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 # 032-999-01-002-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This lesson is no longer valid for CE credit after 12/31/03.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

COVER STORY

NEW DRUG APPROVALS OF 2000—Part 1

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.

The year 2000 saw 27 new molecular entities (NMEs) approved. But by the end of the year, an early approval, alosetron (Lotronex, Glaxo Wellcome), a treatment for irritable bowel syndrome, was removed from the market. The Food & Drug Administration had received postmarketing reports of 49 cases of ischemic colitis and 21 cases of severe constipation.

The year was also marked by the addition of three antidiabetic medications—an oral hypoglycemic and two variations of insulin. Also making its debut was a representative of the first entirely new antibiotic class introduced in 35 years. The military also got into the act. It obtained approval for a topical product designed to provide protection against chemical warfare agents. Perhaps the most controversial approval was that of mifepristone, also known as RU-486.

Other approvals included a couple of anticoagulants, a new local anesthetic for dental use, and an over-the-counter topical therapy for cold sores. Part 1 covers 13 NMEs. Part 2, which will appear in the March 5 issue, will cover the remaining NMEs and summarize the six new biological agents approved last year.

This year's review includes a new feature—a pronunciation guide for generic and brand names. When reading the on-line version of these articles, click on the generic and brand names to hear the words pronounced.

ARGATROBAN (ar-GAA-truh-ban)

Texas Biotechnology Corp. andSmithKline BeechamFDA rating: 1-S

Argatroban is a synthetic derivative of L-arginine. It serves as a direct inhibitor of thrombin and offers lifesaving protection against clots for patients with heart disease and stroke who become allergic to, or are intolerant of, the commonly prescribed anticoagulants. About 5%-10% of patients who are at risk for blood clots and who take heparin eventually become intolerant to it.

Indication: Argatroban is indicated as an anticoagulant for the prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia.

Pharmacology: Upon intravenous infusion, argatroban binds reversibly to the active site of the thrombin molecule and thus inhibits the action of thrombin to activate fibrinogen to form fibrin. Unlike heparin, it does not require the presence and joint action of the cofactor, antithrombin III. Argatroban is able to inhibit the action of thrombin, whether free or associated with a clot.

Contraindications: Argatroban should not be used in patients with any overt bleeding or a hypersensitivity to any component of the product. Concurrent use with heparin is contraindicated.

Precautions: Argatroban is intended only for intravenous injection. Any other parenteral anticoagulant should be terminated before argatroban is started. Because hemorrhage can occur anywhere in the body, an unexplained fall in blood pressure or hematocrit, or any other unexplained symptom, should cause consideration of a hemorrhagic explanation. Argatroban must be used with great caution in persons who have any disease entailing a danger of bleeding. Safety and efficacy have not been established for patients less than 18 years of age. Use of argatroban by nursing mothers could lead to serious adverse effects in the children.

Drug interactions: Antiplatelet agents or oral hypoprothrombinemic agents, such as warfarin or aspirin, if used concurrently with argatroban, may increase the risk of bleeding. No interaction has been noted from concurrent use of acetaminophen, digoxin, or erythromycin.

Adverse effects: Among 568 argatroban-treated patients, the highest rate of major bleeds was 2.3% in patients with gastrointestinal (GI) hemorrhage, versus 1.6% for matched historical controls. For minor bleeds, the maximal rate was again for those occurring in the GI tract at a rate of 14.4% versus 18.1% for historical controls. However, minor bleeds from the genitourinary tract, and decreases of hemoglobin and hematocrit, were 11.6% and 10.4%, respectively, which was appreciably higher than for controls.

Nonhemorrhagic adverse events reported at rates greater than control were: hypotension, fever, diarrhea, nausea, and vomiting.

Dosage and availability: Argatroban is supplied as a concentrated solution (100 mg/ml), which must be diluted 100-fold before its infusion with 0.9% sodium chloride solution, 5% dextrose injection, or Lactated Ringer's injection. Use 2.5 ml per 250 ml of diluent or 5.0 ml per 500 ml of diluent. The product should be discarded if the solution is cloudy or shows an insoluble precipitate. Prepared dilutions should not be exposed to direct sunlight. They are stable up to 48 hours if stored in the dark at 2° to 8°C.

The recommended initial dosage for adults without hepatic deficit is 2 mcg/kg per minute as a continuous infusion; any dose adjustment should not exceed 10 mcg/kg/min. For patients with heparin-induced thrombocytopenia and hepatic impairment, the initial dose should be reduced to 0.5 mcg/kg/min.

Patient monitoring: Before initiating use of argatroban, a baseline activated partial thromboplastin time (aPTT) should be obtained and monitoring continued by this means for any needed dosage adjustment.

Patient counseling: Not applicable.

ARSENIC TRIOXIDE

Trisenox (TRI-seh-nox)Cell TherapeuticsFDA rating: 1-PV

The FDA again approved an ill-famed agent (reminiscent of the recent thalidomide approval) in giving orphan drug status to the classic poison, arsenic trioxide (ATO). The drug is indicated for anticancer therapy.

Indication: ATO is indicated for induction of remission and consolidation in cases of acute promyelocytic leukemia (APL) shown to be refractory to, or having relapsed from, use of retinoid and anthracycline chemotherapy.

ATO also has been approved for treatment of multiple myeloma and for the myelodysplastic syndromes (diseases in which bone marrow fails to produce enough normal white blood cells) that may develop following certain drug therapies or radiation.

Pharmacology: The mechanism of action for ATO is not completely known. In vitro, human promyelocytic leukemic cells show signs of DNA fragmentation that may indicate early apoptotic cell death. ATO also causes damage or degradation of a fusion protein, PML-RAR alpha.

Contraindications: Hypersensitivity to any form of arsenic dictates against its use. It should not be used in a state of preexisting QT interval prolongation.

New molecular entities approved in 2000

Precautions: ATO administration should be only under the supervision of physicians who are experienced in the management of acute leukemia. The FDA required a black box warning regarding serious ECG abnormalities, including prolonged QTc or the potentially fatal torsade de pointes, and the condition known as "APL differentiation syndrome" (APL-DS). This condition may involve threatening pericardial and pleural effusions, can be fatal, and must be treated immediately with high-dose (10 mg b.i.d.) IV dexamethasone therapy at first suspicion of its presence. No data are available to support the use of this product in persons with impaired hepatic or renal function; the latter is more likely to be critical to its use because clearance occurs mainly by renal excretion. Arsenic trioxide is classed as a human carcinogen.

Drug interactions: No formal assessment of possible drug-drug interactions with ATO has been made. The methyl transferases involved in metabolism of ATO are not part of the CYP enzyme system. Concurrent use with other agents that can either prolong the QT interval (some antiarrhythmics, thioridazine) or cause abnormalities of electrolytes (diuretics or amphotericin B) should be avoided.

Adverse effects: In clinical trials, most patients showed some drug-related adverse events; the most common were leukocytosis, edema, fatigue, nausea/vomiting, diarrhea, abdominal pain, dyspnea, cough, rash, itching, headache, and dizziness. They generally did not require cessation of therapy. Severe adverse reactions include: APL-DS and hyperleukocytosis (each 7.5%), prolonged QTc interval (40%; one out of 40 with torsade de pointes), atrial dysrhythmia (5%), and hyperglycemia (5%).

