Jim Middleton, BS, RPh

Alpha- and beta-blocking drugs areused in the treatment of hypertension,and when 1 drug can combine the receptorblockade, it should be expected toenhance therapeutic outcomes. Carvedilol,a nonselective beta-blocker withselective alpha-1 blocking actions,appears to offer better results thanagents possessing only 1 variety ofreceptor-blocking activity. Carvedilol isavailable in 3.125-, 6.25-, 12.5-, and 25-mg tablet strengths from Apotex Inc,Caraco Pharmaceutical Laboratories, andMylan Laboratories.

The beneficial actions for beta-blockersin congestive heart failure are basedon theoretical action, suggesting adecrease of sympathetic outflow at thecardiac level or an alteration in reninrelease. The additional effect of alpha-1blockade with carvedilol results in generalperipheral arterial and venous dilation,with the effects on standing blood pressurebeing the most pronounced.

In general, beta-blockers are indicated for the treatment of hypertension,angina, and heart failure.Although carvedilol can be used asmonotherapy, it is usually employed inconjunction with other drug managementoptions (digoxin, thiazides, angiotensin-converting enzyme [ACE] inhibitors)to increase patient survival andreduce the frequency of hospitalization.

The nonselectivity of the beta-blockingeffect of carvedilol means that bronchialasthma is a specific contraindication toits use, with deaths reported followingeven a single dose. It also is not recommendedin the presence of hepaticimpairment or among the elderly.

The additive hypoglycemic effectsassociated with beta-blockers generallyrequire additional care among diabeticpatients.

Dosing for hypertension starts at 6.25mg twice daily, with an upper limit of 25mg twice daily. For congestive heart failure,the dose is 3.125 mg twice daily,gradually titrating to response or to amaximum of 6.25 mg twice daily. Oraldosing is little affected by food. In polytherapy,however, carvedilol should beadministered 2 hours prior to an ACEinhibitor to reduce orthostatic hypotensionand other symptoms of general vasodilation.In addition, cessation of therapyshould be done gradually to preventrebound pressor effects.

Among patients hospitalized with congestiveheart failure or left ventricular cardiacdysfunction, dischargeuse of drugs withbeta-blocking effects hasshown a significant reductionin mortality.

Extended-release verapamil(PM) is available in capsule form in100-, 200-, and 300-mg strengths fromMylan Laboratories. Indications for verapamilinclude the management ofPrinzmetal-variant, unstable, or chronicstable angina; hypertension; and to controlventricular rates at rest or with concurrentatrial fibrillation. It also is used toprevent the recurrence of paroxysmalsupraventricular tachycardia.

The effect of calcium channel blockerssuch as verapamil on cardiac conductioncan create serious adverse effects, andwhile the frequency is under 2% overall,they can range from asymptomatic firstdegreeatrioventricular block to seriousthird-degree block. Other adverse effectsfrom oral administration are seen in over6% of users, requiring a reduction indose. The severity of the side effects increaseswith concurrent use of betablockersor digoxin. In some cases, thenegative inotropic effects associatedwith verapamil can actually cause congestiveheart failure or pulmonary edema.The most common complaint frompatients regarding verapamil is constipation.

To treat hypertension with the extended-release capsule version of verapamil(PM), the usual adult dose is 200 mg atbedtime, with upward titration to a maximumof 400 mg at bedtime. Blood pressuremeasurements should be carefullymonitored. 

The strong protein binding affinity for verapamilimplies that other drugs (eg, aspirin, phenytoin, warfarin)could disrupt stabilized blood levels.Dosing with beta-blockers and digoxinrequires careful monitoring to preventtoxicity and excessive hypotension.

Verapamil requires a reduced doseamong the elderly and should be usedcautiously with hepatic or renal impairment.Verapamil also may both prolongthe effect of alcohol and increase bloodconcentrations by up to 17%. Althoughverapamil should be taken with food,grapefruit poses a potential interactionand should be avoided during this therapy.

Articles

PRODUCT profiles

Amlodipine Besylate andBenazepril Hydrochloride

The combination of a calcium channelblocker with an angiotensin-convertingenzyme (ACE) inhibitor representspart of a trend in pharmacologictherapy: expecting that 2 agents willcomplement each other and representan improvement in patient adherenceto treatment.

Calcium channel blockers, such asamlodipine, appear to work well regardlessof patients? ethnic origin,although African Americans respond tocalcium channel blockers better thanto ACE inhibitors or beta-blockingdrugs.

