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AIDS ANTIVIRAL NON-NUCLEOSIDES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Non-nucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral agents are used in the treatment of HIV infection or acquired immunodeficiency syndrome (AIDS). They are inhibitors of viral reverse transcriptase with activity against HIV-1.
    B) Nevirapine and efavirenz do not inhibit HIV-2 retrovirus (RT). They do inhibit p24 antigen production. Nevirapine also inhibits mutant isolates of HIV resistant to AZT and displays synergy with AZT in inhibiting AZT-sensitive virus. Emivirine inhibits retrovirus of HIV-1 via allosteric interactions. RT binding characteristics of emivirine appear to differ from those of other NNRTIs, which may confer greater potency.

Specific Substances

    A) GENERAL TERMS
    1) Antiviral non-nucleosides, AIDS
    2) Non-nucleosides, AIDS antiviral
    3) HIV, AIDS antiviral non-nucleosides
    ATEVIRDINE
    1) Atevirdine mesylate
    2) 1-(3-(Ethylamino)-2-pyridyl)-4-((5-methoxyindol-2-yl)carbonyl)piperazine
    3) U-87201E (atevirdine mesylate)
    4) U-87201 (atevirdine)
    5) U-85961
    6) Molecular Formula: C21-H25-N5-O2
    7) CAS 136816-75-6 (atevirdine)
    8) CAS 138540-32-6 (atevirdine mesylate)
    DELAVIRDINE
    1) Delavirdine mesylate
    2) U-90152S
    3) Molecular Formula: C22-H28-N6-O3-S, -CH4-O3-S
    4) CAS 147221-93-0
    EFAVIRENZ
    1) (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-
    2) (trifluoromethyl)-2H-3,1-benzoxazin-2-one
    3) DMP-266
    4) Molecular Formula: C14-H9-ClF3-NO2
    EMIVIRINE
    1) Coactinon
    2) I-EBU
    3) MKC-442
    ETRAVIRINE
    1) Molecular Formula: C20-H15-Br-N6-O
    NEVIRAPINE
    1) 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido
    2) (3,2-b:2,3-e)-(1,4)diazepin-6-one
    3) BI-RG-587
    4) BIRG-0587
    5) Molecular Formula: C15-H14-N4-O
    6) CAS 129618-40-2
    RILPIVIRINE
    1) R-278474
    2) TMC-278
    3) CAS 500287-72-9

    1.2.1) MOLECULAR FORMULA
    1) DELAVIRDINE MESYLATE: C22H28N6O3S.CH4O3S
    2) EFAVIRENZ: C14H9ClF3NO2
    3) ETRAVIRINE: C20H15BrN6O
    4) NEVIRAPINE: C15H14N4O
    5) RILPIVIRINE HYDROCHLORIDE: C22H18N6.HCl