Symptoms of acute arsenic toxicity indicating overdosage include: muscle weakness, convulsions, and/or confusion. These call for the immediate cessation of arsenic trioxide and consideration of beginning chelation therapy with dimercaprol (3 mg/kg) by IM injection every four hours until toxicity has subsided. Then penicillamine, 250-mg oral doses, may be given to a maximum of four/day.

Dosage and availability: The product is available as a sterile, nonpyrogenic solution for injection containing 10 mg of arsenic trioxide per 10-ml, single-use ampule. The solution is to be diluted with 100-250 ml of 5% Dextrose Injection, USP, or 0.9% sodium chloride injection, USP, using proper aseptic technique. The ATO solution may not be mixed with other medications. Unused original or diluted solutions must not be saved for later use but disposed of following proper methods for an anticancer agent that may itself be a carcinogenic material.

For treating APL, it is recommended that ATO be given intravenously (IV) at a dose of 0.15 mg/kg body weight daily until bone marrow remission is shown. A central venous catheter is not required. Induction doses should not number more than 60. Subsequent consolidation dosing begins three to six weeks after induction and consists of 0.15 mg/kg IV daily for 25 doses over a period up to five weeks. The IV dose should be infused over one or two hours, but this may be extended up to four hours if acute vasomotor reactions occur.

Patient monitoring: ECG monitoring is critical in view of the potential for serious abnormalities of cardiac conduction. Patients must also be monitored for the occurrence of CNS behavioral deviations that might indicate overdosage, requiring intervention.

Patient counseling: Women of childbearing age should be advised against becoming pregnant while taking arsenic trioxide therapy because of a high risk for fetal toxicity. Effective contraceptive method(s) should be employed. Neither should breastfeeding continue during this therapy because of passage of the drug via the milk.

BALSALAZIDE DISODIUM (bal-SAL-uh-zide)

Colazal (CO-lah-zal)Salix PharmaceuticalsFDA rating: 1-S

Balsalazide is a nonsulfonamide prodrug of the active anti-inflammatory moiety, mesalamine or 5-ASA (5-aminosalicylic acid), which has been the basis for several older medications for ulcerative colitis, especially sulfasalazine. Balsalazide is the first new chemical entity approved by the FDA to treat ulcerative colitis in 10 years. It is not expected to be available in the United States until the first quarter of 2001.

Indication: Balsalazide is indicated for the treatment of mildly to moderately active ulcerative colitis, a chronic and debilitating inflammatory disease of the GI tract. It is approved for a course of therapy lasting only up to 12 weeks. If drug therapy is ineffective, colectomy may be necessary.

Pharmacology: Balsalazide disodium is a prodrug that releases 5-ASA into the colonic lumen. Cleaving by bacterial azo-reductase enzymes releases the active moiety. The fact that the parent compound is inert enables the accurate delivery, from an oral formulation, of a high level of the 5-ASA to the colonic mucosa. The therapeutic action is by an unknown mechanism but appears to be topical rather than systemic. It is hypothesized that the drug may inhibit the mucosal synthesis of important pro-inflammatory metabolites of arachidonic acid such as prostanoids and leukotrienes.

Contraindications: The product is precluded from use by hypersensitivity to it or its metabolites or to other salicylate compounds.

Precautions: This drug should be used during pregnancy only if it is clearly needed. Safety for use during lactation has not been demonstrated. Because other mesalamine products have shown renal toxicity, balsalazide should be used with caution, and with careful monitoring, by persons with a history of, or with current, renal disease. Safety and efficacy for pediatric use have not been established.

Drug interactions: No drug interaction studies have been conducted. Theoretically, antibiotic therapy could interfere with release of the active moiety.

Adverse effects: During the course of clinical trials, the most commonly reported side effects (5% to 8%) were headache, abdominal pain, nausea, and diarrhea; the rates did not clearly differ from those for a placebo. During postmarketing there are reports of a few cases of Kawasaki syndrome or hepatotoxicity, sometimes fatal, that were not seen earlier.

Dosage and availability: Balsalazide disodium is provided as 750-mg capsules. The usual adult dose is three capsules three times a day for eight weeks.

Patient monitoring: Like all agents that release 5-ASA, balsalazide has a potential for nephrotoxicity; thus, regular monitoring of renal function is mandatory.

Patient counseling: Women should be counseled to consult their physician if pregnancy occurs or is planned.

CETRORELIX (SEH-tro-REH-lix)

Cetrotide (SEH-tro-tide)Asta Medica Inc.FDA rating: 1-S

There are estimates that as many as one in every six couples now seeks medical help to overcome a problem of infertility. Cetrorelix, a synthetic decapeptide, may be used to control ovarian stimulation as part of a regimen of assisted reproduction. It is claimed to be able to make assisted reproduction not only more convenient but also safer. As an antagonist at gonadotropin hormone-releasing hormone (GnRH) receptors, it is the first such agent to be approved for therapeutic use.

Indication: Cetrorelix is indicated for the prevention of premature LH surges and, thus, premature ovulation in women undergoing controlled ovarian stimulation.

Pharmacology: By a positive feedback response to estradiol at mid-cycle, there is liberation of GnRH that results in a surge of luteinizing hormone (LH) release. This, in turn, induces the ovulation of a most-developed follicle from one of the ovaries. Cetrorelix competes at membrane receptors for GnRH in the anterior pituitary, where GnRH ordinarily induces synthesis and release of follicle-stimulating hormone (FSH) from specific pituitary cells. Thus, regulation of LH surge and ovulation may be achieved via the use of cetrorelix. The effect is reversible after its discontinuation.

Contraindications: Cetrorelix should not be used under these conditions: hypersensitivity to the peptide or to other extrinsic peptide hormones, to GnRH or analogs or to mannitol, or an existing state of pregnancy or lactation. Fetal absorption or abnormalities occurred when pregnant animals were exposed to cetrorelix. The drug is not intended for use by patients older than 65 years.

Precautions: If self-administration is planned, the patient must be well informed on proper use via the patient package insert (PPI). Only physicians qualified and experienced in fertility therapy should prescribe cetrorelix. Pregnancy must first be excluded.

Drug interactions: No formal studies of drug-drug interactions with cetrorelix have been performed.

Adverse effects: Severe anaphylactoid symptoms were observed in one patient exposed for seven months to cetrorelix for an indication other than fertility. However, no drug-related allergic reactions were reported during clinical trials for GnRH-suppression therapy. Elevation of enzymes (ALT, AST, GGT, or alkaline phosphatase) has been noted in 1%-2% of women receiving cetrorelix. The clinical significance of such changes was not determined. The incidence of an ovarian hyperstimulation syndrome was 3.5% in a sample of n=949. Nausea (1.3%) and headache (1.1%) were rarely reported. Local injection site reactions were transient, mild, and of short duration.

Dosage and availability: Cetrorelix acetate is marketed as an injectable after reconstitution. The sterile lyophilized powder is supplied in a glass vial, along with a solvent prefilled syringe containing Sterile Water for Injection. It is intended for subcutaneous (SC) use. The 1.0-ml vials supply 0.25 mg, and the 3.0-ml vials provide 3 mg of cetrorelix as the peptide (not acetate), as well as 54.8 or 164.4 mg of mannitol.

