Tranylcypromine

IN THIS ARTICLE, I'll acquaint you with seven new drugs marketed in the first half of 2002, including:

* olmesartan medoxomil, a new angiotensin II receptor blocker indicated for hypertension

* frovatriptan succinate, a triptan indicated for migraine headaches

* ertapenem sodium, the third carbapenem antibiotic to hit the market. Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information regarding each drug's safety during pregnancy and breast-feeding. Also consult the package insert, your pharmacist, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions* for all drugs.

Antihypertensive drug

Olmesartan medoxomil

A dose a day keeps hypertension at bay.

Olmesartan medoxomil (Benicar; Sankyo, Forest) is the seventh angiotensin II receptor blocker (ARB) to be marketed in the United States. Angiotensin II is a potent vasoconstrictor; inhibiting its action relaxes blood vessels and lowers blood pressure. Unlike angiotensin-converting enzyme (ACE) inhibitors, which inhibit the enzyme that catalyzes the conversion of angiotensin I to angiotensin II, olmesartan and other ARBs directly block the binding of angiotensin II to receptor sites.

Like other ARBs, olmesartan is indicated to treat hypertension and may be used alone or in combination with another antihypertensive drug, most often a thiazide diuretic. A combination formulation that also contains hydrochlorothiazide is under development.

Olmesartan and other ARBs are generally well tolerated and cause few adverse reactions. Unlike ACE inhibitors, ARBs don't block the breakdown of bradykinin, so they're unlikely to cause coughing, a common adverse reaction to ACE inhibitors. Comparative studies haven't proven one ARB to be superior to another in the treatment of hypertension, but all are less effective in black patients than in others.

Some ARBs can be given twice daily to improve the antihypertensive response. However, olmesartan has a relatively long half-life and its action persists for 24 hours, so switching to the less-convenient twice-daily dosage schedule offers no advantage.

Precautions: (1) Use caution when giving olmesartan to patients who are volume-- or salt-depleted, including those taking diuretics, and lower the dosage if indicated to prevent symptomatic hypotension. (2) Use caution in patients with renal impairment or renal artery stenosis because ARBs can cause changes in renal function. (3) Olmesartan is contraindicated for use during pregnancy; discontinue it as soon as possible if the patient becomes pregnant. Adverse reaction: dizziness Supplied as: 5-mg, 20-mg, and 40-mg film-coated oral tablets

Dosage: Initially, 20 mg once a day (in patients who aren't volume-depleted); may be increased to 40 mg/day after 2 weeks

Nursing considerations: (1) Tell the patient that olmesartan may be taken without regard to food.

(2) Warn a female patient of childbearing potential not to become pregnant during therapy and tell her to notify her health care provider immediately if she becomes pregnant while taking olmesartan. (3) Monitor the patients blood pressure to check for hypotension and evaluate the effectiveness of therapy. Drug for migraine

Frovatriptan succinate

New triptan trips up headaches.

The sixth triptan marketed to treat migraine headaches, frovatriptan succinate (Frova; Elan, UCB) relieves pain by constricting cranial vessels, inhibiting neuropeptide release, and reducing nerve impulse transmission along trigeminal pain pathways. It's indicated to treat acute migraine with aura (classic migraine) or without aura (common migraine) in adults. Besides easing headache pain, it may relieve the nausea, vomiting, photophobia, and phonophobia associated with migraine attacks. Frovatriptan isn't indicated for basilar or hemiplegic migraines or for migraine prophylaxis.

Overall, the triptans are similar in effectiveness. Because of individual differences, however, some patients may respond better to one than another. In clinical trials, frovatriptan was less effective than other triptans for some patients because of its relatively slow onset of action. But in those for whom it works, it may be better at preventing recurring headaches because of its long duration of action.

Precautions: (1) Contraindicated in patients with ischemic heart disease, such as angina pectoris and myocardial infarction (MI), and in those with signs and symptoms consistent with ischemic heart disease, coronary artery vasospasm, or other significant cardiac disease. (2) Contraindicated in patients with uncontrolled hypertension. (3) Contraindicated in patients with cerebrovascular disease (such as stroke or transient ischemic attacks). (4) Contraindicated in patients with peripheral vascular disease or intestinal ischemia.

