A NEW HIV COMBINATION DRUG IS THE FIRST OF ITS KIND

* The three-in-one medication is taken once daily.

* The combination drug poses a greater potential for drug-drug interactions.

The U.S. Food and Drug Administration has approved Atripla (efavirenz, emtricitabine, tenofovir) for the treatment of HIV-1 infection in adults. It's the first drug to combine three widely used antiretrovirals into a single-tablet, once-a-day, fixed-dose combination to be taken either alone (as a complete treatment option) or in combination with other antiretrovirals.

Atripla consists of emtricitabine (Emtriva) and tenofovir (Viread), two HIV nucleoside reverse transcriptase inhibitors, and efavirenz (Sustiva), an HIV nonnucleoside reverse transcriptase inhibitor.

This is the first time that two pharmaceutical manufacturers (in this case, Bristol-Myers Squibb and Gilead Sciences) have collaborated to produce a treatment for HIV or AIDS. (A third company, Merck, holds distribution rights to efavirenz and is working with the other two companies.) The same precautions, warnings, and adverse effects that apply to each of the individual drugs apply to Atripla. Because it is metabolized by the cytochrome P-450 system, this combination drug carries warnings for numerous drug-drug interactions. All other drugs being taken, including herbal supplements and over-the-counter medications (as well as vitamins), should be checked to determine whether an interaction with any of them has been identified. Also, a black box on the labeling warns of the risk of lactic acidosis.

It's anticipated that Atripla will simplify adherence to an HIV regimen, which is essential to minimize the development of drug resistance. Patients prescribed Atripla should be advised to read the medication guide accompanying each prescription filled, in the event that new information, such as that concerning other drug interactions, has been added.

U.S. Food and Drug Administration. FDA news: FDA approves the first once-a-day three-drug combination tablet for treatment of HIV-1. 2006 Jul 12. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01408.html; Gilead Sciences Inc. [Label information]: Atripla (efavirenz 600 mg, emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg). 2006 Jul. http://www.fda.gov/cder/foi/label/2006/021937lbl.pdf.

A NEW INDICATION FOR PEGASPARGASE

* A first-line treatment for acute lymphoblastic leukemia.

* Administration is much less frequent.

Pegaspargase (Oncaspar) is now approved as a first-line treatment for newly diagnosed acute lymphoblastic leukemia (ALL) as one part of a chemotherapy regimen. When first approved, pegaspargase was indicated for use in the treatment of ALL only in patients allergic to asparaginase (Elspar), the standard treatment up to this time.

A major advantage to pegaspargase therapy is that it is administered by IM injection or IV infusion no more frequently than once every 14 days, in contrast with the dosing for asparaginase therapy, which depending on the protocol may be administered for up to 28 days during each round of drug treatment.

U.S. Food and Drug Administration. FDA news: FDA approves Oncaspar for newlydiagnosed acute lymphoblastic leukemia. 2006 Jul 24. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01419.html; Enzon Pharmaceuticals. [Label information]: Oncaspar (pegaspargase) intravenous or intramuscular injection. 2006 Jul. http://www.fda.gov/cder/foi/label/2006/103411s5052lbl.pdf.

TWO PUBLIC HEALTH ADVISORIES ON ANTIDEPRESSANTS ARE ISSUED

* The combination of triptans and either selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors may result in "serotonin syndrome."

* When treating depression in pregnant women, the risks and benefits of drug therapy must be carefully weighed.

The U.S. Food and Drug Administration (FDA) recently issued two public health advisories. One advisory addressed new safety information about taking triptans in combination with either selective serotonin reuptake inhibitors (SSRIs) or selective serotonin- norepinephrine reuptake inhibitors (SNRIs), and the other, the complex decision making involved in treating depression in pregnant women.