Cetrorelix is administered during the early- to mid-follicular phase of the menstrual cycle after ovarian stimulation with a gonadotropin preparation on day two or three.

Patient monitoring: Initially, tests to exclude pregnancy must be performed. In case of a history of liver problems, tests for elevation of hepatic enzymes may be appropriate.

Patient counseling: The patient must be well acquainted with proper technique and scheduling when cetrorelix is to be self-administered. A PPI is included with the product. It covers the preparation and administration of the drug and should be reviewed with the patient at the time of dispensing.

CEVIMELINE HCl (seh-VIH-meh-leen)

Evoxac (EE-vo-zak)Snow Brand PharmaceuticalsFDA rating: 1-S

In Sjögren syndrome, there is a failed coordination of neural, vascular, and secretory glandular functions. Recent findings suggest that this stems from an autoimmune state in which there is lymphocytic infiltration of the glands. Either lymphokines or an auto-antibody may then block the response of acetylcholine receptors. A new medication for stimulation of secretory gland function in Sjögren syndrome is the muscarinic agonist cevimeline. Previously, the sole option for this condition was pilocarpine.

Indication: The FDA has approved cevimeline for treating the symptoms of xerostomia (dry mouth) in patients with Sjögren syndrome. Data are now being gathered to support an indication for treatment of dry eyes.

Pharmacology: Cevimeline is an agonist at muscarinic cholinergic receptors; like other muscarinic agonists, such as pilocarpine, it can activate secretion of exocrine glands, such as salivary and lacrimal glands, via M2 receptors. Because the action of such agonists extends also to the myocardium and to the smooth muscle of the GI and GU tracts, unwanted effects in these systems are possible. However, cevimeline has greater specificity for M2 receptors than for the M3 receptors of the myocardium.

Contraindications: The drug is contraindicated in patients who have a hypersensitivity to any constituent of the product, persons having poorly controlled asthma, or those receiving treatment for acute iritis or narrow-angle glaucoma.

Precautions: Caution is advised when using cevimeline in the presence of cardiovascular disease (e.g., history of angina pectoris or myocardial infarct), because of its slowing of heart rate and altering of cardiac conduction. Use of cevimeline requires caution also in persons having well-controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease because of a tendency to narrow airways. Interference with visual acuity and depth perception may require avoidance of driving at night or other hazardous activities under reduced-lighting conditions. Caution is indicated when cevimeline is used in a patient having a history of kidney or gallstones, as the smooth muscle contracting effects may precipitate complications in the urinary or biliary tract. Cevimeline should be used during pregnancy only if the potential benefit justifies undefined fetal risk. There are no data to define safety and efficacy for pediatric patients. There should be particular care in using this therapy in elderly patients because of the potential for adverse events.

Drug interactions: Cevimeline may have adverse additive effects on cardiac conduction with beta-adrenergic blocking drugs, or on various systems in conjunction with other drugs that enhance cholinergic activity. Conversely, the drug might oppose the intended antimuscarinic action of other medicines. Drugs that inhibit or compete for the isozymes CYP 2D6 and/or 3A3/4 are likely to oppose inactivation of cevimeline and increase the risk for unwanted effects. For example, fluoxetine and paroxetine exert a substantial inhibition of CYP 2D6.

Adverse effects: In a U.S. clinical trial involving 484 patients who received from 30 mg t.i.d. to 60 mg t.i.d. cevimeline, there was 11% discontinuation owing to adverse events. Events associated with muscarinic agonism included, in descending order of frequency: excess sweating, nausea, rhinitis, diarrhea, hypersalivation, urinary frequency, asthenia, flushing, and polyuria. Only the first three were observed at clearly higher rates than for the placebo control group. These and a variety of other possible effects represent exaggerated parasympathetic activities.

Dosage and availability: Cevimeline is provided in white hard-gelatin capsules containing 30 mg of the active ingredient. The recommended dose is one capsule three times a day. Data do not support the use of higher doses.

Patient monitoring: Patients having significant renal or hepatic insufficiency should receive particular monitoring for their pharmacodynamic responses to cevimeline; it is unknown whether they may show modified pharmacokinetics with the drug.

Patient counseling: Patients should be made aware of the side effects that are possible; they should be warned that they might not be able to drive safely at night because of visual effects with limited light. They should be mindful of a need for rehydration if they experience profuse sweating. Women who might consider taking cevimeline during lactation should consult their pediatrician.

COLESEVELAM (KOE-le-SEV-e-lam)

Welchol (WELL-call)GelTexFDA rating: 1-S

Colesevelam is a nonabsorbable polymer that acts as a high-capacity bile acid sequestering agent.

Indication: Colesevelam is indicated for the treatment of elevated LDL cholesterol in primary hypercholesterolemia, either alone or in conjunction with inhibitors of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA). Before therapy is initiated, secondary causes of hypercholesterolemia should be excluded and a full lipid profile obtained.

Pharmacology: Colesevelam exerts a nonsystemic lipidemia-lowering action by sequestering bile acids, including the major bile acid in humans, glycocholic acid. This blocking of reabsorption and the normal recycling of bile acids has an end result of increasing the clearance of LDL cholesterol (LDL-C) from the blood and, thus, decreasing the serum LDL-C. When bile acids are decreased, there must be an up-regulation of the enzyme for increasing their synthesis from cholesterol, cholesterol 7-*-hydroxylase. The increased need for cholesterol causes the liver to raise the level of the cholesterol-synthesizing enzyme, HMG-CoA, while also increasing the number of LDL receptors. These changes cause a higher clearance of LDL-C from the blood.

Contraindications: Patients with bowel obstruction should not use colesevelam. Because it has not been tested in persons having a triglyceride level greater than 300 mg/dl, caution should be used in treating any such patients. It may be necessary to exercise caution in treating a patient having susceptibility to deficiency of the fat-soluble vitamins—A, D, E, and K—as their absorption depends on the presence of bile acids. Colesevelam is contraindicated in those who have shown hypersensitivity to any of the components of the medication.

Precautions: Safety and efficacy have not been established in persons with swallowing disorders or GI motility disorders, or in those who have had major GI surgeries. Thus, use in such patients should be with caution. Safety and efficacy for use by pediatric subjects have not been established.

Drug interactions: Colesevelam was not found to have a significant effect on the absorption of: digoxin, lovastatin, metoprolol, quinidine, valproic acid, or warfarin, which are known to interact with other lipid-lowering agents. It did decrease the absorption and AUC (11%) for a sustained-release verapamil preparation, but the clinical impact of this is uncertain.

Adverse effects: Colesevelam is said to have a lower rate of side effects than is seen with a current bile acid sequestrant, cholestyramine. The most common side effects are constipation, flatulence, dyspepsia, and headache. The possible impairment of absorption of vitamins by pregnant women has not been studied.

Dosage and availability: Colesevelam is made available as 625-mg tablets. The initial dosage recommended is three tablets twice daily with meals or six tablets once a day with a meal. This may be increased to seven per day. When used in conjunction with an inhibitor of HMG-CoA, four to six of the colesevelam 625-mg tablets may be taken either separately or at the same time, with a meal or meals.

Patient monitoring: Maintenance of therapeutic response may be monitored by means of standard analyses for LDL-C, HDL-C, APO-B, TG, and TC.