Available Forms Sources

    A) FORMS
    1) DELAVIRDINE is available as 100 mg and 200 mg tablets (Prod Info RESCRIPTOR(R) oral tablets, 2006).
    2) EFAVIRENZ is available as 50 mg, 100 mg and 200 mg capsules, and as 600 mg tablets (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2007).
    3) ETRAVIRINE is available as 100 mg tablets (Prod Info INTELENCE(TM) oral tablets, 2008).
    4) NEVIRAPINE is available as 200 mg tablets and as a suspension (50 mg/5 mL) (Prod Info VIRAMUNE(R) oral tablets, suspension, 2007).
    5) RILPIVIRINE is available as 25 mg tablets (Prod Info EDURANT(R) oral tablets, 2011).
    B) USES
    1) Non-nucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral agents are used in combination with other antiretroviral agents for the treatment of HIV infection or acquired immunodeficiency syndrome (AIDS) (Prod Info EDURANT(R) oral tablets, 2011; Prod Info INTELENCE(TM) oral tablets, 2008; Prod Info VIRAMUNE(R) oral tablets, suspension, 2007; Prod Info SUSTIVA(R) oral capsules, oral tablets, 2007; Prod Info RESCRIPTOR(R) oral tablets, 2006).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are used in the treatment of HIV-1 infection. This class includes etravirine, delavirdine mesylate, efavirenz, nevirapine, and rilpivirine.
    B) PHARMACOLOGY: NNRTIs bind adjacent to the active site of HIV-1 reverse transcriptase causing conformational change and thus inactivation of the enzyme.
    C) TOXICOLOGY: Toxicological effects are generally extensions of adverse effects.
    D) EPIDEMIOLOGY: Overdose is uncommon and severe sequelae from acute overdose is rare. Adverse effects and drug interactions, however, are common.
    E) WITH THERAPEUTIC USE
    1) COMMON: Headache, dizziness, transaminitis, rash, nausea, vomiting, diarrhea, paresthesias, psychiatric disturbances, and hyperlipidemia are the most commonly reported adverse effects.
    2) Other adverse effects specific to each drug include: DELAVIRDINE: rash (36%), hepatitis (rare), Stevens-Johnson syndrome (rare), neutropenia (rare). EFAVIRENZ: headache, dizziness, impaired concentration, abnormal dreams, or other CNS/psychiatric disturbances (52%), rash (27%), transaminitis, fever, hyperlipidemia. ETRAVIRINE: rash, peripheral neuropathy, toxic epidermal necrolysis (rare), hepatitis (rare). NEVIRAPINE: rash (7%), pruritus, hepatitis (1%), Stevens-Johnson syndrome (0.3%), fever. Hypersensitivity syndrome (HHS) has been described approximately 4 weeks following the therapeutic use of nevirapine. Generalized maculopapular rash, eosinophilia, enlarged lymph nodes, fever, and hepatosplenomegaly developed.
    3) DRUG INTERACTIONS: DELAVIRDINE: A CYP3A4 substrate and inhibitor and a CYP2C9 inhibitor; carbamazepine, phenobarbital, rifampin, and phenytoin may decrease delavirdine concentrations; may increase plasma concentrations of other CYP3A4 substrates. EFAVIRENZ: A CYP3A4 substrate and inducer, and a CYP2B6 substrate; may decrease phenobarbital, phenytoin, carbamazepine, and methadone concentrations; may cause false positive tetrahydrocannabinol tests. ETRAVIRINE: A CYP3A4 substrate and inducer, a CYP2C9 substrate and inhibitor, and a CYP2C19 substrate and inhibitor; may increase the INR when administered with warfarin; may decrease etravirine concentrations when administered with phenytoin, carbamazepine, or phenobarbital; may increase digoxin concentrations. NEVIRAPINE: A CYP3A4 substrate and inducer, and a CYP2B6 substrate; may cause methadone withdrawal; may decrease plasma concentrations of oral contraceptives; may decrease ketoconazole concentrations; administration with rifampin may decrease nevirapine concentrations.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: The majority of patients will have minimal or no symptoms following overdose. Mild transaminitis may occur in the setting of overdose. Psychiatric disturbances characterized by mania, agitation, and sometimes somnolence have been observed in overdose. Abdominal pain, nausea, and vomiting have been reported. Transient mild neutropenia and hyperlactemia developed in an infant after intravenous overdose.
    0.2.20) REPRODUCTIVE
    A) Etravirine, nevirapine, rilpivirine, and emtricitabine/rilpivirine/tenofovir are classified as FDA pregnancy category B, delavirdine is classified as FDA pregnancy category C, and efavirenz and efavirenz/emtricitabine/tenofovir are classified as FDA pregnancy category D. In animal studies, teratogenicity was not observed with etravirine, nevirapine, or rilpivirine; however, malformations (anencephaly, unilateral anophthalmia, microphthalmia, and cleft palate) have been demonstrated with efavirenz use in monkeys and ventricular septal defects have been reported with delavirdine use in rats. In humans, there have been reports of neural tube defects, one report of ventricular septal defect, placental transfer, maternal hepatotoxicity, and ectopic pregnancies with some of these agents. In animal studies, delavirdine and efavirenz were secreted into the milk of lactating rats. Nevirapine is considered the preferred NNRTI in pregnant women receiving combination antiretroviral therapy (ART). However, initiation of nevirapine therapy in pregnant women with CD4 cell counts greater than 250 cells/mm(3) should be considered only if the benefits clearly outweigh the risks for potentially life-threatening hepatotoxicity and nevirapine has been shown to be excreted in human breast milk.

