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Product Information

September 1996

Clarithromycin (Biaxin) Dosage:

NIAID has issued a warning against use of clarithromycin in a dose of 2 gm/day or greater. The concern is based on analyses from two studies (ACTG 157 and a CPCRA study) that showed increased mortality in groups given clarithromycin at this dose compared to lower doses. Thus, the standard clarithromycin dose for both prophylaxis and treatment is 500 mg bid. It should be noted that the cause of death in these cases is not known, and analysis of available data shows that most of the mortality in the two trials was due to common HIV-related complications.

Clofazimine (Lamprene) Warning:

Analysis of several comparative trials of various regimens for treatment of M. avium infection have shown increased mortality rates in patients receiving clofazimine (see NEJM 335:377, 1996). Based on this experience, NIAID has issued a warning against the use of clofazimine for the treatment of MAC.

Spontaneous Bleeding of Hemophiliacs Receiving Protease Inhibitors:

The FDA has received reports from Germany and France of spontaneous bleeding in 16 hemophiliacs (A and B). There were 10 with ritonavir and 6 with indinavir. The bleeding consisted of cutaneous hematomas and hemarthroses, and bleeding occurred after a mean duration in therapy of 12 days. All had CD4 counts <50/mm3 and most were receiving multiple drugs. There is no pathophysiologic explanation for this association and many feel that the rate of spontaneous bleeds in hemophiliacs is sufficiently high to preclude any meaningful interpretation. Nevertheless, in view of these reports, the FDA and the manufacturers recommend that health care providers monitor hemophiliacs who are taking protease inhibitors. The FDA also stated that hemophiliacs receiving protease inhibitors should not have them stopped and there should not be reluctance to initiate protease inhibitors in hemophiliacs. Unexpected spontaneous bleeding in hemophiliacs receiving protease inhibitors should be reported to 800-FDA-1088 or FAX: 800-FDA-0178.

Amplicor HIV-1 Monitor Test to Quantitate HIV-1 RNA Levels in Plasma:

The FDA approved this test in June 1996. The threshold for detection is 400 HIV RNA copies/ml, and the test range is 400-750,000 copies/ml.

Nevirapine (Viramune):

It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that was approved by the FDA in June 1996. The standard regimen is 200 mg daily for two weeks followed by 200 mg bid. Nevirapine must be used in combination with nucleoside analogs. The greatest experience is with nevirapine combined with AZT, AZT plus ddI or AZT plus ddC; experience with this drug combined with 3TC or d4T is limited. Protease inhibitors should not be used in combination with nevirapine. The major side effect is rash, noted in 18% of recipients. This is morbilliform and pruritic, usually on the trunk and extremities, and it usually occurs during the first four weeks of treatment. It is dose related. If the rash is noted during the "lead-in phase" (first two weeks), there should be a delay in administration of the full dose. Rash noted during the maintenance dose phase will often resolve with continued treatment. The drug should be discontinued if the rash is severe or accompanied by fever. The price of Viramune (AWP) is $3.96/100mg capsule. A more complete review of this drug is provided in the July 1996 issue of the Hopkins HIV Report.

Delavirdine (Rescriptor) Available Through a Treatment IND:

Delavirdine mesylate is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is available from Pharmacia-Upjohn through an expanded access program. To date, approximately 2,700 patients have received this drug. The usual dose is 400 mg (four 100 mg tablets) every eight hours in combination with at least one additional antiretroviral agent. Enrollment criteria include informed consent, a CD4 count of <300/mm3, failure on current therapy or clinical progresssion, and availability for follow-up visits at three month intervals. For patient enrollment or further information about this program call 1-800-779-0070.

Ritonavir (Norvir) Dosing Regimen:

The standard dose of ritonavir (600 mg twice daily) has been associated with high rates of gastrointestinal intolerance. This drug produces the highest levels during the first week after initiation of therapy, and blood levels then decline to a steady state that is achieved after two weeks. The dose titration schedule suggested to improve compliance but still achieve therapeutic levels is the following:

  • Day 1 and 2 - 300 mg bid
  • Day 3 through 5 - 400 mg bid
  • Day 6 through 13 - 500 mg bid
  • Day 14 and thereafter - 600 mg bid.

The manufacturer warns that patients must reach the 600 mg bid dose by day 14. Patients should be warned "that they may be sicker than they have ever been before," but the side effects are usually temporary and often subside in about four weeks.

Dosing Recommendations for Saquinavir Plus Ritonavir:

These recommendations are based on the studies of W. Cameron et al as presented in Vancouver and are now sanctioned by Abbott and Hoffman-LaRoche. The trial used two regimens of ritonavir plus saquinavir in 65 patients with CD4 counts of 100 - 500/mm3 and a mean viral burden of 70,000 copies/ml. Analysis at 6 weeks showed 85% had > 2 log decrease in viral burden and 50% had no detectable virus (< 200 copies/ml). Recommendations for dosing based on this experience:

  • For protease inhibitor naive patients: start ritonavir at 300 mg bid, and dose escalate to 400 - 600 mg bid by day 14*. Add saquinavir 400 mg bid at day 7.

