a) CASE REPORT: Twin females, born at 32 weeks gestation to a 33-year-old woman diagnosed prenatally with HIV infection and treated with antiretroviral therapy, were also given antiretroviral therapy, consisting of zidovudine initially, with the addition of lopinvair/ritonavir (LPT/RTV) combination therapy approximately 12 hours after birth, at a dose of 300/75 mg/m(2)/dose every 12 hours. At 6-days-old, twin A experienced a decrease in heart rate (60 to 80 bpm from a baseline of 120 to 150 bpm). The patient was intubated the next day due to respiratory and cardiac insufficiency, and an echocardiogram revealed dilated cardiomyopathy of the left atrium and ventricle and a decreased ejection fraction of 40%. Despite supportive care and discontinuing LPT/RTV therapy, the patient's condition continued to deteriorate with repeat ECG's demonstrating sinus bradycardia with first degree AV block, and right bundle branch block. However, 4 days after LPT/RTV cessation, the patient recovered with normalization of sinus rhythm. Twin B also experienced a decrease in heart rate at 6-days-old (110 to 120 bpm from a baseline of 130 to 160 bpm), although an ECG revealed normal sinus rhythm. LPT/RTV therapy was discontinued and, 72 hours later, the heart rate normalized. Both patients completed a 6-week course of zidovudine therapy, with no signs of cardiac abnormalities, and no evidence of HIV infection (McArthur et al, 2009).

a) Adverse effects occurring in 2% or less of patients in clinical trials have included: seizures, tremor, ataxia, dizziness, confusion, amnesia, headache, depression, abnormal dreams, hallucinations, insomnia, lethargy, and psychosis (Prod Info INVIRASE(R) oral capsules and oral tablets, 2010; Prod Info NORVIR(R) oral solution, oral tablet, 2010; Prod Info CRIXIVAN(R) oral capsules, 2010).
b) Headaches are a commonly reported adverse effect of the protease inhibitors, with 28% of patients in one ritonavir clinical trial reporting this (Markowitz et al, 1995).
c) CNS toxic effects, including hallucinations, disorientation, and vertigo, were reported in an HIV-positive patient after an initial dose of amprenavir oral solution, with propylene glycol as an excipient. Twelve hours later the patient took a second dose with symptoms returning with increased severity. The oral solution was stopped; toxicity was thought due primarily to propylene glycol (estimated ingested amount, 950 mg/kg/day) (James et al, 2001).

a) CASE REPORT: A 47-year-old man presented with vomiting, abdominal pain, and a headache approximately 9 hours after intentionally ingesting 270 tablets of a combination medication containing lopinavir and ritonavir (total dose ingested 54 g lopinavir and 13.5 g ritonavir), as well as 8.25 mg of warfarin. The patient also developed a diffuse erythematous and pruritic rash. At admission, plasma concentrations of lopinavir and ritonavir were 57,234 mcg/L (lopinavir reference range: 5500 to 9600 mcg/L) and 25,776 mcg/L, respectively. All symptoms resolved within 20 hours following supportive therapy. Repeat plasma concentrations of lopinavir and ritonavir, obtained 16 days post-discharge following initiation of therapeutic dosing of 3 tablets twice daily, were 8448 mcg/L and 184 mcg/L, respectively (Roberts et al, 2008).

a) Therapy with protease inhibitors for HIV infections commonly results in diarrhea (Sherman & Fish, 2000). Indinavir and ritonavir are associated with a high degree of nausea (up to 30% for ritonavir and 12% for indinavir) and vomiting (up to 17% for ritonavir) and diarrhea (up to 23% for ritonavir) (Prod Info NORVIR(R) oral solution, oral tablet, 2010; Prod Info CRIXIVAN(R) oral capsules, 2010). Discontinuation of therapy has been necessary in a small percent of patients due to the severity of the gastroenteritis (Danner et al, 1995; Markowitz et al, 1995). 11% of patients in a high dose saquinavir (7200 mg/day) clinical trial experienced grade 2 vomiting and diarrhea (Shapiro et al, 1996). Gastrointestinal events are most frequently observed in patients treated with either ritonavir alone or in combination with saquinavir, as well as in patients receiving nelfinavir (Bonfanti et al, 2000).

a) In a report of 79 cases of indinavir overdoses, 52 were associated with adverse events. The amount ingested was available for 48 cases. Doses ranged from 2.8 g to 48 g (mean 13 g) in 10 acute overdose cases. Thirty-three of the 48 cases were chronic overdose ingestions of indinavir ranging from an extra 200 milligrams to 1000 milligrams per dose for a period up to 73 days. Gastrointestinal symptoms (ie, nausea, vomiting, abdominal pain) occurred in 54% (28/52) of patients following indinavir overdose (Lehman et al, 2003).
b) CASE REPORT: An overdose of indinavir 6 g, 10 Bactrim DS tablets and alcohol in an adult, resulted in mild abdominal pain and nausea, which resolved over 4 hours (Burkhart et al, 1998).
c) CASE REPORT: A 47-year-old man presented with vomiting, abdominal pain, and a headache approximately 9 hours after intentionally ingesting 270 tablets of a combination medication containing lopinavir and ritonavir (total dose ingested 54 g lopinavir and 13.5 g ritonavir), as well as 8.25 mg of warfarin. Diarrhea also occurred prior to presentation (4 hours post-ingestion) and a diffuse erythematous and pruritic rash developed post-presentation. At admission, plasma concentrations of lopinavir and ritonavir were 57,234 mcg/L (lopinavir reference range: 5500 to 9600 mcg/L) and 25,776 mcg/L, respectively. All symptoms resolved within 20 hours following supportive therapy. Repeat plasma concentrations of lopinavir and ritonavir, obtained 16 days post-discharge following initiation of therapeutic dosing of 3 tablets twice daily, were 8448 mcg/L and 184 mcg/L, respectively (Roberts et al, 2008).