Patient counseling: The patient should be made aware that the medication is to be taken with liquid at meals either once or twice daily as directed by the physician. Patients should inform their physician if they become pregnant, are planning to do so, or are breastfeeding.

GEMTUZUMAB OZOGAMICIN (gem-TOO-zoo-mab)

Mylotarg (MY-lo-targ)Wyeth-AyerstFDA rating: 1-PV

Gemtuzumab ozogamicin solution for injection is the first targeted monoclonal antibody for use as a chemotherapy agent. It also is the first drug specifically approved to treat relapsed acute myeloid leukemia (AML) patients and the first in a new class of anticancer agents that utilizes the principle of "antibody-targeted chemotherapy." This antibody-targeted chemotherapy is based on a proprietary "linker" technology that combines a potent antitumor antibiotic with a monoclonal antibody that binds to an antigen found on cancer cells.

Indication: The FDA supported an accelerated approval for gemtuzumab ozogamicin for the treatment of patients aged 60 or older with relapsed CD33-positive AML who are poor candidates for conventional combination chemotherapy. If untreated, AML is rapidly fatal. For current treatment regimens, only about 20% of AML patients survive five years or longer.

Pharmacology: Gemtuzumab ozogamicin consists of a recombinant humanized IgG antibody linked to a potent cytotoxic antineoplastic antibiotic, calicheamicin. The antibody portion binds specifically to the CD33 antigen, which is a glycoprotein that commonly is expressed on the surface of both normal and leukemic myeloid blast cells, but not on normal undifferentiated hematopoietic stem cells. This permits the selective targeting of myeloid cells. After binding to the CD33 molecule, there is an internalization of the antibody-calicheamicin complexed with CD33 by endocytosis. Within the lysosome, there is release of the calicheamicin derivative that diffuses into the cell nucleus where it binds to DNA, causing strand breakage and cell death. The fact that normal as well as the leukemic myeloid cells are affected means that there will commonly be a substantial degree of myelosuppression.

Contraindications: The agent must not be used by any person who is hypersensitive to either gemtuzumab ozogamicin or to product components—anti-CD33 antibody (hP67.6), calicheamicin, or the inactive ingredients.

Precautions: Gemtuzumab ozogamicin should be administered only under the supervision of a physician who is experienced in use of cancer chemotherapy agents. Severe myelosuppression will occur in all patients receiving this drug in the recommended doses. All patients who receive leukemia therapies have an elevated risk of developing opportunistic infections and/or bleeding events because of deficits of both leukocytes and platelets. Patients who received gemtuzumab ozogamicin showed severe neutropenia (98%), severe thrombocytopenia (99%), and anemia (47%). Thus, careful hematologic monitoring is required.

Gemtuzumab ozogamicin can produce a postinfusion symptom complex of fever and chills and, less commonly, hypotension and dyspnea during the first 24 hours after infusion. The vital signs must be monitored during infusion and for four hours following infusion. Some patients developed severe liver function abnormalities, which were generally transient and reversible. Caution should be exercised when administering gemtuzumab ozogamicin to patients with existing hepatic or renal deficit. Also, it may cause fetal harm if administered to a pregnant woman. Gemtuzumab ozogamicin may provoke the tumor lysis syndrome for which prophylactic use of hydration and allopurinol is required to avoid adverse consequences of hyperuricemia.

Drug interactions: No formal drug-drug interaction studies have been conducted for gemtuzumab ozogamicin.

Adverse effects: The most common adverse events with gemtuzumab ozogamicin were fever, chills, nausea/vomiting/diarrhea, abdominal pain, stomatitis, dyspnea, asthenia, headache, neutropenia, epistaxis, thrombocytopenia, and hypokalemia. As for serious adverse effects, there was a 4% rate of severe mucositis. However, hair loss, a generally common side effect of antineoplastic chemotherapy, was not seen with gemtuzumab ozogamicin.

Dosage and availability: Gemtuzumab ozogamicin is supplied as 5 mg of lyophilized powder in 20-ml amber glass vials because of sensitivity to direct or indirect sunlight and unshielded fluorescent light. The contents are to be reconstituted into 5 ml of Sterile Water for Injection, USP. After storage at 2°-8°C, the powder should be allowed to reach room temperature before the solution is made. Vials should be inspected visually for complete dissolution and an absence of discoloration or particulate matter. Preparation of the solution should be done in a biological safety hood with the fluorescent lighting off. The solution may be kept for up to eight hours before its usage if refrigerated and light-protected. The proper volume is withdrawn from a vial and added to a 100-ml bag of 0.9% sodium chloride solution within a UV light-protectant bag. Contents of the IV bag should be used immediately.

The recommended dosage of gemtuzumab ozogamicin is 9 mg per square meter of body surface area by IV infusion over two hours. The solution MUST NOT be given as an intravenous push or bolus. Prior to onset of the infusion, patients should receive prophylactic doses of diphenhydramine, 50 mg p.o., and acetaminophen, 650-1000 mg p.o. Two more doses of acetaminophen in the same amount may be added at four and eight hours if needed. Vital signs must be monitored during and for four hours after the infusion. A second dose should be given with 14 days in between, whether full hematologic recovery has occurred or not. IV infusion may, but need not, use a central line, but the line used should pass through a 1.2-micron terminal filter.

Patient monitoring: Because patients treated with gemtuzumab ozogamicin are quite likely to experience severe thrombocytopenia, severe neutropenia, and/or anemia, careful hematologic monitoring is required. The high likelihood of systemic infections demands close monitoring so that proper anti-infective therapy can be instituted at the earliest signs of infection. Other appropriate testing includes electrolyte levels, tests of hepatic function, complete blood counts, and platelet counts.

Patient counseling: Any history of renal or hepatic injury must be elicited, as that is a serious consideration for disqualifying the patient from this therapy.

INSULIN ASPART (AAH-spart)

NovoLog (NO-vah-log)Novo Nordisk PharmaceuticalsFDA rating: 1-S

Insulin aspart is an analog of human insulin that differs only regarding the nature of one amino acid. It is produced by cultures of baker's yeast via recombinant DNA methodology. Whereas regular human insulin requires people with diabetes to inject their doses of insulin 30 minutes before eating, insulin aspart has a more rapid absorption, quicker onset, and a shorter duration of action. An immediate initiation of blood sugar lowering after its injection permits diabetes patients to inject themselves with insulin aspart immediately prior to eating rather than 30 minutes before. This affords patients an enhanced flexibility of diabetes control.

Indication: Insulin aspart is indicated for the control of hyperglycemia in treatment of adults with diabetes mellitus (DM). Its rapid onset and short duration of action compared with those of regular insulin allow its use as a before-meal component of therapy that must include a longer-acting form of insulin, especially for all Type 1 DM patients.

Pharmacology: Insulin binds to the insulin receptors of muscle and fat cells and lowers blood glucose by facilitating cellular uptake of glucose and by simultaneously inhibiting the output of glucose from the liver. A single substitution of aspartic acid for the amino acid proline at position B28 in insulin aspart reduces the tendency of the insulin molecule to form hexamers, as is seen with regular human insulin. Without that reaction, insulin aspart remains in a state allowing more rapid absorption after SC injection than for regular human insulin. Maximal lowering of blood glucose by insulin aspart occurs at one to three hours after injection, and the duration of its effect is three to five hours, contrasting with five to eight hours after regular human insulin.