Laboratory Monitoring

    A) Measurement of a basic metabolic panel, complete blood count, and liver enzymes should be performed in cases where adverse effects or overdose are suspected.
    B) Right upper quadrant ultrasound should be considered to evaluate for alternative etiologies of transaminitis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Supportive care remains the mainstay of care. Benzodiazepines or antipsychotics may be used for agitation or manic symptoms. Mild transaminitis can be monitored and no specific treatment is indicated. Nausea and vomiting should be treated with antiemetics.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care is the mainstay of care in severe toxicity. Withdrawal of the offending agent is imperative to improvement in severe adverse reactions. Stevens-Johnson syndrome should be treated with supportive care and consideration of corticosteroid and IV immunoglobulin therapy. Granulocyte colony stimulating factor (GCSF) should be considered for neutropenia complicated by infection felt to be secondary to nevirapine. Hepatic failure should prompt consultation with a transplant center.
    C) DECONTAMINATION
    1) PREHOSPITAL: No prehospital decontamination is indicated. Prehospital care should focus on assessment of vital signs and general supportive care.
    2) HOSPITAL: Activated charcoal may be considered for patients that present early after overdose if they are awake, alert, and willing to drink the charcoal. Gastric lavage has no role in the management of non-nucleoside reverse transcriptase inhibitor (NNRTI) overdose.
    D) AIRWAY MANAGEMENT
    1) Respiratory depression is not expected with overdose of NNRTIs. However coingestants must be considered and airway protection should be employed as needed for airway protection.
    E) ANTIDOTE
    1) There is no specific antidote for NNRTI toxicity.
    F) ENHANCED ELIMINATION
    1) Hemodialysis and whole bowel irrigation have no role in the management of NNRTI overdose.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Suicidal patients should be referred to a health care facility. Asymptomatic patients with inadvertent ingestions of NNRTIs can be observed at home.
    2) OBSERVATION CRITERIA: Asymptomatic or mildly symptomatic patients should be observed for 4 to 6 hours, primarily monitoring signs of coingestant toxicity.
    3) ADMISSION CRITERIA: Patients with severe toxicity should be admitted. Patients with Stevens-Johnson syndrome or hepatic failure should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Infectious disease should be consulted if a change to anti-retroviral therapy is indicated. Hepatic failure should prompt consultation with a transplant center.
    H) PITFALLS
    1) Failure to consider drug-drug interactions and toxicity of coingestants. Failure to consider the possibility of hepatitis as an adverse effect following therapeutic administration. Failure to restart NNRTI therapy quickly can lead to rapid viral resistance.
    I) PHARMACOKINETICS
    1) DELAVIRDINE: Rapidly absorbed, 60% to 100% bioavailable; highly protein bound (98%); hepatic metabolism with approximately 50% renal and 45% fecal elimination of metabolites; half-life 2 to 11 hours.
    2) EFAVIRENZ: Moderate absorption (40%), peak concentrations 3 to 5 hours; highly protein bound (99%); volume of distribution 2 to 4 L/kg; hepatic metabolism; excretion approximately 65% fecal and 35% urinary elimination; half-life 52 to 76 hours.
    3) ETRAVIRINE: Highly protein bound (99%); hepatic metabolism and fecal elimination; half-life 41 hours.
    4) NEVIRAPINE: Bioavailability 90%, peak concentration 2 to 4 hours; protein binding 60%; extensive hepatic metabolism with 80% renal and 10% fecal elimination of metabolites; half-life 25 to 30 hours.
    J) TOXICOKINETICS
    1) No data are available regarding toxicokinetics; however, little difference in drug half-lives is expected in overdose since the drugs are almost entirely hepatically cleared by CYP isoforms that are not saturable.
    K) DIFFERENTIAL DIAGNOSIS
    1) Other etiologies of hepatic failure (ie, acetaminophen, iron, carbon tetrachloride, etc.) should be considered. Medical etiologies (ie, portal vein thrombosis, viral hepatitis, hepatic abscess, or Budd-Chiari malformation) should be ruled out in cases of adverse drug effect.

Range Of Toxicity

    A) OVERDOSE: A full month supply of many of these agents has been ingested in overdose without clinical effects, although toxicity can occur at therapeutic doses with all non-nucleoside reverse transcriptase inhibitors (NNRTIs). ADULT: Psychomotor agitation developed after 15.6 grams and 54 grams efavirenz in adults. PEDIATRIC: An ingestion of 200 mg of nevirapine (40 times the recommended dose of 2 mg/kg/day) instead of the prescribed 200 mg of nelfinavir in an 8-day-old infant resulted in mild transient neutropenia and hyperlactatemia.
    B) THERAPEUTIC DOSE: DELAVIRDINE: ADULT: 400 mg three times daily. PEDIATRIC (age 16 years or older): 400 mg three times daily. EFAVIRENZ: ADULT: 600 mg/day. PEDIATRIC: 10 kg to less than 15 kg: 200 mg/day; 15 kg to less than 20 kg: 250 mg/day; 20 kg to less than 25 kg: 300 mg/day; 25 kg to less than 32.5 kg: 350 mg/day; 32.5 kg to less than 40 kg: 400 mg/day; 40 kg or more: 600 mg/day. ETRAVIRINE: ADULT: 200 mg twice daily. NEVIRAPINE: ADULT: 200 mg twice daily. PEDIATRIC: 150 mg/m(2) twice daily (Max: 400 mg/day).