a) Other gastrointestinal effects occurring in moderate degree in a small percent of patients in clinical trials include: pancreatitis, colitis, esophagitis, mouth ulcers, dysphagia, taste perversions (up to 11% of patients), flatulence and eructation (Prod Info NORVIR(R) oral solution, oral tablet, 2010; Prod Info INVIRASE(R) oral capsules and oral tablets, 2010; Prod Info CRIXIVAN(R) oral capsules, 2010).

a) Acute severe hepatitis developed in 3 AIDS patients after exposure to indinavir; each patient was being treated with a complex multidrug regimen. Hepatitis occurred between 4 and 38 days after initiation of the protease inhibitor, indinavir (Brau et al, 1997).
b) CASE REPORT: Acute hepatitis was reported in a 46-year-old male following 2 doses of the antiretroviral combination saquinavir, ritonavir, and stavudine. The patient was also receiving valproate, phenobarbital, and primidone; the authors suggested a cytochrome P450 dependent drug interaction may have played a role in toxicity. Hepatic enzyme levels returned to normal within 2 weeks. Antiretroviral therapy was restarted with indinavir, stavudine, and lamivudine with no return of abnormal liver function tests (Vandercam et al, 1998).
c) Acute hepatitis was reported in 0.5% of patients who were receiving darunavir and ritonavir as combination therapy during a clinical development program (n=3063) (Prod Info PREZISTA(TM) oral tablets, 2008).

a) Nephrolithiasis, or kidney stones, with or without hematuria, and with flank pain occurred in 9% of indinavir treated patients in clinical trials and less than 2% of ritonavir treated patients (Prod Info CRIXIVAN(R) oral capsules, 2010; Prod Info NORVIR(R) oral solution, oral tablet, 2010). This is presumably related to crystallization of the drug (Mellors et al, 1995; F Massari , 1995; Olyaei et al, 2000). Indinavir stones are radiolucent, thus abdominal x-ray is not indicated. When symptoms of nephrolithiasis are present, radiographic imaging should be performed to reveal any obstruction (Lerner et al, 1998). Kidney stones was associated with renal dysfunction and resolved with temporary interruption of therapy and with hydration (Prod Info CRIXIVAN(R) oral capsules, 2010). The highest incidence of renal toxicity among protease inhibitors is reported following indinavir therapy (Bonfanti et al, 2000a).
b) Renal atrophy developed after long-term therapy with indinavir in 2 male AIDS patients. Elevated serum creatinine and pyuria resolved after replacing indinavir with nelfinavir therapy (Hanabusa et al, 1999).
c) Crystal nephropathy, or nephrolithiasis, (characterized by elevated serum creatinine, reduced concentrating ability of kidney, leukocyturia, and renal parenchymal image abnormalities) has been reported as a frequent complication of indinavir therapy (Boubaker et al, 1998; Kopp et al, 1997; Marroni et al, 1998; Ascher & Lucy, 1997). Characteristic crystals, birefringent with plate and starburst structures, are formed by indinavir in the urine.
d) CASE REPORT: 2 cases of oliguric acute renal failure due to indinavir crystalluria and nephrolithiasis, with obstructive uropathy, were reported. In both cases the renal failure resolved following discontinuation of indinavir and administration of intravenous fluids (Berns et al, 1997).
e) CASE REPORT: A 39-year-old woman developed hypertension (180/115 mmHg) and renal atrophy, seen on renal ultrasonography, within about one year of starting indinavir therapy. Indinavir was stopped and replaced with nelfinavir. Her pyuria resolved and blood pressure decreased significantly at her follow-up one month later (Cattelan et al, 2000).

a) In a report of 79 cases of indinavir overdoses, 52 were associated with adverse events. The amount ingested was available for 48 cases. Doses ranged from 2.8 g to 48 g for 10 acute overdose cases. Thirty-three of 48 cases ingested a chronic overdose of indinavir ranging from an extra 200 milligrams to 1000 milligrams per dose for a period up to 73 days. Nephrolithiasis was reported in 40% (21/52) of patients (Lehman et al, 2003).

a) Therapy with indinavir can result in crystalluria and potentially severe urinary tract obstruction. Symptomatic crystalluria associated with indinavir therapy was reported in a 26-year-old female. No evidence of stones was noted. Crystalluria resolved spontaneously after discontinuation of indinavir and substitution with nelfinavir (Famularo et al, 2000).

a) Chronic therapy with indinavir has been known to cause crystalluria and nephrotoxicity. Elko & Robertson (2001) reported an acute overdose of 16 to 24 grams of indinavir in a 30-year-old male (not HIV positive) which resulted in severe lower back pain and hematuria. Initial urinalysis was positive for blood, protein and crystals. Serum creatinine peaked at 2.1, with a BUN of 4. Symptoms resolved within 72 hours and serum creatinine normalized to 1.1 and the patient was discharged (Elko & Robertson, 2001).

