a) ZALCITABINE: Ototoxicity with hearing loss and tinnitus was reported in an AIDS patient taking alternating therapy with zalcitabine and zidovudine. On rechallenge with zalcitabine, hearing disturbance again recurred. The ototoxicity resolved on discontinuation of zalcitabine (Powderly et al, 1990).

a) ZIDOVUDINE/LAMIVUDINE: Nasal signs and symptoms have been reported in 20% of adult patients receiving lamivudine plus zidovudine therapy; 11% of patients receiving zidovudine alone experienced these adverse effects (Prod Info EPIVIR(R) oral tablets, solution, 2008).

a) ZALCITABINE therapy has been associated with rare incidences of mouth ulcers, more than with other NRTIs (Carr & Cooper, 2000).

a) Nucleoside analogs have been reported to exacerbate cardiomyopathy and congestive heart failure (Prod Info HIVID(R) oral tablets, 2002).

a) ZALCITABINE: Fewer than 3% of patients in zalcitabine clinical trials experienced the following: dysrhythmia, atrial fibrillation, hypertension, palpitations, tachycardia, and ventricular ectopy (Prod Info HIVID(R) oral tablets, 2002).

a) DIDEOXYADENOSINE (DDA): Both Fluoro-dideoxyadenosine (F-ddA) and dideoxyadenosine (ddA) (investigational drugs) produced dose-dependent cardiac lesions in rat studies. The deaminated catabolites of both agents were essentially non-toxic. Toxicity appeared related to Cmax rather than total exposure, with doses of 250 mg/kg producing significant cardiomyopathy. Toxicity was greater following treatment with F-ddA as opposed to ddA probably because F-ddA is deaminated 20 times more slowly than ddA (Donzanti et al, 1995).
b) FddA and FddL: Myocardial degeneration and necrosis was evident at necropsy in rats administered FddA or FddL 500 to 1000 mg/kg/day either orally or intravenously (Comereski et al, 1993).

a) ZIDOVUDINE/LAMIVUDINE: Cough has been reported in 18% of adult patients receiving lamivudine plus zidovudine as compared to 13% in patients receiving zidovudine alone (Prod Info EPIVIR(R) oral tablets, solution, 2008).
b) ABACAVIR: Respiratory distress may be one of the manifestations of hypersensitivity reactions associated with this agent. The potential of hypersensitivity reaction should be evaluated prior to the reinstitution of therapy in patients (Carr & Cooper, 2000).

a) Painful distal symmetrical peripheral neuropathy is the major dose-limiting toxicity of the nucleoside analogs (most often seen with didanosine, stavudine, and zalcitabine). It often progresses to severe pain requiring narcotics. It generally is abrupt in onset and rapidly progresses. Histologically, axonal degeneration is evident (Anon, 1989; Cooley et al, 1990; Lambert et al, 1990) Yarchoan et al, 1990; (Merigan et al, 1989; Merigan & Skowron, 1990; Skowron, 1995; Murray et al, 1995; Petersen et al, 1995; Simpson & Tagliati, 1995; Prod Info Zerit(R),, 2002; Moyle & Sadler, 1998; Moore et al, 2000; Carr & Cooper, 2000; Falco et al, 2002).
b) STAVUDINE: 19% to 24% of stavudine treated patients have required dosage reductions due to painful peripheral neuropathies (Petersen et al, 1995). Stavudine-induced peripheral neuropathy is dose-dependent (Moyle & Sadler, 1998).
c) ZALCITABINE: All patients in a high-dose zalcitabine clinical trial experienced painful, predominantly sensorimotor peripheral neuropathy. Mean onset was 7.7 weeks (Berger et al, 1993). After stopping zalcitabine, some patients experience a period of symptom intensification, referred to as "coasting", lasting for several weeks to months (Moyle & Sadler, 1998). Severe peripheral neuropathy necessitating discontinuation of therapy occurs in about 10% of patients. Carey (2000) reports that the incidence of peripheral neuropathy is infrequent when zalcitabine is used in combination with other antiretrovirals (Carey, 2000).
d) Risk factors predisposing patients to peripheral neuropathies include: history of peripheral nervous system disease, heavy alcohol consumption, or a low serum cobalamin level (Fichtenbaum et al, 1995).
e) LAMIVUDINE: Lamivudine is reported to be the least neurotoxic of this class of drugs. However, it has been reported to potentiate an underlying peripheral neuropathy in a 33-year-old man with AIDS (Cupler & Dalakas, 1995).

a) ABACAVIR: Headache has been reported in pediatric patients with a frequency of 16% (Prod Info Ziagen(TM), abacavir, 1998).
b) ZIDOVUDINE/LAMIVUDINE: Headache is a common effect, occurring in 35% of patients on combination lamivudine and zidovudine, and 27% on zidovudine monotherapy (Prod Info EPIVIR(R) oral tablets, solution, 2008).

a) INCIDENCE: Pancreatitis, with abdominal pain and elevated amylase has been reported to occur at a rate of <1% to 6% of patients in the following decreasing order of drug use: didanosine > lamivudine/zalcitabine (Carr & Cooper, 2000). Alcohol and pentamidine may aggravate pancreatitis resulting from NRTIs. Pancreatitis is a well-documented adverse effect of stavudine and didanosine ((Anon, 2001)).
b) ZALCITABINE: Fatal pancreatitis has been reported following zalcitabine therapy, however, this is not a common effect (Prod Info HIVID(R) oral tablets, 2002).
c) ZIDOVUDINE/ZALCITABINE: Fatal hemorrhagic pancreatitis was reported in a 45-year-old woman treated concurrently with zidovudine and zalcitabine (Aponte-Cipriani et al, 1993).
d) It has been suggested that the development of hypertriglyceridemia may serve as a marker for patients at risk of developing pancreatitis (Tal & Dall, 1993).

a) LAMIVUDINE: Diarrhea, which does not appear to be dose dependent, may be severe enough to necessitate discontinuance of medication, and may be accompanied by nausea and vomiting in patients receiving lamivudine (Pluda et al, 1995).
b) STAVUDINE: Kline et al (1995) reported a 68% incidence of diarrhea, which was not dose-related, in pediatric patients (Kline et al, 1995).

a) ABACAVIR causes nausea, vomiting, diarrhea and loss of appetite in adults and children with a frequency of greater than 10% (Prod Info Ziagen(TM), abacavir, 1998). In clinical trials of abacavir alone, gastrointestinal disturbance was the primary adverse effect in adults (Foster & Faulds, 1998).
b) ZIDOVUDINE/LAMIVUDINE: Nausea has occurred in 33% of patients treated with lamivudine plus zidovudine and 29% of zidovudine mono therapy patients in 1 study (Prod Info EPIVIR(R) oral tablets, solution, 2008).

a) LAMIVUDINE/EFAVIRENZ: A 17-year-old developed lower abdominal pain and then began vomiting 5 hours after ingesting lamivudine 3.9 g and efavirenz 15.6 g (Boscacci et al, 2006).

a) ZALCITABINE: Therapy with zalcitabine has been associated with rare esophageal ulceration(Prod Info HIVID(R) oral tablets, 2002; Indorf & Pegram, 1992). Local pill-induced injury has been suggested as the etiology of zalcitabine-induced esophageal ulceration.
b) LAMIVUDINE: Oral ulcerations/lesions have been reported in patients receiving lamivudine (van Leeuwen et al, 1995; Pluda et al, 1995).