Serotonin syndrome. The FDA cautioned that a "life-threatening condition called serotonin syndrome may occur when triptans [a class of migraine medications] are used together" with an SSRI or an SNRI. Serotonin syndrome is more likely to occur when starting or increasing the dose of a triptan, SSRI, or SNRI. Although rare, when most severe, serotonin syndrome can result in cardiovascular shock and even death. Symptoms of serotonin syndrome include restlessness, hallucinations, loss of coordination, tachycardia, rapid changes in blood pressure, elevated body temperature, hyperreflexia, nausea, vomiting, and diarrhea.

Antimigraine drugs belonging to the "triptan" class (5- hydroxytryptamine receptor agonists) stimulate serotonin receptors located on cranial blood vessels and sensory nerves of the trigeminal vascular system. Both SSRIs and SNRIs inhibit the reuptake of serotonin; SNRIs inhibit the reuptake of norepinephrine as well. They each allow more serotonin to be available for use at the synapse. When an SSRI is taken in combination with a triptan, "serotonin syndrome" may result from a rapid increase in serotonin levels in the central nervous system and excessive serotonin stimulation.

* Triptans include naratriptan (Amerge), almotriptan (Axert), frovatriptan (Frova), sumatriptan (Imitrex), rizatriptan (Maxalt and Maxalt-MLT), eletriptan (Relpax), and zolmitriptan (Zomig and Zomig-ZMT).

* SSRIs include citalopram (Celexa), escitalopram (Lexapro), paroxetine (Paxil), fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (generic only), and the combination drug olanzapine-fluoxetine (Symbyax).

* SNRIs include duloxetine (Cymbalta) and venlafaxine (Effexor and Effexor XR).

NPs who prescribe any of these drugs should obtain a thorough drug history. If it's determined that the possible benefits outweigh the potential risks, patients should receive thorough information on serotonin syndrome. The patient should be followed closely if a triptan and an SSRI or SNRI are used together, especially at initiation or when increasing dosage, and advised to seek immediate attention if symptoms of serotonin syndrome emerge.

Treating depression in pregnant women. The SSRIs constitute the class of antidepressant drugs most commonly prescribed in the United States. Although generally safe and well tolerated, SSRIs present substantial considerations when used during pregnancy. This public health advisory is derived from two recent studies. The first details the risk of relapse of major depression among women who discontinue antidepressant use during pregnancy. The longitudinal investigation by Cohen and colleagues in the Journal of the American Medical Association examined 201 pregnant women who either maintained, increased, decreased, or discontinued antidepressant treatment in pregnancy. Eligible women had a history of major depression prior to pregnancy, were less than 16 weeks into their pregnancy, were euthymic (not depressed) for at least three months before their last menstrual period, and currently or recently (less than 12 weeks before the last menstrual period) receiving antidepressant treatment. Results showed that women who discontinued medication were five times more likely to relapse into depression during pregnancy than were women who maintained medication.

The second study demonstrated that exposure to SSRIs during late pregnancy is associated with six times the increase in the relative risk of developing persistent pulmonary hypertension of the newborn (PPHN). The article by Chambers and colleagues in the New England Journal of Medicine is part of a large case-control study of risk factors for PPHN. Of the 377 infants with PPHN, 14 had been exposed to an SSRI after the 20th week of gestation; six of the 886 infants in the control group had been so exposed. Neither the use of SSRIs before the 20th week of pregnancy nor the use of other antidepressants at any time during pregnancy appeared to be associated with an increased risk of PPHN. Because the number of infants exposed to an SSRI after 20 weeks of gestation was small, individual drugs in the SSRI class could not be analyzed to determine whether greater risk was posed by any of them over others. Further study is necessary. Although rare-approximately one or two per 1,000 babies in the United States develop PPHN-the condition is associated with illness and death in infants. Therefore, the FDA has requested manufacturers of all drugs that contain an SSRI to include a statement in the prescribing information describing the risk of PPHN.

