Daptomycin

IN THIS ARTICLE, you'll learn about nine new drugs that hit the market recently, including:

* daptomycin, first in a new class of antibiotics for complicated skin infections

* vardenafil HCl and tadalafil, prescribed to treat erectile dysfunction

* enfuvirtide, emtricitabine, and atazanavir sulfate, three antiretroviral drugs.

Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drugs safety during pregnancy and breast-feeding. Also consult the package insert, a pharmacist, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions* for all these drugs.

First in its class for complicated skin infections

Daptomycin (Cubicin, Cubist) is the first of a new class of antibacterial drugs designated as cyclic lipopeptides. Binding to bacterial cell membranes, daptomycin inhibits DNA and RNA synthesis, killing the bacteria. Given intravenously (I.V.) once daily, this drug is indicated to treat complicated skin and skin structure infections caused by susceptible strains of Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae (equisimilis), and vancomycin-susceptible strains of Enterococcus faecalis.

Highly active against aerobic Gram-positive bacteria, daptomycin has a spectrum of action similar to nafcillin, oxacillin, vancomycin, and linezolid. It's being tested as a treatment for other types of infections, including bacteremia and endocarditis.

Precautions: (1) Discontinue daptomycin in patients with unexplained signs and symptoms of myopathy in conjunction with creatine kinase (CK) elevations above 1,000 units/liter and in patients without symptoms whose CK is more than 10 times the upper limit of normal. (2) Temporarily suspend statin use in patients who are to be treated with daptomycin because of the risk of skeletal muscle effects and complications such as rhabdomyolysis. (3) Because of rare reports of peripheral neuropathy associated with daptomycin, use it with caution in patients taking other drugs that may cause peripheral neuropathy. (4) Extend the dosage interval in patients with severe renal insufficiency (creatinine clearance of less than 30 ml/minute).

Adverse reactions: injection-site reactions, constipation, nausea, diarrhea, headache, insomnia, pseudomembranous colitis, elevations in serum CK, myopathies

Supplied as: single-use vials containing 250 or 500 mg of the drug as a lyophilized powder

Dosage: 4 mg/kg I.V. once every 24 hours for 7 to 14 days. In patients on hemodialysis or continuous ambulatory peritoneal dialysis, the recommended dosage is 4 mg/kg once every 48 hours.

Nursing considerations: (1) Store unopened vials in the refrigerator. When reconstituted and diluted, the solution can be stored for up to 12 hours at room temperature and up to 48 hours in the refrigerator. (2) Reconstitute the drug with 0.9% sodium chloride injection as directed in the package insert. Then dilute the reconstituted solution with 0.9% sodium chloride injection as directed for I.V. infusion. (3) Don't administer daptomycin through the same I.V. line as other medications. (4) Monitor anticoagulant activity in patients also taking warfarin. (5) Monitor the patient for muscle pain or weakness, particularly of the hands and feet. (6) Monitor CK levels weekly; more frequently if the patient develops unexplained elevations in CK during therapy. (7) If the patient is on hemodialysis, give the drug after hemodialysis on dialysis days, if possible.

Boosting the power of HIV therapy

Enfuvirtide (Fuzeon; Roche, Trimeris) is the first of a new class of fusion inhibitors that fight human immunodeficiency virus (HIV) infection. Because this drug has a different mechanism of action than other antiretroviral drugs, cross-resistance with other antiretroviral drugs is unlikely to occur. Given subcutaneously (S.C.), it's indicated for combination therapy in patients who've developed resistance to other antiretroviral drugs. Monotherapy, which could allow resistance to therapy to develop sooner, isn't recommended.

Other antiretrovirals inhibit the action of enzymes essential for replication of HIV-1. In contrast, enfuvirtide stops the virus from entering cells by inhibiting fusion of viral and cellular membranes. When added to an existing antiretroviral regimen, enfuvirtide reduced HIV RNA concentrations at a greater rate than the existing regimen alone.

Unlike protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs), enfuvirtide doesn't interact with other medications via metabolic pathways. This gives it an advantage over these other drug classes, which are implicated in many drug interactions.

Approved under the Food and Drug Administration's (PDAs) accelerated approval process, enfuvirtide is far more expensive than other antiretroviral drugs, costing an estimated $20,000 per year. Although the drug initially was available through just one source, that restriction no longer applies.

Precautions: (1) Use enfuvirtide only in combination with other antiretroviral drugs. (2) Discontinue therapy if the patient has a hypersensitivity reaction to enfuvirtide.