a) A case series of 6 patients with acute liver failure associated with nucleoside analogue HIV-1 therapy has been reported. Five of the 6 died. Development of acute liver failure was sudden and did not appear to be related to duration or type of antiretroviral therapy, and was not predicted by monitoring of liver function. Median duration of therapy was 12.5 months and median time to onset of liver failure following introduction of new therapy was 8 weeks. A predominantly hepatocellular pattern was noted. Liver biopsy revealed mitochondrial toxicity in 1 case and confluent hepatocellular necrosis, inflammation and cholestasis in the other cases (Clark et al, 2002).
b) Fatal portal hypertension, liver failure, and mitochondrial dysfunction have been reported in a patient who had recovered from HIV-1 nucleoside analogue-induced hepatitis and lactic acidemia more than 18 months earlier. The authors suggest a delayed progression to non-cirrhotic portal hypertension and chronic liver failure with persistent mitochondrial dysfunction following a recovery from nucleoside-analogue-induced acute hepatitis and lactic acidosis (Carr et al, 2001).
c) ZALCITABINE: Rare cases of liver failure, lactic acidosis, and hepatomegaly with steatosis have been reported with zalcitabine therapy (Prod Info HIVID(R) oral tablets, 2002).

a) LAMIVUDINE has been reported to cause a reactivation of Hepatitis B in a 29-year-old man with chronic HBV infection (Honkoop et al, 1995).

a) Typically, liver disease due to NRTI therapy is associated with lactic acidosis and massive liver steatosis and failure. The incidence of liver failure and lactic acidosis in a retrospective study of a cohort of HIV-infected patients treated with NRTI was reported to be 1.3 per 1000 person-years of follow-up (Bleeker-Rovers et al, 2000). The manufacturers of lamivudine and stavudine have issued warnings concerning lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, with the therapeutic use of these drugs (Prod Info EPIVIR-HBV(R) oral tablets, oral solution, 2004; Prod Info ZERIT(R) oral capsules, oral solution, 2006).
b) The syndrome of lactic acidosis and hepatic steatosis, a complication of nucleoside reverse-transcriptase inhibitors, has been associated with riboflavin deficiency. Luzzati et al (1999) reported a patient with severe lactic acidosis and hepatic steatosis who responded to riboflavin treatment (50 mg/day) with rapid recovery (within 4 days) (Luzzati et al, 1999).

a) ADEFOVIR: At doses of 120 mg/day for greater than 6 months, 40% of patients in clinical trials developed signs of incipient renal tubular damage, a Fanconi-like syndrome (Gilden, 1998).
b) TENOFOVIR

a) Nucleoside reverse transcriptase inhibitors have been associated with an abrupt onset of lactic acidosis (type "B") and hepatic steatosis or an insidious onset in patients with AIDS. Lactic acidosis is uncommon, but when it occurs, it is not readily reversible after discontinuation of the drugs and with normal therapy and mortality rate is high. This syndrome may result in death from progressive lactic acidosis, hypotension, and multiorgan failure (Fouty et al, 1998; Mokrzycki et al, 2000; Brivet et al, 2000; Carr et al, 2000; Miller et al, 2000; Lonergan et al, 2000; ter Hofstede et al, 2000; Bleeker-Rovers et al, 2000; Coghlan et al, 2001; Carr et al, 2001; Megarbane et al, 2001; Falco et al, 2002).
b) INCIDENCE: Some degree of lactic acidosis has been reported to occur in approximately 15% of patients receiving NRTI therapy. Differences in the relative incidence of lactic acidosis between different agents or different combinations have not been established (Carr & Cooper, 2000; Moyle, 2000). The presence of asymptomatic hyperlactatemia was studied in 83 HIV-infected, nucleoside analogue-treated patients. Two thirds had 2 or more risk factors for hyperlactatemia and 11% had more than 4 risk factors. Two patients had a lactate level more than 1.5 times the upper limit of normal. There were no reports of symptomatic hyperlactatemia or lactic acidosis during the study (Wohl et al, 2004).
c) MORTALITY: Lactate serum levels of >10 mM appear to be associated with a higher mortality (Falco et al, 2002a). In a retrospective study of 39 patients (34 from previously published literature) with severe lactic acidosis related to nucleoside analogue therapy, an initial lactate level of greater than 9 mmol/L was useful in predicting mortality. In patients with initial lactate levels of greater than 9 mmol/L 3 of 20 survived, while 17 of the 19 patients with initial lactate of less than 9 mmol/L survived(Claessens et al, 2003).
d) Lactic acidosis and hepatic steatosis were reported as a possible syndrome related to riboflavin deficiency in HIV-infected patients taking nucleoside reverse-transcriptases inhibitors. A 35-year-old pregnant patient with this syndrome was non-responsive to sodium bicarbonate. When therapy was changed to riboflavin (50 mg/day orally), she recovered rapidly (4 days) with a fall in blood lactate to normal values (Luzzati et al, 1999).
e) PREGNANCY: The FDA has issued a warning concerning an increased risk of severe or fatal lactic acidosis in pregnant women who take the combination of HIV drugs, stavudine and didanosine, with other antiretroviral agents. Pancreatitis is also a well-documented complication of stavudine and didanosine (Prod Info ZERIT(R) oral capsules, oral solution, 2006).
f) CASE REPORT: A 46-year-old woman, taking stavudine, lamivudine, indinavir and amitriptyline for 4 months, developed lactic acidosis (6.4 mmol/L), decreased BUN (1.8 mmol/L) and significant hepatic steatosis on abdominal CT. A riboflavin deficiency was suspected and confirmed. Therapy with 50 mg riboflavin resolved the lactic acidosis and raised her BUN into a normal range (Fouty et al, 1998).
g) CASE REPORT: An HIV-infected patient taking NRTI was reported with fulminant axonal neuropathy with lactic acidosis and acute hyperglycemia. Liver function was normal. Serum lactate levels declined over a 2 week period following discontinuation of NRTI, but the neuropathy was irreversible, and the patient died due to multiple organ failure (Verma et al, 1999).
h) CASE SERIES: Six cases of fatal lactic acidosis were reported in patients taking stavudine (6 patients), lamivudine (5 patients), and didanosine (1 patient). All patients had manifestations consistent with mitochondrial toxicity including lipodystrophy, myositis, fatty hepatitis, pancreatitis, and peripheral neuropathy. Although antiretroviral therapy was discontinued and aggressive treatment with fluid resuscitation, riboflavin, and bicarbonate was given, all patients died of persistent circulatory collapse (Sheng et al, 2004).

a) ZALCITABINE has been associated with thrombocytopenia in only 1% to 3% of patients in clinical trials and appears to be dose related (Prod Info HIVID(R) oral tablets, 2002).
b) LAMIVUDINE: Thrombocytopenia occurred in 23% of pediatric patients with abnormal baseline levels receiving lamivudine alone (Prod Info Epivir(R), lamivudine, 2001).
c) STAVUDINE: No significant thrombocytopenia has been reported in clinical studies (Browne et al, 1993; Sandstrom & Oberg, 1993). The manufacturer reports an incidence of 3% to 5% thrombocytopenia (platelets < 50,000 cells/mm(3)) in a Phase 3 trial (Prod Info Zerit(R),, 2002).