a) Acute renal failure induced by ritonavir has been reported (Bochet et al, 1998). Increases in serum creatinine have occurred between 4 and 21 days after initiating therapy. Re-challenges of ritonavir resulted in increases in serum creatinine (Deray, 1998). In a retrospective analysis of serum creatinine levels in a cohort of 87 patients, a significant increase (>50% from baseline) was found in 13.7% of the patients. A median increase in serum creatinine of 109 micromoles/L was reported.
b) Duong et al (1996) reported acute renal dysfunction in 3 patients within 10 to 15 days of starting ritonavir therapy. A 54-year-old male developed renal failure 10 days after introduction of ritonavir in his therapy which also included didanosine and other drug therapy. Renal function returned to normal, and the patient was rechallenged with ritonavir alone, which was again associated with an increase in serum creatinine (Duong et al, 1996).
c) Witte et al (1999) reported 2 cases of indinavir-induced nephrolithiasis leading to anuria and acute renal failure. Nephrolithiasis was reported 2 weeks and 2 months, respectively after the addition of 800 mg indinavir sulfate 3 times daily to the therapy regimen in these patients. Renal function returned to normal in both patients following symptomatic therapy.

a) Other reported adverse genitourinary effects occurring in less than 2% of patients in clinical trials have included: hydronephrosis, proteinuria, urolithiasis, hematuria, dysuria, urinary tract infections, and renal colic (Prod Info CRIXIVAN(R) oral capsules, 2010; Prod Info NORVIR(R) oral solution, oral tablet, 2010; Prod Info INVIRASE(R) oral capsules and oral tablets, 2010).

a) Male sexual dysfunction, with erectile dysfunction, lack of libido, and inability to ejaculate has been reported as an adverse effect of protease inhibitors (Colebunders et al, 1999). Martinez et al (1999) measured slightly increased 17-beta estradiol in 5 male patients with sexual dysfunction with an otherwise normal endocrinological evaluation (Martinez et al, 1999).

a) Hypermenorrhea with resultant anemia has been associated with ritonavir therapy, which has resolved after discontinuing ritonavir (Nielsen, 1999). It is not known if other protease inhibitors have the same adverse effect.

a) CASE REPORT: A 47-year-old man developed a diffuse erythematous and pruritic rash after intentionally ingesting 270 tablets of a combination medication containing lopinavir and ritonavir (total dose ingested 54 grams lopinavir and 13.5 grams ritonavir). The rash spontaneously resolved and the patient was discharged home following psychiatric assessment (Roberts et al, 2008).

a) FIRST TRIMESTER EXPOSURE:
b) SECOND/THIRD TRIMESTER EXPOSURE:
c) UNSPECIFIED TRIMESTER:

a) There have been sufficient numbers of first trimester exposures to atazanavir to detect at least a 2-fold increase in risk of birth defects. No increases in birth defects overall have been observed in data collected from the Antiretroviral Pregnancy Registry. Prevalence of birth defects associated with maternal first trimester atazanavir use was 1.9% compared with the total United States population-based prevalence of 2.7% (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
b) In a retrospective analysis of atazanavir use in 33 pregnancies (31 women; 20 receiving atazanavir at conception), there were 26 births, 2 miscarriages at 12 and 16 weeks, and 5 continuing pregnancies. None of the infants required phototherapy and there were no birth defects reported (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

a) There are no adequate and well-controlled studies of atazanavir/cobicistat use in pregnant women. Therefore, atazanavir/cobicistat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Treatment-experienced patients taking an H2-receptor antagonist and/or tenofovir DF during the second or third trimester should not be administered atazanavir/cobicistat (Prod Info EVOTAZ(TM) oral tablets, 2015).

a) CASE REPORTS: Two case reports described HIV-positive women treated with combination antiretroviral therapy (including darunavir in both cases) during pregnancy who delivered healthy, normal babies at term. The first case was a 19-year-old whose regimen, initiated 21 weeks before conception, included etravirine 200 mg twice daily, darunavir 600 mg twice daily, and raltegravir 400 mg twice daily, as well as other antiretrovirals; antibiotics were also given continuously beginning at conception. A 2.7 kg infant was delivered at 40 weeks’ gestation with no dysmorphic features or cardiac, respiratory, or neurological abnormalities. The infant had negative HIV status at birth and at 2 months of age. The second case described a 17-year-old whose medications, initiated at 4 months’ gestation, included etravirine 200 mg twice daily and darunavir 600 mg twice daily, together with other antiretrovirals, antibiotics, and amlodipine. A 3.2 kg infant was delivered by cesarean section at 39 weeks' gestation with no congenital or metabolic abnormalities. The infant tested negative for HIV at birth and at 4 months of age. Cord serum drug levels were not collected from either infant (Jaworsky et al, 2010).
b) CASE REPORT: A 33-year-old HIV-infected woman who received darunavir during pregnancy gave birth to a healthy infant. The patient, who had been initiated on antiretroviral therapy approximately 14 months prior, had discontinued therapy upon becoming pregnant. Subsequently, she was reinitiated on a twice-daily regimen of lopinavir/ritonavir and emtricitabine/tenofovir disoproxil fumarate. Two weeks later, lopinavir/ritonavir was stopped due to continued diarrhea and she was initiated on a once-daily regimen of darunavir 900 mg/ritonavir 100 mg along with the emtricitabine/tenofovir. At this time, her CD4 count was 639 cells/mcL, with an undetectable viral load. At pregnancy week 18, a low darunavir plasma trough concentration of 1280 nanograms (ng)/mL was detected. The patient admitted to self-reducing her darunavir dose to 600 mg/day to decrease pill burden number. The dose was adjusted to darunavir 800 mg/ritonavir 100 mg per day. At week 21, darunavir trough concentration was 1877 ng/mL. At week 38, she delivered a healthy baby boy. Maternal viral load was undetectable and the CD4 count was 876 cells/mcL at the time of delivery. Darunavir levels during delivery (3 hr post-dose) were 4086 ng/mL, 430 ng/mL, 980 ng/mL, and 380 ng/mL in maternal blood, cord blood, amniotic fluid, and cervicovaginal fluid, respectively. These corresponded to ratios (to maternal plasma) of 0.11 for cord blood, and 0.24 and 0.09 for amniotic and cervicovaginal fluid, respectively. At 1 month of age after 6 weeks of zidovudine, the infant had a negative HIV-1 DNA PCR test with no laboratory abnormalities (Ivanovic et al, 2010).
c) CASE REPORT: A healthy infant was born to a 41-year-old woman who received a HAART regimen that included darunavir during pregnancy. The patient, who was positive for hepatitis C virus and HIV, was initiated on and failed an antiretroviral (ARV) regimen of zidovudine, lamivudine, and indinavir followed by 3 other ARV regimens. She was evaluated for a salvage regimen and found to have multidrug-resistant HIV when pregnancy was confirmed. Subsequently, the patient was instructed to discontinue ARVs. At week 28 of gestation, she was started on a darunavir, enfuvirtide, zidovudine, and lamivudine HAART regimen. Viral load (VL) was less than 400 copies/mL and her CD4 count was 180 cells/mm(3) (13%) within 45 days of the ARV therapy. At weeks 34 and 36 of gestation, maternal samples showed adequate darunavir trough concentrations of 3010 and 3470 nanograms/mL, respectively. Two hours prior to delivery at 38 weeks' gestation, the patient received the last ARV dose. During surgery, she received conventional IV zidovudine. The infant, who was in good health, was immediately initiated on boosted zidovudine for 4 weeks. In the infant, HIV-polymerase chain reactions at birth, and at 2 and 6 months were negative for HIV (Sued et al, 2008).

