Trade name: Crixivan (Merck Research Laboratories)
Form: 100, 200 and 400 mg capsules.
Clinical trials: Phase I/II trials show a dose-dependent antiviral effect; with 600-800 mg tid, the mean decrease in viral burden was 1-1.5 logs in those receiving monotherapy and >2 logs with combination therapy using indinavir plus a nucleoside analog. Indinavir + AZT +ddI in patients with CD4 <500/mm 3 and viral burden > 20,000 copies/ml showed a mean CD4 count increase of 80-90/mm 3 and decrease in viral burden of >2 logs at 24 wks (3rd Annual Retroviral and Opportunistic Infection Meeting, Washington, DC, 2/96, Abstract 200). Similar results were noted with indinavir + AZT + 3TC in patients with CD4 counts of 50-400/mm 3 and median viral burden 40,000 copies/ml; at 26 weeks the mean CD4 count increase was 100/mm 3 and the decrease in viral burden was >2 logs.
Dose: 800 mg po tid in fasting state; always use in combination, usually with a nucleoside analog.
Pharmacology: Bioavailability--Absorption is best with fasting state C max = peak > 200 nM; 8 hrs post dose--8
nM (95% inhibition at 25-100 nM in vitro)
T 1/2 serum--1.5-2 hr.
Excretion--Metabolized, mostly through hepatic glucuronidation and p450 dependent pathways. Urine shows 5012% unchanged
- Asymptomatic increase in indirect bilirubin to 2.5 mg/ml without increase in transaminase noted in 10-15% of patients.
- Nephrolithiasis = hematuria in 2-15%. Should take 48 oz fluid daily.
- Less common: increased transminase levels, headache, nausea, vomiting, diarrhea, metallic taste, fatigue, insomnia, blurred vision,
dizziness, rash thrombocytopenia.
- Nucleoside analogs (AZT, ddI, ddC, d4T and 3TC): none known.
- Ketoconazole: increases levels of indinavir by 70%.
- Rifampin and rifabutin: decreases level of indinavir and increases levels of rifampin or rifabutin.
Trade name:Norvir (Abbott Laboratories)
Form:100 mg capsules; cost (AWP): 168 caps (2-week supply)--$257.
Clinical trials: Phase I/II trials have shown that ritonavir as a single agent has dose-related antiviral activity with
median maximum reduction in viral load of 1.7-1.9 logs at 4-8 weeks and median increases in CD4 counts of 230/mm
3 at 32 weeks (NEJM 1995; 333: 1534; NEJM 1995; 333:1528). A phase III trial of ritonavir plus nucleoside analogs in
patients with CD4 counts <100/mm
3 showed a 58% decrease in AIDS-defining events or death in ritonavir recipients compared to those continued on
nucleoside analogs alone (3rd Conference on Retroviruses and Opportunistic Infection, Washington, DC, January 28-February 1, 1996,
Abstract LB6(a). This is the only protease inhibitor that received "traditional approval," a decision based on the demonstration
of a clinical benefit.
Dose: 600 mg po bid
T 1/2 serum: 3-4 hrs
C max: 7-11 mg/ml (2.1 mg/ul = 95% inhibitory concentration)
Elimination: Metabolized to 5 metabolites primarily by cytochrome P450 3A; 11% excreted in urine and 86% in feces.
Side effects: Dose related--GI intolerance (nausea, vomiting, diarrhea, taste perversion and/or abdominal pain in
30-50%) and circumoral or peripheral paresthesias (5%). GI intolerance was sufficiently severe to require discontinuation in 15-25% of
participants in initial clinical trials, but the formulation marketed appears to be better tolerated. Cholesterol levels increase 30-40%, and
triglyceride levels increase 200-300%. Triglyceride levels>1500 mg/ml were noted in 3-10%. Other side effects are asthenia (15-25%),
and elevated transaminase (3-7%).
