Evotaz
(atazanavir / cobicistat)Dosage & Administration
Evotaz Prescribing Information
Indications
EVOTAZ® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in the following populations [see Dosage and Administration (2.2 , 2.3)]:
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- Adult patients
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- Pediatric patients weighing at least 35 kg.
Limitations of Use
Use of EVOTAZ in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Clinical Pharmacology (12.4)].
Laboratory Testing Prior to Initiation and During Treatment with EVOTAZ
Renal Testing
Renal laboratory testing should be performed in all patients prior to initiation of EVOTAZ and continued during treatment with EVOTAZ. Renal laboratory testing should include estimated creatinine clearance, serum creatinine, and urinalysis with microscopic examination [see Warnings and Precautions (5.5, 5.6)]. Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.3)].
When coadministering EVOTAZ with tenofovir disoproxil fumarate (tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein at baseline and routinely monitor during treatment. In patients with chronic kidney disease, also monitor serum phosphorus [see Warnings and Precautions (5.4)].
Hepatic Testing
Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of EVOTAZ and continued during treatment with EVOTAZ [see Warnings and Precautions (5.7)].
Recommended Dosage
EVOTAZ is a fixed-dose tablet containing 300 mg of atazanavir and 150 mg of cobicistat. The recommended dosage of EVOTAZ is one tablet taken once daily orally with food [see Clinical Pharmacology (12.3)] in HIV-1-infected treatment-naïve and treatment-experienced:
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- Adult patients
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- Pediatric patients weighing at least 35 kg
Administer EVOTAZ in conjunction with other antiretroviral agents [see Drug Interactions (7)]. Dose separation may be required when taken with H2-receptor antagonists or proton-pump inhibitors [see Drug Interactions (7.2, 7.3)].
Dosage in Patients with Renal Impairment
EVOTAZ is not recommended in treatment-experienced patients with HIV-1 infection who have end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
EVOTAZ coadministered with tenofovir DF is not recommended in patients with estimated creatinine clearance below 70 mL/min. Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
Not Recommended in Patients with Any Degree of Hepatic Impairment
EVOTAZ is not recommended in patients with any degree of hepatic impairment [see Warnings and Precautions (5.7), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
Not Recommended During Pregnancy
EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals due to substantially lower exposures of cobicistat and consequently, lower exposures of atazanavir, during the second and third trimesters. An alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ [see Use in Specific Populations (8.1)].
EVOTAZ tablets contain 342 mg atazanavir sulfate, equivalent to 300 mg of atazanavir, and 150 mg of cobicistat and are oval, biconvex, pink, film-coated, and debossed with “3641” on one side and plain on the other side.
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to EVOTAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals [see Dosage and Administration (2.5)]; use of an alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ. Pharmacokinetic data from studies conducted in pregnant individuals receiving cobicistat showed substantially lower exposures during the second and third trimesters, and consequently also for the coadministered antiretroviral agent. Consult the full prescribing information for cobicistat for additional information. Pharmacokinetic data from the evaluation of atazanavir and cobicistat in a limited number of pregnant individuals showed a similar trend in lower exposures of the antiretroviral component, atazanavir.
Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. Atazanavir use during pregnancy has been evaluated in a limited number of individuals. Available data from the APR show no increase in the risk of overall major birth defects for atazanavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15−20%.
In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of the components of EVOTAZ (atazanavir or cobicistat) to pregnant rats and rabbits (see Data). During organogenesis in the rat and rabbit, atazanavir exposures (AUC) were similar to those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir), while exposures were up to 1.4 (rats) and 3.3 (rabbits) times human exposures at the maximal recommended human dose (MRHD) of 150 mg (see Data).
Clinical Considerations
EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ (see Risk Summary).
Maternal Adverse Reactions
Atazanavir
Reports of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant individuals using atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome.
Hyperbilirubinemia occurs frequently in patients who take atazanavir, including pregnant individuals. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.
Fetal/Neonatal Adverse Reactions
Atazanavir
Infants exposed to atazanavir in utero may develop severe hyperbilirubinemia during the first few days of life.
Data
Human Data
Atazanavir
The APR has received prospective reports of live births following exposure to atazanavir-containing regimens during pregnancy, including 1361 exposures in the first trimester and 737 exposures in second/third trimester. Birth defects occurred in live births in 30 of 1361 (2.2%, 95% CI: 1.5% to 3.1%) with first trimester exposure to atazanavir-containing regimens and 17 of 737 (2.3%, 95% CI: 1.3% to 3.7%) with second/third trimester exposure to atazanavir-containing regimens. There was no increase in the overall rate of birth defects for atazanavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.