Contraindications: Insulin aspart may not be used in patients having hypersensitivity to it or to any other component of the formulation. It is contraindicated also for use during an episode of hypoglycemia.

Precautions: The rapid onset of insulin aspart requires that a meal must follow immediately after an injection. Type 1 DM patients must be taking another, longer-acting form of insulin. Hypoglycemia and hypokalemia are possible adverse effects for any form of insulin; other drugs that promote hypoglycemia are described below (see "Drug interactions"). Potassium-lowering drugs such as diuretics increase risk of hypokalemia. Patients having these medication factors or pathologic factors that may elevate their susceptibility to these states require extra caution in therapy.

Drug interactions: Many medicinal agents can affect glucose metabolism so as to alter the required dose of insulin. In such instances, extra careful blood glucose monitoring is required in light of a possible need for dose adjustment.

Classes and agents that synergize and increase the risk for hypoglycemia include: the oral antidiabetic agents, inhibitors of angiotensin converting enzyme (ACE) or monoamine oxidase (MAO), salicylates, fibrates, sulfonamide antibacterials, disopyramide, propoxyphene, fluoxetine, and octreotide. Examples of drugs that may reduce the efficacy of insulin and require a greater dosage include: diuretics, phenothiazines, sympathomimetic agents, thyroid hormones, corticosteroids, danazol, niacin, somatotropin, isoniazid, estrogens, or progestogens (oral contraceptives). Some drugs may interact in either direction with insulin, including beta-adrenergic blockers, alcohol, clonidine, pentamidine, and lithium salts. Some agents may dangerously obscure the signs of hypoglycemia; these include beta-adrenergic blockers, clonidine, guanethidine, and reserpine.

Adverse effects: All insulin therapy may be associated with hypoglycemia, worsening of diabetic retinopathy, lipodystrophy, localized injection-site reactions, pruritus and skin rash, allergic reactions, sodium retention, and edema. Of these, acute hypoglycemia is the most common adverse effect.

Dosage and availability: Insulin aspart is supplied as 100 units/ml in either 10-ml vials or 3-ml PenFill cartridges to be used with a NovoPen 3 Insulin Delivery Device. If insulin aspart is to be mixed with NPH human insulin, it should be drawn into the syringe first, and the injection should be given immediately after the mixing. The recommended storage temperature for the product is between 2° and 8°C (36° to 46°F). Do not allow the product to freeze and do not use it if it has been frozen.

Patient monitoring: Self-monitoring of blood glucose should be supplemented by periodic checks on hemoglobin glycosylation level. For patients having renal or hepatic deficits, an especially careful glucose monitoring and a possible adjustment of insulin aspart dosage may be necessary.

Patient counseling: Broad patient education on diabetes management is highly desirable, if not essential. The diabetes patient should be quite mindful that the rapid onset of action with insulin aspart requires that an injection be followed immediately by a meal. Also, its shorter duration of action requires that Type 1 DM patients must employ another longer-acting insulin to maintain adequate glucose control around the clock. Patients must be made aware that any change in insulin regimen should be done cautiously and only under a physician's supervision, and that blood glucose monitoring should never be neglected. Also, they need to be aware that their insulin requirement may be altered during emotional disturbances, illness, or other sources of stress. Female patients should be advised to consult their physician if they intend to become pregnant, do become pregnant, or are planning to breastfeed, as insulin aspart has not been evaluated under these conditions. Be sure to inform the patient that the product should be refrigerated before usage, but DO NOT allow the product to freeze and DO NOT use it if it has been frozen.

INSULIN GLARGINE (GLAR-jean)

Lantus (LAN-tuhs)Aventis PharmaceuticalsFDA rating: 1-S

Insulin glargine is the first long-acting recombinant human insulin analog to be approved by the FDA. Its potency is nearly the same as that of human insulin, and it is intended for use by once-daily injection to maintain antihyperglycemic action through the 24 hours with a reduced risk of nocturnal hypoglycemia compared with prior formulations.

Indication: For once-daily SC injection in the treatment of adult and pediatric patients with Type 1 DM, or in adults with Type 2 DM who need long-acting insulin for the basal control of hyperglycemia.

Pharmacology: Insulin glargine is a product of recombinant DNA technology, consisting of human insulin modified in two ways. The first modification changes the isoelectric point of the molecule from pH 5.4 to 6.7, making it more soluble at a slightly acid pH and less soluble at the neutral pH found in SC injection sites. The second alteration maintains stability at the pH 4.0 of the formulation.

When delivered into tissues of neutral pH, the insulin is precipitated, which delays its absorption into the circulation from the SC depot. This provides a relatively constant mobilization profile that has no clear peak (unlike NPH insulin) but has a glucose-lowering effect that is spread across 24 hours.

Glargine insulin acts like other insulins to lower blood glucose by stimulating the glucose uptake of peripheral tissues, especially by fat and skeletal muscle, as well as by inhibiting hepatic glucose production. It also inhibits lipolysis by adipocytes, inhibits proteolysis, and enhances protein synthesis.

Contraindications: Hypersensitivity to the agent, insulin glargine, is a contraindication to its use.

Precautions: Glucose monitoring is recommended for all patients with diabetes. Any change in insulin type or dosage should be made with caution and only under medical supervision. Insulin glargine MUST NOT be diluted or mixed with any other preparation of insulin or other solution because doing so may cause a delayed onset of action.

Drug interactions: Numerous agents that alter glucose metabolism will affect the response to insulin glargine. According to the manufacturer's information, examples of those that may exaggerate hypoglycemia are oral hypoglycemics, ACE inhibitors, MAO inhibitors, disopyramide, propoxyphene, salicylates, sulfonamides, fibrates, fluoxetine, and octreotide.

Agents that may oppose the glucose-lowering effects of insulin glargine include: danazol, corticosteroids, diuretics, sympathomimetics, isoniazid, phenothiazines, estrogens and progestogens (oral contraceptives), somatropin, and thyroid hormones.

Medications that may either raise or lower the response to doses of insulin glargine are beta-adrenergic blockers, pentamidine, lithium, clonidine, and ethanol. Moreover, agents having sympatholytic action may mask the signs of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine.

Adverse effects: Like all insulin products, an extreme overdose of insulin glargine can cause life-threatening hypoglycemia. Other adverse events are allergic reactions, skin reactions (e.g., injection-site responses, pruritus and rash), lipodystrophy, sodium retention, and edema. Therapy with human insulins has been associated with aggravation of diabetic retinopathy; insulin glargine data are insufficient to support such a conclusion.

Dosage and availability: Insulin glargine is supplied as a clear aqueous solution that contains 100 IU per ml, in either 5- or 10-ml vials, or in 3-ml cartridges for use only in the OptiPen One Insulin Delivery Device.

Patient monitoring: Glucose monitoring is fundamental for control of all DM therapy. Monitoring of the clinical response is especially important for patients taking other medications affecting glucose metabolism and/or regulation (see "Drug interactions," above).