Benazepril is an example of a prodrug,converted in the liver to its activeform, known as benazeprilat. In general,ACE inhibitors such as benazeprilcause vasodilation and then indirectlyinhibit the actions of aldosterone. Theeffect of this inhibition allows for a shiftin balance between angiotensin II andbradykinin, resulting in the reduction invascular tone, an increase in sodiumexcretion, and ultimately diuresis.

ACE inhibitors also are demonstratingbeneficial effects involving their localizedactions on various endocrine systems,with the inflammatory processes,and on the development of atherosclerosiswithin arterial walls. Although anACE inhibitor may not reverse existingplaque, it may still stabilize it, preventingits rupture and the ensuing complications.

Together, amlodipine and benazeprilare indicated for the treatment of casesof hypertension where single-agenttherapy has been proven ineffective.The once-daily generic capsule form ofNovartis? Lotrel is marketed by TevaPharmaceutical Industries Ltd.

Careful monitoring of blood pressureis important during treatment with thiscombination of an ACE inhibitor andcalcium channel blocker, especially duringinitial titration or later upwardadjustments in dose. Dosage adjustmentsshould be made at monthlyintervals. In addition, ACE inhibitors cancause renal impairment and a hepaticsyndrome that initially appears ascholestatic jaundice. Patients takingthis combination should be periodicallymonitored for elevations in renal orhepatic enzymes.

Alone, amlodipine (Norvasc, PfizerInc) has already been available as a single-entity generic drug for the treatmentof hypertension, as has benazepril(Lotensin, Novartis). This particular combinationis available in amlodipinestrengths of 2.5, 5, and 10 mg withbenazepril in either 10- or 20-mgstrengths.

With the potential for catastrophicconsequences of a subarachnoid hemorrhage,quick therapeutic response isessential. The principal goal of drugtreatment is to prevent delayedischemic effects associated with cerebralvasospasms that can result fromthe hemorrhage. Nimodipine, a calciumchannel blocker with preferentialcentral nervoussystemactivity, is usedto reduce theincidence andseverity of the ischemic events. Nimodipineis available as 30-mg capsulesfrom Caraco Pharmaceutical Laboratoriesand Barr Pharmaceuticals Inc.

The administration of nimodipine followinga diagnosis of subarachnoidhemorrhage should begin within 96hours. Dosing has been determined byspeculation and observation ratherthan through controlled clinical trials,given the nature of the condition. Whentreatment with nimodipine is startedwithin 72 to 96 hours at doses of 20 mgto 90 mg (generally 60 mg) every 4hours for 16 to 21 days, however, thereis a reduction in frequency and severityof documented ischemic episodes. OneBritish study did indicate that oralnimodipine can reduce ?poor outcomes?(a poor outcome being theeuphemism for death or a vegetativestate) by 40% and cerebral infarction by34%. A Canadian study noted a nonstatisticallysignificant increase in mortalitydespite the reduction in delayedischemic neurologic outcomes. The useof nimodipine following acute ischemicstroke is being examined, with someevidence suggesting a reduction inmortality.

Nimodipine is also showing variablesuccess in treatment of vascular migraineand cluster headache. Treatmentin these conditions is usually 120 mgdaily in divided doses and takes up to 4months for benefits to emerge. Otherstudies are exploring the use of nimodipinein chronic focal epilepsy and ageassociatedmemory loss secondary todementia or Alzheimer?s disease.

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

A closer look at new FDA actions

Terbinafine hydrochloride (HCl) is thought to disrupt the integrity of fungal cell membranes by reducing membrane levels of ergosterol. Although the drug is indicated for onychomycosis, this ability to disrupt fungal membranes extends to other species, including causes of 

. Terbinafine is available generically as 250-mg tablets from Apotex Corp and Teva Pharmaceuticals Ltd.

Due to significant first-pass metabolism, bioavailability of terbinafine is only 40%. Although the drug is extensively metabolized, clearance is quickly reduced to 50% among patients with renal or hepatic impairment. In addition, hepatic inhibition of CYP 2D6 from terbinafine results in elevated levels of dextromethorphan, tricyclic antidepressants, selective serotonin reuptake inhibitors, and ?-blockers. Other drug interactions involve aripiprazole, carvedilol, codeine, desipramine, haloperidol, imipramine, methadone, mirtazapine, and thioridazine.

At its most extreme, hepatic disruption from treatment by this antifungal has resulted in death or the need for liver transplantation. Generally, these situations are linked to a previously undiagnosed, underlying hepatic pathology.