(5) Contraindicated within 24 hours of treatment with another triptan or an ergot-- type medication such as ergotamine or dihydroergotamine because of the risk of an additive vasospastic reaction. (6) Use caution in patients also being treated with a monoamine oxidase type A inhibitor such as tranylcypromine (Parnate); avoid concomitant use if possible. (7) Use caution in patients being treated with a selective serotonin reuptake inhibitor such as fluoxetine (Prozac) because of infrequent reports of weakness, hyperreflexia, and incoordination.

Adverse reactions: dizziness, fatigue, flushing, headache, paresthesia, hot or cold sensation, dry mouth, chest pain; rarely, cardiovascular or cerebrovascular events (MI, coronary artery vasospasm, arrhythmias, stroke, cerebral or subarachnoid hemorrhage), peripheral vascular ischemia, and colonic ischemia with abdominal pain and bloody diarrhea

Supplied as: 2.5-mg oral tablets

Dosage: Initially, 2.5 mg with fluids. If headache recurs after initial relief, give another 2.5-mg dose at least 2 hours after the first dose. Total daily dosage: not to exceed 7.5 mg administered at intervals of at least 2 hours

Nursing considerations: (1) The bioavailability of frovatriptan is unaffected by food, but food delays peak concentrations by about 1 hour. (2) It's not known whether a second dose of frovatriptan would be effective in a patient who doesn't respond to the first dose. (3) If the patient has risk factors for coronary artery disease (CAD), such as hypertension, diabetes, smoking, or obesity, he should undergo a cardiovascular evaluation and not use frovatriptan unless he's reasonably free from underlying disease. If frovatriptan is prescribed for a patient with CAD risk factors, he should take the first dose under medical supervision. (4) Urge a patient who's an intermittent long-term user of frovatriptan or who has risk factors associated with CAD to undergo periodic cardiovascular evaluations.

Antibiotic

Ertapenem sodium

Broad-spectrum action in parenteral form

The third carbapenem antibiotic to be marketed in the United States, ertapenem sodium (Invanz, Merck) has a broad spectrum of action that includes many Gramnegative and Gram-positive aerobic and anaerobic bacteria. Like the other carbapenems (imipenem and meropenem), its administered parenterally.

Indications for ertapenem include moderate to severe community-acquired pneumonia, complicated skin and skin structure infections, complicated intraabdominal infections, complicated urinary tract infections, and acute pelvic infections caused by susceptible strains of bacteria.

Ertapenem has a longer duration of action than imipenem and meropenem and is administered just once every 24 hours (versus every 6 or 8 hours, respectively, for the other two drugs). This more convenient dosage regimen gives it an advantage over the other drugs in its class.

Precautions: (1) Contraindicated in patients with known hypersensitivity to any of the carbapenems or in patients with a history of an anaphylactic reaction to a penicillin or any other betalactam antibiotic, including the cephalosporins.

(2) Intramuscular (I.M.) injection of ertapenem is contraindicated in patients who are hypersensitive to local anesthetics of the amide type (such as lidocaine) because lidocaine is used as a diluent when the drug is prepared for LM. administration. (3) Use cautiously in patients with a history of seizures, which were experienced by a very small number of patients in clinical studies. (4) Reduce the dosage in patients with severe renal insufficiency (creatinine clearance less than 31 ml/minute).

(5) Because of the potential seizure risk associated with higher concentrations of the antibiotic, the concurrent use of probenecid to extend the half-life of ertapenem isn't recommended.

Adverse reactions: diarrhea, local reactions at the infusion site (such as extravasation and phlebitis), nausea, headache, vaginitis; rarely, seizures

Supplied as: a lyophilized powder in single-dose vials in an amount equivalent to 1 gram of ertapenem

Dosage: 1 gram once a day for up to 14 days intravenously (I.V.), or up to 7 days I.M. Consult the product labeling for special dosage considerations for patients with renal impairment, including those on dialysis.