Patient counseling: The patient must be fully aware that insulin glargine MUST NOT be mixed with any other insulin preparation. The insulin must be used only if the solution is clear, colorless, and lacking any particles. Changing of one's insulin dosing must be done cautiously and only under direct medical supervision. Patients should be reminded that hypoglycemia may occur, and its timing is likely to differ from that which they may have encountered in using another insulin product. Extremes of blood glucose may be accompanied by impairment of ability to concentrate and react. The supervising physician should be informed of any occurrence of allergic reactions or other skin reactions. DM patients should inform their physician if they become pregnant or intend to do so. All diabetes patients need to be well educated on self-care, glucose monitoring, good injection techniques, dietary regulation, and recognizing and handling of hypoglycemia.

LINEZOLID (lin-NEH-zuh-lid)

Zyvox (ZY-vox)Pharmacia Corp.FDA rating: 1-P

Linezolid represents a new class of synthetic antibacterial agents, the oxazolidinones. This is the first completely new class of antibacterials to be introduced in 35 years.

Indication: Linezolid is indicated for the treatment of resistant gram-positive bacterial infections in adults. These include pneumonias (both hospital- and community-acquired), skin infections (uncomplicated or complicated), and vancomycin-resistant Enterococcus (VRE) infections caused by indicated bacteria. This includes approval for use in: complicated skin infections or nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA); concurrent bacteremia associated with vancomycin-resistant Enterococcus faecium; or concurrent bacteremia associated with community-acquired pneumonia caused by the penicillin-susceptible Streptococcus pneumoniae.

Pharmacology: Linezolid acts against bacteria by blocking protein synthesis at a very early point in the process, which differs from any other antibacterial. Therefore, cross-resistance is unlikely. Without such protein production, bacteria cannot reproduce. The spectrum of activity includes not only resistant aerobic gram-positive bacteria but also some anaerobic and gram-negative species.

Contraindications: Linezolid is contraindicated for patients having a known hypersensitivity to any component of the formulation.

Precautions: Because linezolid inhibits MAO, caution should be exercised when using the drug in persons having uncontrolled hypertension or hyperthyroidism, carcinoid syndrome, or pheochromocytoma. These conditions are responsible for excess release of (or sensitivity to) norepinephrine or serotonin. Pseudomembranous colitis must be considered in any patient who presents with diarrhea after using an antibacterial agent such as linezolid. This condition may range in severity from mild to life-threatening. The etiology may be a superinfection by Clostridium difficile.

Drug interactions: Linezolid is not metabolized by P450 enzymes and does not inhibit or induce their activity. Thus, it is not subject to interaction with many medications that are metabolized by that enzyme system. It is possible to coadminister warfarin or phenytoin without dosage problems. Neither is there a pharmacokinetic interaction with gentamicin or aztreonam. Because linezolid is a reversible, nonselective inhibitor of MAO, it may interact with adrenergic agents, e.g., to enhance the pressor activity of tyramine found in foods or to synergize such vasoconstrictors as phenylpropanolamine or pseudoephedrine. One study found that a potentiation of serotonergic actions occurred when healthy volunteers took linezolid in conjunction with dextromethorphan. There are no data as yet concerning possible interactions with any of the SSRIs. However, the potential for an interaction exists, due to the ability of the SSRIs to potentiate the action of serotonin.

Adverse effects: Linezolid is generally well tolerated; its adverse-event profile in human trials was similar to that of positive controls. The most common events reported were diarrhea (8.3%), headache (6.5%), nausea (6.2%), and vomiting (3.7%). These were usually mild to moderate in intensity and limited in duration.

Dosage and availability: Linezolid is supplied for IV infusion as a sterile isotonic solution containing 200 mg/ml, as film-coated compressed tablets containing 400 or 600 mg, and as an oral suspension providing 100 mg/5 ml. Depending upon the infecting organism, the dosage ranges from 400 mg to 600 mg every 12 hours for 10 to 28 days. The tablets have 100% bioavailability, allowing physicians to use the IV and tablet forms interchangeably without a dosage adjustment. The agent may be taken orally without regard for presence of food in the stomach. Dose adjustments are not needed for geriatric patients or across genders.

Patient monitoring: Certain patients—those having a bleeding problem, those taking a medicine that lowers count or inhibits platelet function, or those having a prior state of thrombocytopenia—should have periodic monitoring of their platelet levels while taking linezolid.

Patient counseling: Inform patients that oral linezolid may be taken with or without food. Phenylketonuric persons should not take the suspension, as it contains phenylalanine while the tablets do not. These patients should consult with their physician if they have hypertension or are taking vasoconstrictor medication, SSRIs, or other antidepressants. They should be advised to avoid ingesting large quantities of foods or beverages containing tyramine, e.g., fermented, pickled, or aged items (such as cheeses or dried meats); sauerkraut; soy sauce; tap beers; or red wines.

LOPINAVIR (lo-PIN-uh-vir)/

RITONAVIR (ri-TAHN-uh-vir)Kaletra (kuh-LEE-tra)AbbottFDA rating: 1,4-P

This is a product consisting of a coformulation of lopinavir—a new anti-HIV protease inhibitor—and ritonavir, which was marketed in 1996 as a protease inhibitor. In this case, however, ritonavir is included for the sole purpose of amplifying plasma levels of the lopinavir by its metabolic inhibition. Both capsules and an oral solution are available.

Indication: Lopinavir/ritonavir is provided for treatment of HIV-1 infection in adults or in pediatric patients aged six months and older. It is intended to be used jointly with other antiretroviral agents.

Pharmacology: Lopinavir acts as an inhibitor of HIV protease enzyme, which is essential to the production of mature new virions via the cleavage of a polyprotein (Gag-Pol). The resulting viral particles are immature and noninfectious. Development of resistance has been detected in vitro but has not yet been characterized in vivo.

Contraindications: This product must not be used in any patient having hypersensitivity to either lopinavir or ritonavir. Because the ritonavir component is an inhibitor of the P450 isoenzyme CYP 3A, this product should not be used concurrently with certain drugs that depend upon CYP 3A for biotransformation. Contraindicated because of possible dangerous enhancement of their toxicity are: flecainide, propafenone, astemizole, all of the available ergot alkaloids, midazolam, triazolam, pimozide, and two agents recently withdrawn in the United States—terfenadine and cisapride. Other agents that should not be combined with this agent, because they may reduce the antiviral response from lopinavir and thus favor the development of resistance, include rifampin and St. John's wort (Hypericum perforatum).

Precautions: Accidental ingestion of the oral solution by a child could cause a significant level of toxicity from the ethanol in the vehicle, even approaching lethality. Because lopinavir is metabolized mainly by the liver, its use in hepatic-deficient persons should be approached with caution, as plasma levels may be increased.

Drug interactions: See "Contraindications," above. In addition, potentially significant or significant interactions involve other protease inhibitor anti-HIV agents plus the reverse transcriptase inhibitors. Furthermore, numerous drugs from many other pharmacologic classes need to be considered regarding some potentially significant interactions. For example, the level of cardiovascular adverse side effects from sildenafil may be increased, as may a risk for myopathy from HMG-CoA reductase inhibitors. (Consult manufacturer's product information for full details of both groups of interactions.)

