NEW DRUG APPROVALS OF 2000 - Part 2

March 5, 2001

DRUG APPROVALS FOSR 2000 - Part 2

 

CONTINUING EDUCATION

Published through an educational grant from WYETH-AYERST LABORATORIES
TRENDS IN PHARMACY AND PHARMACEUTICAL CARE

This is part of an ongoing CE program of The University of Mississippi School of Pharmacy and DRUG TOPICS

The University of Mississippi School of Pharmacy is approved by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education. Accredited in every state requiring CE. ® ACPE # 032-999-01-004-H01

This lesson is no longer valid for CE credit after 12/31/03.

CREDIT:

This lesson provides two hours of CE credit and requires a passing grade of 70%.

OBJECTIVES:

Upon completion of this article, the pharmacist should be able to describe for the new molecular entities approved in 2000:

  • Therapeutic use

  • Mechanism of action

  • Pharmacological properties

  • Potential drug interactions

  • Recommended route of administration and dosing schedule

  • Dosage forms and storage properties

  • Counseling information for patients

GOAL:

To provide information about all the new molecular entities approved in 2000

NEW DRUG APPROVALS OF 2000—Part 2

Jump to:Choose article section... ARTICAINE/EPINEPHRINE BIVALIRUDIN (BY-va-luh-RU-din) DOCOSANOL (doh-KAH-suh-nol) NATEGLINIDE (nuh-TEH-gluh-nide) OXCARBAZEPINE (ox-car-BAY-zuh-peen) PANTOPRAZOLE SODIUM (pan-TOH-pruh-zole) POLYTETRAFLUOROETHYLENE & PERFLUOROALKYLPOLYETHER RIVASTIGMINE TARTRATE (rih-vuh-STIG-meen) TINZAPARIN SODIUM (TIN-zuh-PAIR-in) TRIPTORELIN (TRIP-to-REH-lin) UNOPROSTONE ISOPROPYL (OO-no-PROS-tone) VERTEPORFIN (VIR-tih-POR-fin) ZONISAMIDE (zon-IH-suh-mide)

By W. Marvin Davis, Ph.D.,

Professor, Department of Pharmacology Research Institute of Pharmaceutical Sciences University of Mississippi School of Pharmacy and

Michael C. Vinson,

Pharm.D., M.S., Associate Professor, Department of Pharmacy Practice Bureau of Pharmaceutical Services University of Mississippi School of Pharmacy
Special thanks to Priscilla McCoy of McCoy Associates Strategic Naming and Branding, for assistance in developing the pronunciation guides.

ARTICAINE/EPINEPHRINE

Septocaine (SEHP-to-caine)Deproco/SeptodontFDA rating: 1-S

Articaine is an amide-type local anesthetic that is combined with an adrenergic vasoconstrictor, epinephrine. It has been marketed overseas for decades, where it is applied for intravenous regional anesthesia, epidural anesthesia, dental infiltration, or nerve block and axillary brachial plexus block.

Indications: Articaine is indicated for local, infiltrative, or conductive anesthesia in both simple and complex dental and periodontal procedures.

Pharmacology: Like other local anesthetics, articaine blocks the generation and conduction of nerve impulses through one or more of several mechanisms—by increasing thresholds of electrical excitation in nerves, by slowing the rate of rise of the action potential, and by lowering the propagation of nerve impulses. The onset of anesthesia with articaine occurs within one to six minutes after injection, and the duration of complete anesthesia is about one hour to 2.5 hours.

Systemic absorption of local anesthetics can produce effects on the central nervous and cardiovascular systems. At toxic blood levels, local anesthetics depress cardiac conduction and excitability, leading to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. Moreover, myocardial contractility may be depressed and peripheral vasodilation may occur, leading to decreased cardiac output and hypotension.

Because epinephrine is added as a vasoconstrictor to slow the absorption of articaine into the general circulation, a need for dosage reduction is likely in pediatric patients, elderly persons, and patients with cardiac and/or hepatic disease.

Contraindications: Patients having a known history of hypersensitivity reactions to local anesthetics of the amide type or patients with a known hypersensitivity to sodium metabisulfite (present as stabilizing agent) should not receive this medication.

Precautions: Accidental intravascular injection may be associated with convulsions, followed by central nervous system or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Dental practitioners and/or clinicians who employ local anesthetic agents should be well versed in diagnosis and management of emergencies that may arise from their use. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use.

Patients with peripheral vascular disease or hypertensive vascular disease may exhibit exaggerated vasoconstrictor response to the epinephrine component of this product. Ischemic injury or necrosis may result.

Articaine hydrochloride solution contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.

It is not known whether articaine is excreted in human milk, as are many other drugs. Thus, caution should be exercised when it is to be administered to a nursing mother. Because there are no adequate, well-controlled studies in pregnant women, articaine should be used during pregnancy only if the potential benefit justifies a potential risk to the fetus.

Because studies have not been performed in patients with hepatic dysfunction, articaine should be used with caution in persons with a severe hepatic disease. It also should be used with caution in case of cardiovascular deficit; such patients may be poorly able to compensate for functional changes associated with slow atrioventricular conduction produced by the local anesthetics.

Drug interactions: Administration of local anesthetic solutions that contain epinephrine to patients who are taking a monoamine oxidase inhibitor or a tricyclic antidepressant may precipitate severe, prolonged hypertension. Thus, concurrent use of such agents should generally be avoided. If concurrent therapy is necessary, careful patient monitoring is essential. In case of such reactions, phenothiazines or butyrophenones may be used to reduce or reverse the pressor effect of epinephrine. Articaine should be used with caution in patients during or following the administration of potent general anesthetic agents, as risk of cardiac arrhythmias increases under such conditions.

Adverse effects: These are similar to ones known for other amide-type local anesthetics, which may include: dizziness, hypotension, anxiety, agitation, confusion, drowsiness, nausea, vomiting, or hypersensitivity. In more extreme reactions, convulsions, respiratory depression and/or respiratory arrest, with cardiovascular stimulation or depression, have been reported. These reactions may have arisen from intra-arterial injection of the local anesthetic. Acute emergencies from local anesthetics are generally related to high plasma levels as a result of overdosage, accidental intravascular or subarachnoid injection of the solution, or abnormally slow metabolic degradation of the compound. Persons receiving dental blocks should be observed constantly. Resuscitative equipment and personnel for treating adverse reactions should be immediately available.

Dosage and availability: For normal, healthy adults, the maximum dose of articaine HCl administered by submucosal infiltration and/or nerve block should not exceed 7 mg/kg (0.175 ml/kg) or 3.2 mg/lb (0.0795 ml/lb) of body weight. The use of articaine in children under four years of age is not recommended. The quantity to be injected should be determined by the age and weight of the child and the magnitude of the operation. Articaine is supplied as a sterile aqueous injection, a solution that contains articaine HCl 4% (40 mg/ml) with 1:100,000 epinephrine bitartrate. It is made available in 1.7-ml glass cartridges.

Patient monitoring: Careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness should be conducted with every local anesthetic injection. Anxiety and restlessness, dizziness, tinnitus, blurred vision, tremors, depression, or drowsiness may be early warning signs of central nervous system toxicity.

Patient counseling: The patient should be informed in advance of the possibility of temporary loss of sensation and muscle function following infiltration and nerve block injections. Inquiry should be made to determine if a woman may be pregnant or is breast-feeding.