Adverse reactions: injection-site reactions, eosinophilia, insomnia, peripheral neuropathy, hypersensitivity reactions, cough, sinusitis, decreased appetite, myalgia, diarrhea, nausea, fatigue

Supplied as: single-use vials of 108 mg of lyophilized powder. When reconstituted with sterile water, the concentration is 90 mg/ml.

Dosage: 90 mg twice a day, injected S.C. into the upper arm, anterior thigh, or abdomen. For children ages 6 to 16, the recommended dosage is 2 mg/kg twice a day, up to a maximum of 90 mg twice a day.

Nursing considerations: (1) When reconstituting the drug, don't shake the vial; foaming increases the time needed for the powder to dissolve. Instead, gently tap the vial for 10 seconds, then roll it gently between your hands. (2) When the powder starts to dissolve, set the vial aside until the powder has dissolved completely, which may take up to 45 minutes. (3) You can prepare two doses at the same time. Give one dose and store the other in the refrigerator. Use it within 24 hours. (4) Rotate injection sites, avoiding sites that reacted to an earlier injection. (5) Monitor patients for signs and symptoms of bacterial pneumonia, particularly if the patient smokes or has a history of lung disease. Some patients developed pneumonia during clinical trials with enfuvirtide, although whether the drug was to blame isn't clear.

Once-a-day dosing reduces the patienf s pill burden.

Emtricitabine (Emtriva, Gilead Sciences), the seventh nucleoside reverse transcriptase inhibitor (NRTI) approved by the FDA, has properties similar to lamivudine and is used in combination therapy with other antiretroviral agents. This drug's once-a-day dosing is an advantage for patients with HIV infection who must take many pills daily. By reducing the daily pill burden, emtricitabine may encourage adherence to the treatment regimen.

Another advantage to emtricitabine is its relatively low risk of serious adverse reactions. For example, compared with NNRTIs, protease inhibitors, and some other NRTIs, emtricitabine is less likely to interact with other drugs. So far, certain problems associated with other NRTIs, such as pancreatitis, hypersensitivity reactions, and hematologic toxicity, haven't been reported with emtricitabine.

Like lamivudine, emtricitabine demonstrates activity against hepatitis B virus (HBV). However, this isn't yet a labeled indication for emtricitabine.

Like other NRTIs, emtricitabine labeling includes a black-box warning regarding the risk of lactic acidosis and severe hepatomegaly with steatosis, which are rare but potentially fatal adverse reactions.

Precautions: (1) Administer with caution to patients with risk factors for liver disease. (2) Lengthen the dosage interval in patients with impaired renal function. see the product labeling for details.

Adverse reactions: diarrhea, nausea, rhinitis, rash, asthenia, cough, headache, hyperpigmentation of palms and soles (usually mild), lactic acidosis or severe hepatomegaly with steatosis (rare)

Supplied as: 200-mg oral capsules

Dosage: 200 mg once a day

Nursing considerations: (1) Test the patient for chronic HBV infection before beginning antiretro viral therapy and monitor her for exacerbation of HBV infection after treatment with emtricitabine ends. (2) Tell her that she can take each dose without regard to food.

Protease inhibitor offers longer action with once-daily dosing.

Atazanavir sulfate (Reyataz, Bristol-Myers Squibb) is the seventh HIV protease inhibitor to hit the market, joining amprenavir, indinavir, lopinavir, ritonavir, nelfinavir, and saquinavir. This drug is indicated for use in combination with other antiretroviral drugs to treat HIV-1 infection. Preliminary studies suggest that atazanavir may be most effective when used in a regimen that also includes ritonavir and two NRTIs.

Atazanavir is less likely than other protease inhibitors to increase blood lipid levels. In many patients treated with other protease inhibitors, these increases have warranted treatment with a lipid-lowering medication that may interact with the protease inhibitor, complicating therapy. However, like other protease inhibitors, atazanavir is extensively metabolized via the CYP 3A4 metabolic pathway and has the potential to interact with many other drugs.

The drug's longer duration of action and once-a-day administration gives it an advantage over other protease inhibitors by helping to reduce the pill burden for patients taking multiple medications.

Precautions: (1) Contraindicated in patients with severe hepatic insufficiency. (2) Contraindicated in patients taking midazolam, triazolam, ergot derivatives, pimozide, cisapride, lovastatin, simvastatin, and bepridil because atazanavir may cause life-threatening increases in plasma concentrations of these drugs. (3) Don't use concurrently with rifampin or St. John's wort, which reduce plasma concentrations of atazanavir and may cause treatment failure and drug resistance. Consult the product labeling for other potential drug interactions and precautions. (4) Contraindicated for use in infants under age 3 months because of the risk of kemicterus. (5) Because atazanavir may prolong the PR interval on electrocardiogram (ECG), use it with caution in patients with myocardial conduction system defects and those taking other drugs that prolong the PR interval.