Adverse effects: Most prominent among the treatment-emergent adverse effects in adult patients also receiving HIV antiviral drugs from another class were diarrhea, nausea, and vomiting. All others occurred at rates < 3.5%. In pediatric patients, only rash occurred at a rate of 2% or greater. Pancreatitis, including cases with fatal outcomes, has been observed; marked triglyceride elevations may be a risk factor. Patients with advanced HIV disease are at higher risk, as are those with a history of pancreatitis. Instances of new-onset DM, exacerbation of prior diabetes, or hyperglycemia have been reported in some HIV-infected patients taking protease inhibitor therapies. The incidence and causal basis for these events are not known.

Dosage and availability: Lopinavir/ritonavir is provided in soft-gelatin capsules that contain a 4:1 ratio, 133.3 mg and 33.3 mg, respectively. The hydroalcoholic oral solution provides 400 mg and 100 mg, respectively, in each 5 ml. It also contains many inactive solubilizing, stabilizing, or flavoring ingredients.

Recommended storage is at 36°-46°F (2°-8°C). The recommended adult dosage is 400/100 mg (three capsules or 5.0 ml) twice a day with food. For children six months to 12 years of age, the recommended dosage is 12 mg/kg of lopinavir and 3 mg/kg of ritonavir twice daily for those who weigh from seven to < 15 kg, or 10 mg/kg of lopinavir and 3 mg/kg of ritonavir twice daily for those weighing 15-40 kg. This should be taken with food. (Doses as volume of the oral solution per body weight are supplied by the manufacturer in the product information.)

Patient monitoring: Efficacy is monitored in terms of the levels of HIV RNA and of CD4 cell count. Elevations of serum lipase or amylase may indicate developing pancreatitis; thus, such lab measures would be desirable if any adverse symptoms suggest that possibility, e.g., abdominal pain, nausea, and vomiting.

Patient counseling: If capsules or solution are kept at room temperature, rather than in a refrigerator, they should be used within two months. Exposure to excessive heat should be avoided. The PPI should be made available for the patient to comply with the product's label, "ALERT: Find out about drugs that should NOT be taken with KALETRA." The list is rather extensive and includes:

• Dihydroergotamine, ergonovine, ergotamine, and methylergonovine such as Cafergot, Migranal, D.H.E. 45, Ergotrate maleate, Methergine, and others

• Halcion (triazolam)

• Hismanal (astemizole)

• Orap (pimozide)

• Propulsid (cisapride)

• Rhythmol (propafenone)

• Seldane (terfenadine)

• Tambocor (flecainide)

• Versed (midazolam)

• Rifampin, also known as Rimactane, Rifadin, Rifater, or Rifamate

• St. John's wort (Hypericum perforatum)

• Mevacor (lovastatin)

• Zocor (simvastatin)

• Lipitor (atorvastatin)

• Baycol (cerivastatin)

The PPI explains the reason for avoiding each drug or drug class.

MELOXICAM (meh-LOX-i-cam)

Mobic (MO-bik)Boehringer IngelheimFDA rating: 1-S

Meloxicam is a new addition to the nonsteroidal anti-inflammatory drug (NSAID) family in the United States, but it has a track record of prior use in millions of patients across more than 100 countries. Chemically, it is a member of the enolic acid group. It is claimed to have GI tolerability comparable to that of placebo.

Indication: Meloxicam is indicated for relief of the symptoms and signs of osteoarthritis.

Pharmacology: Like other NSAIDs, meloxicam is believed to produce its anti-inflammatory, analgesic, and antipyretic effects by inhibition of cyclooxygenase and consequent lowering of prostaglandin synthesis and release.

Contraindications: Meloxicam is contraindicated for patients with known hypersensitivity to the agent. It should not be given to persons who have a history of urticaria, asthma, or other allergic-type reactions after taking aspirin or other NSAIDs. It should not be recommended for women who are or may become pregnant. Use in severely renal-impaired patients is not recommended.

Precautions: GI ulceration can develop with little or no warning. Patients and physicians should be alert to the earliest signs and symptoms of GI bleeding. Meloxicam should be used with caution in patients with asthma or in the presence of fluid retention, heart failure, or hypertension. Based on animal studies, the use of meloxicam during the third trimester of pregnancy or during lactation should be avoided. Safety and efficacy for pediatric use have not been determined. Hepatic function tests may show a minimal elevation in up to 15% of patients.

Drug interactions: Reports that NSAIDs reduce the efficacy of ACE inhibitors should be considered. Concurrent ingestion of aspirin tends to lower the clearance of meloxicam and may be expected to enhance the potential for adverse events. As with other NSAIDs, meloxicam showed a reduction of lithium clearance rate, presumably because of its action on renal prostaglandin. Similarly, the natriuretic effects of furosemide or thiazides tend to be reduced by NSAIDs. Prior treatment for four days with cholestyramine will increase the clearance of meloxicam. Methotrexate, cimetidine, and digoxin showed no pharmacokinetic interaction with meloxicam. Patients taking an oral anticoagulant must be monitored for any change in its clinical endpoints.

Adverse effects: Tolerability to meloxicam in clinical trials was good. The most common effects associated with the use of meloxicam were diarrhea, dyspepsia, and nausea, but these generally occurred in fewer than 5% of patients, levels equivalent to a placebo group.

Dosage and availability: The recommended dose, both initially and for maintenance in osteoarthritis, is one 7.5-mg tablet daily. Some patients may gain additional benefit by increasing the dose to 15 mg once daily; this is the maximum recommended dose. Patients having severe renal failure or needing dialysis should not exceed 7.5 mg per day. If a prospective patient is dehydrated, therapy should be delayed until after he or she is rehydrated. Tablets may be taken without regard to timing of meals.

Patient monitoring: Any patient reporting possible hepatic effects should be fully evaluated for functional changes. Patients who are taking anticoagulants, as well as those who have a platelet or other clotting disorder, should be monitored for their clotting status because of NSAIDs' action to hinder platelet aggregation.

Patient counseling: Patients should be warned to report to their physicians any signs or symptoms of GI ulceration, bleeding, skin rash, weight gain, or edema. Patients should know the warning signs and symptoms of hepatic toxicity (e.g., nausea, fatigue, lethargy, pruritus, flu-like symptoms). Patients should be mindful to stop therapy and seek immediate medical attention if such symptoms appear.

MIFEPRISTONE (MIF-eh-PRIH-stone)

Mifeprex (MIF-eh-prex)Danco LaboratoriesFDA rating: 1-P

Mifepristone is a substituted 19-nor steroid having antiprogestational action that permits its use to oppose the maintenance of pregnancy. Final approval by the FDA of this agent, which has been used for an abortion by more than 500,000 women in Europe, came in the midst of a continuing moral and political opposition and after many delays. It is not to be available through pharmacies but exclusively through direct physician dispensing, not only by abortion clinic doctors but also by hospital-based obstetricians and gynecologists, as well as properly trained primary care physicians.

Indication: Mifepristone is indicated for the medical termination of intrauterine pregnancy through 49 days after the start of a woman's last period. This enables termination of an early-stage pregnancy by a nonsurgical method.

