Profiles on New Drugs
Trade name: Crixivan (Merck Research Laboratories) Drug Interactions: Trade name:Norvir (Abbott Laboratories) Trade name: Invirase (Hoffman-LaRoche) Note: The minimum effective dose is 1800 mg/day. Studies with saquinavir + AZT or ddC show mean CD4 count increases of 30-50/mm 3 at 16-48 weeks and decreases in viral RNA levels averaging 0.5 log. Monotherapy with saquinavir shows minimal effect on surrogate markers. The FDA has approved saquinavir for use in combination with any approved nucleoside analog, although the only studies that have been done are with saquinavir plus AZT and/or ddC. When saquinavir was added to AZT after prolonged AZT use, there was little evidence of activity by AZT. Studies of viral burden show combination treatment is more effective with mean decreases of 0.5-1.0 log compared to 0.1-0.2 log for saquinavir alone. Higher doses of saquinavir (3600-7200 mg/d) produced greater antiviral effect and CD4 response. Trade name: Epivir (Glaxo Wellcome)
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 metabolites.
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 be sought.
Form and price: 200 mg cap at $1.75/200 mg ($5800/year)
Reimbursement: Hotline and Medical Needs Program 800-282-7780.
Class: Protease inhibitor
Indications (FDA labeling): Indicated for advanced HIV infection in combination with nucleoside analogs
Trials: Three trials have evaluated saquinavir plus ddC and/or AZT in 810 patients:
Resistance:Genotypic resistance at L90M (most common, 3-fold decrease in sensitivity) and G48V (less common, 30-fold decrease in sensitivity). There is no established cross-resistance with other protease inhibitors such as invirase and ritonavir. The initial experience with AZT plus saquinavir for 8-12 months suggests delayed resistance to AZT compared to AZT monotherapy.
Dose: 600 mg po tid. (Doses of 3.6 and 7.2 gm/day produce greater activity in terms of CD4 counts response and decreases in viral burden of up to 2 logs: dose of 1800 mg/d was approved by FDA because this was the dose used in phase 3 trials.)
Pharmacology:Bioavailability: absorption is 4% with high-fat diet (1,000 calories with 60 gm fat). Should be taken within 2 hours of fatty meal to increase absorption.
T 1/2: 1-2 hours
Elimination: 96% biliary excretion via cytochrome P450; 1% urine. Dose modification in renal failure or liver failure: no data.
Side effects: GI intolerance with nausea, abdominal pain and diarrhea in 4-6% (dose related); headache.
Drug interactions: Rifampin reduces saquinavir levels by 80%, rifabutin by 40%; other drugs that may reduce saquinavir levels are phenobarbital, phenytoin, dexamethasone, and carbamazepine. Recommendation for MAC prophylaxis is clarithromycin rather than rifabutin. Ketoconazole increases levels of saquinavir 150%; itraconazole and fluconazole presumably incrase levels as well. Saquinavir may increase levels of terfenadine or astemizole (and presumably cisapride) with possible serious arrhythmias. It may also increase levels of calcium channel blockers, clindamycin, dapsone, quinidine and triazolam.
Pregnancy: Class B. Studies in rats showed no teratogenicity or embryotoxicity.
Forms and price: 150 mg tablets at $3.11/tab
Oral solution 10 mg/ml, bottles of 240 ml at $49.76/240 ml.
Patient assistance program: 1-800-722-9294 (Mon-Fri 8:30 a.m.-7:00 p.m. EST)
Class: Nucleoside analog
Efficacy: Four comparative trials with 3TC plus AZT versus monotherapy in about 1,000 participants revealed that the combination was superior based on surrogate marker end points. At 24 weeks the mean CD4 cell increase was 20-75/mm 3. Results with 3TC or AZT alone were inferior (NEJM 1995; 333:11). The presumed explanation for the superior results with AZT plus 3TC appears to be the re-establishment of susceptibility to AZT (Science 1995; 269:696). This drug is also very active vs. hepatitis B virus in vitro and the initial clinical experience is good (NEJM 1995; 333:11).
