episodes andthen removed. Increasing the dose ofclozapine during these times can be effectivebut will increase the likelihood ofunwanted side effects.

Clozapine has been used successfullyin childhood-onset schizophrenia in a limitednumber of treatment-resistant situations,with a maximum daily dose of 525mg. Its safety, however, has not beenestablished in children or adolescentsunder the age of 16.

Side Effects and Drug Interactions

Contraindications to the use of clozapineinclude concurrent myeloproliferativedisorders, preexisting bone marrowdepression, or a history of clozapineinducedagranulocytosis.

Since its initial clinical trials, clozapinehas been associated with potentially lifethreateningagranulocytosis. As a result,this drug is available only through distributionchannels that ensure that periodicblood tests are given prior to the dispensingof each supply of medication,and that patients are registered in a single,national master database.

The supply of clozapine generally islimited to 1-week quantities. When apatient has a record of normal weeklywhite blood counts (WBCs) and absoluteneutrophil counts (ANCs) for a 6-monthperiod, however, the frequency of testingand the amount of drug dispensed maybe changed to 2-week intervals. If, after 1year, all remains normal, this interval maybe further extended to 4 weeks.

In cases of moderate leukopenia (WBCbetween 2000 and 3500 cells/mm3),clozapine use is suspended while daily,then twice weekly, WBCs and ANCs areperformed until blood counts reach normallevels. Clozapine dosing may thenbe reinstated, with weekly blood workfor a year.

In cases of severe leukopenia (WBCunder 2000 cells/mm3) or agranulocytosis(ANC under 500 cells/mm3), clozapineis discontinued. The patient must bemonitored daily, then twice weekly, andthen weekly for at least 4 weeks afterlaboratory values return to normal.

Clozapine use during pregnancy,although prolactin-sparing, is consideredunwise because of the (theoretical) possibilityof agranulocytosis and seizureinduction in the developing fetus.

Clinical Outlook

Whereas newer, atypical antipsychoticdrugs provide broad-spectrum treatmentfor schizophrenia with fewer side effectsthan earlier agents, the side effects theydo produce may be equally severe andrequire careful monitoring.

Clozapine is available as 25-and 100-mg tablets from Caraco PharmaceuticalLaboratories, IVAX Laboratories Inc,Mylan Pharmaceuticals Inc, and UDLLaboratories Inc.

Finasteride Tablets

Benign prostatic hypertrophy (BPH)remains one of the most common medicalconditions among men past the ageof 70. BPH represents a collection of urinarysymptoms including the sensationof an incompletely empty bladder,impairment of the urine stream, nocturia,and daytime frequency.

Research has identified a limited populationof men with genetically low levelsof testosterone-converting enzymeswho have smaller prostate glandsthroughout life and never develop BPH.Regulating that enzyme in the rest of thepopulation has become a method fortreating the symptoms of BPH.

By obstructing the activity of thesteroid enzyme type II 5-αreductase, finasteride inhibitsthe conversion of testosteroneto dihydrotestosterone(DHT). DHT, a morepotent androgen, is associatedwith hyperplasia of theprostate gland, with the additionalpressure on the bladderand the urethra contributing to thesymptoms of BPH. During treatment,finasteride reduces serum concentrationsof DHT by ~70%, while average circulatingtestosterone levels increasefrom 10% to 20% (yet remain withinphysiologic parameters).

Finasteride is indicated for theimprovement of symptoms associatedwith BPH, to reduce the risk for acute urinaryretention, and to diminish thepotential need for prostatectomy ortransurethral resection of the prostate.

Dosing

The dose for finasteride is 5 mg daily,with DHT suppression noted within 8hours after the first dose. The productmay be taken as a single-drug treatmentfor BPH, but it can work synergisticallywith the α-blocking agent doxazosin(urethral tone being modulated by aadrenergicreceptors).

Adverse Effects

Whereas finasteride can result in adecrease in serum PSA of ~50%, thiseffect will occur even in the presence ofprostate cancer. During treatment withfinasteride, therefore, it is important tounderstand that the PSA values can beartificially low and that subsequent elevationsshould be inflated by a factor of2, because this increase may be due tothe presence of a less-benign prostaticcondition. It also should be noted thatthe use of finasteride has no significanteffect on the overall incidence ofprostate cancer, nor does its use provideany clinical benefit in the treatment ofprostate cancer.

During the first year of treatment withfinasteride, sexual dysfunction (impotenceand decrease in libido) appears tooccur more often than in placebo groupsused in comparative studies. It is interestingto note, however, that after thefirst year the active and the placebogroups describe the same frequencyof dysfunction.

Pregnant or potentially pregnantwomen should not handle broken orcrushed finasteride tablets because ofthe potential for transdermal drugabsorption and the probability of risk to adeveloping male fetus.

Outlook

The goal in treating BPH is to reduceurinary symptoms, prevent the progressionof the condition, and improve thequality of life despite recommendedlifestyle restrictions—cutting back onfluid intake after 7 pm and limiting theoverall use of salt, spices, caffeine,chocolate, and alcohol.

Finasteride is available in 5-mg tabletsfrom Teva Pharmaceuticals.

Meloxicam Tablets

The well-publicized shortcomings ofcyclooxygenase-2 (COX-2) inhibitorshave prompted clinicians to seek alternativesfor providing pain relief to patientssuffering from osteoarthritis or other inflammatoryconditions. Meloxicam actuallyis classified as a COX-2 inhibitor inother countries. In the United States,however, it remains in the category ofnonsteroidal anti-inflammatory drugs(NSAIDs), with its COX-2 inhibition beingconsidered more "preferential" than"selective," when compared with conventionalagents such as ibuprofen.