Adverse reactions: nausea, headache, rash, jaundice and scierai icterus, hyperbilirubinemia, prolonged PR interval on ECG, hyperglycemia or diabetes mellitus, body fat redistribution or accumulation (central obesity, "buffalo hump," peripheral and facial wasting, breast enlargement, "cushingoid" appearance)

Supplied as: 100-mg, 150-mg, and 200-mg capsules

Dosage: 400 mg once a day. In patients with moderate hepatic insufficiency, dosage may be reduced to 300 mg/day.

Nursing considerations: (1) Tell the patient to take each dose with food. (2) Warn him that the drug may cause yellowing of the skin or eyes, which usually is reversible when the drug is discontinued. Tell him to contact his health care provider if this cosmetic change disturbs him and warn him not to stop the drug or change the dosage without his provider's guidance. (3) Administer atazanavir and histamine^sub 2^ receptor antagonists as far apart as possible (preferably by 12 hours) and at least 2 hours before or 1 hour after antacids and buffered tablets. (4) Monitor a patient with hemophilia for bleeding; atazanavir may increase bleeding risks.

The first drug approved for severe Alzheimer's dementia

Alzheimer's disease affects about 4.5 million Americans, robbing them of memory, judgment, and the ability to reason. The first drugs developed to treat Alzheimer's were the reversible cholinesterase inhibitors, including donepezil. Memantine HCl (Namenda, Forest), which has been used in Germany for about 20 years, works differently than these drugs by targeting N-methyl D-aspartate receptors in the central nervous system. Persistent activation of these receptors is thought to contribute to Alzheimer's symptoms.

Approved for treatment of moderate to severe Alzheimer's dementia, memantine slows worsening of symptoms and may even improve symptoms in some patients. However, it's not a cure and doesn't seem to prevent or delay neuro-degeneration.

In studies, memantine was well tolerated by most patients and unlikely to cause the gastrointestinal adverse reactions commonly experienced by patients taking cholinesterase inhibitors. Memantine can be used alone or in combination with cholinesterase inhibitors and is also being evaluated for treatment of neuropathic pain in patients with conditions such as diabetes.

Precautions: (1) Not recommended in patients with severe renal impairment. (2) Use with caution in patients with increased urinary pH from diet changes or concurrent medications such as sodium bicarbonate or carbonic anhydrase inhibitors. Alkalinization of the urine may increase reabsorption of memantine, raising the risk of adverse reactions.

Adverse reactions: dizziness, confusion, headache, constipation

Supplied as: 5-mg and 10-mg film-coated oral tablets

Dosage: 5 mg once a day, increased by 5 mg each week to a target dosage of 10 mg twice a day. See the package insert for details.

Nursing consideration: Reduce the dosage as ordered for patients with moderate renal impairment.

Two new options for men with erectile dysfunction.

Like sildenafil (Viagra), these two oral drugs recently approved for erectile dysfunction are phosphodiesterase type 5 (PDE5) inhibitors, which require sexual stimulation to be effective. They work by triggering smooth muscle relaxation in blood vessels supplying the penis, which increases blood flow to the penis and creates an erection.

Although the three drugs haven't been directly compared with one another, they appear to be similarly effective. However, because individual responses vary, some men may prefer one drug to the others.

Tadalafil has a longer duration of action than sildenafil or vardenafil (about 36 hours versus 5 hours), which may allow greater spontaneity in sexual relations. However, the longer duration of action also prolongs the patient's risk of adverse reactions.

Contraindications and precautions for these drugs are generally similar. All of them potentiate the hypotensive effects of nitrates, so they shouldn't be prescribed for men taking nitrates (such as nitroglycerin and isosorbide dinitrate). For the same reason, vardenafil and tadalafil are contraindicated in men taking alphaj-adrenergic blockers (although patients taking tamsulosin may take tadalafil-more on this later). In contrast, sildenafil may be used in patients also taking alpha-blockers.

All PDE5 inhibitors are contraindicated for men for whom sexual activity isn't recommended because of a cardiac condition. These drugs aren't recommended for men with hypotension, uncontrolled hypertension, unstable angina, uncontrolled arrhythmias, severe heart failure, recent history of stroke or myocardial infarction (MI), or hereditary degenerative retinal disorders, including retinitis pigmentosa.