The success of terbinafine derives from its ability to distribute in high concentrations into the hair and nail matrix beds, and to remain in these tissues for several weeks to months after discontinuation of the drug. Adult dosing for onychomycosis is an oral daily dose of 250 mg, running 6 weeks for fingernails and 12 weeks for toenails. The use of unapproved "pulse" dosing with 500 mg daily for the first week of the month has variable success.

To prevent unnecessary interactions or hepatic damage, the nail specimen should be cultured to determine the nature of the suspected infection. As the prolonged treatment necessary for dermatologic infections would suggest, reactions such as Stevens Johnson syndrome or toxic epidermal necrolysis are possible, yet rare.

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

Cefdinir for Oral Suspension, 250 mg/5 mL

Lupin Pharmaceuticals Inc (Baltimore, Md)

May 8, 2007 - Lupin Pharmaceuticals Inc announced that the FDA approved its abbreviated new drug application for Cefdinir for Oral Suspension, 250 mg/5 mL. With this approval, Lupin adds to its already existing line of Cefdinir products. Lupin was the first company to receive final FDA approval for the capsule form and the lower-strength suspension on May 19, 2006, and May 31, 2006, respectively. Cefdinir is indicated for the treatment of patients with mild-to-moderate infections caused by susceptible bacteria.

Cipro XR Tablets (Bayer Pharmaceuticals Corp)

March 26, 2007 - Mylan Laboratories announced the launch of its first-to-market generic product Ciprofloxacin Extended-release (ER) Tablets. The FDA approved Mylan Pharmaceuticals' abbreviated new drug application for 500- and 1000-mg strengths of Ciprofloxacin ER tablets on March 22, 2007. Ciprofloxacin ER tablets are indicated for the treatment of uncomplicated urinary tract infections (acute cystitis) caused by 

; complicated urinary tract infections caused by 

; and acute uncomplicated pyelonephritis caused by 

Barr Laboratories Inc, a subsidiary of Barr Pharmaceuticals Inc (Woodcliff Lake, NJ)

Nimotop Capsules, 30 mg (Bayer Pharmaceuticals Corp)

May 2, 2007 - Barr Laboratories announced that it received final FDA approval to manufacture and market generic Nimodipine Capsules. Nimodipine, a calcium channel blocker, is indicated for the improvement of neurologic outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms, regardless of their postictus neurologic condition (ie, Hunt and Hess Grades I-V).

Capsules: 30 mg (not to be administered intravenously or by other parenteral routes)

Ranbaxy Pharmaceuticals Inc, a wholly owned subsidiary of Ranbaxy Laboratories Ltd (Guragon, India)

April 25, 2007 - Ranbaxy Pharmaceuticals announced that it received FDA approval to manufacture and market Pravastatin Sodium Tablets, 10, 20, 40, and 80 mg, with 180-day market exclusivity for the 80-mg strength. Pravastatin is indicated in the treatment or primary prevention of coronary events, such as in hypercholesterolemic patients without clinically evident coronary heart disease. It is also indicated to reduce the risk of myocardial infarction, reduce the risk of undergoing myocardial revascularization procedures, and reduce the risk of cardiovascular mortality with no increase in death from noncardiovascular causes. In addition, pravastatin is indicated for treatment in the secondary prevention of cardiovascular events.

generic times product news

Amlodipine besylate is a calciumchannel blocker used for the treatmentof hypertension and angina. Under currentclinical definitions of hypertension,calcium channel blockers are introducedat stage 2 (systolic pressure of160 mm Hg or greater or diastolic pressureof 100 mm Hg or greater) generallyin combination with a thiazide diuretic.To minimize the risk of orthostatichypotension, initiation of treatmentwith 2 antihypertensive agents shouldbe done cautiously among patientswith diabetes, the elderly, or patientswith autonomic dysfunction.

The release of Mylan Pharmaceuticals'and Greenstone Ltd's amlodipinebesylate affords clinicians theopportunity to develop creative genericbasedtherapies involving calcium channelblockers, angiotensin-convertingenzyme (ACE) inhibitors, and statins—treatments more often associated withbrand name combination products. Thegeneric equivalent to Norvasc (PfizerInc), amlodipine besylate is available asa single preparation for once-dailyadministration in 2.5-, 5-, and 10-mgstrengths. Mylan Pharmaceuticals is thefirst and only company to receive FDAapproval for its abbreviated new drugapplication for amlodipine besylatetablets. Simultaneous with Mylan'slaunch, Greenstone Ltd, Pfizer's genericsubsidiary, launched its own authorizedgeneric.