Indications: FDA approved "for use in combination with retrovir (AZT) for the treatment of HIV infection when an antiretroviral therapy is warranted based on clinical and/or immunologic evidence of disease progression.
T 1/2: 5-7 hours; Intracellular T 1/2: 12 hours
CNS penetration: 10%
Elimination: Renal accounts for 71%
Dose modification in renal failure:
Trade name: Crixivan (Merck Research Laboratories)
Trade name:Norvir (Abbott Laboratories)
Trade name: Invirase (Hoffman-LaRoche)
Note: The minimum effective dose is 1800 mg/day. Studies with saquinavir + AZT or ddC show mean CD4 count increases of 30-50/mm 3 at 16-48 weeks and decreases in viral RNA levels averaging 0.5 log. Monotherapy with saquinavir shows minimal effect on surrogate markers. The FDA has approved saquinavir for use in combination with any approved nucleoside analog, although the only studies that have been done are with saquinavir plus AZT and/or ddC. When saquinavir was added to AZT after prolonged AZT use, there was little evidence of activity by AZT. Studies of viral burden show combination treatment is more effective with mean decreases of 0.5-1.0 log compared to 0.1-0.2 log for saquinavir alone. Higher doses of saquinavir (3600-7200 mg/d) produced greater antiviral effect and CD4 response.
Trade name: Epivir (Glaxo Wellcome)
|>50 ml/min||150 mg bid|
|30-49 ml/min||150 mg qd|
|15-29 ml/min||150 mg, then 100 mg qd|
|5-14 ml/min||150 mg, then 50 mg qd|
|<5 ml/min||50 mg, then 25 mg qd|
Dose regimen: 150 mg po bid; adults <50 kg should receive 2 mg/kg bid
Side effects: 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%).
Pregnancy: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.
Interactions: TMP-SMX (1 DS daily) increases levels of 3TC; however, the implications for therapy are unclear.
Amphotericin B Lipid Complex
Trade Name: Abelcet (Liposome Co.)
Form and price: 20 ml vials with 100 mg Amphotericin B. Cost = $107/vial or $430/infusion; conventional Amphotericin B = $21/50 mg vial.
Product information: The lipid complex form substantially affects the pharmacology properties and toxicity. For more information, call 1-800-335-5476.
Regimen: 5 mg/kg/day (usually 4 vials). Infuse at concentration 1 mg/ml infused at rate of 2.5 mg/kg/hr.
Indications: (FDA labeling): "Aspergillosis in patients who are refractory to or intolerant of conventional Amphotericin B." Note: This drug should be effective in any clinical setting in which Amphotericin B is used. The restriction to Aspergillosis is because this is the only infection in which there was a large clinical experience in the FDA filing. Penetration across the blood-brain barrier is reduced. The major potential advantage of this formulation of Amphotericin B is the reduced toxicity. Patients with creatinine levels >2.5 mg/ml with Amphotericin B had decreases in creatinine when given Abelcet. In comparison with conventional Amphotericin B (0.7 mg/kg/day) for candidiasis, the relative frequencies of renal failure with serum creatinine elevations to 2 mg/ml was 24% vs 42% favoring the lipid complex form (package insert).
Bioavailability: Not absorbed; with IV infusions of 5 mg/kg/d compared to conventional Amphotericin B at 0.6 mg/kg/d--serum levels are comparable and volume of distribution and clearance are much higher reflecting tissue uptake.
Side effects: Major advantage is reduced nephrotoxicity, compared to Ampho B in dose of 0.7 mg/kg/day. Fever and chills are common during first 1-2 hrs of infusion. Anaphylaxis has been reported in one patient.
Monitor:CBC, liver function tests, electrolytes (esp K+ and Mg) and creatinine at regular intervals.
Drug interactions: Similar to Ampho B.
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 freezing 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 19%).
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.