BIVALIRUDIN (BY-va-luh-RU-din)

Angiomax (AN-gee-oh-max)The Medicines Co.FDA rating: 1-S

Bivalirudin is a synthetic 20-amino acid peptide comprising an analog of the 65-amino acid leech-derived anticoagulant, recombinant hirudin. It was designed and developed as a therapeutic alternative to heparin.

 

Table 1
Biological products approved in 2000

Generic nameTrade nameManufacturerIndication

Antihemophilic Factor (Recombinant)ReFactoGenetics Institute Inc.Control and prevention of hemorrhagic episodes and for short-term routine and surgical prophylaxis in patients with hemophilia A
BCG, Live bladderPACISBioChem Pharma Inc.Treatment of carcinoma-in-situ (CIS) in the absence of associated invasive cancer of the
Botulinum Toxin Type B painMYOBLOCElan PharmaceuticalsTreatment of cervical dystonia to reduce the severity of abnormal head position and neck
Crotalidae Polyvalent Immune Fab (Ovine)CroFabProtherics Inc.Treatment of minimal and moderate North American Crotalidae envenomation
Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein)PrevnarLederle LaboratoriesImmunization of infants two, four, six, and 12-15 months of age to prevent invasive pneumococcal disease
TenecteplaseTNKaseGenentech Inc.Reduction of mortality associated with acute myocardial infarction (AMI)

 

Indications: Bivalirudin is approved as an anticoagulant for use as an alternative to heparin in patients with unstable angina who undergo the artery-clearing procedure known as percutaneous transluminal coronary angioplasty (PTCA). The drug was developed to prevent clotting that may provoke coronary occlusion, as coronary thrombosis is a major risk during and after the PTCA procedure. Bivalirudin is approved for use only with aspirin, as it has been studied only in patients who were receiving aspirin therapy.

Pharmacology: Bivalirudin exerts a specific antithrombin action because of its being an analog of the leech anticoagulant hirudin. It was developed based on knowledge of the active residues of hirudin that are required for its binding to thrombin, by which it exerts a direct action as a thrombin inhibitor. Unlike heparin, bivalirudin is not dependent upon antithrombin III as a cofactor, which provides a potential advantage over conventional heparin therapy. Other advantages are that bivalirudin can inactivate either soluble or clot-bound thrombin, there are no endogenous natural inhibitors (as exist for heparin), and there is continuing activity after clearance from plasma via thrombin-bound molecules. Neither hirudin nor bivalirudin has produced thrombocytopenia, as has heparin.

Contraindications: For bivalirudin, these may include cerebral aneurysm, intracranial hemorrhage, or any other active major bleeding, as well as a known hypersensitivity to bivalirudin or its formulation components.

Precautions: Conditions that dictate special caution in the use of bivalirudin include: asthma or allergies; hematologic disorders (blood dyscrasias or thrombocytopenia); recent surgery or trauma; gastrointestinal ulceration and hypertension, because of a higher risk of hemorrhage; and hepatic or renal disease, which may require dose adjustment.

Drug interactions: Bivalirudin safety and effectiveness have not been established when used in conjunction with platelet inhibitors other than aspirin, such as glycoprotein (GP) IIb/IIIa inhibitors. However, drug-drug interaction studies have been conducted with the ADP antagonist ticlopidine, with the (GP)IIb/IIIa inhibitor abciximab, and with low molecular weight heparins. While data are too limited to allow conclusions regarding efficacy and safety in combination with these agents, the data showed no evidence of pharmacodynamic interactions.

Adverse effects: As with all anticoagulants, the dominant adverse potential of bivalirudin is for bleeding, although serious hemorrhages have been rather infrequent. The most common nonbleeding side effects included back pain, pain, nausea, headache, and hypotension. The incidence of these events was comparable in the bivalirudin and heparin groups.

Dosage and availability: Bivalirudin is available in 250-mg vials for intravenous administration; it is not intended for use by intramuscular injection; and it should not be mixed with any other medicines before or during administration. The medication should be reconstituted with 5 ml of Sterile Water for Injection, then further diluted in 50 ml of 5% Dextrose in Water or 0.9% Sodium Chloride to a final concentration of 5 mg/ml. Patients who are undergoing coronary angioplasty receive an IV bolus of bivalirudin, 1 mg/kg, followed by a continuous infusion of 2.5 mg/kg/hour for four hours and 0.2 mg/kg/ hour for up to 20 hours if necessary. The medication should be used with aspirin 300-325 mg PO daily.

Patient monitoring: Laboratory parameters to be monitored may include the activated partial thromboplastin time (aPTT); the activated clotting time (ACT); prothrombin time (PT); hemoglobin/hematocrit, red blood cell, and platelet counts; renal and liver function tests; and stool tests for occult blood.

Patient counseling: Patients should be alerted to report signs of bleeding, such as epistaxis or urinary or gingival bleeding.

DOCOSANOL (doh-KAH-suh-nol)

Abreva (uh-BREE-va)Avanir Pharmaceuticals FDA rating: 1-S

Eighty percent of adults in the United States are said to be carriers of the virus that causes cold sores, but only a small percentage of persons seek professional care. In approving docosanol as a topical treatment for recurrent oral-facial infections by herpes simplex, the Food & Drug Administration took the unusual action of granting initial marketing approval of the drug as an over-the-counter product.

Indications: Docosanol is indicated for treatment of the cutaneous manifestations of infections by the herpes simplex virus (HSV), which is responsible for cold sores or fever blisters.

Pharmacology: Docosanol exerts an antiviral action against lipid-enveloped viruses (which includes herpes simplex virus types 1 and 2) but not toward nonenveloped viruses. It is believed to interfere with the viruses' entry into their target cells and their subsequent migration to or entry into the cell nucleus. It is possible that intracellular metabolism of docosanol is a prerequisite for its showing antiviral activity, as its anti-herpes activity was proportional to the degree of its cellular metabolism in one study.

Contraindications: Known hypersensitivity to docosanol.

Precautions: Particular caution may be required when using docosanol in persons having a prior history of allergic responses to medications applied topically.

Drug interactions: Not relevant because of insignificant systemic exposure after topical administration.

Adverse effects: Burning and stinging at the site of cream application have been reported. No systemic toxicity was observed after high doses in animal studies by either topical or systemic administration.

Dosage and availability: Docosanol is available as a 10% cream in a 2-gm tube. Treatment should be initiated at the first onset of any sign or symptom of a recurrence of a sore or blister (e.g., tingling, redness, itch, or appearance of a bump). The cream is to be applied five times daily until the cold sore is healed. Timing of the doses is not critical, but administration should be as evenly spaced throughout the day as possible.

Patient monitoring: Physical examination should be conducted for signs of topical adverse response indicating an allergic reaction, especially for persons who may experience persistent burning following its application.

Patient counseling: Patients should be advised that early treatment will aid in resolving the cold sore sooner. They should use enough cream to completely cover the sore, but a thin layer is all that is necessary. Cosmetics should be removed from the affected area prior to applying docosanol but may be applied over the medication. Application of lipstick or other cosmetics should be done with a separate applicator such as a cotton swab to prevent possible spread of the infection to other areas.

NATEGLINIDE (nuh-TEH-gluh-nide)

Starlix (STAR-lix)NovartisFDA rating: 1-S

Nateglinide is a new entry in the class of oral antidiabetic agents for use in type 2 diabetes mellitus. It differs in structure from the sulfonylureas in being a D-phenylalanine derivative.