These drugs should be used cautiously in men with conditions (such as sickle-cell disease) that may predispose them to priapism or who have anatomic deformation of the penis.

Tell patients to seek immediate medical attention if an erection persists for more than 4 hours or if they experience chest pain or other symptoms of MI.

All three drugs may be taken without regard to food. Here are some considerations specific to each of the new drugs.

Vardenafil

Vardenafil HCl (Levitra; GlaxoSmithKline, Bayer HealthCare) can prolong the QT interval, so it's not recommended for patients with congenital QT prolongation or in patients taking Class IA or Class III antiarrhythmics. Reduce the dosage in patients taking a CYP 3A4 inhibitor, which may increase the activity of vardenafil.

Adverse reactions to vardenafil include headache, flushing, rhinitis, dyspepsia, and ophthalmologic adverse reactions, such as blurred vision.

Vardenafil is contraindicated in men being treated with an alpha-blocker. Of the three PDE5 inhibitors, vardenafil has the most restrictive labeling on this point.

Vardenafil is available as 2.5-mg, 5-mg, 10-mg, and 20-mg film-coated tablets.

The usual starting dose for most patients under age 65 is 10 mg, to be taken about 60 minutes before sexual activity. The dosage may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg, depending on patient response. The maximum recommended dosing frequency is once a day.

A starting dose of 5 mg and a maximum dose of 10 mg are recommended for patients age 65 and older and for those with moderate hepatic impairment. The drug hasn't been evaluated in patients with severe hepatic impairment. Dosage adjustments aren't necessary in patients with impaired renal function. see the package insert for other dosage guidelines.

Tadalafil

Of the three agents for erectile dysfunction, tadalafil (Cialis; Icos, Lilly) has the longest duration of action. Tadalafil's half-life is about 18 hours, compared with about 4 hours for sildenafil and vardenafil.

Tadalafil is contraindicated in patients taking alpha-blockers, unless they're taking tamsulosin in a dosage of 0.4 mg once a day.

Adverse reactions to tadalafil include headache, dyspepsia, back pain, myalgia, pain in the limbs, nasal congestion, and flushing.

The drug is available as 5-mg, 10-mg, and 20-mg film-coated tablets. The recommended starting dose is 10 mg, which may be increased to 20 mg or reduced to 5 mg depending on patient response.

The dosage shouldn't exceed 10 mg once a day in patients with mild or moderate hepatic impairment. see the package insert for more dosage guidelines.

A patient who experiences angina after taking tadalafil should seek immediate medical attention and not take a nitrate or nitroglycerin for 48 hours after using tadalafil. This is at least twice as long as the appropriate interval between doses of sildenafil or vardenafil and a nitrate because of tadalafil's longer half-life.

Easier to live with than spironolactone

Recent studies have shown that adding spironolactone, an aldosterone receptor antagonist, to the standard drug regimen for severe heart failure reduces the risk of death by 30%. But the drug causes significant endocrine adverse reactions such as gynecomastia, impotence, and menstrual disorders.

Eplerenone (Inspra, Pfizer), the second aldosterone receptor antagonist developed, is less likely to cause these adverse reactions. The drug was initially approved in 2002 for hypertension, but marketing was delayed until it also received approval as a treatment for heart failure following an MI.

More than a third of patients who survive an Ml develop heart failure. Eplerenone is indicated to prolong the survival of stable post-Mi patients with left ventricular systolic dysfunction (an ejection fraction of 40% or less) and clinical evidence of heart failure.

At higher dosages, eplerenone also is indicated for treating hypertension, alone or in combination with other antihypertensive drugs.

An important risk associated with eplerenone is hyperkalemia, which can cause fatal arrhythmias. Consult the package insert for guidelines on monitoring serum potassium levels before and during therapy.

Precautions: (1) Contraindicated in patients with serum potassium levels greater than 5.5 mEq/liter. (2) Contraindicated in patients with hypertension who also are taking potassium supplements or potassiumsparing diuretics. (3) Contraindicated (or use with caution) in patients with impaired renal function or diabetes (see the package insert for specific clinical parameters). (4) Contraindicated in patients taking potent CYP 3A4 metabolic pathway inhibitors (such as ketoconazole, itraconazole, nefazodone, clarithromycin, troleandomycin, ritonavir, and nelfinavir), which may significantly increase serum eplerenone concentrations. Closely monitor patients taking less-potent CYP 3A4 inhibitors (such as erythromycin, verapamil, and fluconazole) and reduce the dosage of eplerenone as indicated. (5) Closely monitor patients taking eplerenone and lithium concurrently for signs and symptoms of lithium toxicity. (6) Concurrent use of eplerenone and a nonsteroidal antiinflammatory drug (NSAID) may reduce eplerenone's effects. Consult the package insert for more details about potential drug interactions.