Drug Interaction: Potent inhibition of cytochrome P450 isoforms will presumably increase levels of multiple drugs
metabolized by this mechanism. Ritonavir is expected to produce large increases in the plasma concentrations of the following drugs:
amiodarone, astemizole, bepridil, bupropion, cisapride, clozapine, encainide, flecainide, meperidine, piroxicam, propafenone, propoxyphene,
quinidine, rifabutin, and terfenadine. These agents have recognized risks of arrhythmias, hematologic abnormalities, seizures, or other
potentially serious adverse effects and should not be given with ritonavir. Ritonavir co-administration is also likely to produce large
increases in these highly metabolized sedatives and hypnotics: alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam,
triazolam, and zolpidem. Due to the potential for extreme sedation and respiratory depression from these agents, they should not be given
with ritonavir. Co-administration increases levels of erythromycin, clarithromycin, fentanyl, oxycodone, coumadin, carbamazepine, tricyclic
antidepressants, calcium channel blockers, neuroleptics and oral hyoglycemics. There is a reduction in levels of theophylline, atovaquone
and lorazepam. There is also a reduction in levels of estradiol with oral contraceptives so that alternative methods of birth control should
Experience in >35,000 patients given 3TC through Treatment IND and 4 therapeutic trials in 1,000 patients showed minimal toxicity. Infrequent complications include headache, nausea, diarrhea, abdominal pain and insomnia. Comparison of side effects in 251 patients given 3TC plus AZT and 230 patients given AZT alone in four trials (A3001, A3002, B3001, and B3002) indicated no clinical laboratory complications uniquely associated with 3TC. Pancreatitis has been noted in 15% of pediatric patients given 3TC. The most common side effects in patients given 3TC plus AZT are headache (35%), nausea (18%), neuropathy (12%), neutropenia (7%), and anemia (3%).
Category C. No studies have been done in patients. Some evidence of early embryolethality was seen in rabbit studies, but no effect was seen with rats using doses up to 130 times the dose recommended for patients. To monitor maternal-fetal outcomes, an Antiretroviral Pregnancy Registry has been established: (800) 722-9292 x58465.
TMP-SMX (1 DS daily) increases levels of 3TC; however, the implications for therapy are unclear.
Trade name: Daunoxome (NeXstar Pharmaceuticals)
Form and price: 50 mg vials for IV use; $200-250 vial with 2 vials q 2 wks: $1000/month.
Product information: Daunorubicin is an anthracycline g lycoside which inhibits RNA and DNA synthesis. The
liposomal preparation utilizes a liposomal carrier system that gives a favorable pharmacokinetic profile at the site of KS due to enhanced
tumor uptake and slow intracellular release. Drug concentrations within KS lesions show daunorubicin levels that are 10-fold greater than
those achieved with conventional preparations of daunorubicin.
- Extensive cutaneous Kaposi sarcoma which is unresponsive or inappropriate for local treatment with intralesional vinblastine or
- visceral Kaposi sarcoma.
Drug regimen: 40-60 mg/m
2 given intravenously q 2 wks.
Clinical trial:Clinical study of 227 patients with KS randomized to Daunoxome (40 mg/m
2 versus standard ABV chemotherapy (Adriamycin 10 mg/m
2, Bleomycin 15 mg and Vincristine 1 mg) every two weeks showed stable disease or improvement in 85% of both groups.
There was a significant decrease in side effects in the dauoxome group for fatigue (17 vs 29%), neuropathy (3 vs 20%) and alopecia (4 vs
Major: Neutropenia in 15-30%; anemia and thrombocytopenia are less common. Monitor CBC. Withhold therapy if ANC
prior to next cycle is <750/mm
3. May respond to G-CSF. Neuropathy: 3%
Minor: Alopecia: 4% (reversible with discontinuation). Back pain, flushing and chest tightness is noted in <5%
during first 5 minutes of infusion. This usually resolves with discontinuation of infusion and resumption at a slower rate.
Drug interactions: May be given with antiretroviral agents. AZT will increase neutropenia. Drugs with a narrow
therapeutic margin should have increased monitoring for toxicity and measurement of levels. The following should be co-administered with
caution: acetaminophen, aspirin, oxycodone, ethambutol, lorotadine, fluoxetine (Prozac), desipramine, lorazepam (Ativan) and temazepam
(Restoril). Combination with saquinavir produces a possibly advantageous incrase in saquinavir produces a possibly advantageous increase
in saquinavir levels, although this potential drug interaction has not been studied in patients and the combination should not be used until
these data are available. Drugs that incrase cytochrome P450 activity presumably decrease levels of ritonavir, phenobarbital, carbamazepine,
dexamethasone, phenytoin, rifampin and rifabutin.