Indications: FDA approval provides for the use of nateglinide for monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. In addition, it provides for its concurrent use with metformin to improve glycemic control.

Pharmacology: The hypoglycemic mechanism of nateglinide is more like that of repaglinide than those of the sulfonylureas. It stimulates insulin release, acting directly on pancreatic beta-cells to inhibit ATP-sensitive potassium channels. However, nateglinide offers a more rapid onset and a short duration of hypoglycemic action, compared with the sulfonylureas and with the action of repaglinide on beta-cells. It has been shown to lower the postprandial hyperglycemia more than the sulfonylureas can, and thus it may improve glycemic control in type 2 diabetes mellitus.

Contraindications: Contraindications include prior hypersensitivity to nateglinide, type 1 insulin-dependent diabetes mellitus, or a state of diabetic ketoacidosis, as insulin is required in the latter cases.

Precautions: Particular caution is required in the following circumstances: renal impairment with a potential need for dose adjustment; hepatic dysfunction with a potential increase in drug plasma levels and/or an enhanced sensitivity to its hypoglycemic effects, which may require dose adjustment; adrenal or pituitary insufficiency or malnutrition because of the potential for an enhanced hypoglycemic effect; infection, trauma, surgery, or unusual stress with a potential for loss of glycemic control requiring use of insulin; pregnancy or breast-feeding, for which clinical data are lacking and in which use of insulin is preferred.

Drug interactions: Caution is required in case of concurrent therapy with inhibitors of cytochrome CYP3A4 (e.g., erythromycin and ketoconazole) because of a risk for reduced metabolism and consequent enhanced toxicity of nateglinide, or in concurrent therapy with inducers of cytochrome CYP3A4 (e.g., rifampin or St. JOhn's wort) because of the likelihood for a reduction in the hypoglycemic effect of nateglinide. Thiazides, corticosteroids, thyroid products, and sympathomimetics may reduce the hypoglyemic action of Starlix and other oral antidiabetic drugs, while NSAIDs, salicylates, MAOIs, and nonselective beta-adrenergic blocking agents may potentiate the hypoglycemic effect.

Adverse effects: Hypoglycemia is the major concern; signs and symptoms of hypoglycemia have occurred in 2% to 3% of type 2 diabetic patients treated with oral nateglinide for up to three months. However, the hypoglycemia is generally mild, with symptoms of increased sweating (7%), tremor (6%), dizziness (3%), and asthenia (1.7%). Gastric upset and other gastrointestinal symptoms have been reported in diabetic patients treated with nateglinide.

Dosage and availability: The recommended starting and maintenance dose is 120 mg three times daily, one to 30 minutes before meals. Patients who are near their target HbA1C may be started and maintained on 60 mg TID, one to 30 minutes before meals. Nateglinide is supplied as tablets containing 60 or 120 mg.

Patient monitoring: Therapeutic monitoring parameters include fasting and postrandial blood glucose and glycosylated hemoglobin levels. Laboratory parameters of adverse effects include complete blood counts and routine blood chemistry. A record should be kept of body weight.

Patient counseling: Patients should be aware of the need to recognize and report to their physician the occurrence of hypoglycemic signs and symptoms: blurred vision, behavior change, drowsiness, anxiety, hunger, cold sweats and confusion, or adverse effects consisting of gastrointestinal symptoms. Moreover, they should know what to do when hypoglycemic symptoms occur, such as eating glucose tablets or gel, corn syrup, honey, or sugar cubes; drinking fruit juice, a nondiet soft drink, or sugar dissolved in water; and to obtain emergency medical assistance if the symptoms are severe.

Women should be made aware that nateglinide is not recommended for use in pregnancy or during breast-feeding. Proper dosing includes skipping a dose if a meal is skipped and adding a dose if an extra meal is eaten, but never doubling doses. Patients need to be made mindful of the critical importance of adhering to recommended regimens of exercise, diet, and blood glucose monitoring.

OXCARBAZEPINE (ox-car-BAY-zuh-peen)

Trileptal (tri-LEHP-tal)NovartisFDA rating: 1-S

Oxcarbazepine is an analog of a long-used anticonvulsant, carbamazepine, but it differs in being associated with a lower rate of serious adverse events of a hematopoietic or dermatologic nature.

Indications: Oxcarbazepine is indicated for use as monotherapy or as an adjunctive agent in treatment of partial seizures in adults and as adjunctive therapy for partial-onset seizures in children aged four to 16.

Pharmacology: The precise mechanism by which oxcarbazepine exerts its antiepileptic effect is unknown. There is evidence that its activity is exerted primarily through its monohydroxy-metabolite (known as MHD). Electrophysiological studies of an in vitro model of epilepsy show that voltage-sensitive sodium channels are blocked, thus stabilizing hyperexcited neural membranes. There is reduction of any repetitive neuronal firing and a decreased propagation of impulses. These actions are sufficient to stop the spread of a seizure through the brain.

Contraindications: Oxcarbazepine should not be used in patients with a known hypersensitivity to oxcarbazepine or to any of the components of the product.

Precautions: Prior known hypersensitivity to carbamazepine might predict an elevated risk for a like response to oxcarbazepine. The product does not have the "black box" warnings required for carbamazepine (regarding aplastic anemia or agranulocytosis). However, leukopenia and thrombocytopenia have been observed in some patients taking oxcarbazepine. The agent has been associated with skin rashes, purpura, and hot flashes; thus, a patient's history of serious skin reactions to other medications might be a significant precaution concerning its use.

Drug interactions: Oxcarbazepine may interact by enhancing the metabolic inactivation of contraceptive steroids, rendering them less effective. Similar drug-drug interactions may occur with felodipine and verapamil.

Adverse effects: More common side effects in clinical trials were nausea and emesis; drowsiness; headache; visual abnormalities, including diplopia; abdominal pain; and upper respiratory tract infections. Others seen at rates greater than or equal to 5% were diarrhea, constipation, dyspepsia, nervousness, ataxia, and dizziness.

However, significant hyponatremia (serum sodium level <125 mmol/L) can develop, but it is generally seen less often (2.5%) than the adverse events cited above. It also is usually asymptomatic and does not require adjustment of therapy. There is no significant difference between placebo and oxcarbazepine regarding side effects that commonly have concerned people with epilepsy: difficulty in concentrating, memory problems, incoordination, coarsening of facial features, hirsutism, gingival hyperplasia, weight gain, tremor, hair loss, or skin rashes.

Dosage and availability: Oxcarbazepine is supplied as tablets that contain 150, 300, or 600 mg. Therapy is initiated at 300 mg twice daily and can be adjusted at weekly intervals, as indicated by the patient's response, by a maximum of 600 mg/day to the recommended daily dose of 600 mg twice daily. Doses above 1200 mg daily may be more effective in some patients, but tolerance is compromised at doses of 2400 mg/day due to CNS side effects. The tablets can be taken with or without food.

Patient monitoring: The manufacturer recommends periodic monitoring of serum sodium levels when patients are being maintained on oxcarbazepine. This is especially necessary if the patient takes another drug that tends to decrease sodium levels, e.g., a natriuretic.

Patient counseling: Patients should be asked about a possible prior use of carbamazepine and any adverse reactions, because 25%-30% of those with a prior history of such reactions will experience hypersensitivity while taking oxcarbazepine. Indications of hypersensitivity require immediate cessation of drug intake.