Women who are pregnant or who are considering becoming pregnant should consult their prescribers before stopping antidepressant therapy. Drug administration can be stopped, but only under supervision and in accordance with the prescribing information. These patients should be monitored closely for possible relapse into depression.

U.S. Food and Drug Administration. FDA public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. 2006 Jul 19. http://www.fda.gov/CDER/DRUG/advisory/SSRI_SS200607.htm; U.S. Food and Drug Administration. FDA public health advisory: treatment challenges of depression in pregnancy. 2006 Jul 19. http://www.fda.gov/cder/drug/advisory/SSRI_PPHN200607.htm; Cohen LS, et al. JAMA 2006;295(5): 499-507.; Chambers CD, et al. N Engl J Med 2006;354(6):579-87.

DRUG THERAPY APPROVED FOR HUNTER SYNDROME

* A rare disease receives its first drug treatment option.

* Close monitoring for life- threatening hypersensitivity reactions is necessary.

The U.S. Food and Drug Administration (FDA) has approved idursulfase (Elaprase) as the first drug therapy for Hunter syndrome (also known as mucopolysaccharidosis type 2), a rare, X-linked recessive disorder in which the body does not produce enough iduronate-2-sulfatase, an enzyme needed to break down complex sugars produced in the body. The disorder is diagnosed in one in 65,000 to 132,000 children. The juvenile form (early-onset and severe) of Hunter syndrome becomes apparent as children reach one to three years of age and results in severe mental retardation, aggressive behavior, spasticity, progressive growth delay, and respiratory and cardiac problems. The late-onset form (diagnosed after the age of 10) has a slower disease progression, with mild or no mental deficiency. Symptoms of both forms include large skull, coarse facial features, progressive deafness, joint stiffness, and enlargement of the liver and spleen. Life expectancy is 10 to 20 years (early-onset form) and 20 to 60 years (late-onset form).

Idursulfase, an enzyme replacement therapy, is a purified form of human iduronate-2-sulfatase produced by recombinant DNA technology to help break down complex sugars and prevent their buildup in the body. Patients who received a weekly IV infusion of idursulfase in a 53-week clinical trial walked significantly farther in six minutes than did patients who received a placebo. In addition, sustained reduction in liver and spleen size were noted in patients receiving idursulfase but not in those receiving placebo.

Anaphylactic reactions, which may be life threatening, have been observed in some patients during idursulfase infusions. The most serious adverse events reported during the clinical trial were hypersensitivity reactions including respiratory distress, hypoxia, hypotension, angioedema, and seizure. The most frequent were hypoxic episodes. Notable serious adverse reactions included one case each of cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory failure, infection, and arthralgia. Other reported adverse effects included fever, headache, cutaneous reactions (rash, pruritus, erythema, urticaria), and hypertension, the frequency of which decreased with continued use.

Because of the potential for severe hypersensitivity reactions, the drug should be administered where the patient can be monitored closely and emergency equipment is available. Patients who have severe hypersensitivity reactions can continue treatment with idursulfase if they are treated either beforehand or concurrently with corticosteroids or antihistamines or both. In addition, the infusion rate should be slowed.

The cost of treatment with idursulfase is estimated at $300,000 per patient per year, making it one of the most expensive drugs on the market.

Because no longer-term trials with idursulfase have yet been conducted, a registry, the Hunter Outcome Survey, has been set up to monitor the drug's long-term effects and to gain additional information on Hunter syndrome. Registration is voluntary; patients and physicians are encouraged to participate. Information about the Hunter Outcome Survey is available at http://www.hunterpatients.com or by calling OnePath at (866) 888-0660.

U.S. Food and Drug Administration. FDA news: FDA approves first treatment for Hunter syndrome. 2006 Jul 24. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01418.html; Shire Human Genetic Therapies Inc. [Prescribing information]: Elaprase (idursulfase) solution for intravenous infusion. 2006 Jul. http://www.elaprase.com/ElaprasePI40-0120_REV_0_GT4.pdf.