Nursing considerations: (1) For I.V. use, reconstitute vial contents with 10 ml of water for injection, bacteriostatic water for injection, or 0.9% sodium chloride injection. Transfer the solution to 50 ml of 0.9% sodium chloride injection and infuse over 30 minutes. Complete the infusion within 6 hours of reconstituting the drug. (2) For I.M. use, reconstitute vial contents with 3.2 ml of 1% lidocaine injection (without epinephrine). Give the solution within 1 hour of preparation by deep LM. injection into a large muscle mass, such as the gluteal muscle or lateral part of the thigh. (3) Don't use diluents containing dextrose and don't mix or infuse ertapenem with other medications. (4) Monitor the patient for diarrhea, which may indicate pseudomembranous colitis-a potential complication associated with most antibiotics.

Anti-inflammatory drug

Valdecoxib

Third selective COX-2 inhibitor to hit the market

Valdecoxib (Bextra; Pfizer, Pharmacia), a nonsteroidal anti-inflammatory drug (NSAID), joins celecoxib and rofecoxib as the third selective cyclooxygenase-2 (COX-2) inhibitor to be marketed in the United States. Older NSAIDs such as ibuprofen inhibit the action of both cyclooxygenase enzymes (COX-1 and COX-2) required for the synthesis of prostaglandins. Inhibiting COX-1, which isn't necessary for antiinflammatory effects, also inhibits the role of prostaglandins in protecting gastric mucosa and may lead to gastrointestinal (GI) adverse reactions. Given at therapeutic doses, the selective COX-2 inhibitors offer the same anti-inflammatory benefits as the older COX-1 and COX-2 inhibitors with a lower risk of serious GI adverse reactions.

Valdecoxib is indicated for symptom relief in osteoarthritis, adult rheumatoid arthritis, and primary dysmenorrhea. Unlike aspirin and some other older NSAIDs, valdecoxib and the other selective COX-2 inhibitors don't inhibit platelet aggregation, so they're not an appropriate substitute for aspirin for cardiovascular prophylaxis.

Precautions: (1) Contraindicated in patients who've experienced asthma, urticaria, or allergic-type reactions after taking aspirin or another NSAID because of the risk of anaphylactic reactions. (2) Like celecoxib (but not rofecoxib), valdecoxib is contraindicated in patients who have demonstrated allergic-type reactions to sulfonamides. (3) Valdecoxib has infrequently caused serious skin reactions. Discontinue use of valdecoxib at the first appearance of a skin rash or any other sign of hypersensitivity (4) Use caution in patients with a history of peptic ulcer disease or GI bleeding or with risk factors for GI bleeding, such as treatment with oral corticosteroids or anticoagulants, older age, smoking, and alcoholism. (5) Use caution in patients with fluid retention, hypertension, or heart failure because fluid retention and edema have been experienced by some patients treated with NSAIDs. (6) Monitor for adverse renal effects in patients on long-term NSAID therapy, elderly patients, patients with impaired renal or hepatic function or heart failure, and those taking a diuretic or ACE inhibitor. Not recommended for patients with severe renal impairment. (7) Monitor for adverse hepatic effects, which have been rarely reported with other NSAIDs. Not recommended for patients with severe hepatic impairment. (8) Closely monitor patients taking warfarin concurrently; valdecoxib may increase international normalized ratio values. (9) Valdecoxib may decrease the natriuretic effect of thiazide diuretics and furosemide, decrease the antihypertensive effect of ACE inhibitors, and increase the serum concentration of lithium, increasing the risk of lithium toxicity. Valdecoxib is metabolized via the CYP 3A4 and CYP 2C9 pathways and may interact with medications that inhibit these pathways, such as fluconazole. See the product labeling for a complete list of potential drug interactions.