a) ZALCITABINE: Neutropenia has been reported as a dose dependent adverse effect in 17% of patients in clinical trials of zalcitabine, and leukopenia in 13% (Prod Info HIVID(R) oral tablets, 2002).
b) LAMIVUDINE: Dose related neutropenia has been reported. Doses of 20 mg/kg resulted in a trend toward progressively decreasing neutrophil counts in 1 study. This did not occur at lower doses. Neutropenia of less than 1000/mm(3) was reported in 2 of the 15 patients on the higher dose. Neutropenia occurred on rechallenge (Pluda et al, 1995).
c) STAVUDINE: Bone marrow toxicity is not substantial following therapeutic stavudine in available studies (Browne et al, 1993; Dunkle et al, 1990; Sandstrom & Oberg, 1993; Skowron, 1995).

a) LAMIVUDINE: In pediatric patients receiving lamivudine alone, anemia occurred in 24% who were anemic prior to initiation of therapy. Anemia occurred in 2% with prior normal baselines (Prod Info Epivir(R), lamivudine, 2001). A retrospective study, conducted by Khawcharoenporn et al (2007), found that lamivudine was strongly associated with macrocytosis (OR=24.6 [2.9 to 3223], p=0.001) (Khawcharoenporn et al, 2007).

a) DESCRIPTION: Hypersensitivity may manifest as an erythematous, maculopapular, pruritic, and confluent rash with or without fever. The rash usually begins after 1 to 3 weeks of therapy and is most prominent on the body and arms. Chills and fever, myalgias, and arthralgias are often prominent and may precede the rash, particularly with abacavir. Rash or fever occurring greater than 8 weeks after onset of therapy is usually due to another agent (Carr & Cooper, 2000).
b) ABACAVIR: Abacavir has been reported to induce life-threatening hypersensitivity syndromes in 5% to 8% of patients, manifested by cutaneous, gastrointestinal and/or respiratory symptoms. Risk factors include female gender, non-African ethnicity, and certain genetic HLA haplotypes. With drug re-challenge, multi-organ failure and death have occurred (Stekler et al, 2006; Carr & Cooper, 2000).
c) ZALCITABINE: A transient symptom complex of cutaneous eruptions (maculovesicular in nature), fever, malaise, and aphthous ulcers have been a relatively frequent complication of zalcitabine therapy in AIDS patients. This usually occurs during the first 4 to 6 weeks of therapy (McNeely et al, 1989) Yarchoan et al, 1988; (Merigan et al, 1989; Merigan & Skowron, 1990; Broder, 1990).
d) LAMIVUDINE: Skin rashes and/or pruritus have been reported in approximately 10% of patients during oral therapy with lamivudine (Pluda et al, 1995; van Leeuwen et al, 1995).
e) LAMIVUDINE: Henoch-Schonlein purpura has been reported in 1 patient following therapy with oral lamivudine in doses of 12 mg/kg/day, resulting in discontinuance of therapy (Pluda et al, 1995).

a) LAMIVUDINE: A 17-year-old developed a generalized, pruritic, maculopapular rash 1 day after ingesting lamivudine 3.9 g and efavirenz 15.6 g (Boscacci et al, 2006).

a) INCIDENCE: Stevens-Johnson syndrome or toxic epidermal necrolysis develops in less than 0% to 5% of NRTI treated patients. These have not been reported with abacavir therapy (Carr & Cooper, 2000).

a) TRICITABINE/EMTRICITABINE can cause hyperpigmentation of the skin and nails (Luther & Glesby, 2007).

a) LAMIVUDINE: Hair loss has been reported in 5 of 16 patients in a lamivudine clinical trial (Fong, 1994).

a) STAVUDINE: Creatine phosphokinase was greater than 5 times normal in 7 out of 41 patients in a clinical trial of stavudine (Murray et al, 1995).
b) ZIDOVUDINE/LAMIVUDINE: During a clinical trial, 8% of patients receiving lamivudine plus zidovudine experienced myalgias (Prod Info EPIVIR(R) oral tablets, solution, 2008).

a) ZALCITABINE: Dose related arthralgias have been reported during zalcitabine therapy (Merigan & Skowron, 1990; Broder, 1990).

a) TENOFOVIR: Bone pain occurred in 12 of 22 patients diagnosed with tenofovir-associated renal toxicity. Osteomalacia was confirmed in 7 patients via an isotope bone scan. All 7 patients had an elevated alkaline phosphatase concentration after initiating therapy with tenofovir (Woodward et al, 2009).

a) CASE REPORT: Verma et al (1999) reported acute hyperglycemia (blood glucose ranging between 128 and 251 mg%) with fulminant axonal neuropathy and lactic acidosis in a patient taking NRTI therapy. A toxic neuropathic reaction was suggested by the parallel association of lactic acidosis and hyperglycemia with mixed sensory and motor axonal degeneration (Verma et al, 1999).

1) Morbilliform/maculopapular rash
2) Fever (often precedes rash)
3) Myalgias, fatigue
4) Mucosal ulceration

a) Abnormal laboratory values have included: lymphopenia, increased liver function tests, and occasionally increased creatine kinase levels or thrombocytopenia. With continued dosing, symptoms worsen, but resolve within a few days on discontinuation of therapy. With drug re-challenge, multi-organ failure and death may result. Fatalities have been reported.
b) Initial presentation of fatal hypersensitivity reactions has included respiratory symptoms of dyspnea, cough, or pharyngitis. Delays in diagnosis of hypersensitivity can result in continuation of abacavir, or re-introduction of the drug, resulting in life-threatening hypotension and death (Anon, 2000).

a) There have been sufficient numbers of first trimester exposures to abacavir to detect at least a 2-fold increase in the 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 abacavir use was 3% (25 of 823 births; 95% confidence interval, 2% to 4.5%) compared with the total United States population-based prevalence of 2.7% (Prod Info ZIAGEN(R) oral tablets, oral solution, 2015a; Prod Info EPZICOM(R) oral tablets, 2015a; Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

a) A slight increase in birth defects overall has been observed in data collected from the Antiretroviral Pregnancy Registry. Prevalence of birth defects associated with maternal first-trimester didanosine use was 4.6% (19 of 409 births; 95% confidence interval (CI), 2.8% to 7.2%) compared with the total United States population-based prevalence of 2.7%. No pattern of defects was discovered (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
b) After a single oral didanosine dose of 375 mg in 2 women, maternal blood levels were 295 and 629 nanograms (ng)/mL; corresponding fetal blood levels were 42 and 121 ng/mL. Amniotic fluid levels were less than 5 ng/mL and 135 ng/mL, respectively (Pons et al, 1991).

a) There have been sufficient numbers of first trimester exposure to emtricitabine 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 emtricitabine use was 2.3% (21 of 899 births; 95% confidence interval, 1.4% to 3.5%), 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).

a) There have been sufficient numbers of first trimester exposures to lamivudine to detect at least a 1.5-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 lamivudine use was 3.1% (127 of 4088 births; 95% confidence interval, 2.6% to 3.7%) compared with the total United States population-based prevalence of 2.7% (Prod Info EPIVIR(R) oral tablets, oral solution, 2015b; Prod Info EPZICOM(R) oral tablets, 2015a; Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).