Meloxicam has analgesic, antipyretic,and anti-inflammatory properties. It providesonly symptomatic relief forosteoarthritis and, like other NSAIDs,does not reverse the destruction of jointtissues as the disease progresses.

Dosing

Meloxicam has a one-time daily doseof 7.5 to 15 mg, taken with or withoutfood or milk. Doses above 15 mg have notbeen shown to have added benefit forpain relief. Children with juvenile rheumatoidarthritis are dosed by weight at 0.125mg/kg, to a daily maximum of 7.5 mg.

Adverse Effects

The addition of a blackboxwarning from theFDA may have dampenedsome of the enthusiasmfor meloxicam as a COX-2alternative. The warningstates that "NSAIDs maycause an increased risk of serious cardiovascularthrombotic events, myocardialinfarction, and stroke, which can be fatal.This risk may increase with duration ofuse. Patients with cardiovascular disease(CVD) or risk factors for CVD may be atgreater risk." The risk for heart attacksfrom meloxicam, in fact, has been reportedas higher than that of the discontinuedCOX-2 inhibitor rofecoxib (Vioxx).

Meloxicam also can result in hypertensionor a worsening of hypertensivesymptoms. It should be used with cautionin patients with preexisting gastric ulcersor a history of gastric bleeding. It maycontribute to renal dysfunction with prolongeduse. The potential for increasedgastrointestinal (GI) bleeding requiresadditional monitoring if the patient also isbeing treated with warfarin.

Patients should be educated on andadvised to report signs of CV reactions(angina, dyspnea), GI bleeding, or hepatotoxicity(fatigue, jaundice, lethargy).

Because of these potential adverseeffects, the lowest possible effectivedose and the shortest possible durationof therapy to achieve treatment goalsshould be employed in using meloxicam.

Outlook

The resurgence of interest in meloxicamas a COX-2 "selective" inhibitor alternative,along with the substantial cost savingsfrom its generic form, may increasethe popularity of this particular NSAID.

Meloxicam is available as 7.5-and 15-mg tablets from companies includingTeva Pharmaceuticals, Mylan Pharmaceuticals,and Caraco Pharmaceuticals.

Metronidazole Vaginal Gel0.75%

Clinical Update

Bacterial vaginosis is a noninflammatorycondition in which the normal vaginalflora (ie, Lactobacillus) isreplaced by a synergisticmixture of Gardnerella vaginalis,various anaerobic bacteria,and Mycoplasmahominis. Up to 40% ofwomen affected are asymptomatic.Thus the absence orpresence of a vaginal discharge is anunreliable indicator of infection.Symptomatic bacterial vaginosis (amineodordischarge) should be treated,regardless of pregnancy status.

Metronidazole is a bactericidal treatmentcommonly employed to treat bacterialvaginosis. Five-day intravaginaltherapy results in cure rates comparablewith those of 7-day oral regimens.

Dosing

Intravaginal use of metronidazoleemploys a 0.75% concentration of thedrug, in gel form. Commercial preparationsinclude a vaginal applicator, whichdispenses approximately 37.5 mg ofmetronidazole with each 5 g of gel. Foronce-daily dosing, intravaginal administrationshould be done at bedtime for 5consecutive days'. The drug also may beadministered twice daily (morning andevening), also over 5 consecutive days.

Precautions and Adverse Effects

The most common adverse effectsinclude vaginal discharge and localizedirritation. Undiagnosed vaginal Candidainfections may become prominentlysymptomatic during treatment with theproduct. This effect occurs in 6% to 10%of patients. Abdominal or pelvic discomfortalso is possible, and darkened urineis a rare occurrence. Dizziness andheadache have been reported 2% to 5%of the time. Leukopenia has been reportedin less than 2% of patients.

Patients suffering from severe hepaticdisease will have a slower rate ofmetronidazole metabolism, causing drugand metabolite accumulation. Although itis generally well-tolerated otherwise, themanufacturers recommend cautious useof metronidazole vaginal gel in the presenceof hepatic impairment.

If the vaginal infection is caused byTrichomonas vaginalis, intravaginal treatmentis less than half as effective as oraltreatment. The reason is that vaginalapplications produce subtherapeuticserum concentrations, and systemiceffectiveness is necessary to controlTrichomoniasis. Whereas combinationtherapy with oral metronidazole often isemployed in refractory cases, evidence islacking to demonstrate that concurrentoral and vaginal administration is moreeffective than oral therapy alone.

Women should be instructed not toengage in vaginal intercourse or to usedouches during the entire course of therapy,because these activities reduce theeffectiveness of the metronidazole gel.

Although systemic absorption is slightwith the use of the vaginal preparation,the concurrent use of oral anticoagulantsmay still be affected. Similarly, whereas adisulfiram-like interaction would seemunlikely with the vaginal preparation ofmetronidazole, there has been at leastone case of such a reaction followingingestion of alcohol during treatment.

Outlook

Bacterial vaginosis is the most commonform of infectious vaginitis, althoughit may often be asymptomatic. Amongpregnant women, it has a prevalence rateof 12% to 50%, and it has been identifiedas a potential risk factor for prematuredelivery. Thus treatment of symptomaticcases is essential.

The bactericidal agent metronidazole iseffective as an oral and intravaginal treatmentfor bacterial vaginosis. The intravaginalroute offers a more rapid recoverywith a lower likelihood of systemicadverse effects.

Metronidazole is available as an intravaginalgel in concentrations of 0.75%from Upsher-Smith Laboratories (Vandazole).

Mr. Middleton is an instructor of pharmacologyat Kellogg Community College in Battle Creek, Mich.