Patients should be made aware of the possible signs of hyponatremia, nausea, malaise, headache, lethargy, and confusion and that such signs must be reported to their physician. They should also be warned to anticipate possible dizziness or drowsiness and that they should avoid driving or operating other machinery until they have adequately assessed their response and their ability to safely perform such tasks.

As for other antiepileptic drugs, gradual—not abrupt—cessation is necessary to minimize or avoid an increased seizure frequency and/or severity. Caution is required in consumption of alcoholic beverages while taking oxcarbazepine, as there may be addition of their sedative actions. Because oxcarbazepine may reduce the efficacy of a hormonal contraceptive, effective non-hormonal contraception should be strongly recommended to women taking this medication.

PANTOPRAZOLE SODIUM (pan-TOH-pruh-zole)

Protonix (pro-TAHN-ix)Wyeth-AyerstFDA rating: 1-S

Esophageal erosion is a chronic disorder resulting from a reverse flow (reflux) of gastric acid into the lower esophagus; it is one of the more serious manifestations of GERD (gastroesophageal reflux disease). Pantoprazole is the latest addition to a popular class of gastrointestinal (GI) drugs, the proton pump inhibitors (PPIs), for use against problems associated with excess gastric acid secretion. It has been marketed in 60 other countries since 1994 and has been prescribed for more than 27 million persons, including for use jointly with various antibiotics to eradicate H. pylori infection to remedy peptic ulcer disease.

Indications: Pantoprazole is indicated for short-term treatment (up to eight weeks) in the healing and symptomatic relief of erosive esophagitis. If lesions have not healed in that time, an additional eight-week course of therapy may be considered. However, safety and efficacy beyond 16 weeks have not yet been determined.

Pharmacology: Pantoprazole, like prior PPIs, acts by inhibiting the cellular proton pumps in the stomach responsible for the physiological gastric secretion of hydrochloric acid. It suppresses the final step in acid production by covalent binding at two sites on the enzyme (H+, K+)-ATPase at the secretory surfaces of the gastric parietal cells. This effect is dose-related; it produces suppression of both basal and stimulated gastric acid secretion irrespective of the stimulus. Persistence of the enzyme binding results in an antisecretory effect lasting more than 24 hours.

Contraindications: Patients having known hypersensitivity to any component of the formulation should not use pantoprazole.

Precautions: The medication is carcinogenic in rodents, causing rare types of GI tumors; the human significance of this is uncertain.

Pregnant women should use pantoprazole only when it is clearly needed; their physician should evaluate continuing drug use during breast-feeding. No dose adjustment is required for elderly patients or for those with renal impairment or mild to moderate hepatic deficit. Safety and effectiveness for pediatric patients have not been established.

Drug interactions: Clinically significant drug-drug interactions based on hepatic enzymes have not been detected in many combinations tested with pantoprazole. Because it lowers the level of gastric acid, pantoprazole may hinder the absorption of medicines such as ketoconazole, ampicillin esters, and iron.

Adverse effects: The most frequently reported side effects among 11,100 patients taking pantoprazole in clinical trials were headache, diarrhea, flatulence and abdominal pain, which occurred in about the same rates as for those taking a placebo or doses of nizatidine, 150 mg b.i.d., a positive control.

Dosage and availability: Pantoprazole is available as a 40-mg delayed-release, enteric-coated yellow tablet. The usual dosage is one tablet daily for eight weeks. Patients who have not healed after the course of therapy may be considered for an additional eight weeks of treatment. No adjustment of dosage is recommended on account of age, renal impairment, or in patients undergoing hemodialysis.

Patient monitoring: Postmarketing reports of several types of serious adverse events (e.g., severe dermatologic, neurologic, or allergic conditions) suggest that careful monitoring for possible adverse reactions is warranted.

Patient counseling: Patients should be told of the small possibility of headache or diarrhea and instructed to swallow the tablets whole—not chewed, split, or crushed. They should give their doctor and pharmacist a record of all medications being taken with or without a prescription.

POLYTETRAFLUOROETHYLENE & PERFLUOROALKYLPOLYETHER

SERPACWA (sir-PACK-wuh) (Skin Exposure Reduction Paste Against Chemical Warfare Agents) U.S. Army Office of the Surgeon GeneralFDA rating: 1-P

This is an agent intended for use by military forces as part of their protection against chemical warfare agents that would injure exposed skin surfaces.

Pharmacology: Mechanism of action is only as a physical barrier.

Contraindications: None

Precautions: SERPACWA is intended solely for cutaneous use but is not to be applied to the eyes or the mouth. Smoking products should not be handled, as their contamination with SERPACWA and subsequent combustion will lead to the generation of harmful fumes. Inhalation of the fumes result in a flu-like syndrome called "polymer fume fever." The severity of the reaction depends upon the amount of exposure and the number of exposures. SERPACWA's package insert states, "Polymer fume fever should not be regarded as a transitory or benign condition."

Drug interactions: The concurrent use of DEET-containing insect repellents reduced SERPACWA's protective effects. Subsequent testing demonstrated that removing the DEET with a dry towel before applying SERPACWA partially restored the protective effects. Other topical substances found to interfere with the protective effects include some camouflage paints (loam and sand) and possibly permethrin.

Adverse effects: The military conducted tests to evaluate the irritating or allergic sensitization effects of SERPACWA. It was found that the drug did not cause such reactions when used alone or in the presence of ultraviolet light. Application to 20% of the body surface area did not interfere with normal heat exchange. Further, there were no adverse events found after five hours of exposure to the skin.

Dosage and availability: An 84-gm container of the cream is applied to provide a thin, barely noticeable white film layer.

Personnel Information: SERPACWA is to be used in conjunction with and applied prior to donning MOPP gear. Personnel should be cautioned about handling smoking products while using SERPACWA and should be instructed to avoid burning clothing or gear that is contaminated with the paste. DEET removal should be done only with a dry towel, not with water or moist towelette.

RIVASTIGMINE TARTRATE (rih-vuh-STIG-meen)

Exelon (EHK-suh-lon)NovartisFDA rating: 1-S

In the United States, Alzheimer's disease (AD) is the fourth-leading cause of death after cardiovascular diseases, cancer, and stroke, affecting up to four million adults. It commonly causes a serious memory loss, loss of the ability to perform daily activities, gross personality changes, and even psychosis before its eventual fatal outcome. Rivastigmine is the first new medication for AD in three years and only the third-ever available.

Indications: For treatment of mild to moderate dementia of the Alzheimer's type.

Pharmacology: Rivastigmine acts as a reversible inhibitor of the enzyme cholinesterase in brain cells, thus sparing acetylcholine (ACh) from being inactivated and enhancing its function as a neurotransmitter. ACh plays an important role in both memory and cognition by means of cholinergic pathways from the hippocampus to the cerebral cortex. The number of cholinergic neurons and levels of ACh become dramatically deficient in persons with AD. Thus, its making ACh functionally more available is believed to be the mechanism by which rivastigmine improves memory and cognitive functions, especially while the impairment is only mild to moderate. Because loss of the ACh-secreting cells is progressive, the therapeutic benefit may be expected to diminish over time.

Contraindications: Rivastigmine should not be used in patients with known hypersensitivity to rivastigmine, other carbamate derivatives, or other components of the formulation.