Calcium channel blockers such asamlodipine besylate appear to workwell regardless of the ethnicity of thepatient, although African Americansrespond to calcium channel blockersbetter than to ACE inhibitors or betablockingdrugs. This response to drugcategories levels out once a diuretic isadded to the therapy.

Recently, amlodipine besylate hasbeen given additional duties in combinationpreparations. This represents generalacceptance of integrated diseasestates. Although synergy is a conceptwelcomed in drug therapeutics,it is greeted withless enthusiasm whenhypertension and dyslipidemiaare involved. Theseoften-coexistent risk factorscreate damage to thecardiovascular system inexcess of expectations foreither condition alone.

The unwelcome synergybetween hypertension anddyslipidemia can be treatedwith favorable synergism. Combiningamlodipine besylate with atorvastatincreates the branded product known asCaduet. This single-tablet treatment iseffective in reducing both blood pressureand lipid levels.

The use of amlodipine besylate incombination products extends to enhancedactivity against hypertension.For this hybrid, the ACE inhibitorbenazepril is employed.

-receptor antihistamines are mainstays oftreating disorders of the gastrointestinal(GI) tract. Many H

-receptor antihistaminesare available generically at a substantialsavings to patients, and now varietiesof PPIs are following suit.

Rabeprazole is the latest generic PPI toreach the market. Rabeprazole, thegeneric equivalent of Aciphex (Eisai CoLtd), is available from Teva Pharmaceuticalsas 20-mg tablets.

Most cases of peptic ulcers may occurin the presence of normal acid secretionwhen nonsteroidal anti-inflammatorydrugs or 

are alsopresent, challenging factors that diminishor disrupt the mucosal defenses presentin the GI tract.

In general, PPIs inhibit gastric acidsecretion through binding at adenosinetriphosphataselevels, the final commonpathway for gastric acid secretion. Allexamples undergo extensivehepatic metabolism, and allare important factors in eradicating

and treatingpeptic ulcer disease, gastroesophagealreflux disease,Zollinger-Ellison syndrome,and upper GI bleeding.

Ulcers recur in 50% to 90%of patients within a yearwhen single-agent therapy isemployed; this recurrencecan be reduced to as low as10% after a year when amoxicillin orclarithromycin is added to aid in theeradication of 

The choice of a specific PPI is generallybased on cost, formulation, and overallsafety profile. Since PPIs require activelysecreting proton pumps to be fully effective,dosing should occur 30 minutesbefore a meal, generally breakfast. If asecond dose is required, it should betaken ~10 to 12 hours after this morningdose. Rabeprazole appears unique in itslikelihood to have fewer drug interactionswith caffeine, diazepam, phenytoin,and warfarin than other PPIs. This isthought to be due to its partiallyreversible binding to the proton pumpprocess. 

Mr. Middleton is an instructor of pharmacology

generic times: product profiles

The hazards of misinterpretingsound-alike and look-alike drugs arebecoming an increasing concernamong clinicians. In 2005, the FDA distributeda letter warning about medicationerrors involving the beta-blockermetoprolol, whose brand name Toprolwas being confused with Topamax andTegretol on some hospital orders andoutpatient prescriptions. The lettersuggested using both brand and genericnames when ordering this trio ofmedications.

Metoprolol, indicated for the treatmentof hypertension, angina, andheart failure, has recently becomeavailable as a generic in its extended-releaseversion. Current genericsources for metoprolol extended-releasetablets are limited to the 25-mgstrength, available from Par PharmaceuticalCompanies Inc and Sandoz.

Unlike some beta-blocking drugs,metoprolol demonstrates selectiveinhibition of beta

adrenergic receptorsat low doses. Only at higher doses doesbeta

The exact mechanism of effect ofbeta-blockers has not been fully determined.Some studies suggest a decreasein sympathetic outflow from thecentral nervous system; others note asuppression of renin release. At thecardiac level, the reduction of heartrate and blocking of catecholaminebasedactivity is thought to explain itseffectiveness for angina.

Metoprolol is available in extended-releaseformulations to enhance convenienceand patient adherence. Forhypertension, the extended-releasedose begins with a daily dose of 25 to100 mg, with a 400-mg daily maximum.For angina, polymorphic ventriculartachycardia, and prophylaxis of heartattack, the initial daily dose is 100 mg,with the same 400-mg daily limit.Elderly patients should initiate treatmentwith 25 to 50 mg daily as a singledose, with increases at 1-to 2-weekintervals.

Unlike many extended-release formulations,scored metoprolol can bedivided into half tablets with a constantdrug delivery over 24 hours. Nevertheless,the whole or half tabletsshould not be further chewed orcrushed.