Adverse reactions: dyspepsia, nausea, diarrhea, rash

Supplied as: 10-mg and 20-mg tablets

Dosage: 10 mg once a day for osteoarthritis and rheumatoid arthritis; 20 mg twice a day as needed for dysmenorrhea

Nursing considerations: (1) Tell the patient that she can take valdecoxib without regard to food. (2) Inform her that she may not obtain consistent pain relief until she's been taking the drug for several days. (3) Teach her to report signs and symptoms of liver toxicity, such as jaundice, itching, or right upper quadrant tenderness. (4) Tell her to report any rash, unexplained weight gain, edema, overt GI bleeding, or signs of occult bleeding, such as dark, tarry stools.

Antihistamine

Desloratadine

Sneeze relief without sedation

Categorized as a nonsedating antihistamine, desloratadine (Clarinet, Schering) joins loratadine (Claritin) and fexofenadine (Allegra) in the small group of antihistamines considered unlikely to cause sedation. All these drugs appear similar in effectiveness, although individual patients may respond better to one drug than another.

Desloratadine is indicated for the relief of nasal and nonnasal symptoms of seasonal allergic rhinitis and perennial allergic rhinitis and for relief of pruritus and hives associated with chronic idiopathic urticaria.

The most commonly reported adverse reactions associated with desloratadine during treatment of allergic rhinitis were pharyngitis and dry mouth. In studies, it provided relief of rhinitis symptoms without decreasing pulmonary function, so it appears safe for patients with mild to moderate asthma. Although currently available only with a prescription, the wide margin of safety demonstrated in clinical trials makes it a likely candidate for nonprescription status.

Desloratadine has a longer duration of action than loratadine, and the recommended dosage is 5 mg once a day This may be an advantage for patients who need two doses a day of loratadine for symptom relief. An initial dosage of 5 mg every other day is recommended for patients with renal or hepatic impairment. Desloratadine is available in 5-mg tablets and 5-mg rapidly disintegrating tablets (Reditabs), which dissolve rapidly when placed on the tongue.

Neither food nor grapefruit juice affects the drug's bioavailability so tell the patient she can take it without regard to meals.

Immunomodulator

Pimecrolimus

Topical relief for eczema

Millions of Americans suffer from atopic dermatitis (eczema), a chronic inflammatory disease characterized by scaling, pruritus, and inflammation. Treatment typically includes emollients and topical corticosteroids, but some patients don't respond adequately to these therapies or experience adverse reactions, such as skin atrophy and striae, to topical corticosteroids.

Pimecrolimus (Elidel, Novartis) is indicated for topical short-term and intermittent long-term therapy for mild to moderate atopic dermatitis in nonimmocompromised patients age 2 or older, in whom conventional therapies have failed or caused unacceptable adverse reactions. It's thought to act by inhibiting the production of inflammatory cytokines by T lymphocytes and preventing the release of inflammatory cytokines and mediators from mast cells.

Pimecrolimus cream contains the drug in a 1% concentration. Its applied to affected skin twice a day and rubbed in gently and completely. It can be used on all skin surfaces, including the head, neck, and intertriginous areas. Don't apply an occlusive dressing. Treatment can continue for as long as symptoms persist, but the patient should be reevaluated if symptoms persist for more than 6 weeks.

Pimecrolimus doesn't cause skin atrophy or other dermatologic adverse reactions associated with corticosteroids, so it may be preferred to corticosteroids for treatment of lesions on visible areas, such as the face or neck. However, one clinical study comparing it with the corticosteroid betamethasone valerate found it to be less effective.

Possible adverse reactions to pimecrolimus include application site symptoms (such as a burning sensation) and headache. Application site symptoms are usually mild to moderate, persist for only about 5 days, and resolve as the eczema responds to treatment. In pediatric patients, adverse events reported at a significantly higher incidence with pimecrolimus compared with the drug vehicle alone (the cream without the drug) included cough, pyrexia, nasopharyngitis, influenza, pharyngitis, and viral infection.

Patients with eczema are predisposed to skin infections. Infections should be treated appropriately before the patient begins therapy with pimecrolimus. Treatment may be associated with an increased risk of varicella zoster virus infection, herpes simplex virus infection, and eczema herpeticum. Don't apply the cream to an area of active cutaneous viral infection.