Precautions: Clinical studies of rivastigmine have shown no significant increase over a placebo group in incidence of peptic ulcer disease or gastrointestinal bleeding. However, because of the increased cholinergic activity induced, all cholinesterase inhibitors may be expected to increase gastric acid secretion. Therefore, rivastigmine should be used with caution in patients having a history of peptic ulcer or gastro-intestinal bleeding or in those who use NSAIDs. The increased vagal activity provoked by cholinesterase inhibition requires caution in using rivastigmine in a person with sick sinus syndrome or other supraventricular deviations in cardiac conduction. Episodes of syncope have been reported in 3% of patients taking 6 to 12 mg/day of rivastigmine, but 2% of a placebo group.

Drug interactions: Because rivastigmine is metabolized by esterases rather than hepatic P450 enzymes, it does not interact with drugs metabolized by that system. Studies showed no interaction with warfarin, digoxin, diazepam, or fluoxetine. Neither was there any influence on rivastigmine's pharmacokinetics by these or other medicines commonly prescribed: NSAIDs, antacids, antihypertensives, calcium-channel or beta-adrenergic blockers, antidiabetic agents, salicylates, or antianginal agents.

The mechanism of rivastigmine will naturally lead to synergism with any other cholinesterase inhibitor or cholinomimetic agent, and likewise antagonism with any anticholinergic medication.

Adverse effects: In controlled clinical trials on rivastigmine, the most common adverse events seen were asthenia, dyspepsia, nausea and emesis, anorexia, and weight loss. These side effects were usually transient and generally mild to moderate in severity, and they occurred more frequently as dosage was increased. Weight loss occurred more often among women receiving high doses in clinical trials than among men.

Dosage and availability: Rivastigmine tartrate is supplied as oral capsules that contain 1.5, 3.0, 4.5, and 6.0 mg (as the base) and as a 2.0 mg/ml solution. The recommended starting dose is 1.5 mg twice daily. If this dose is well tolerated, and after a minimum of two weeks of exposure, the dose may be increased to 3.0 mg b.i.d. Further increases to 4.5 mg b.i.d. and to 6 mg b.i.d. (the maximum dose is 12 mg/day) also must depend on establishing good tolerance of the current dose and may be considered only after at least two weeks at that dose level.

Patient monitoring: Caregivers should inform the physician of any side effects that may develop, such as those of the GI tract.

Caregiver counseling: The patient's caregiver should be aware that a high incidence of GI symptoms—nausea and vomiting, anorexia, and weight loss—may occur, and of the need to keep the physician informed and to give the medicine with food.

TINZAPARIN SODIUM (TIN-zuh-PAIR-in)

Innohep (IN-no-hep)DuPont PharmaceuticalsFDA rating: 1-S

Tinzaparin sodium is a new low molecular weight heparin having antithrombotic activity. Enzymatic depolymerization of porcine heparin is employed in its production.

Indications: The drug is indicated for treatment of acute symptomatic deep vein thrombosis, with or without pulmonary embolism, when administered in conjunction with warfarin sodium. Safety and efficacy have not been established for pediatric use.

Pharmacology: Tinzaparin sodium inhibits several reactions in the clotting cascade that lead to the formation of fibrin clots, either in vitro or in vivo. It serves as a powerful co-inhibitor with antithrombin III, a primary endogenous plasma protease inhibitor acting against several activated coagulation factors, e.g., factors Xa and IIa (thrombin). Activated partial thromboplastin time (aPTT) is prolonged, while the prothrombin time (PT) usually remains in the normal range. Tinzaparin manifests no fibrinolytic action to lyse existing clots. It may exert the same effects as heparin that are unrelated to its anticoagulant function.

Contraindications: Tinzaparin is contraindicated in patients with active major bleeding, those with a history of heparin-induced thrombocytopenia, or patients having hypersensitivity to heparin, tinzaparin, sulfites, benzyl alcohol, or pork products. Neither should tinzaparin be used in neonates, because of a potential fatal reaction to benzyl alcohol among premature infants.

Precautions: Tinzaparin is intended only for subcutaneous, not intramuscular or intravenous, injection. It cannot be quantitatively interchanged (unit for unit) with heparin or other low molecular weight heparins. Like all anticoagulants, it should be used only with great caution in various conditions carrying liability for hemorrhage: severe uncontrolled hypertension; bacterial endocarditis; acquired or congenital bleeding disorders (including hepatic failure and amyloidosis); ulcerative or angiodysplastic gastrointestinal disease; hemorrhagic stroke; soon after brain, spinal, or ophthalmologic surgery; diabetic retinopathy; or when under treatment with platelet inhibitors. Thrombocytopenia may be expected at a 1% rate. Elderly patients and patients with renal insufficiency may show reduced elimination of tinzaparin and should be dosed with caution. As there are not adequate safety data for use in pregnancy, such application must be only if it is clearly needed. Similarly, caution is required regarding possible use while a woman is breast-feeding.

Drug interactions: Tinzaparin should be used only with great caution and good justification concurrently with either oral anticoagulants or platelet inhibitors (including the salicylates, NSAIDs, dipyridamole, dextran, sulfinpyrazone), or thrombolytic agents. No interactions have been reported with other medications.

Adverse effects: Bleeding is the most common event; however, the risk of major bleeding is low. Accidental overdose may lead to bleeding incidents shown by nosebleed, hematuria, or tarry stools. Protamine sulfate can be used as antidotal treatment if there is evidence of extreme overdose (e.g., hematomas or internal hemorrhage), but it is not able to completely neutralize the action of tinzaparin and may itself cause life-threatening adverse events (severe hypotension or anaphylactoid reaction).

The FDA required a "black box" warning of possible spinal or epidural hematomas during use of tinzaparin if the patient is subject to spinal or epidural anesthesia or other spinal puncture. Such hematomas could be causative for long-term or permanent paralysis. The risk is greater with use of an indwelling epidural catheter or concurrent use of agents altering hemostasis such as NSAIDs, platelet inhibitors, or other anticoagulants.

Local reactions of irritation, pain, bruises, or hematoma may occur at injection sites. There may be anaphylactic/anaphylactoid reactions in association with use of tinzaparin. The various adverse events reported in clinical studies of tinzaparin were at rates quite similar to rates for heparin use (0.6% to 4.7%). During the postmarketing surveillance, priapism requiring even surgical intervention has been reported.

Dosage and availability: Tinzaparin sodium is provided as an injectable solution for use only by subcutaneous administration in conjunction with warfarin sodium. It should not be mixed with other injections or infusions.

Recommended adult dose is 175 anti-Xa units per kg body weight per day for at least six days and until an adequate anticoagulant response to warfarin is achieved.

Each 2-ml vial contains 20,000 anti-Factor Xa international units (IU) per ml plus 3.1 mg/ml of sodium metabisulfite as a stabilizer and 10 mg/ml of benzyl alcohol as preservative.

Patient monitoring: Frequent patient monitoring for indicators of neurological impairment is needed when patients receiving tinzaparin are subject to spinal/ epidural anesthesia or spinal puncture (see "Adverse effects"). In case minor bleeding events or easy bruising is noted, the patient should be carefully observed for possible evidence of major bleeding. Plasma levels of tinzaparin cannot be measured directly. Neither PT nor aPTT can be used to monitor bioactivity of tinzaparin, so these measures would not be routinely required. The levels of anti-Xa and anti-IIa activities are biomarkers for the therapeutic response to tinzaparin.