  • For patients taking saquinavir (600 mg tid): reduce saquinavir to 400 mg bid (total daily dose of 800 mg/day) and add ritonavir starting at 300 mg bid. Dose escalate ritonavir to 400 - 600 mg bid by day 14*.

  • For patients taking ritonavir: add saquinavir 400 mg bid.

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    *Note: The maintenance dose of ritonavir may be 400-600 mg bid (800-1200 mg/day) when combined with saquinavir depending on tolerance. The therapeutic trial using ritonavir plus saquinavir did not include nucleoside analogues; thus, the addition of these agents to the above regimen is arbitrary.

Glaxo-Wellcome Plans to Market a 300 mg AZT Tablet in October 1996, and a combination tablet of AZT (300 mg) plus 3TC (150 mg) for twice daily dosing should be available in the summer of 1997.

Pregnancy Registry for Anti-retroviral Agents:

A registry has been established to determine the safety of nucleoside analogues and saquinavir during pregnancy. Monitored drugs include AZT, ddI, d4T, ddC, 3TC and saquinavir. Ritonavir and indinavir are not yet included. The safety of AZT appears established for the 2nd and 3rd trimesters, but information about the safety of AZT in the first trimester and for other antiretroviral agents throughout pregnancy is lacking. The registry will prepare a semi-annual report of its findings. This is a joint project including Bristol-Myers Squibb, Glaxo-Wellcome and Hoffman-LaRoche, with an advisory panel that includes representation from the CDC, NIH and multiple medical specialties. Health care professionals should report prenatal exposures to:

Antiretroviral Pregnancy Registry
Worldwide Epidemiology
P.O. Box 13398
Research Triangle Park, NC 27709-9976
Tel (919)315-8465 (collect) or
(800) 722-9292 ext. 38465;
FAX (919)315-8981

Reports of prenatal exposures to ritonavir should be reported to Abbott (800)633-9110 and to indinavir should be reported to Merck (800) 672-6372.

ddI (Videx) Available in New Formulation:

ddI buffered tablets have been reformulated to improve patient acceptance. The new tablets are 35% smaller in volume, are softer, making them easier to chew, and have a new mandarin orange flavor. For patients who prefer to disperse tablets in water, this can be done more rapidly with the new formulation. Everything else about the new form is the same: the standard dose for persons over 60 kg is 200 mg in two tablets twice daily or 250 mg of the powder form; both forms should be taken on an empty stomach, meaning at least one hour before or two hours after a meal. Two tablets should be thoroughly chewed, manually crushed, or dispersed in at least one ounce of water. Available strengths are 25, 50, 100 and 150 mg tablets; the buffered powder for oral solution is available in strengths of 100, 167 and 250 mg single-dose foil packets. For further information call Bristol-Myers Squibb at 1-800-426-7644.

Amphotericin B (Fungizone) Available as Oral Suspension:

Bristol-Myers Squibb has released an oral suspension of amphotericin B for treatment of oral candidiasis. This drug is poorly absorbed, so the average serum concentration after 14 days of therapy with 400-600 mg/day is only 0.05 ug/ml. Thus, this should be used only for topical treatment of thrush and not for Candida esophagitis or systemic fungal infections. The drug is supplied at a concentration of 100 mg/ml in 24 ml bottles. The suggested dose is one ml (100 mg) four times daily. The bottle should be shaken before using, and the suspension should be dropped directly on the tongue using the calibrated dropper that is provided. Activity is by direct contact with oral lesions, so the patient should swish the medication in the mouth as long as possible before swallowing. The AWP for a 24ml bottle (1 week supply) is $26.25. The recommended duration of treatment is two weeks, but some patients will require longer courses.

Azithromycin (600 mg tablets):

The FDA approved azithromycin for MAC prophylaxis in June 1996 with a standard dose of 1,200 mg weekly. This drug has previously been available only as a 250 mg capsule, but Pfizer now has a 600 mg tablet to accommodate this new recommendation. The average wholesale price (AWP) is about $14.50 per tablet, so the recommended dose (two tablets once weekly) will cost $29.00/week. This is about the same as the price for five 250 mg tablets with an AWP of $30.20/week, and is substantially less expensive than clarithromycin ($45.64/week for 500 mg twice daily) or rifabutin ($49.56/week for 300 mg/day). Nevertheless, the least expensive option is the one gram powder packet of azithromycin which is marketed for treatment of infections involving Chlamydia trachomatis. The cost is about $15.00/packet; for those who worry about the possible suboptimal dosing (1,000 mg vs. the 1,200 mg used in MAC prophylaxis trials), another option is a one gram powder packet plus one 250 mg tablet with an AWP of approximately $21.00.