a) There have been sufficient numbers of first trimester exposure to stavudine to detect at least a 2-fold increase in risk of birth defects. No increases in birth defects overall with stavudine have been observed in data collected from the Antiretroviral Pregnancy Registry. Prevalence of birth defects associated with maternal first trimester stavudine use was 2.5% (20 of 801 births; 95% confidence interval, 1.5% to 3.8%) 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) In a prospective cohort study, maternal use of tenofovir disoproxil fumarate any time during pregnancy was not associated with increased risk for infant adverse birth outcomes of low birth weight (LBW) or small for gestational age (SGA) compared with tenofovir-unexposed infants; however, tenofovir-exposed infants had a slightly lower mean age-appropriate length and head circumference at 1 year. The incidence of tenofovir use was 21% (449/2029 HIV-infected mothers), with a median duration of 4.8 months; 13% had first trimester exposure. Based on adjusted odds ratios (aOR), tenofovir exposure was not associated with LBW (aOR, 0.87; p=0.4) or SGA (aOR, 1.04; p=0.88) at birth; further adjustment for gestational age did not affect the results. There was also no association with tenofovir exposure and newborn length-for-age z-scores (LAZ) and head circumference-for-age z-scores (HCAZ). However, at age 1 year, infants exposed in utero to tenofovir-containing combination antiretroviral therapy had slightly but statistically significantly lower adjusted mean LAZ (-0.17 vs -0.03; p=0.04) and HCAZ (0.17 vs 0.42; p=0.02) compared with those unexposed to tenofovir. These results correspond approximately to a mean 0.41 cm shorter length and a mean 0.32 cm smaller head circumference at 1 year in the tenofovir-exposed infants (Siberry et al, 2012).
b) There have been sufficient numbers of first trimester exposures to tenofovir 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 tenofovir use was 2.3% (31 of 1370 births; 95% confidence interval, 1.5% to 3.2%) 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) There have been sufficient numbers of first trimester exposures to zidovudine to detect at least a 1.5-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 zidovudine use was 3.3% (124 of 3789 births; 95% confidence interval, 2.7% to 3.9%) 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) According to one study, there is a possible link between mitochondrial dysfunction and perinatal administration of prophylactic nucleoside analogues, specifically zidovudine. Eight children exposed to zidovudine in-utero had mitochondrial dysfunction. Of these, 5 presented with delayed neurological symptoms and 2 of these died, while 3 were symptom-free but had severe biological or neurological abnormalities (Blanche et al, 1999).
c) In zidovudine-exposed, but HIV-uninfected infants, transient anemia and other blood abnormalities (ie, neutropenia, thrombocytopenia, and lymphopenia), as well as hyperlactatemia have been documented (Venhoff & Walker, 2006).

a) In human studies with emtricitabine, there was no difference in the risk of major birth defects compared to the background rate of birth defects (Prod Info ODEFSEY(R) oral tablets, 2016; Prod Info DESCOVY(R) oral tablets, 2016).

a) In a retrospective analysis of pregnant women infected with highly viremic hepatitis B virus (HBV) (defined as HBV-DNA levels of 6 or more log(10) copies/mL prior to treatment) and who received oral tenofovir disoproxil fumarate 300 mg once daily beginning in the third trimester, 11 Asian women gave birth to 11 infants who did not have birth defects or congenital malformations. Maternal use of tenofovir was started at the medial gestational age of 29 weeks (range, 28 to 32 weeks) and the median duration of use before delivery was 10 weeks (range, 7 to 12 weeks). Serum HBV-DNA levels were significantly reduced in the mother at delivery compared with baseline (mean, 5.25 +/- 1.79 vs 8.87 +/- 0.45 log(10) copies/mL, respectively; p less than 0.01). At birth and subsequently, all infants received appropriate immunoprophylaxis with hepatitis B immunoglobulin and vaccination. At 28 to 36 weeks after birth, all infants were hepatitis B surface antigen negative. While these preliminary results suggest that tenofovir use in the third trimester was safe and effective in preventing vertical transmission from highly viremic HBV-infected mothers, larger, prospectively randomized and controlled studies are needed to confirm these findings (Pan et al, 2012).
b) In a prospective cohort study of prevention of mother-to-child HIV transmission in HIV-infected pregnant women with intrapartum dosing of tenofovir disoproxil fumarate 600 mg, there were no significant neonatal adverse effects and the median ratio of tenofovir concentrations in cord blood to maternal plasma was 0.73 (range, 0.26 to 1.95). Women administered one dose of 600 mg tenofovir at the onset of active labor or up to 8 hours before a planned cesarean section (group 1, n=13 women and 10 infants) had infants with 76 ng/mL median tenofovir cord BCs, with a higher median cord BC with cesarean deliveries (94 ng/mL). The median BC in all group 1 infants fell to 12 ng/mL by 12 hours postpartum. In groups 2 (n=7 women and 7 infants) and 3 (n=8 women and 9 infants), women received one dose of tenofovir 900 mg intrapartum and infants received a tenofovir dose 4 mg/kg post delivery; in group 3, women and infants also received emtricitabine 600 mg and 3 mg/kg, respectively. The median tenofovir cord BC was lower than group 1 (68 ng/mL), but higher with cesarean sections (110 ng/mL). Infants had a median tenofovir BC of 29 ng/mL before postpartum dosing, and was 46 ng/mL and 30 ng/mL within 24 and 36 hours, respectively, of dosing (n=14) (Flynn et al, 2011).
c) In a retrospective case series of 15 pregnant HIV-infected women in an urban clinic, tenofovir was well-tolerated without serious adverse events; however, long-term evaluation of tenofovir's effects on childhood growth and a larger prospective evaluation are warranted. Between 2001 and 2005, 15 women received tenofovir (standard dose) as a part of highly active antiretroviral therapy (HAART) for 16 pregnancies to prevent mother-to-infant transmission of HIV. The median nadir CD4+ count was 191 cells per microliter (range, 0 to 676). Two women were treated with tenofovir at the beginning of the pregnancy, 13 women started tenofovir at a median of 19 weeks gestation, and 3 women began treatment during the third trimester. Median exposure to tenofovir in utero was 127 days. All women received intravenous zidovudine during delivery. Complications were reported in 9 pregnancies, but they were not related to tenofovir treatment. Fifteen women had successful deliveries at a median of 36 weeks gestation, with a median birth weight of 3255 g. One neonate was born at 30 weeks and weighed 2500 g. Overall, in a cohort of heavily treatment-experienced women, tenofovir was an adequately tolerated component of HAART (Nurutdinova et al, 2008).

a) Animal studies conducted with the individual components of the product suggest that abacavir and lamivudine are transferred to the fetus through the placenta. Fetal malformations and developmental toxicities were reported in animals administered abacavir at doses up to 35 times the human exposure. Embryonic and fetal toxicities as well as offspring toxicities were reported with abacavir at doses approximately half of the above mentioned dose. Administration of lamivudine at doses approximately 35 times the recommended adult dose showed evidence of early embryolethality. There were no reports of teratogenicity. Teratogenicity was not reported with zidovudine administration at doses up to 600 mg/kg/day, however, embryofetal toxicity was observed. Maternal toxicity and an increase in fetal malformations was reported with zidovudine doses approximately 350 times peak human plasma concentrations (Prod Info TRIZIVIR oral tablets, 2015).

a) In animal studies, no adverse effects were observed at emtricitabine doses up to 108 times the recommended daily dose for humans (Prod Info ODEFSEY(R) oral tablets, 2016; Prod Info DESCOVY(R) oral tablets, 2016).
b) In embryofetal toxicity studies of emtricitabine in animals at exposures of up to approximately 120-fold higher than human exposure based on AUC at the recommended daily doses, there was no increase in fetal variations or malformations (Prod Info TRUVADA(R) oral tablets, 2012; Prod Info EMTRIVA(R) oral capsule, solution, 2012).