Pharmacology: Mifepristone competes at hormone receptors for progesterone to block endometrial and myometrial effects of progesterone that are essential to preparing the lining of the uterus for a fertilized egg, and to maintaining the pregnancy. The treatment sensitizes the uterine muscle to contraction-inducing activity of the prostaglandins. Thus, when mifepristone is followed by the prostanoid agent, misoprostol, there is optimal uterine stimulant activity; pregnancy is aborted, and the expulsion of the embryo most likely occurs at the woman's home. Associated bleeding and cramping are a normal part of the process. Women may experience bleeding of a degree similar to or greater than a heavy menstrual period. They may anticipate continued bleeding or spotting for an average of nine to 16 days. Mifepristone also exerts antiglucocorticoid and weak antiandrogenic activities.

Contraindications: Use of mifepristone and misoprostol for the termination of pregnancy is contraindicated in patients having any of the following conditions: history of hypersensitivity to mifepristone, misoprostol, or other prostaglandin; confirmed or suspected ectopic pregnancy or undiagnosed uterine mass (the procedure will not terminate an ectopic pregnancy); having an IUD in place; chronic adrenal failure or other reasons for long-term corticosteroid therapy; current anticoagulant therapy, hemorrhagic disorders, or an inherited porphyria; inadequate access to medical facilities equipped to provide emergency treatment of incomplete abortion, blood transfusions, and emergency resuscitation from first visit until discharged by the responsible physician; inability to understand the effects of the procedure or to comply with its regimen; lack of review of the Medication Guide and the Patient Agreement provided.

Precautions: Excessive bleeding may require use of vasoconstrictors, curettage, IV infusions of saline and/or blood transfusions. Use of the procedure is assumed to require preventive measures similar to those taken before and during a surgical abortion to prevent Rh immunization. There are no data on the safety and efficacy of mifepristone in women having chronic medical conditions such as cardiovascular, respiratory, hypertensive, hepatic, or renal disease; severe anemia; heavy smoking; or insulin-dependent DM. Women who are above 35 years of age and who also smoke 10 or more cigarettes per day should be treated with caution, because such women generally were excluded from clinical trials. Ultrasonographic or clinical examination is necessary to confirm complete termination of pregnancy after this treatment procedure.

Drug interactions: Mifepristone is metabolized via CYP 3A4; thus, interactions with drugs metabolized by this route are possible. Due to its slow elimination, mifepristone may inhibit the metabolism of other drugs dependent upon this system.

Adverse effects: In some cases, women may have severe hemorrhage and may need to contact their physician immediately. A few women who take this agent will need a surgical procedure to end the pregnancy or to stop heavy bleeding. Side effects may include nausea and vomiting, headache, or diarrhea (from intestinal muscle activation by misoprostol).

Dosage and availability: Mifepristone tablets are light yellow in color, cylindrical, and biconvex, containing 200 mg of the steroid. A woman using this method makes three visits to a doctor's office or clinic over a two-week period. At the first visit, she receives an FDA-approved Medication Guide, which explains how the "early option" works; she is counseled and given three tablets of mifepristone. Two days later she returns, receives two tablets each containing 200 mcg of misoprostol. A follow-up visit about 12 days later is to confirm that the pregnancy has been terminated.

Patient monitoring: Changes in human chorionic gonadotropin (hCG) will not aid in determining successful termination of the pregnancy until at least 10 days after the drug has been given.

In cases where excessive bleeding occurs, hemoglobin, hematocrit, and RBC should be monitored.

Patient counseling: Patients should be provided with the Medication Guide on their first visit to the clinic. This guide addresses frequently asked questions about the medication and includes a Patient Agreement form which documents that the required counseling took place. Although the mifepristone is to be administered in a doctor's office or clinic, pharmacists can be of help by having a copy of the guide and being available to answer any questions their patients might have.

References are available on 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. After being approved in March 2000, alosetron was removed from the market in November because of:

a. Reports of lack of effect
b. Reports of severe constipation
c. Reports of liver damage
d. Excessive incidence of anaphylaxis

2. Argatroban:

a. Should be administered at half the usual dose when given with heparin
b. Is a dietary supplement
c. Is indicated for the treatment of thrombosis in patients with heparin-induced thrombocytopenia
d. Requires the presence of antithrombin III in order to work

3. Balsalazide disodium is approved for a course of therapy of no more than:

a. One year
b. 48 weeks
c. 24 weeks
d. 12 weeks

4. Compared with its metabolite, balsalazide disodium:

a. Is more active
b. Is less active
c. Has the same activity
d. Has no activity at all

5. Cetrorelix should be administered only by physicians qualified and experienced in fertility therapy.

a. True
b. False

6. In treating xerostomia, cevimeline acts as a:

a. Nicotinic agonist
b. Nicotinic antagonist
c. Muscarinic agonist
d. Muscarinic antagonist

7. Cevimeline should be used with caution when treating patients with cardiovascular disease, because the drug may:

a. Cause tachycardia
b. Cause bradycardia
c. Cause pericardial effusion
d. Cause mitral valve regurgitation

8. Which of the following is not a side effect of colesevelam?

a. Dyspepsia
b. Headache
c. Flatulence
d. Diarrhea

9. When dosing colesevelam, the regimen may be given as:

a. One tablet four times daily
b. Two tablets three times daily
c. Three tablets twice daily
d. Four tablets once daily

10. Severe myelosuppression occurs in all patients receiving gemtuzumab ozogamicin.

a. True
b. False

11. The primary advantage of insulin aspart over regular human insulin is insulin aspart's:

a. Smaller dosing requirements
b. Longer duration of action
c. Stability when frozen
d. Quicker onset and shorter duration of action

12. When counseling a patient about using insulin aspart, the pharmacist should stress:

a. The importance of eating a meal immediately after taking a dose
b. That the patient should never let his or her serum glucose get below 110 mg/dl
c. This form of insulin should not be mixed with others
d. The patient must not eat until at least an hour after dosing

13. Insulin glargine:

a. Offers a lower potential for nocturnal hypoglycemia through its longer duration of action
b. Can be mixed with other forms of insulin to tailor a patient's regimen
c. Is a short-acting form of human insulin
d. Derives its long duration of action by precipitating in the acid pH of the tissues into which it is injected

14. Insulin glargine is indicated for:

a. Patients with Type 1 diabetes only
b. Adult patients only
c. Patients with Type 1 or Type 2 diabetes who need more control
d. The rapid correction of severe hyperglycemia

15. The spectrum of activity of linezolid includes resistant aerobic gram-positive bacteria and also some anaerobic and gram-negative species.

a. True
b. False

16. A patient taking pseudoephedrine who is prescribed linezolid might be put at risk for:

a. Hypertension
b. Hypotension
c. Reduced effectiveness of the antibiotic
d. Hepatotoxicity

17. The presence of ritonavir in lopinavir/ritonavir is for the purpose of:

a. Preventing lopinavir from causing neurotoxicity
b. Lending its antiviral effect to provide synergistic activity
c. Solubilizing the lopinavir for the oral solution
d. Inhibiting metabolism of the lopinavir

18. In clinical trials, the incidence of gastrointestinal side effects with meloxicam generally were:

a. 10% to 12%
b. 7% to 8%
c. Less than 5%
d. Less than 1%

19. The maximum recommended dose of meloxicam is:

a. 7.5 mg daily
b. 15 mg daily
c. 30 mg daily
d. 45 mg daily

20. The use of mifepristone to terminate a pregnancy requires three visits to the clinic.

a. True
b. False

 

Marvin Davis. New Drug Approvals--2000 Part 1. Drug Topics 2001;3:51.