a) There are no adequate and well-controlled studies of atazanavir/cobicistat use in pregnant women. Therefore, atazanavir/cobicistat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (Prod Info PREZCOBIX(TM) oral tablets, 2015).

a) There are no adequate and well-controlled studies of fosamprenavir use in pregnant women. In a small, retrospective, observational study (COL108577) of HIV-positive pregnant women, fosamprenavir-based Highly Active Antiretroviral Therapy (HAART) was well-tolerated and had favorable immunological and virological responses in all women without harm to their infant. Data for 9 mother-infant pairs were reviewed. Six of the nine women were treatment-naive to HAART at baseline. In addition to fosamprenavir, HAART regimens included boosting with either ritonavir (n=7), zidovudine/lamivudine (n=6), tenofovir/emtricitabine (n=1), didanosine/emtricitabine (n=1), or abacavir/lamivudine (n=1). Across the study, improvements were noted in both viral load and CD4+ T-cell count. Compared with baseline, at delivery, viral loads decreased for 8 of the women. One woman with undetectable viral load (less than 50 copies/mL) at baseline, had undetectable viral load at delivery. Increases in CD4+ T-cell counts were noted in all 9 women. Infants showed no CNS abnormalities, experienced no significant adverse effects, and all tested negative for HIV (Martorell et al, 2010).

a) There have been sufficient numbers of first trimester exposures to indinavir to detect at least a 2-fold increase in risk of birth defects. No increases in birth defects overall with indinavir have been observed in data collected from the Antiretroviral Pregnancy Registry. Prevalence of birth defects associated with maternal first trimester indinavir use was 2.1% (6 of 286 births; 95% confidence interval (CI), 0.8% to 4.5%) compared with the total United States population-based prevalence of 2.7% (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
b) A report describing the outcomes of 23 pregnancies in women who were treated with indinavir as part of their antiretroviral therapy concluded that the use of protease inhibitors appears to be generally safe in mothers and their infants. The infants exposed to indinavir had an average weight of 3116 g, with no increase in prematurity when compared with other HIV-infected women who were not treated with protease inhibitors.(Morris et al, 2000a).

a) Data from the Antiretroviral Pregnancy Registry found no difference in the risk of overall major birth defects in pregnant women exposed to lopinavir or ritonavir compared to the background rate of major birth defects. There was a 1.5-fold and 2-fold increase in the risk of overall birth defects and birth defects in the cardiovascular and genitourinary systems, respectively, when pregnant women were exposed to either lopinavir or ritonavir during the first trimester (Prod Info KALETRA(R) oral tablets, oral solution, 2015).
b) There have been sufficient numbers of first trimester exposures to lopinavir/ritonavir to detect at least a 2-fold increase in risk of birth defects. No increases in overall birth defects with antiretroviral regimens containing lopinavir have been observed in prospective data collected from the Antiretroviral Pregnancy Registry. Among live births, the prevalence of birth defects associated with first-trimester use of lopinavir/ritonavir was 2.4% (21 of 883; 95% confidence interval, 1.5% to 3.6%) compared with the total United States population-based prevalence of 2.7% (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

a) A report describing the outcomes of 39 pregnancies in women who were treated with nelfinavir as part of their antiretroviral therapy concluded that the use of protease inhibitors appears to be generally safe in mothers and their infants. The infants exposed to nelfinavir had an average weight of 2824 g, with no increase in prematurity when compared with other HIV-infected women who were not treated with protease inhibitors (Morris et al, 2000b).