Asymptomatic and reversible elevations of the aspartate and alanine aminotransferases may occur during treatment with tinzaparin; thus, such tests must be interpreted cautiously before a diagnosis of cardiac or hepatic pathology.

Patient counseling: The patient should be lying supine or in a sitting position for injections deep into the posterolateral abdominal wall. The sites should be alternated from right to left daily. The whole length of the needle should penetrate into a skin fold held tightly between thumb and forefinger throughout delivery of the solution. To reduce bruising, do not rub the site after injection.

TRIPTORELIN (TRIP-to-REH-lin)

Trelstar Depot (TREL-star DEE-po) Debio/Pharmacia FDA rating: 1-S

Triptorelin is a synthetic analog of luteinizing hormone-releasing hormone (LHRH or GnRH); it is a decapeptide that acts as an agonist and actually has greater potency than the naturally occurring LHRH. The pamoate ester of triptorelin provides a depot form for use by intra-muscular (IM) injection once a month.

Indications: Triptorelin is indicated for the palliative therapy of advanced prostate cancer. It offers an alternative treatment for prostate cancer when orchiectomy or estrogen treatment is either not indicated or unacceptable to the patient.

Pharmacology: The action of this medication is to produce a pharmacological castration by a blockage of testosterone secretion. When given continuously in therapeutic dosage, triptorelin acts as a potent inhibitor of the secretion of the gonadotropin essential to testosterone output. Following its initial administration, there is a transient surge in the circulating levels of gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) as well as testosterone and estradiol. However, with chronic and continuous release, usually two to four weeks into therapy, there is a sustained decrease in LH and FSH secretion, and a marked reduction of testicular hormone secretion occurs in men (and ovarian secretion in women). The reduction of serum testosterone is at a level typically seen in surgically castrated men. Consequently, the androgen-dependent prostate cells lose a stimulus to proliferate.

Contraindications: Prior hypersensitivity to triptorelin, other LHRH agonists, or LHRH is a contraindication for triptorelin. It is contraindicated in pregnancy, as it may cause fetal damage.

Precautions: There have been a few reports of hypersensitivity, e.g., anaphylactic shock or angioedema. Triptorelin may cause fetal damage if given in pregnancy.

Drug interactions: No tests of pharmacokinetic drug-drug interactions have been conducted. However, the action of drugs that cause hyperprolactinemia (dopaminergic antagonists) may be capable of interfering with the action of triptorelin.

Adverse effects: The initial surge of LH and testosterone may temporarily aggravate symptoms of prostate cancer, possibly causing bone pain; neuropathy; hot flushes; hematuria; urethral or bladder outlet obstruction; and, rarely, spinal cord compression, which might cause weakness or paralysis of the legs. Bone loss due to estrogen deficiency has also been reported to occur during long-term triptorelin therapy.

Dosage and availability: This product consists of a sterile, lyophilized microgranule formula supplied in a single-dose vial. When 2 ml of Sterile Water for Injection are added to the vial (no other diluent should be utilized!), a suspension is formed that contains 3.75 mg (as the peptide base) of triptorelin pamoate, the recommended monthly intramuscular dosage. Reconstitution is to be accomplished following the instructions in the product insert. Shake well to ensure that particles are thoroughly dispersed to obtain a uniform suspension, which will appear milky. If not used immediately, the suspension must be discarded.

Patient monitoring: Biochemical monitoring of triptorelin response consists of measuring testosterone and the prostate specific antigen. Because of potential early adverse effects (see above), patients with metastatic vertebral lesions or upper urinary tract obstruction should be closely monitored for adverse changes during early weeks of therapy.

Patient counseling: Patients should be informed of the nature of adverse responses likely in the early weeks of treatment and of the need to inform a physician if neurological signs occur, possibly indicating spinal cord compression.

UNOPROSTONE ISOPROPYL (OO-no-PROS-tone)

Rescula (REH-sku-la)CIBA Vision/NovartisFDA rating: 1-P

Unoprostone isopropyl is the first agent of the class of docosanoids to be applied in glaucoma therapy. It comprises an advance over earlier glaucoma therapies because it not only reduces pressure within the eye but also accomplishes that aim without some of the unwanted systemic effects regularly seen for other therapies. It became a major glaucoma therapy in Japan after being marketed in 1994 and more than 250,000 patients having been treated.

Indications: Unoprostone isopropyl is indicated for the lowering of intraocular pressure (IOP) in patients with open-angle glaucoma or with ocular hypertension who are intolerant of other IOP-lowering medications or who are insufficiently responsive (failed to achieve target IOP after multiple measurements over time) to another IOP-lowering medicine. It has not been evaluated for treatment of angle closure and inflammatory or neovascular glaucoma.

Pharmacology: Although docosanoids are related to prostaglandins, unoprostone isopropyl does not act through prostaglandin receptors. Thus, while it lowers IOP efficiently by enhancing the outflow of aqueous humor, it is virtually free of any prostaglandin-like side effects. Animal data suggest that it also improves the ocular blood flow, which could comprise another favorable action toward maintaining a healthy visual system. Unoprostone isopropyl has demonstrated long-term efficacy without any reduction of response over time.

Contraindications: Hypersensitivity to any component of the formulation, which includes benzalkonium 0.015% as a preservative, is a contraindication for unoprostone. Also, unoprostone should not be used in case of a prior intraocular inflammation, such as uveitis.

Precautions: Unoprostone isopropyl acts locally in the eye, and is virtually free of systemic side effects. However, the agent has not been examined in persons with a deficient renal or hepatic function. Bacterial keratitis may occur from any multiple-dose ophthalmic product that becomes contaminated in usage. Unoprostone should not be used while wearing contact lenses, because benzalkonium may be adsorbed to them. Lenses should be removed before use of the drops and may be reinserted 15 minutes after instillation of the unoprostone. Because there are not adequate studies to establish safety, this agent should be used in pregnancy only when the potential value warrants potential fetal risk. Safety of pediatric use remains unestablished.

Drug interactions: Unoprostone isopropyl can be safely combined with all other available drugs for treating glaucoma. Its use with inflow-reducing drugs such as beta-adrenergic blockers makes an optimal synergistic combination. Local application does not allow systemic levels sufficient to be involved in systemic drug-drug interactions.

Adverse effects: Unoprostone isopropyl acts locally in the eye and is virtually free of systemic side effects. A prospective postmarketing surveillance study has detected merely a 0.4% rate of systemic side effects. The most common ocular adverse events (10%-25% rate) were burning or stinging, itching, dry eyes, increased length of the eyelashes (10%-14%), and conjunctival injection.

Events occurring at 5%-10% rate were abnormal vision, eyelid disorder, foreign body sensation, or lacrimation disorder. Occurring at 1%-5% rate were blepharitis, cataract, conjunctivitis, corneal lesion, ocular discharge, hemorrhage or pain, keratitis, irritation, photophobia, and vitreous disorder. Also, events at <1% rates included color blindness, corneal deposits, edema or opacity, diplopia, hyperpigmentation of the eyelid or iris, increased number of eyelashes, iritis, optic atrophy, ptosis, retinal hemorrhage, and a visual-field defect.