Metoprolol should be avoided in thepresence of sick sinus syndrome orsinus-mediated bradycardia, in severeperipheral artery disease, and duringthe final 2 trimesters of pregnancy.Beta blockade presents a challengewith concurrent bronchial diseasestates, such as asthma. Metoprolol hasgreater beta

specificity, however, andwith careful monitoring can be employedwith coexisting bronchospasticdisorders.

Patients with diabetes may experienceadditive hypoglycemic effectswith beta-blockers; metoprolol appearsto be well-tolerated among thispatient population. The use of calciumchannel blockers such as verapamilor diltiazem, however, may still potentiatebradycardia or induce heartblock.

Other drug interactions includeenhanced vertigo with alpha-blockingdrugs such as prazosin or terazosin;bradycardia and hypotension may beamplified with concurrent use of selectiveserotonin reuptake inhibitors andphenothiazines, or drugs that inhibitthe CYP2D6 metabolic enzyme.

Several naturopathic treatmentsmay also affect metoprolol activity bytheir action on the body's vasopressorresponse. Gotu kola, licorice, andephedra may interfere with the hypotensiveeffects of metoprolol, whilehawthorn and quinine may enhancethe blood pressure-lowering effects inunpredictable ways.

When beta-blocker therapy is to bewithdrawn, it should be done slowly toavoid rebound tachycardia, hypertension,or cardiac ischemia.

Metoprolol extended-release tabletsoffer a more effective means of maintaininguniform plasma levels and therapeuticresponse than their immediate-release relatives. At a single dailydose, they offer a convenient opportunityto promote adherence, especiallyamong patients receiving therapy involvingmultiple drugs.

Sjögren's syndrome is a disease thatcrosses all populations, locations, andage groups. Women are more prone tothe condition, with the average age forpeak symptoms occurring betweenages 40 and 60 years. The salivaryglands are infiltrated by lymphocytes,decreasing parotid flow of saliva. Themain symptom of xerostomia may becombined with dry eyes and can alsobe a consequence of connective tissuediseases such as rheumatoid arthritisor lupus.

Treatment of Sjögren's syndrome isdirected at the xerostomia, with cholinergicstimulation being considered amost effective therapy. Pilocarpine is aclassic cholinergic agent useful for thiscondition, now available generically in2 strengths. The 5-mg tablets are availablefrom Sandoz, Actavis, RoxaneLaboratories, and Lannett Co Inc. The7.5-mg tablets are manufactured byActavis.

A classic stimulator of the salivationlacrimation-urination-defecation response,pilocarpine is a cholinergic drug that actsupon muscarinic receptors.

In addition to Sjögren's syndrome,pilocarpine tablets are useful in treatingxerostomia resulting from cancerradiation therapy to the neck and head.

Dosing for Sjögren's syndrome isgenerally 5 mg, taken up to 4 timesdaily. For xerostomia secondary to cancertherapy, the dose generally beginsat 5 mg 3 times daily, with titration upto 10 mg 3 times daily. Most patientsrequire a total daily dose of 20 mg.Single doses above 10 mg and totaldaily doses above 30 mg are not recommended.The dosing should be continuedfor a minimum of 90 days toobtain maximum effectiveness.

Whereas taking pilocarpine tabletsafter eating helps reduce some of itsuntoward gastrointestinal effects, highfatmeals will diminish its effective rateof absorption.

Pilocarpine tablets are contraindicatedfor patients with poorly controlledasthma, glaucoma, or severe hepaticimpairment. Caution is also necessarywith the presence of gallstones, nephrolithiasis,or biliary tract disease. Thecholinergic nature of pilocarpine bringsgastrointestinal effects of diarrhea,nausea, vomiting,and excessive salivation.Sweating is also likely.

The use of oral pilocarpine is not recommended forpatients under the age of 6 years.Atropine is the favored antidote inthe case of overdose, with epinephrine employedto treat possible respiratory or cardiovascularconsequences of oral pilocarpine use.

Although oral pilocarpine maybe effective in reducingxerostomia caused by antidepressantsand other drugs, theFDA has not grantedapproval forthat indication dueto lack of specificclinical studies.

Sjögren's syndrome, initially countedamong the registry of rare disorders, isnow considered the second most commonautoimmune rheumatic disease,with an incidence in nearly 3 millionpeople in the United States alone. Italso represents a major health problemamong women that is regarded asunderdiagnosed or treated. Fortunately,symptomatic treatment is availablewith the generic versions of pilocarpinetablets. 