a) There have been sufficient numbers of first trimester exposures to ritonavir to detect at least a 2-fold increase in risk of birth defects. No increases in birth defects overall have been observed in data collected from the Antiretroviral Pregnancy Registry. Prevalence of birth defects associated with maternal first trimester ritonavir use was 2.2% (39 of 1741; 95% confidence interval, 1.6% to 3%) compared with the total United States population-based prevalence of 2.7% (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
b) A report describing the outcomes of 5 pregnancies in women who were treated with ritonavir as part of their antiretroviral therapy concluded that the use of protease inhibitors appears to be generally safe in mothers and their infants. The infants exposed to ritonavir in the Morris study had an average weight of 2805 g, with no increase in prematurity when compared with other HIV-infected women who were not treated with protease inhibitors (Morris et al, 2000c).

a) A report describing the outcomes of 34 pregnancies in women who were treated with saquinavir as part of their antiretroviral therapy concluded that the use of protease inhibitors appears to be generally safe in mothers and their infants. The infants exposed to saquinavir had an average weight of 3001 g with no increase in prematurity when compared to other HIV-infected women who were not treated with protease inhibitors (Morris et al, 2000d).

a) CASE REPORT: No teratogenic effects were found in the infant of a multidrug-resistant, HIV-1-positive woman following tipranavir and enfuvirtide therapy during the third trimester of pregnancy, although maternal hepatotoxicity was noted. A 34-year-old woman treated for 2 years with antiretroviral therapy regimens (including ritonavir-boosted lopinavir and later, zidovudine, lamivudine, and nevirapine) was switched at 28 weeks gestation to zidovudine, lamivudine, tenofovir, ritonavir-boosted tipranavir and enfuvirtide therapy following a viral load increase to 28,600 copies/mL and the detection of NRTI and NNRTI mutations. The viral load had decreased to 503 copies/mL by delivery at 37 weeks gestation. While no enfuvirtide was detected in cord blood, the tipranavir area under the curve at 12 hours measured 44.5 mcg/mL x hour, with a ratio of cord blood to maternal blood of 0.41 (15.6 and 36.8 mcg/mL, respectively). The 2740 g female infant was delivered via emergency cesarean section in response to fetal distress (cause undetermined). She was briefly intubated and received surfactant and packed erythrocytes to treat meconium aspiration and anemia, respectively. The mother had developed grade 4 hepatotoxicity (AST 883 units/L), which subsided after delivery with no further treatment. Following a 4-week course of zidovudine, the infant had repeatedly tested negative for HIV by her 12-month follow-up (Weizsaecker et al, 2011).

a) There was no evidence of teratogenicity when animals were exposed to atazanavir at doses up to 1.2 times those seen at the recommended human dose (Prod Info REYATAZ(R) oral capsules, oral powder, 2015).

a) MICE, RATS, RABBITS: In studies in mice, rats, and rabbits treated with darunavir, no signs of embryotoxicity or teratogenicity were evident. However, due to limited bioavailability, darunavir plasma exposures averaged approximately 50% in mice and rats, and only 5% in rabbits compared to those achieved in humans at the recommended clinical dose, boosted with ritonavir (Prod Info PREZISTA(R) oral film coated tablets, 2010).

a) RATS: There were no effects on embryofetal development when rats were given fosamprenavir at 2 times the human dose (0.7 times the human exposure when ritonavir is used concomitantly). Rabbits given 0.8 times the human dose (0.3 times the human exposure when ritonavir is used concomitantly) had an increased incidence of spontaneous abortions (Prod Info LEXIVA(R) oral suspension, oral tablets, 2010).
b) RABBITS: At one-twentieth the human dose in rabbits, there was an increase in minor skeletal malformations in the pups that resulted from deficient ossification of the femur, humerus, and trochlea (Prod Info LEXIVA(R) oral suspension, oral tablets, 2010).

a) RATS, RABBITS: In rats, embryonic and fetal developmental toxicities, such as early resorption, decreased fetal viability and weight, and skeletal abnormalities, were evident at maternally toxic doses, representing exposures that were approximately 0.7-fold and 1.8-fold that of lopinavir and ritonavir exposures, respectively, seen in humans at therapeutic doses. Furthermore, development toxicity in the form of a decrease in pup survival between birth to postnatal day 21 was observed in a peri- and postnatal study in rats. However, no treatment-related malformations were noted in pregnant rats and rabbits exposed to lopinavir/ritonavir. In rabbits, embryonic or fetal developmental toxicities were not observed at maternally toxic doses, representing exposures that were approximately 0.6-fold and 1-fold that of lopinavir and ritonavir exposures, respectively, seen in humans at therapeutic doses (400 mg/100 mg twice daily) (Prod Info KALETRA(R) oral film coated tablets, oral solution, 2012).

a) RATS, RABBITS: Developmental toxicities (early resorptions, decreased fetal weight and ossification delays and developmental variations) were reported in rats administered maternally toxic doses of ritonavir equivalent to approximately 30% of that achieved with the proposed therapeutic dose. Developmental toxicity (resorptions, decreased litter size and decreased fetal weights) was also observed in rabbits administered maternally toxic doses of ritonavir equivalent to 1.8 times the proposed therapeutic dose based on a body surface area conversion factor (Prod Info NORVIR(R) oral capsules, 2010).

a) RATS, RABBITS: There was no evidence of teratogenicity when pregnant rats and rabbits were exposed to tipranavir at doses up to 1000 mg/kg/day and 150 mg/kg/day, respectively (approximately 1.1- and 0.1-fold human exposure). Fetal toxicity, including reduced sternebrae ossification and body weights, was reported at doses of 400 mg/kg/day and greater (approximately 0.8-fold human exposure at the recommended dose). In rats and rabbits, there was no evidence of fetal toxicity at doses of 40 mg/kg/day and 150 mg/kg/day, respectively (approximately 0.2-fold and 0.1-fold the exposure in humans at the recommended dose). In another rat study, there were no adverse effects at a dose of 40 mg/kg/day (approximately 0.2-fold human exposure); however, there was pup growth inhibition and maternal toxicity when rats were given tipranavir at doses of 400 mg/kg/day (approximately 0.8-fold human exposure). There was no effect on post-weaning functions at any tipranavir dose tested (Prod Info APTIVUS(R) oral capsules, oral solution, 2010).