About 1% of patients treated with pimecrolimus developed skin papillomas or warts. If these lesions worsen or don't respond to conventional therapy, the practitioner may discontinue therapy until the lesions resolve.

About 1% of patients developed lymphadenopathy, which was usually related to an infection that responded to conventional antibiotic therapy.

Very little of pimecrolimus is absorbed systemically, so its unlikely to interact significantly with other drugs or cause systemic immunosuppression. However, because of the potential for increased systemic absorption, it's not recommended for use in patients with Netherton's syndrome (a rare autosomal disorder of keratinization characterized by dry scaly skin, skin atrophy, and hair shaft abnormalities). Although photosensitivity reactions weren't observed in clinical trials, advise the patient to minimize or avoid exposure to natural or artificial sunlight. Also tell him to contact his provider if he has a severe application site reaction or if the reaction persists for more than a week.

Drug for hereditary tyrosiremia

Nitisinone

Orphan drug prolongs survival.

Hereditary tyrosinemia type 1 (HT-1) is a rare metabolic disorder occurring at a rate of about 1 in 100,000 births. Characterized by accumulation of toxic metabolites, its associated with progressive liver failure, increased risk of hepatocellular carcinoma, coagulopathy, porphyria-like neurologic crisis, and progressive renal tubular dysfunction, leading to secondary hypophosphatemia and rickets.

Many patients with the acute form of HT-1 die in their first year of life. Those with the subacute or chronic form may not develop symptoms until after 6 months of age, and symptoms worsen at a slower rate than with the acute form. Treatment involves dietary restriction of tyrosine and phenylalanine and possibly liver transplant, although this doesn't allay renal symptoms.

Nitisinone (Orfadin, Rare Diseases Therapeutics) is indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of HT-1. By inhibiting the catabolism of tyrosine, it helps prevent accumulation of toxic metabolites. In clinical trials, the 4-year survival rate of children who were less than 2 months old at the time of diagnosis was 88%, compared with 29% in patients treated with dietary restrictions alone. Patients treated with nitisinone also experienced a marked reduction in early-onset liver failure and porphyric crisis.

Nitisinone is associated with ocular adverse reactions (conjunctivitis, corneal opacity, keratitis, photophobia), dermatologic reactions (exfoliative dermatitis, maculopapular rash, pruritus, dry skin), neurologic problems (mental retardation and developmental delay), and transient thrombocytopenia or leukopenia. To minimize risks and maximize treatment benefits, a nutritionist with expertise in treating patients with disorders such as HT-1 should design and monitor an appropriate low-protein diet deficient in tyrosine and phenylalanine.

To reduce the risk of ocular problems, the patient should undergo a slitlamp eye examination before starting therapy and whenever ocular signs and symptoms occur. Monitor liver function and white blood cell counts regularly.

Nitisinone is supplied in 2-mg, 5-mg, and 10-mg capsules. The recommended initial dosage is 1 mg/kg/day divided for morning and evening administration and given at least 1 hour before a meal. For young children, the capsules may be opened and the contents suspended in a small amount of water, formula, or applesauce immediately before use.

The estimated cost of therapy for a newly diagnosed patient is $12,000 a year. Because the dosage increases as the patient's weight increases, the cost for an older child could rise to $60,000 a year.

* Common adverse reactions are italicized throughout this article.

SELECTED REFERENCES

Drug Facts and Comparisons. St. Louis, Mo., Facts and Comparisons, Inc., 2003. Nursing2003 Drug Handbook. Springhouse, Pa., Springhouse Corp., 2003. Physicians' Desk Reference, 57th edition. Montvale, NJ., Medical Economics, 2003.

BY DANIEL A. HUSSAR, PHD

Remington Professor of Pharmacy

Philadelphia College of Pharmacy * University of the Sciences in Philadelphia, Pa.

Copyright Springhouse Corporation Feb 2003
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