Dosage and availability: Unoprostone isopropyl is supplied as a clear isotonic 0.15% buffered aqueous ophthalmic solution in a 5-ml volume in a polypropylene dropper bottle. Recommended dosage is one drop twice a day.

Patient monitoring: Compliance monitoring may be a need for some patients because of the serious consequence of potential vision loss associated with uncontrolled glaucoma. Periodic IOP measurements are required to confirm that a sufficient therapeutic response is maintained.

Patient counseling: Patients should be informed of the possibility of a gradual change in iris color, increasing the brown pigment, which may be irreversible. They should be warned to avoid touching the eye surface or eyelashes with the tip of the container so as to prevent bacterial contamination of the solution, which might cause a serious corneal infection and injury, even loss of vision. Patients must be aware of the need to contact the ophthalmologist if they suffer ocular trauma or develop ocular conditions such as conjunctivitis or eyelid redness and possible infection. If another topical eye medication is to be administered, it should be instilled at least five minutes apart. In case of ocular surgery, the continued use of a multidose eye product is inadvisable unless approved by a physician.

VERTEPORFIN (VIR-tih-POR-fin)

Visudyne (VIH-zhoo-dine)CIBA Vision and QLT Photo TherapeuticsFDA rating: 1-P

Verteporfin, a light-activated agent for photodynamic therapy, is the first drug to receive FDA approval for treating age-related macular degeneration (AMD). This condition is the leading cause of blindness in people over the age of 50 in the Western world. An estimated 500,000 new patients around the world develop wet AMD every year, consisting of an abnormal growth of blood vessels across the macula, the central part of the retina. These vessels leak serum and blood into the tissue, causing a blister to form under the retina. This leads to scar tissue and a large blind spot. Persons who develop the condition will lose the ability to read, drive, or recognize faces in as few as two months to three years.

Indications: Verteporfin is to be used for the treatment of age-related macular degeneration in patients whose condition shows predominantly the classical subfoveal choroidal neovascularization (CNV).

Pharmacology: Verteporfin therapy comprises a two-step procedure in a physician's office. Verteporfin, a photosensitizing agent, is injected intravenously (IV) into the patient's arm; then a photodynamic activation of the drug is accomplished by shining an especially designed nonthermal 689-nm laser light into the eye under treatment. Once it has been activated, the verteporfin acts to cause a closing-off of abnormal blood vessels that are the source of the pathology.

Contraindications: Verteporfin should not be used for persons with porphyria or having a hypersensitivity to any constituent of the product.

Precautions: After receiving verteporfin, any exposure of the skin or eyes to direct sunlight or bright indoor lighting should be avoided for five days. Thus, it is also vital that standard precautions against extravasation be diligently employed. If extravasation occurs, an immediate interruption of the infusion and an application of cold compresses is necessary. Furthermore, the area affected requires special protection from light exposure until all signs of extravasation have disappeared. Verteporfin is not useful for patients with longstanding vision loss or for those whose retina has already been significantly damaged by AMD. There are no data supporting safety of usage in persons with moderate to severe impairment of hepatic function. Only the approved laser light sources should be used. Overdose of verteporfin would prolong the interval of photosensitivity and might cause permanent loss of vision by damaging the normal retinal vessels.

Drug interactions: No human drug interaction studies are available. Biotransformation of verteporfin is limited, and by means of plasma and hepatic esterases; thus, verteporfin seems unlikely to be involved in any metabolic drug-drug interactions. However, many drugs may synergize the effects of verteporfin because they also exert a photosensitizing action: tetracyclines, sulfonamides, phenothiazines, sulfonylureas, thiazides, and griseofulvin. Possible enhancers via increased endothelial uptake are the calcium-channel blockers, polymyxin B, or radiation. Some that might oppose verteporfin's action would be radical scavengers or quenchers, such as beta-carotene, ethanol, dimethyl sulfoxide, mannitol, or formate. Also opposing its action could be inhibitors of clotting, vasoconstriction or platelet aggregation (e.g., thromboxane A2 inhibitors).

Adverse effects: The most frequently reported adverse events attributed to verteporfin were injection site irritation, visual problems (blurring or decreased visual field or acuity), and headaches. In more than 3,400 treatments, the rate of photosensitivity reactions was less than 0.6%.

Dosage and availability: Verteporfin is made available as a 15-mg lyophilized dark-green cake in a single-use glass vial. It is intended only for IV injection. Reconstitution is recommended using rubber gloves and eye shielding to protect against cutaneous or mucosal contact by the pharmacist. Accidental exposure would require measures described below under "Patient counseling." Spills should be wiped up with a damp cloth; materials must be disposed in such a way as to avoid human exposure.

Patient monitoring: It would be desirable that a family member or other caregiver be fully aware of the required post-therapy regimen and be prepared to assist in its fulfillment.

Patient counseling: Patients must be very aware that they will be photosensitive after taking a treatment, requiring them to avoid exposure to either direct sunlight or bright indoor lights for five days. Wearing a wristband reminder is recommended. This does not dictate staying in full darkness, as that might prolong the interval of photosensitivity. Should patients' circumstances require them to go outside within five days, they must take strong preventive measures—full skin coverage and dark glasses—to avoid exposure of skin or eyes. Use of UV sunscreens will NOT effectively substitute for such measures, as visible light is provocative.

ZONISAMIDE (zon-IH-suh-mide)

Zonegran (ZON-uh-gran)Elan Corp.FDA rating: 1-S

Another in a recent series of additions to our array of antiepileptic drugs is zonisamide; chemically classed as a sulfonamide, it is unrelated to any previous anti-epileptic drug. It has been marketed in Asia since 1989 by Dainippon, resulting in about one million patient-years of exposure.

Indications: Zonisamide has been approved for the indication of adjunctive use with other drugs for therapy in partial seizures of adults. It also may prove useful as an epilepsy monotherapy.

Pharmacology: The mechanism by which zonisamide exerts its antiepileptic effect is not clearly known. However, it is thought to achieve its anticonvulsant effect through preventing spread of seizures and suppressing a focus from which they originate by virtue of blocking actions at sodium channels and T-type calcium channels. Such actions suppress neuronal hypersynchrony of seizures by stabilizing the neuronal cell membranes. In vivo analyses indicate that zonisamide facilitates both dopaminergic and serotonergic neurotransmission but does not alter postsynaptic GABA or glutamate responses. A weak inhibition of carbonic anhydrase is not believed to contribute appreciably to its in vivo anticonvulsant action.

Contraindications: Patients who are known to be hypersensitive to sulfonamides should not take zonisamide. Because allergic reactions to sulfonamides may be life-threatening, at signs of hypersensitivity or other serious reactions such as a skin rash, zonisamide intake should be immediately discontinued.

Precautions: Caution should be exercised when treating patients having impaired hepatic or renal function with zonisamide because its clearance depends on function of those organs. As for other anticonvulsants, abrupt cessation of zonisamide may bring about an increase in seizure frequency.

Potentially fatal hypersensitivity reactions to sulfonamides that occur rarely may be possible also with zonisamide. These include Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias.

Occurrence of an unexplained skin rash when taking zonisamide is reason to consider cessation of drug intake. If the drug is not withdrawn, close, frequent observation should be followed. The significance of seven deaths of this sort in 11 years of usage in Japan is obscured by concurrent usage of other medications by the decedents.

Drug interactions: Zonisamide does not alter plasma concentrations of other anticonvulsants used concurrently; however, phenobarbital, phenytoin, and carbamazepine can induce enzymes to increase the metabolism and clearance of zonisamide, thus decreasing its half-life.