a) Amprenavir capsules have been classified as FDA pregnancy category C (Prod Info AGENERASE(R) Capsules, 2005). Amprenavir oral solution is contraindicated in pregnancy due to the large amounts of propylene glycol available as an excipient (Prod Info AGENERASE(R) oral solution, 2005).

a) Atazanavir/cobicistat has been classified as FDA pregnancy category B (Prod Info EVOTAZ(TM) oral tablets, 2015).

a) Darunavir has been classified as FDA pregnancy category C (Prod Info PREZISTA(R) oral film coated tablets, 2010).

a) Darunavir/cobicistat has been classified as FDA pregnancy category C (Prod Info PREZCOBIX(TM) oral tablets, 2015).

a) Fosamprenavir has been classified as FDA pregnancy category C (Prod Info LEXIVA(R) oral suspension, oral tablets, 2010).

a) Indinavir has been classified as FDA pregnancy category C (Prod Info CRIXIVAN(R) oral capsules, 2010).

a) Lopinavir/ritonavir has been classified as FDA pregnancy category C (Prod Info KALETRA(R) oral film coated tablets, oral solution, 2012).

a) Nelfinavir has been classified as FDA pregnancy category B (Prod Info VIRACEPT(R) oral powder, oral tablets, 2010).

a) Ritonavir has been classified as FDA pregnancy category B (Prod Info NORVIR(R) oral capsules, 2010).

a) Saquinavir has been classified as FDA pregnancy category B (Prod Info INVIRASE(R) oral capsules, oral tablets, 2010).

a) Tipranavir has been classified as FDA pregnancy category C (Prod Info APTIVUS(R) oral capsules, oral solution, 2010).

a) ATAZANAVIR

a) ATAZANAVIR

a) ATAZANAVIR

a) Data from 2 pharmacokinetic (PK) studies of unboosted indinavir (800 mg 3 times daily) showed significantly lower indinavir plasma concentrations during pregnancy than postpartum. In addition, an intensive PK study of 26 pregnant women receiving boosted indinavir (400 mg indinavir/100 mg ritonavir) twice a day demonstrated that indinavir plasma concentrations were significantly lower during pregnancy than postpartum. However, a small study of 2 women who received indinavir 800 mg and ritonavir 200 mg twice daily showed third-trimester indinavir AUC exceeded that for historical non-pregnant controls (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

a) An increased number of antenatal stillbirths were reported in women receiving polytherapy which included nelfinavir. In four cases, nelfinavir was started in the first trimester and in two other cases it was started in the second trimester. Fetal death occurred between 26 and 31 weeks' gestation (Garcia-Tejedor et al, 2002).

a) A report describing the outcomes of 23 pregnancies in women who were treated with indinavir as part of their antiretroviral therapy concluded that the use of protease inhibitors appears to be generally safe in mothers and their infants. The infants exposed to indinavir had an average weight of 3116 g, with no increase in prematurity when compared with other HIV-infected women who were not treated with protease inhibitors.(Morris et al, 2000a). One study has suggested an association with protease inhibitors and prematurity and an increase in adverse events (Lorenzi et al, 1998).

a) No increases in overall birth defects with antiretroviral regimens containing lopinavir have been observed in prospective data collected from the Antiretroviral Pregnancy Registry. Among live births, the prevalence of birth defects associated with maternal use of lopinavir was 2.2% (16 of 738) with first-trimester exposure and 2.4% (41 of 1720) with second- and third-trimester exposure, compared with the total United States population-based prevalence of 2.7% (Prod Info KALETRA(R) oral film coated tablets, oral solution, 2012).

a) Do not breastfeed while taking atazanavir (Prod Info REYATAZ(R) oral capsules, oral powder, 2015; Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
b) In a study of 3 women, the median ratio of atazanavir concentration in breast milk to that in plasma was 13% (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

a) Infants received a negligible amount of nelfinavir through ingested breast milk according to a phase IIb, open-label, single arm, prevention of mother-to-child HIV transmission clinical trial of pregnant HIV-infected women and their nursing infants. Women received lamivudine 150 mg twice daily, zidovudine 300 mg twice daily, and nelfinavir 1250 mg twice daily starting at 34 weeks of gestation, continuing through labor, and for 6 months postpartum, while infants were exclusively breastfed. The limits of quantification (LOQ) for nelfinavir and its active metabolite hydroxy-t-butyl-amidenelfinavir (M8) in maternal plasma, breast milk and dried blood spots were 10 ng/mL, 10 ng/mL, and 5 ng/mL, respectively. The median concentrations for both nelfinavir and M8, were less than the LOQ (range below LOQ to 30 ng/mL and below LOQ to 32 ng/mL, respectively) for infant dried blood spots. The median concentrations (ng/mL) of nelfinavir in maternal plasma were 2004 (1083 to 3391), 3593 (1920 to 4165), 2490 (1687 to 3463), 1976 (1194 to 2985), and 1990 (1248 to 2720) at delivery and 2, 6, 14, and 24-weeks postpartum, respectively. The median concentrations (ng/mL) of nelfinavir in breast milk were 83 (62 to 253), 358 (200 to 472), 286 (210 to 543), 233 (105 to 442), and 180 (79 to 260), respectively. The median maternal breast milk to plasma ratio of nelfinavir and M8 were 0.12 (interquartile range (IQR), 0.08 to 0.17) and 0.03 (IQR, 0.02 to 0.05), respectively. Nelfinavir concentrations in both plasma and breast milk trended downward and showed no variance in the maternal breast milk to plasma ratio during the final 12-hour interval following the most recent nelfinavir dose (Weidle et al, 2011).