a) Animal studies conducted with the individual components of the product suggest that abacavir and lamivudine are transferred to the fetus through the placenta. Fetal malformations and developmental toxicities were reported in animals administered abacavir at doses up to 35 times the human exposure. Embryonic and fetal toxicities as well as offspring toxicities were reported with abacavir at doses approximately half of the above mentioned dose. Administration of lamivudine at doses approximately 35 times the recommended adult dose showed evidence of early embryolethality. There were no reports of teratogenicity. Teratogenicity was not reported with zidovudine administration at doses up to 600 mg/kg/day, however, embryofetal toxicity was observed. Maternal toxicity and an increase in fetal malformations was reported with zidovudine doses approximately 350 times peak human plasma concentrations (Prod Info TRIZIVIR oral tablets, 2015).
b) Doses of lamivudine up to 130 and 60 times the adult dose in animals did not produce any teratogenic effects (Prod Info EPIVIR(R) oral tablets, solution, 2009).

a) Prenatal exposure to combined maternal treatment with zidovudine and lamivudine was reported to result in significant, although minor, alterations in neurobehavioral development of animals. Early development of prenatally exposed animals was delayed, particularly affecting somatic growth and maturation of several sensorimotor reflexes by one or two days (Venerosi et al, 2001).

a) No evidence of teratogenicity was seen in animals with exposures up to 399 and 183 times, respectively, of that seen at human clinical dosage of 1 mg/kg/day (Prod Info ZERIT(R) oral capsules, solution, 2009).

a) In animal reproduction studies in which animals received tenofovir doses up to 19 times the human dose based on body surface area, there was no evidence of impaired fertility or harm to the fetus (Prod Info VIREAD(R) oral tablets, powder, 2012; Prod Info TRUVADA(R) oral tablets, 2012).

a) In animal studies, no adverse effects were observed at tenofovir alafenamide doses up to 53 times the recommended daily dose for humans (Prod Info ODEFSEY(R) oral tablets, 2016; Prod Info DESCOVY(R) oral tablets, 2016).

a) During animal studies with single-agent administration, there were no reports of teratogenicity or adverse effects on reproductive function with elvitegravir at doses up to 23 times the recommended human dose RHD) or with cobicistat at doses up to 3.8 times the RHD. There was no reported increase in fetal variations or malformations with administration of emtricitabine at doses up to approximately 108 times the RHD. Similarly, there was no evidence of impaired fertility or fetal harm due to administration of tenofovir alafenamide at doses approximately 53 times greater than the RHD (Prod Info GENVOYA(R) oral tablets, 2015).

a) Animal studies conducted with the individual components of the product suggest that abacavir and lamivudine are transferred to the fetus through the placenta. Fetal malformations and developmental toxicities were reported in animals administered abacavir at doses up to 35 times the human exposure. Embryonic and fetal toxicities as well as offspring toxicities were reported with abacavir at doses approximately half of the above mentioned dose. Administration of lamivudine at doses approximately 35 times the recommended adult dose showed evidence of early embryolethality. There were no reports of teratogenicity. Teratogenicity was not reported with zidovudine administration at doses up to 600 mg/kg/day, however, embryofetal toxicity was observed. Maternal toxicity and an increase in fetal malformations was reported with zidovudine doses approximately 350 times peak human plasma concentrations (Prod Info TRIZIVIR oral tablets, 2015).

a) Abacavir has been classified as FDA pregnancy category C (Prod Info ZIAGEN(R) oral tablets, solution, 2008a).

a) Abacavir/dolutegravir/lamivudine combination therapy has been classified as FDA pregnancy category C (Prod Info TRIUMEQ(R) oral tablets, 2014).

a) Abacavir/lamivudine has been classified as FDA pregnancy category C (Prod Info EPZICOM(R) oral tablets, 2009).

a) Abacavir/lamivudine/zidovudine has been classified as FDA pregnancy category C (Prod Info TRIZIVIR oral tablets, 2015).

a) Cobicistat/elvitegravir/emtricitabine/tenofovir has been classified as FDA pregnancy category B (Prod Info STRIBILD(TM) oral tablets, 2012).

a) Delavirdine has been classified as FDA pregnancy category C (Prod Info RESCRIPTOR(R) oral tablets, 2008).

a) Didanosine has been classified as FDA pregnancy category B (Prod Info VIDEX(R) pediatric powder for oral solution, 2010).

a) Efavirenz/emtricitabine/tenofovir has been classified as FDA pregnancy category D (Prod Info ATRIPLA(R) oral tablets, 2010).

a) Emtricitabine has been classified as FDA pregnancy category B (Prod Info EMTRIVA(R) oral capsule, solution, 2012).

a) Emtricitabine/rilpivirine/tenofovir has been classified as FDA pregnancy category B (Prod Info COMPLERA(TM) oral tablets, 2011).

a) Although human studies with emtricitabine show no difference in the risk of major birth defects compared to the background rate of birth defects, there are not enough data to evaluate the use of emtricitabine/rilpivirine/tenofovir alafenamide during pregnancy (Prod Info ODEFSEY(R) oral tablets, 2016).
b) Patients exposed to emtricitabine/rilpivirine/tenofovir alafenamide during pregnancy may register with the Antiretroviral Pregnancy Registry by calling 1-800-258-4263 (Prod Info ODEFSEY(R) oral tablets, 2016).

a) Emtricitabine/tenofovir has been classified as FDA pregnancy category B(Prod Info TRUVADA(R) oral tablets, 2012).

a) Administer emtricitabine/tenofovir alafenamide to a pregnant woman only if the potential benefit outweighs the potential risk to the fetus.(Prod Info DESCOVY(R) oral tablets, 2016).
b) Patients exposed to emtricitabine/tenofovir alafenamide during pregnancy may register with the Antiretroviral Pregnancy Registry by calling 1-800-258-4263 (Prod Info DESCOVY(R) oral tablets, 2016).

a) Lamivudine has been classified as FDA pregnancy category C (Prod Info EPIVIR(R) oral tablets, solution, 2008).

a) Stavudine has been classified as FDA pregnancy category C (Prod Info ZERIT(R) oral capsules, solution, 2009).

a) Tenofovir has been classified as FDA pregnancy category B (Prod Info VIREAD(R) oral tablets, powder, 2012).

a) The combination substance of tenofovir alafenamide/cobicistat/elvitegravir/emtricitabine has been classified as FDA pregnancy category B (Prod Info GENVOYA(R) oral tablets, 2015).
b) Use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk. Patients exposed to cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide during pregnancy may register with the Antiretroviral Pregnancy Registry by calling 1-800-258-4263 (Prod Info GENVOYA(R) oral tablets, 2015).

a) Zalcitabine has been classified as FDA pregnancy category C (Prod Info HIVID(R), 2002).
b) NOTE: Zalcitabine is no longer available in the United States (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2010).

a) Zidovudine has been classified as FDA pregnancy category C (Prod Info RETROVIR(R) oral tablets, capsules, syrup, 2008).

a) Three cases of fatal lactic acidosis, with and without pancreatitis, were reported in pregnant women taking stavudine and didanosine in combination with other antiretroviral drugs. Several nonfatal cases in pregnant women (with and without pancreatitis) were also reported. Although it has been suggested that women may be at an increased risk of developing lactic acidosis and liver toxicity, it is unclear if pregnancy potentiates these known adverse events ((Anon, 2001)).

a) CASE REPORT: Hepatotoxicity was reported in a 28-year-old pregnant woman receiving antiretroviral treatment with zidovudine, lamivudine, and efavirenz. At week 18 of gestation and about 5 months after antiretroviral therapy initiation, she presented with sclera icterus and jaundice. Lab values showed elevated transaminases and bilirubin. Following discontinuation of her medications, transaminase levels declined, but hyperbilirubinemia persisted until post-delivery. Lab values returned to normal five months after delivery of a viable infant (Hill et al, 2001).