Adverse effects: The most commonly observed adverse events from zonisamide therapy are somnolence, dizziness, headache, nausea and vomiting, agitation/irritability, and anorexia. Many of these events are dose-related. In U.S. and European randomized control trials, there was a 2.2% rate of discontinuance because of skin rash versus none for the placebo subjects.

Zonisamide use has been associated frequently with CNS-related events: psychiatric symptoms (depression or psychosis), psychomotor slowing, difficulty in concentration, speech or language (word-finding), or sleepiness and fatigue (which were more likely at doses of 300-500 mg/day).

Dosage and availability: Zonisamide is supplied as 100-mg capsules. The initial daily dose should be 100 mg daily, which may be increased to 200 mg/day (in either once- or twice-daily doses as directed by the prescriber) after two weeks and maintained for at least another two weeks. The dose may then be increased to 300 mg/day or 400 mg/day as needed, with the dosage being maintained for at least two weeks at each dosage to allow for achieving a steady state. Zonisamide may be taken with or without food.

Patient monitoring: Consideration should be given to periodic renal function monitoring.

Patient counseling: Patients should be made aware of the range of possible side effects. They should be warned not to drive a vehicle or to operate other complex machinery until they have clearly gauged their psychomotor responses to zonisamide to be certain how it affects their performance in such contexts. Patients should be warned to contact their physician immediately if they develop a skin rash or other allergic symptoms, if their seizures worsen, if they develop signs or symptoms that may indicate kidney stones (such as sudden back or abdominal pain or blood in the urine), or if they should develop any of these: fever, sore throat, mouth sores, or easy bruising.

Patients should be advised to drink six to eight glasses of water a day to help prevent kidney stones, which have occurred in some patients. They also should be cautioned not to abruptly cease taking their medication, because to do so likely will provoke an increased occurrence of seizures.

Because zonisamide has potential to cause birth defects, patients should be advised to use contraceptives while taking the drug and to notify their physician if they become pregnant or intend to become pregnant during therapy. Pregnant patients continuing to take zonisamide should discuss with their physician any intent to breast-feed the newborn infant.

References are available upon request.

TEST QUESTIONS

Write your answers on the answer form appearing below (photocopies of the answer form are acceptable) or on a separate sheet of paper. Mark only one correct answer.

1. Articaine is an amide-type local anesthetic, which means that, in excess, it might cause all the following unwanted effects except:

a. Depression of the myocardial conduction system
b. Peripheral vasodilation
c. Decreased cardiac output
d. Hypertension

2. Accidental intravascular injection of articaine may manifest in all of the following immediate ways except:

a. Convulsions
b. Coma
c. Hepatotoxicity
d. Cardiorespiratory depression

3. Which one of bivalirudin's actions is similar to that of heparin?

a. It does not require the presence of endogenous antithrombin III as a cofactor.
b. It acts only to block the activation of prothrombin.
c. It has no natural endogenous antagonists.
d. It has a continuing activity after plasma levels have been cleared.

4. Which one of the following was NOT reported as a common non-hemorrhagic side effect of bivalirudin?

a. Back pain
b. Nausea
c. Elevated blood pressure
d. Headache

5. Docosanol is effective against the lipid-enveloped viruses but not the nonenveloped viruses.

a. True
b. False

6. Docosanol is currently approved only for use against:

a. HIV
b. Hepatitis C virus
c. Herpes simplex virus
d. Polio virus

7. Characteristics of nateglinide include all of the following except:

a. Its duration is longer than that of the sulfonylureas
b. Its mechanism is similar to that of repaglinide
c. Its action has more rapid onset than that for sulfonylureas
d. It may be used only in patients with type 2 diabetes mellitus

8. Conditions requiring particular caution for use of nateglinide, because insulin may be necessary to obtain the full therapeutic effect needed, include all except:

a. Accidental trauma or surgery
b. Adrenal insufficiency
c. Infections
d. Pregnancy

9. What percentage of patients with a history of sensitivity to carbamazepine is likely to experience similar reactions to oxcarbazepine?

a. 2%-4%
b. 12%-16%
c. 25%-30%
d. 60%-63%

10. What is the approximate incidence of significant hyponatremia in patients taking oxcarbazepine?

a. 1.25%
b. Around 2.5%
c. Around 6.3%
d. >12.5%

11. The mechanism of action of PPIs, such as pantoprazole, results in suppression of:

a. Basal secretion of gastric acid, but not stimulated secretion
b. Stimulated secretion of gastric acid but not basal secretion
c. Both basal and stimulated secretion of gastric acid
d. Neither basal nor stimulated secretion of gastric acid

12. Pantoprazole:

a. Tablets must be swallowed whole
b. Tablets may be crushed and mixed with applesauce for patients who have difficulty swallowing
c. Is available in a liquid formulation
d. Must be administered in smaller doses for patients with renal impairment

13. Pantoprazole may interact with iron salts by:

a. Enhancing absorption of the iron salts due to gastric acid inhibition
b. Increasing urinary elimination of iron salts due to producing alkaline urine
c. Reducing the effectiveness of the pantoprazole due to the ionic character of the iron salts
d. Decreasing absorption of the iron salts due to increased gastric pH

14. Smoking should be avoided when using polytetrafluoroethylene and perfluoroalkylpolyether paste (SERPACWA) because:

a. SERPACWA is explosive
b. If smoking products are contaminated with SERPACWA, harmful fumes may be generated when the product is burned
c. Smoking reduces the effectiveness of SERPACWA through enhanced hepatic metabolism
d. SERPACWA enhances the cardiovascular effects of nicotine

15. The dosage of rivastigmine tartrate is recommended to begin at _____ and can be adjusted gradually to _____ maximum:

a. 3 mg TID and 20 mg maximum
b. 4.5 mg BID and 20 mg maximum
c. 1.5 mg TID and 12 mg maximum
d. 1.5 mg BID and 12 mg maximum

16. To reduce bruising after a dose of tinzaparin, the practitioner should:

a. Give the drug only by the intramuscular route
b. Avoid rubbing the injection site
c. Avoid giving warfarin with tinzaparin
d. Rub the injection site gently in a circular motion

17. As a synthetic analog of luteinizing hormone-releasing hormone, triptorelin offers:

a. A new therapy option for infertility
b. A palliative treatment alternative for prostate cancer
c. A new therapy for benign prostatic hypertrophy
d. An agent to regulate ovulation in postmenopausal women

18. Unoprostone:

a. Works synergistically with beta-adrenergic blocking agents
b. Should not be used with beta-adrenergic blocking agents
c. Works by reducing the production of aqueous humor in the eye
d. Has been studied and found safe for use in pediatric patients

19. In order to work, verteporfin:

a. Must be shaken well before being instilled in the eye
b. Must be activated with a nonthermal 689-nm laser light within three minutes after the eye drops are instilled in the eye
c. Must be refrigerated until just before use
d. Must be activated with a nonthermal 689-nm laser light after the drug is administered intravenously

20. Patients who should not take zonisamide include those with a documented allergy to:

a. Phenytoin
b. Proton pump inhibitors
c. Sulfonamides
d. Carbamazepine

 

 

Marvin Davis. NEW DRUG APPROVALS OF 2000 - Part 2. Drug Topics 2001;5:89.