a) RATS: Amprenavir is excreted into the milk of lactating rats, but the relative concentration is unknown (Prod Info AGENERASE(R) oral solution, 2005).

a) Atazanavir is excreted into milk of lactating rats (Prod Info REYATAZ(R) oral capsules, oral powder, 2015; Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

a) RATS: In a postnatal developmental study in rats, reductions in body weight gain were observed in pups who were exposed to darunavir, alone or in combination with ritonavir, via breast milk. The maximal darunavir plasma exposures achieved in rats were approximately 50% of those achieved in humans at the recommended clinical dose, boosted with ritonavir (Prod Info PREZISTA(R) oral film coated tablets, 2010).

a) RATS: Indinavir is excreted into the milk of lactating rats at concentrations slightly greater than maternal concentrations. The milk-to-plasma ratio was 1.26 to 1.45 (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

a) Lopinavir is excreted into the milk of lactating rats (Prod Info KALETRA(R) oral film coated tablets, oral solution, 2012).

a) RATS: Nelfinavir is excreted into the milk of lactating rats, but the relative concentration is unknown (Prod Info VIRACEPT(R) oral powder, oral tablets, 2010).

a) RATS: Ritonavir is excreted in the milk of lactating rats (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

a) RATS: Amprenavir did not affect the mating or fertility of male or female rats; the development and maturation of sperm were not impaired. No untoward effects on reproduction were found in rats born to female rats who were treated with amprenavir (Prod Info AGENERASE(R) oral solution, 2005).

a) No significant effects on mating, fertility, or early embryonic development were reported in male and female animals administered atazanavir at doses up to 2.3 times the human clinical dose (Prod Info REYATAZ(R) oral capsules, oral powder, 2015).

a) RATS: In a postnatal developmental study in rats, reductions in body weight gain were observed in pups who were exposed to darunavir, alone or in combination with ritonavir, via breast milk. The maximal darunavir plasma exposures achieved in rats were approximately 50% of those achieved in humans at the recommended clinical dose, boosted with ritonavir (Prod Info PREZISTA(R) oral film coated tablets, 2010).

a) RATS: Fosamprenavir did not adversely affect mating, fertility, or the development and maturation of sperm in male and female rats administered a dose 3 to 4 times higher than the maximum recommended human dose (Prod Info LEXIVA(R) oral suspension, oral tablets, 2010)

a) RATS: There were no effects on mating, fertility, or embryo survival in female rats and no effects on mating performance in male rats at doses providing systemic exposure comparable to or slightly higher than with the recommended human dose. Also, there were no effects observed on fertility or fecundity of untreated females mated with treated males (Prod Info CRIXIVAN(R) oral capsules, 2010).

a) RATS: Neither male nor female rats experienced any effects on fertility following lopinavir/ritonavir doses of 10/5, 30/15, and 100/50 mg/kg/day. The exposures at high doses were approximately 0.7-fold and 1.8-fold the exposures at the recommended human therapeutic dose for lopinavir and ritonavir, respectively (Prod Info KALETRA(R) oral film coated tablets, oral solution, 2012).

a) RATS: Nelfinavir did not affect mating or fertility in male or female rats; reproductive performance of offspring born to female rats that had been exposed to nelfinavir from midpregnancy through lactation was not affected (Prod Info VIRACEPT(R) oral powder, oral tablets, 2010).

a) RATS: There was no effect on fertility when rats were exposed to ritonavir at doses approximately 40% (male) and 60% (female) of those achieved with the recommended human therapeutic dose (Prod Info NORVIR(R) oral capsules, 2010).

a) RATS: Fertility and reproduction were not affected in rats given saquinavir at plasma exposures (AUC values) of up to 5 times those achieved in humans at the recommended dose for saquinavir mesylate capsules or approximately 50% of AUC values achieved in humans at the recommended dose for saquinavir soft gelatin capsules (Prod Info INVIRASE(R) oral capsules, oral tablets, 2010).

a) RATS: There was no evidence of fertility in rats that were given tipranavir at doses up to 1000 mg/kg/day (approximately equivalent to the anticipated exposure in humans at the recommended dose of 500/200 mg tipranavir/ritonavir twice daily (Prod Info APTIVUS(R) oral capsules, oral solution, 2010).

a) Monitor ECG in patients with significant exposures, in particular those with pre-existing cardiac dysfunction, for signs of cardiomyopathy and heart failure.

a) Nerve conduction velocity tests may be advisable in patients exhibiting signs/symptoms of peripheral or circumoral neuropathies.

a) Right upper quadrant ultrasound should be considered to evaluate for alternative etiologies of transaminitis.