Cobicistat
The APR has received prospective reports of live births following exposure to cobicistat-containing regimens during pregnancy, including 347 exposures in the first trimester and 79 exposures in the second/third trimester. Birth defects occurred in 13 of 347 (3.7%, 95% CI: 2.0% to 6.3%) live births with first trimester exposure and 1 of 79 (1.3%, 95% CI: 0.0% to 6.9%) with second/third trimester exposure to cobicistat-containing regimens. Among pregnant individuals in the U.S. reference population, the background rate of birth defects is 2.7%. There was no increase in the overall rate of birth defects for cobicistat compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.
Animal Data
Atazanavir
Atazanavir was administered orally to pregnant rats (at 0, 200, 600, and 1920 mg/kg/day) and rabbits (at 0, 4, 15, and 60 mg/kg/day) during organogenesis (on gestation Days 6 through 15 and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with atazanavir at exposures (AUC) approximately 1.2 times higher (rats) and 0.7 times (rabbits) human exposures at the MRHD. In a rat pre- and postnatal developmental study, atazanavir was administered orally at doses of 0, 50, 220, and 1000 mg/kg/day from gestation Day 6 to postnatal Day 20. At a maternal toxic dose (1000 mg/kg/day), atazanavir caused body weight loss or weight gain suppression in the animal offspring at atazanavir exposures (AUC) of approximately 1.3 times higher than human exposures at the MRHD.
Cobicistat
Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation Day 6 to 17. Maternal toxicity was noted at 125 mg/kg/day and was associated with increases in post-implantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.4 times higher than the human exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation Days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3 times higher than exposures at the MRHD.
In a pre- and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation Day 6 to postnatal Day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 0.9 times lower than exposures at the MRHD.
Lactation
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.
There is no information regarding the effects of EVOTAZ on the breastfed infant or on milk production.
Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Cobicistat is present in rat milk (see Data). There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-1 negative infants), (2) developing viral resistance (in HIV-1 positive infants), and (3) adverse reactions in a breastfed infant, instruct individuals with HIV-1 infection not to breastfeed.
Data
Animal Data
Cobicistat: During the prenatal and postnatal development toxicology study at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation Day 10.
Females and Males of Reproductive Potential
Contraception
Atazanavir and cobicistat, components of EVOTAZ, interact with certain oral contraceptives [see Contraindications (4) and Drug Interactions (7.3)]. Nonhormonal forms of contraceptive should be considered.
Pediatric Use
The safety and effectiveness of EVOTAZ for the treatment of HIV-1 infection in pediatric subjects weighing at least 35 kg was established through a study with components of EVOTAZ. Use of EVOTAZ for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial of components of EVOTAZ (Study GS-US-216-0128) in pediatric subjects with HIV-1 infection aged 12 years and older. The safety in these subjects through 48 weeks was similar to that in antiretroviral treatment-naive adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
Safety and effectiveness of EVOTAZ in the pediatric population weighing less than 35 kg have not been established. Atazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus.
Geriatric Use
Clinical studies with the components of EVOTAZ did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of EVOTAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].
Renal Impairment
EVOTAZ is not recommended for use in treatment-experienced patients with HIV-1 infection who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].
Hepatic Impairment
EVOTAZ is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)].
The concomitant use of EVOTAZ and the following drugs in Table 1, are contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Warnings and Precautions (5.8, 5.9), Drug Interactions (7), and Clinical Pharmacology (12.3)].
EVOTAZ is contraindicated:
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- in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product [see Warnings and Precautions (5.2)].
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- when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 5).
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- when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of EVOTAZ (see Table 1).
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- For additional information, including clinical comments and potential impact on exposure levels associated with drugs that are contraindicated with EVOTAZ, refer to Table 5 [see Drug Interactions (7.3)].
Table 1: Drugs Contraindicated with EVOTAZ
| Drug Class | Drugs within class that are contraindicated with EVOTAZ |
|---|---|
| a Refer to Table 5 for sildenafil when administered for erectile dysfunction [see Drug Interactions (7.3)]. | |
| b Refer to Table 5 for parenterally administered midazolam [see Drug Interactions (7.3)]. | |
Alpha 1-adrenoreceptor antagonist | alfuzosin |
Antianginal | ranolazine |
Antiarrhythmics | dronedarone |
Anticonvulsants | carbamazepine, phenobarbital, phenytoin |
Antigout | colchicine (when used in patients with hepatic and/or renal impairment) |
Antimycobacterials | rifampin |
Antineoplastics | irinotecan |
Antipsychotics | lurasidone, pimozide |
Ergot Derivatives | dihydroergotamine, ergotamine, methylergonovine |
GI Motility Agent | cisapride |
Hepatitis C Direct-Acting Antivirals | elbasvir/grazoprevir; glecaprevir/pibrentasvir |
Herbal Products | St. John’s wort (Hypericum perforatum) |
Hormonal Contraceptives | drospirenone/ethinyl estradiol |
Lipid-modifying Agents | lomitapide, lovastatin, simvastatin |
Non-nucleoside Reverse Transcriptase Inhibitor | nevirapine |
Phosphodiesterase-5 (PDE-5) Inhibitor | sildenafila when administered for the treatment of pulmonary arterial hypertension |
Protease Inhibitors | indinavir |
Sedative/hypnotics | triazolam, orally administered midazolamb |
Cardiac Conduction Abnormalities
Atazanavir prolongs the PR interval of the electrocardiogram in some patients. In healthy subjects and in subjects with HIV-1 infection treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.1) and Overdosage (10)]. In clinical trials of atazanavir in subjects with HIV-1 infection that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of subjects treated with atazanavir (n=920) and 5% of subjects (n=118) treated with atazanavir coadministered with ritonavir. Because of limited clinical experience in patients with preexisting conduction system disease (e.g., marked first-degree AV block or second- or third-degree AV block), consider ECG monitoring in these patients [see Clinical Pharmacology (12.2)].