1) ABACAVIR: Yes (rat)
2) DIDANOSINE: 0.5 (human)
3) EMTRICITABINE: 1.2 (human)
4) LAMIVUDINE: 1
5) STAVUDINE: 0.76
6) ZIDOVUDINE: 0.85 (human)
7) ZALCITABINE: 0.3 to 0.5 (rhesus monkey)

a) A meta-analysis of 2123 pregnant women infected with the human immunodeficiency virus did not show a difference in adjusted overall rates of adverse pregnancy events between treated and untreated groups. However, unadjusted rates of premature delivery were lower in treated women compared with those who were not treated; rates of premature and very premature delivery were similar between combination regimens that included and excluded protease inhibitors. The risk of low birth weight was lower among infants born to mothers receiving combination therapy without protease inhibitors (n=396) compared with infants born to women receiving monotherapy (n=1590; odds ratio (OR), 0.58; 95% confidence interval (CI), 0.41 to 0.84). The risk of low birth weight was greater for infants of mothers treated with combination regimens that included protease inhibitors (n=137) than for infants of mothers receiving combination regimens without protease inhibitors (OR, 2.03, 95% CI, 1.16 to 3.54) (Tuomala et al, 2002a).

a) CASE REPORT: An HIV-positive pregnant woman treated with stavudine 40 mg twice a day and lamivudine 150 mg twice a day delivered a healthy, normal child at term. The antiviral treatment was initiated at gestational week 20 and was well-tolerated. The pregnancy was uneventful and fetal growth considered normal. At nine months of age, the child was HIV-negative and developing normally (Ristola et al, 1999).

a) In a retrospective analysis of pregnant women infected with highly viremic hepatitis B virus (HBV) (defined as HBV-DNA levels of 6 or more log(10) copies/mL prior to treatment) and who received oral tenofovir disoproxil fumarate 300 mg once daily beginning in the third trimester, 11 Asian women gave birth to 11 infants who did not have birth defects or congenital malformations. Maternal use of tenofovir was started at the median gestational age of 29 weeks (range, 28 to 32 weeks) and the median duration of use before delivery was 10 weeks (range, 7 to 12 weeks). Serum HBV-DNA levels were significantly reduced in the mother at delivery compared with baseline (mean, 5.25 +/- 1.79 vs 8.87 +/- 0.45 log(10) copies/mL, respectively; p less than 0.01). At birth and subsequently, all infants received appropriate immunoprophylaxis with hepatitis B immunoglobulin and vaccination. At 28 to 36 weeks after birth, all infants were hepatitis B surface antigen negative. While these preliminary results suggest that tenofovir use in the third trimester was safe and effective in preventing vertical transmission from highly viremic HBV-infected mothers, larger, prospectively randomized and controlled studies are needed to confirm these findings (Pan et al, 2012).
b) In a retrospective case series of 15 pregnant HIV-infected women in an urban clinic, tenofovir was well-tolerated without serious adverse events; however, long-term evaluation of tenofovir's effects on childhood growth and a larger prospective evaluation are warranted. Between 2001 and 2005, 15 women received tenofovir (standard dose) as a part of highly active antiretroviral therapy (HAART) for 16 pregnancies to prevent mother-to-infant transmission of HIV. The median nadir CD4+ count was 191 cells/mcL (range, 0 to 676). Two women were treated with tenofovir at the beginning of the pregnancy, 13 women started tenofovir at a median of 19 weeks gestation, and 3 women began treatment during the third trimester. Median exposure to tenofovir in utero was 127 days. All women received intravenous zidovudine during delivery. Complications were reported in 9 pregnancies, but they were not related to tenofovir treatment. Fifteen women had successful deliveries at a median of 36 weeks gestation, with a median birth weight of 3255 g. One neonate was born at 30 weeks and weighed 2500 g. Overall, in a cohort of heavily treatment-experienced women, tenofovir was an adequately tolerated component of HAART (Nurutdinova et al, 2008).

a) Animal studies conducted with the individual components of the product suggest that abacavir and lamivudine are transferred to the fetus through the placenta. Fetal malformations and developmental toxicities were reported in animals administered abacavir at doses up to 35 times the human exposure. Embryonic and fetal toxicities as well as offspring toxicities were reported with abacavir at doses approximately half of the above mentioned dose. Administration of lamivudine at doses approximately 35 times the recommended adult dose showed evidence of early embryolethality. There were no reports of teratogenicity. Teratogenicity was not reported with zidovudine administration at doses up to 600 mg/kg/day, however, embryofetal toxicity was observed. Maternal toxicity and an increase in fetal malformations was reported with zidovudine doses approximately 350 times peak human plasma concentrations (Prod Info TRIZIVIR oral tablets, 2015).

a) Animal studies conducted with the individual components of the product suggest that abacavir and lamivudine are transferred to the fetus through the placenta. Fetal malformations and developmental toxicities were reported in animals administered abacavir at doses up to 35 times the human exposure. Embryonic and fetal toxicities as well as offspring toxicities were reported with abacavir at doses approximately half of the above mentioned dose. Administration of lamivudine at doses approximately 35 times the recommended adult dose showed evidence of early embryolethality. There were no reports of teratogenicity. Teratogenicity was not reported with zidovudine administration at doses up to 600 mg/kg/day, however, embryofetal toxicity was observed. Maternal toxicity and an increase in fetal malformations was reported with zidovudine doses approximately 350 times peak human plasma concentrations (Prod Info TRIZIVIR oral tablets, 2015).
b) There were indications of early embryolethality when lamivudine was given to animals at doses similar to the maximum recommended human dose (Prod Info EPIVIR(R) oral tablets, solution, 2009).

a) In studies in animals, decreased fetal growth and reduced fetal bone porosity was noted within 2 months of exposure when maternal animals received tenofovir at doses 2-fold higher than those used for human therapeutic use (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2010).

a) During animal studies with single-agent administration, there were no reports of teratogenicity or adverse effects on reproductive function with elvitegravir at doses up to 23 times the recommended human dose RHD) or with cobicistat at doses up to 3.8 times the RHD. There was no reported increase in fetal variations or malformations with administration of emtricitabine at doses up to approximately 108 times the RHD. Similarly, there was no evidence of impaired fertility or fetal harm due to administration of tenofovir alafenamide at doses approximately 53 times greater than the RHD (Prod Info GENVOYA(R) oral tablets, 2015).

a) Animal studies conducted with the individual components of the product suggest that abacavir and lamivudine are transferred to the fetus through the placenta. Fetal malformations and developmental toxicities were reported in animals administered abacavir at doses up to 35 times the human exposure. Embryonic and fetal toxicities as well as offspring toxicities were reported with abacavir at doses approximately half of the above mentioned dose. Administration of lamivudine at doses approximately 35 times the recommended adult dose showed evidence of early embryolethality. There were no reports of teratogenicity. Teratogenicity was not reported with zidovudine administration at doses up to 600 mg/kg/day, however, embryofetal toxicity was observed. Maternal toxicity and an increase in fetal malformations was reported with zidovudine doses approximately 350 times peak human plasma concentrations (Prod Info TRIZIVIR oral tablets, 2015).