Daunorubicin Liposome for Advanced HIV-Associated Kaposi's Sarcoma:

The FDA has approved daunorubicin liposome (DaunoXome) for intravenous use as first line cytotoxic treatment of patients with advanced HIV-associated KS. In a clinical trial with 227 HIV-infected persons, this drug was compared to standard treatment with adriamycin, bleomycin and vincristine (ABV). DaunoXome proved equally effective in terms of tumor response, it was well tolerated either alone or in combination with AZT, and there were significantly fewer adverse events. With regard to the latter, the frequency of alopecia was 8% with DaunoXome versus 36% in ABV recipients, and neuropathy occurred in 13% compared to 41% of ABV recipients. Cardiotoxicity, the most worrisome side effect of daunorubicin, is "rare" with DaunoXome. The usual dose is 40 mg/m2 given intravenously over 60 minutes at two week intervals. Due to potential myelosuppression, a CBC should be obtained before each dose, and therapy should be withheld for an ANC <750/mm3. Further information is available from NeXstar Pharmaceuticals at 1-800-403-3945.

Cidofovir (Vistide) Approved by FDA for Treatment of CMV Retinitis:

Cidofovir is active in vitro against CMV, including most ganciclovir-resistant strains; strains resistant to cidofovir are usually cross-resistant to ganciclovir and susceptible to foscarnet. Clinical experience with cidofovir is limited to CMV retinitis. Initial studies of cidofovir for primary therapy of CMV retinitis (Study 106) showed a median time to progression of 120 days; only 3 of 25 patients continued on therapy over 120 days, so that the median time to progression or drug discontinuation was 52 days. For patients with relapse during other therapy for CMV retinitis, the median time to progression with cidofovir (Study 107) was 115 days, and the median time to progression or drug discontinuation was 49 days. Prior studies of primary therapy with ganciclovir and foscarnet show a median time to progression of 50-70 days and about 220 days with the intraocular ganciclovir-release device.

The recommended cidofovir regimen is 5 mg/kg infused over one hour at initial dose, at week one and at week two (induction) and then every two weeks (maintenance). Patients should receive one liter of 0.9% saline IV over 1-2 hours before each cidofovir infusion; a second liter is desired in patients who can tolerate it and should be given with cidofovir or immediately afterward. Probenecid must be given with each dose: 2 gm orally 3 hours prior to the cidofovir infusion and 1 gm at 2 hours and 1 gm at 8 hours after the infusion. Food, anti-nausea agents and antihistamines may be given to reduce GI intolerance or hypersensitivity reactions to probenecid. The major side effect is nephrotoxicity with increases in serum creatinine levels of > 0.4 mg/dL in 20-30%. Dose reduction with renal impairment is: creatinine clearance 41-55 ml/min: 2 mg/kg; 30-40: 1.5 mg/kg; 20-29: 1.0 mg/kg and <19: 0.5 mg/kg. There are no data for use of this drug in patients with pre-existing renal failure. The other major side effect is neutropenia; ANC levels of < 500/mm3 are noted in about 20% and may respond to G-CSF. Ocular hypotonia or Fanconi's syndrome are occasionally encountered. Side effects of probenecid include headache, nausea,vomiting and hypersensitivity reactions with rash, fever and/or anaphylaxis. Patient monitoring should include serum creatinine, urinalysis for proteinuria, and a CBC with differential; these tests should be obtained before each dose. Intraocular pressure should be monitored periodically. The AWP for cidofovir is $589/375 mg vial.

Oral Scrapings to Detect HIV:

The FDA approved OraSure (Epitope Inc.) in June 1996. This test uses a treated cotton pad to scrape tissue from the cheek by rubbing the pad back and forth until wet; the pad is then left still for two minutes. The pad is then placed in a vial and submitted to a lab. The advantage is that OraSure offers an alternative to blood for detection of HIV. The "Subject Information" enclosed with the device acknowledges a 1-2% frequency of false negative results (compared to conventional serology) and a 1-2% frequency of false positive results. Persons with positive OraSure tests are advised to get a standard blood test. The new test will cost about $50-60/test.

Two Home HIV Screening Tests Approved:

The FDA has approved Confide HIV Testing Service (Direct Access Diagnostics, a subsidiary of Johnson & Johnson) as the first over-the-counter home HIV screening test. Blood is obtained by a lancet, and a filter strip with blotted blood is mailed in a protective envelope, using an anonymous code. Callers will learn of negative results through a pre-recorded message, but will be offered an opportunity to talk to a counselor. Persons with positive tests or indeterminant results must talk to a counselor who can provide medical referrals. The cost of the test is $40. This kit is available in all states except California, New York, and Pennsylvania. For more information on the Confide test, call 1-800-THE-TEST.

The FDA approved a second home HIV test kit on July 24, 1996: the Home Access Express Test (Home Access Health Corp., Hoffman Estates, Illinois). The Express Test format and method of reporting results is similar to that described for the Confide test. For more information, call 1-800-HIV-TEST.



  
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This article was provided by Johns Hopkins AIDS Service. It is a part of the publication Hopkins HIV Report.
 
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