Adverse reactions: hyperkalemia, arrhythmias, gynecomastia, vaginal bleeding

Supplied as: 25-mg and 50-mg film-coated oral tablets

Dosage: 50 mg once a day for treatment of heart failure post-Mi. See the package insert for recommended starting dosages and titrations.

Nursing considerations: (1) Monitor serum potassium levels in patients at risk for developing hyperkalemia and adjust the eplerenone dosage as ordered. (2) Tell the patient he can take eplerenone without regard to food. (3) Because eplerenone interacts with many drugs and other products, including over-the-counter products such as NSAIDs and St. John's wort, take a complete drug history and teach the patient to check with his health care provider before taking any other drugs or herbal products.

Keeping growth hormones under control

Acromegaly is a potentially life-threatening disease associated with excessive concentrations of growth hormone. Most patients with this disease have pituitary adenomas. These tumors secrete excess growth hormone, leading to increased production of insulinlike growth factor 1 (IGF-1).

Signs and symptoms of acromegaly include headache, profuse sweating, swelling, joint disorders, changes in facial features, and enlarged hands, feet, and jaw. Because of the increased risk of heart and respiratory disease, diabetes, and cancer, many patients die prematurely.

Treatment for acromegaly includes resection of the pituitary adenoma, radiation, and drug therapy with bromocriptine and octreotide. These drugs inhibit growth hormone secretion but have limited effectiveness and may be poorly tolerated.

Pegvisomant (Somavert, Pfizer) is an analogue of human growth hormone that's been structurally modified to act as a growth hormone receptor antagonist. A protein of recombinant DNA origin, it's been bound to several polyethylene glycol polymers to reduce drug clearance and lengthen the drug's duration of action.

The first drug of its class, pegvisomant is given S.C. to treat acromegaly in patients who haven't responded to other therapies or for whom other therapies aren't appropriate.

The goal of treatment with pegvisomant is to normalize IGF-1 concentrations; in clinical trials, more than 90% of patients met this goal.

Precautions: (1) Monitor patients with diabetes closely because treatment with pegvisomant may increase glucose tolerance. Reduce the dosage of antidiabetic medications as indicated. (2) Conduct baseline liver function tests before starting pegvisomant therapy and monitor for elevated liver function values and other signs and symptoms of liver dysfunction throughout therapy. Consult the product insert for treatment guidelines if liver problems develop.

Adverse reactions: injection-site reaction, back pain, pain, flu syndrome, nausea, diarrhea, abnormal liver function tests

Supplied as: single-use vials containing 10, 15, or 20 mg of pegvisomant protein as lyophilized powder

Dosage: initial dose of 40 mg S.C., given under physician supervision, followed by patient-administered doses of 10 mg/day. Dosages may be increased or decreased by 5-mg increments depending on serum IGF-1 concentrations. The maximum maintenance dosage is 30 mg/day.

Nursing considerations: (1) Show the patient how to reconstitute the drug with 1 ml of sterile water for injection, supplied with the medication. Teach him to gently roll the vial between his hands to dissolve the powder and warn him not to shake the vial, which may denature the drug. (2) Tell him to administer the solution within 6 hours of reconstitution and to store drug vials in the refrigerator. (3) Show him how to rotate injection sites. (4) Monitor his IGF-1 levels 4 to 6 weeks after starting treatment and after dosage adjustments and at least once every 6 months after IGF-1 levels have normalized. (5) Patients taking opioids concurrently may need a higher dosage of pegvisomant to achieve appropriate IGF-1 suppression. (6) Encourage any patient with acromegaly to see his health care provider regularly for checkups so he can monitor his pituitary tumor for expansion.

* Common adverse reactions are italicized throughout this article.

SELECTED REFERENCES

Drug Facts and Comparisons. St. Louis, Mo., Facts and Comparisons. Inc., 2004.

Nursing2004 Drug Handbook. Springhouse, Pa., Lippincott Williams & Wilkins, 2004.

Physicians' Desk Reference, 58th edition. Montvale, N.J., Medical Economics, 2004.

BY DANIEL A. HUSSAR, PHD

Remington Professor of Pharmacy

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

Copyright Springhouse Corporation Jul 2004
Provided by ProQuest Information and Learning Company. All rights Reserved