a) Avoid breastfeeding while taking this drug (Prod Info GENVOYA(R) oral tablets, 2015).
b) It is unknown whether cobicistat, elvitegravir, or tenofovir are excreted into human breast milk. Emtricitabine was detected samples of breast milk from 5 HIV-1 infected mothers. Breastfeeding infants exposed to emtricitabine may be at risk for developing a viral resistance to emtricitabine. Additional adverse effects are currently unknown (Prod Info GENVOYA(R) oral tablets, 2015).

a) Mothers should not breastfeed while taking emtricitabine/rilpivirine/tenofovir alafenamide (Prod Info ODEFSEY(R) oral tablets, 2016).

a) Advise women to avoid breastfeeding during therapy (Prod Info DESCOVY(R) oral tablets, 2016).

a) Abacavir is excreted in the milk of lactating animals (Prod Info ZIAGEN(R) oral solution, oral tablets, 2008).

a) Didanosine and its metabolites have been shown to be excreted in the milk of lactating animals following oral administration (Prod Info VIDEX(R) pediatric powder for oral solution, 2010).

a) In animal studies, no adverse effects were observed at emtricitabine lactation doses up to 60 times the recommended daily dose for humans (Prod Info ODEFSEY(R) oral tablets, 2016).

a) Stavudine is excreted into the milk of lactating animals (Prod Info ZERIT(R) oral capsules, solution, 2009)

a) The drug is excreted into the milk of lactating animals (Prod Info VIREAD(R) oral tablets, powder, 2012; Prod Info STRIBILD(TM) oral tablets, 2012)

a) In animal studies, no adverse effects were observed at tenofovir alafenamide lactation doses up to 14 times the recommended daily dose for humans (Prod Info ODEFSEY(R) oral tablets, 2016).

a) Dosages that resulted in approximately 8 times the human exposure at the recommended dose (based on body surface area comparisons) had no adverse effects on the fertility of male and female animals (Prod Info ZIAGEN(R) oral solution, oral tablets, 2008).

a) Dosages up to 200 mg of delavirdine per kg of body weight per day did not impair fertility in male or female animals (Prod Info RESCRIPTOR(R) oral tablets, 2008).

a) No evidence of impaired fertility has been found in animals receiving up to 14.2 times the estimated human dose of didanosine, based on plasma levels (Prod Info VIDEX(R) pediatric powder for oral solution, 2010).

a) In animal studies, fertility was unaffected at emtricitabine doses approximately 140 times the recommended daily dose for humans (Prod Info ODEFSEY(R) oral tablets, 2016).
b) Normal fertility was seen in the offspring of animals exposed from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose (Prod Info EMTRIVA(R) oral capsule, solution, 2012).

a) No evidence of impaired fertility was seen in animals given stavudine at doses that resulted in peak serum concentrations that were up to 216 times those observed in humans who received a clinical dosage of 1 mg/kg/day (Prod Info ZERIT(R) oral capsules, solution, 2009).

b) There were no effects on fertility, mating performance, or early embryonic development when tenofovir was administered at doses 10 times the human dose based on surface area comparisons to male animals for 28 days prior to mating and to female animals for 15 days prior to mating through day 7 of gestation (Prod Info VIREAD(R) oral tablets, powder, 2012). There was, however, an alteration of the estrous cycle in female animals (Prod Info TRUVADA(R) oral tablets, 2012).

a) In animal studies, fertility was unaffected at tenofovir alafenamide doses approximately 62 times the recommended daily dose for humans (Prod Info ODEFSEY(R) oral tablets, 2016).

a) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

a) Doses far in excess of those administered to humans, have been associated with vaginal neoplasms in female mice and rats. The significance of these findings to humans is not known (Rachlis & Fanning, 1993).

a) Thymic lymphomas have been induced in 3 of 50 mice administered zalcitabine 500 mg/kg/day for 13 weeks, and in 17 of 50 mice receiving 1000 mg/kg/day. This did not occur in mice from the vehicle control group (Sanders et al, 1995).

a) In long-term carcinogenicity studies, increased incidence of liver adenomas were found in female mice at exposures of tenofovir 10 times those observed in humans at the therapeutic dose for HIV infection. In rats, there was no increase in tumor incidence at exposures up to 4 times that observed in humans at the therapeutic dose (Prod Info STRIBILD(TM) oral tablets, 2012).

a) No drug-related increases in tumor incidence were determined in long-term carcinogenicity studies of emtricitabine. Mice administered doses up to 750 mg/kg/day (23 times the human systemic exposure at the therapeutic dose of 200 mg/day) were not found to have drug-related increases in tumor incidence. Rats administered doses up to 60 mg/kg/day (28-fold the human systemic exposure at the therapeutic daily dose) were not found to have drug-related increases in tumor incidence (Prod Info STRIBILD(TM) oral tablets, 2012).

a) Cardiac failure, likely due to acidosis, has been reported; therefore, cardiac monitoring is recommended in the setting of acidosis or chest pain.

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

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) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
c) Monitor CBC with differential.

a) 300 mg twice daily or 600 mg once daily in combination with other antiretroviral agents (Prod Info ZIAGEN(R) oral tablets, oral solution, 2015).

a) 1 tablet (abacavir sulfate 600 mg/lamivudine 300 mg) orally once daily in combination with other antiretroviral agents (Prod Info EPZICOM(R) oral tablets, 2015)

a) The recommended dose is one fixed-dose tablet of abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg orally once daily (Prod Info TRIUMEQ(R) oral tablets, 2014)

a) Type B viral hepatitis, chronic: 10 mg orally once daily (Prod Info HEPSERA(R) oral tablets, 2006).

a) The recommended dose is 1 tablet (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg) orally once daily with food (Prod Info GENVOYA(R) oral tablets, 2015)

a) A recommended dose is a 200-mg capsule orally once daily, or 240 mg (24 mL) as an oral solution administered once daily (Prod Info EMTRIVA(R) capsules, oral solution, 2008).
b) An oral dose of 200 mg once daily as monotherapy has been administered in HIV infection. In chronic hepatitis B, 100 to 300 mg once daily has been given ((Anon, 1999); p 773; Kahn et al, 1998; Murphy, 1999).

a) Recommended adult dose is 1 tablet (emtricitabine 200 mg/rilpivirine 25 mg/tenofovir disoproxil fumarate 300 mg) taken orally once daily (Prod Info COMPLERA(R) oral tablets, 2016).

a) HIV infection, 35 kg or more and CrCl of 30 mL/min or greater: Recommended dose is emtricitabine 200 mg/tenofovir alafenamide 25 mg (1 tablet) orally once daily (Prod Info DESCOVY(R) oral tablets, 2016).

a) HIV prophylaxis: Emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (1 tablet) orally once daily (Prod Info TRUVADA(R) oral tablets, 2016)
b) HIV infection, 35 kg or more: Emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (1 tablet) orally once daily, with or without food (Prod Info TRUVADA(R) oral tablets, 2016)

a) : The recommended dose is 150 mg orally twice daily or 300 mg orally once daily in combination with other antiretroviral agents for treatment of HIV (Prod Info EPIVIR(R) oral tablets, oral solution, 2015a).

a) 60 kg or more: 40 mg orally every 12 hours (Prod Info ZERIT(R) oral capsules, solution, 2009).
b) Less than 60 kg: 30 mg orally every 12 hours (Prod Info ZERIT(R) oral capsules, solution, 2009).