Severe Skin Reactions
Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir [see Contraindications (4) and Adverse Reactions (6.1)]. EVOTAZ should be discontinued if severe rash develops.
Mild-to-moderate maculopapular skin eruptions have also been reported in atazanavir clinical trials. These reactions had a median time to onset of 7.3 weeks and median duration of 1.4 week and generally did not result in treatment discontinuation.
Effects on Serum Creatinine
Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating EVOTAZ, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.
Prior to initiating therapy with EVOTAZ, assess estimated creatinine clearance [see Dosage and Administration (2.1)]. Dosage recommendations are not available for drugs that require dosage adjustments in cobicistat-treated patients with renal impairment [see Adverse Reactions (6.1), Drug Interactions (7.3), and Clinical Pharmacology (12.2)]. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.
New Onset or Worsening Renal Impairment When Used with Tenofovir DF
Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used in an antiretroviral regimen that contained tenofovir DF. Therefore, coadministration of EVOTAZ and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min [see Dosage and Administration (2.3)].
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- When EVOTAZ is used with tenofovir DF, document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment.
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- Measure serum phosphorus in patients with or at risk for renal impairment.
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- Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.
In a clinical trial over 144 weeks (N=692), 10 (2.9%) subjects treated with atazanavir coadministered with cobicistat and tenofovir DF and 11 (3.2%) subjects treated with atazanavir coadministered with ritonavir and tenofovir DF discontinued study drug due to a renal adverse event. Seven of the 10 subjects (2.0% overall) in the cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation, compared to 7 of 11 subjects (2.0% overall) in the ritonavir group. One subject in the cobicistat group had renal impairment at baseline (e.g., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 subjects treated with cobicistat, with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of cobicistat coadministered with atazanavir and tenofovir DF. Renal replacement therapy was not required in any subject.
Chronic Kidney Disease
Chronic kidney disease in patients with HIV-1 infection treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to EVOTAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with EVOTAZ and continued during treatment with EVOTAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking EVOTAZ. In patients with progressive kidney disease, discontinuation of EVOTAZ may be considered [see Dosage and Administration (2.1, 2.3) and Adverse Reactions (6.1)].
Nephrolithiasis and Cholelithiasis
Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 infection receiving atazanavir therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered [see Adverse Reactions (6, 6.1)].
Hepatotoxicity
Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with EVOTAZ and during treatment [see Dosage and Administration (2.4) and Use in Specific Populations (8.7)].
Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
Initiation of EVOTAZ, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving EVOTAZ, may increase plasma concentrations of medications metabolized by CYP3A.
Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of EVOTAZ, respectively.
Increased concentrations of EVOTAZ may lead to:
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- clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from higher exposures of concomitant medications.
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- clinically significant adverse reactions from higher exposures of EVOTAZ.
Decreased concentrations of EVOTAZ may lead to:
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- loss of therapeutic effect of EVOTAZ and possible development of resistance.
See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7.3)]. Consider the potential for drug interactions prior to and during EVOTAZ therapy; review concomitant medications during EVOTAZ therapy; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4)and Drug Interactions (7)].
When used with concomitant medications, EVOTAZ may result in different drug interactions than those observed or expected with atazanavir coadministered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with atazanavir coadministered with ritonavir to certain EVOTAZ interactions [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
Antiretrovirals that are Not Recommended
EVOTAZ is not recommended in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other HIV protease inhibitors or elvitegravir) because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance.
EVOTAZ is not recommended in combination with ritonavir or products containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.
See Drug Interactions (7) for additional recommendations on use with other antiretroviral agents.
Hyperbilirubinemia
Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyltransferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of atazanavir. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin greater than 5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to EVOTAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients [see Adverse Reactions (6)].
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir, a component of EVOTAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Diabetes Mellitus/Hyperglycemia
New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 infection receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Hemophilia
There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.