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) TRANSFUSIONS - In the presence of bone marrow suppression, transfusions and protective measures for granulocytopenia may be needed until recovery of bone marrow function.

a) TREATMENT EXPERIENCED
b) TREATMENT NAIVE

a) The recommended dose is 1 tablet of 300 mg atazanavir/150 mg cobicistat orally once daily with food (Prod Info EVOTAZ(TM) oral tablets, 2015).

a) TREATMENT EXPERIENCED
b) TREATMENT NAIVE

a) The recommended dose is 1 tablet of 800 mg darunavir/150 mg cobicistat orally once daily with food (Prod Info PREZCOBIX(TM) oral tablets, 2015).

a) The usual recommended oral dose is 700 to 1400 mg once or twice daily (Prod Info LEXIVA(R) oral tablets, suspension, 2012).

a) The recommended dose is 800 mg orally every 8 hours. A dose of 1000 mg orally every 8 hours is recommended when indinavir is given with rifabutin (Prod Info CRIXIVAN(R) oral capsules, 2010).

a) The recommended oral dose is 400 mg lopinavir/100 mg ritonavir twice daily, or 800 mg lopinavir/200 mg ritonavir once daily in patients with less than three lopinavir resistance-associated substitutions (Prod Info KALETRA(R) film coated oral tablets, oral solution, 2010).

a) The recommended oral dose is 1250 mg twice daily or 750 mg 3 times daily (Prod Info VIRACEPT(R) oral powder, oral tablets, 2010).

a) The recommended dose is 600 mg orally twice daily (Prod Info NORVIR(R) oral solution, oral tablet, 2010).

a) The recommended dose is 1000 mg orally twice daily in combination with ritonavir (100 mg twice daily) or in combination with lopinavir/ritonavir (400/100 mg) twice daily (Prod Info INVIRASE(R) oral capsules, oral tablets, 2012).

a) The recommended dose is 500 mg orally in combination with ritonavir (200 mg) and administered twice daily (Prod Info APTIVUS(R) oral capsules, oral solution, 2010).

a) CAPSULES
b) ORAL POWDER

a) Safety and efficacy have not been established in pediatric patients younger than 18 years (Prod Info EVOTAZ(TM) oral tablets, 2015).

a) Safety and efficacy have not been established in pediatric patients younger than 3 years (Prod Info PREZISTA(R) oral suspension, oral tablets, 2016).
b) TREATMENT EXPERIENCED/ONE OR MORE SUBSTITUTIONS
c) TREATMENT NAIVE OR TREATMENT EXPERIENCED/NO SUBSTITUTIONS

a) Safety and efficacy have not been established in pediatric patients younger than 18 years (Prod Info PREZCOBIX(TM) oral tablets, 2015).

a) Safety and efficacy have not been established in pediatric patients less than 4 weeks of age (Prod Info LEXIVA(R) oral tablets, suspension, 2012).
b) 4 WEEKS OF AGE AND OLDER: The recommended oral dose ranges from 18 mg/kg to 45 mg/kg twice daily, up to a maximum dose of 700 mg twice daily, administered in combination with ritonavir (Prod Info LEXIVA(R) oral tablets, suspension, 2012).
c) 2 YEARS OF AGE AND OLDER: Alternatively, the recommended dose in protease-inhibitor naive pediatric patients is 30 mg/kg twice daily, administered without ritonavir (Prod Info LEXIVA(R) oral tablets, suspension, 2012).

a) 14 DAYS TO 6 MONTHS OF AGE: The recommended dose is 16 mg lopinavir/4 mg ritonavir per kg (300/75 mg/m(2)) orally twice daily (Prod Info KALETRA(R) film coated oral tablets, oral solution, 2010).
b) 6 MONTHS TO 18 YEARS OF AGE: For patients less than 15 kg, the recommended oral dose ranges from 12 mg lopinavir/3 mg ritonavir per kg to 13/3.25 mg/kg, depending on whether the patient is taking other antiretroviral agents concomitantly. For patients 15 to 40 kg and who are not taking other antiretroviral agents concomitantly, the recommended oral dose is 10/2.5 mg/kg twice daily. For patients 15 to 45 kg and who are taking other antiretroviral agents concomitantly, the recommended oral dose is 11/2.75 mg/kg twice daily (Prod Info KALETRA(R) film coated oral tablets, oral solution, 2010).

a) 2 TO 13 YEARS OF AGE: The recommended oral dose is 45 to 55 mg/kg twice daily or 25 to 35 mg/kg 3 times daily, up to a maximum daily dose of 2500 mg (Prod Info VIRACEPT(R) oral powder, oral tablets, 2010).

a) GREATER THAN 1 MONTH OF AGE: The initial dose is 250 mg/m(2) twice daily, titrated up to 400 mg/m(2) given twice daily in combination with other antiretroviral agents. Maximum dose is 600 mg given twice daily (Prod Info NORVIR(R) oral solution, oral tablet, 2010).

a) OVER 16 YEARS OF AGE: The recommended dose (with low-dose ritonavir) is saquinavir mesylate 1000 mg and ritonavir 100 mg ORALLY twice daily (Prod Info INVIRASE(R) oral capsules, oral tablets, 2012).
b) OVER 16 YEARS OF AGE: The recommended dose with lopinavir 400 mg/ritonavir 100 mg twice daily is saquinavir mesylate 1000 mg orally twice daily; additional ritonavir is not recommended (Prod Info INVIRASE(R) oral capsules, oral tablets, 2012).

a) 2 YEARS OF AGE AND OLDER: The recommended oral dose is 14 mg/kg (375 mg/m(2)) co-administered with ritonavir (6 mg/kg or 150 mg/m(2)) twice daily, up to a MAXIMUM tipranavir dose of 500 mg and a maximum ritonavir dose of 200 mg twice daily (Prod Info APTIVUS(R) oral capsules, oral solution, 2010).

a) >5000 mg/kg (Lehman et al, 2003)

a) >5000 mg/kg (Lehman et al, 2003)

a) >5000 mg/kg (Lehman et al, 2003)

a) >5000 mg/kg (Lehman et al, 2003)