a) The recommended oral dose of tenofovir disoproxil fumarate for HIV-1 or chronic hepatitis B is 300 mg once daily with or without food (Prod Info VIREAD(R) oral tablets, oral powder, 2012).
b) Intravenous tenofovir 1 to 3 mg/kg daily has been administered in HIV infection (Deeks et al, 1998).

a) The recommended dose is 1 tablet (emtricitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg) taken ORALLY once daily (Prod Info ODEFSEY(R) oral tablets, 2016).

a) 3 MONTHS AND OLDER (ORAL SOLUTION): 8 mg/kg twice daily or 16 mg/kg once daily in combination with other antiretroviral agents; MAXIMUM 600 mg daily (Prod Info ZIAGEN(R) oral tablets, oral solution, 2015).
b) PEDIATRIC PATIENTS WEIGHING 14 KG OR GREATER (ORAL TABLETS): If able to swallow tablets, dose according to weight: (Prod Info ZIAGEN(R) oral tablets, oral solution, 2015)

a) WEIGHING 25 KG OR MORE: 1 tablet (abacavir sulfate 600 mg/lamivudine 300 mg) orally once daily in combination with other antiretroviral agents (Prod Info EPZICOM(R) oral tablets, 2015).

a) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info TRIUMEQ(R) oral tablets, 2014)

a) YOUNGER THAN 18 YEARS OF AGE: Safety and efficacy have not been established in pediatric patients (Prod Info STRIBILD(TM) oral tablets, 2012).

a) 12 YEARS OR OLDER, WEIGHING AT LEAST 35 KG: The recommended dose is 1 tablet (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg) orally once daily with food (Prod Info GENVOYA(R) oral tablets, 2015)
b) LESS THAN 12 YEARS: Safety and effectiveness have not been established in patients less than 12 years of age (Prod Info GENVOYA(R) oral tablets, 2015).

a) 0 to 3 MONTHS OF AGE: 3 mg/kg orally once daily (oral solution) (Prod Info EMTRIVA(R) capsules, oral solution, 2008).
b) 3 MONTHS TO 17 YEARS OF AGE: 6 mg/kg administered once daily via an oral solution, up to a MAXIMUM daily amount of 240 mg (24 mL) (Prod Info EMTRIVA(R) capsules, oral solution, 2008).
c) WEIGHING MORE THAN 33 KG: Children who can swallow an intact capsule, 200 mg orally once daily (Prod Info EMTRIVA(R) capsules, oral solution, 2008).

a) 12 YEARS AND OLDER, WEIGHING AT LEAST 35 KG AND CRCL OF 30 ML/MIN OR GREATER: Recommended dose is emtricitabine 200 mg/tenofovir alafenamide 25 mg (1 tablet) orally once daily (Prod Info DESCOVY(R) oral tablets, 2016).
b) YOUNGER THAN 12 YEARS OF AGE OR WEIGHING LESS THAN 35 KG: Safety and efficacy have not been established (Prod Info DESCOVY(R) oral tablets, 2016).

a) 12 YEARS AND OLDER AND WEIGHING AT LEAST 35 KG: Recommended dose is 1 tablet (emtricitabine 200 mg/rilpivirine 25 mg/tenofovir disoproxil fumarate 300 mg) taken orally once daily (Prod Info COMPLERA(R) oral tablets, 2016).
b) YOUNGER THAN 12 YEARS OF AGE OR WEIGHING LESS THAN 35 KG: Safety and efficacy have not been established (Prod Info COMPLERA(R) oral tablets, 2016).

a) HIV INFECTION, 12 YEARS AND OLDER WEIGHING 35 KG OR MORE: Emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (1 tablet) orally once daily (Prod Info TRUVADA(R) oral tablets, 2016)
b) HIV INFECTION, CHILDREN WEIGHING 17 TO 35 KG (Prod Info TRUVADA(R) oral tablets, 2016):

a) CHRONIC HEPATITIS B INFECTION: 2 YEARS OF AGE AND OLDER: 3 mg/kg orally once daily; MAXIMUM 100 mg/day (Prod Info EPIVIR-HBV(R) oral tablets, solution, 2007; Jonas et al, 2002).
b) HIV INFECTION:
c) CHILDREN 3 MONTHS AND OLDER (ORAL SOLUTION): According to the manufacturer, the recommended dosing, in HIV-1 infected pediatric patients, is 4 mg/kg twice daily OR 8 mg/kg once daily; MAX dose 300 mg daily (Prod Info EPIVIR(R) oral tablets, oral solution, 2015a)
d) CHILDREN 3 MONTHS AND OLDER (ORAL TABLET) : According to the manufacturer, the recommended dosing in HIV-1 infected pediatric patients, based on the patient's weight, is as follows (Prod Info EPIVIR(R) oral tablets, oral solution, 2015a):
e) A dose of 2 mg/kg twice daily is recommended for . A dose of 4 mg/kg twice daily is recommended for infants 28 days of age and older (Tremoulet et al, 2007; AIDS Info, 2008; Moodley et al, 1998).

a) BIRTH TO 13 DAYS OLD: 0.5 mg/kg/dose administered orally every 12 hours (Prod Info ZERIT(R) oral capsules, solution, 2009).
b) 14 DAYS OLD AND LESS THAN 30 KG: 1 mg/kg/dose administered orally every 12 hours (Prod Info ZERIT(R) oral capsules, solution, 2009).
c) WEIGHING 30 KG TO LESS THAN 60 KG: 30 mg orally every 12 hours (Prod Info ZERIT(R) oral capsules, solution, 2009).
d) WEIGHING GREATER THAN 60 KG: 40 mg orally every 12 hours (Prod Info ZERIT(R) oral capsules, solution, 2009).

a) TABLETS: The recommended dose is one tablet based on body weight (150, 200, 250, or 300 mg) once daily without regard for food, in patients that weigh at least 17 kg and are able to swallow intact tablets. MAXIMUM DOSE: 300 mg (Prod Info VIREAD(R) oral tablets, powder, 2012).
b) ORAL POWDER: The recommended dose is 8 mg/kg once daily with food. MAXIMUM DOSE: 300 mg (Prod Info VIREAD(R) oral tablets, powder, 2012).

a) TABLETS: The recommended dose is 300 mg ORALLY once daily (Prod Info VIREAD(R) oral tablets, oral powder, 2012).

1) No clinical signs or symptoms were reported in an adult ingesting 6 grams of lamivudine. Hematologic tests remained normal (Prod Info EPIVIR-HBV(R) oral tablets, oral solution, 2004).
2) CASE REPORT: A 17-year-old woman ingested 3.9 g lamivudine and 15.6 g efavirenz. She developed mild agitation and somnolence, described feeling "high, alienated with artificial visual impressions" without hallucinations, had a clumsy gait, and developed abdominal pain and vomiting. The following day she had diarrhea, abdominal cramps and a diffuse pruritic maculopapular rash. Wild bizarre dreams persisted for 5 days. The neurologic effects were likely secondary to the efavirenz (Boscacci et al, 2006).

1) No acute toxicity was reported in patients treated with 12 to 24 times the recommended daily dosage (Prod Info ZERIT(R) oral capsules, oral solution, 2006).

1) Peripheral neuropathy occurred in all patients receiving 6 times the recommended daily dosage by week 10. A patient receiving 25 times the recommended daily dosage experienced rash and fever after 1 and 1/2 weeks necessitating discontinuation of the drug (Prod Info HIVID(R) oral tablets, 2002).