Clinical Effects

Summary Of Exposure

    A) USES: The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are used in the treatment of HIV-1 infection. This class includes etravirine, delavirdine mesylate, efavirenz, nevirapine, and rilpivirine.
    B) PHARMACOLOGY: NNRTIs bind adjacent to the active site of HIV-1 reverse transcriptase causing conformational change and thus inactivation of the enzyme.
    C) TOXICOLOGY: Toxicological effects are generally extensions of adverse effects.
    D) EPIDEMIOLOGY: Overdose is uncommon and severe sequelae from acute overdose is rare. Adverse effects and drug interactions, however, are common.
    E) WITH THERAPEUTIC USE
    1) COMMON: Headache, dizziness, transaminitis, rash, nausea, vomiting, diarrhea, paresthesias, psychiatric disturbances, and hyperlipidemia are the most commonly reported adverse effects.
    2) Other adverse effects specific to each drug include: DELAVIRDINE: rash (36%), hepatitis (rare), Stevens-Johnson syndrome (rare), neutropenia (rare). EFAVIRENZ: headache, dizziness, impaired concentration, abnormal dreams, or other CNS/psychiatric disturbances (52%), rash (27%), transaminitis, fever, hyperlipidemia. ETRAVIRINE: rash, peripheral neuropathy, toxic epidermal necrolysis (rare), hepatitis (rare). NEVIRAPINE: rash (7%), pruritus, hepatitis (1%), Stevens-Johnson syndrome (0.3%), fever. Hypersensitivity syndrome (HHS) has been described approximately 4 weeks following the therapeutic use of nevirapine. Generalized maculopapular rash, eosinophilia, enlarged lymph nodes, fever, and hepatosplenomegaly developed.
    3) DRUG INTERACTIONS: DELAVIRDINE: A CYP3A4 substrate and inhibitor and a CYP2C9 inhibitor; carbamazepine, phenobarbital, rifampin, and phenytoin may decrease delavirdine concentrations; may increase plasma concentrations of other CYP3A4 substrates. EFAVIRENZ: A CYP3A4 substrate and inducer, and a CYP2B6 substrate; may decrease phenobarbital, phenytoin, carbamazepine, and methadone concentrations; may cause false positive tetrahydrocannabinol tests. ETRAVIRINE: A CYP3A4 substrate and inducer, a CYP2C9 substrate and inhibitor, and a CYP2C19 substrate and inhibitor; may increase the INR when administered with warfarin; may decrease etravirine concentrations when administered with phenytoin, carbamazepine, or phenobarbital; may increase digoxin concentrations. NEVIRAPINE: A CYP3A4 substrate and inducer, and a CYP2B6 substrate; may cause methadone withdrawal; may decrease plasma concentrations of oral contraceptives; may decrease ketoconazole concentrations; administration with rifampin may decrease nevirapine concentrations.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: The majority of patients will have minimal or no symptoms following overdose. Mild transaminitis may occur in the setting of overdose. Psychiatric disturbances characterized by mania, agitation, and sometimes somnolence have been observed in overdose. Abdominal pain, nausea, and vomiting have been reported. Transient mild neutropenia and hyperlactemia developed in an infant after intravenous overdose.

Vital Signs

    3.3.3) TEMPERATURE
    A) FEVER: Up to 40% of patients receiving nevirapine monotherapy developed fever with no apparent dose relationship (Cheeseman et al, 1995) . Fever was also reported in 21% of pediatric patients who received efavirenz therapy in combination with other antiretroviral agents (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2007).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) EFAVIRENZ: An HIV-positive male developed BILATERAL MACULOPATHY while on efavirenz. He experienced impaired vision in both eyes, without any other symptoms, 3 months after starting efavirenz, lamivudine, and zidovudine. Despite discontinuation of efavirenz his visual acuity worsened. Serological tests, including cytomegalovirus, were negative. The macular lesion remained unchanged and at 5 months post-discontinuation of efavirenz his vision was limited to hand movements in the left eye (Curi et al, 2001).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) NEVIRAPINE
    1) Somnolence, fatigue and headache have been among the most common adverse effects of nevirapine in clinical trials (Cheeseman et al, 1995; Cheeseman et al, 1993). Other less frequent adverse effects have included irritability and confusion (Cheeseman et al, 1993). These effects do not appear to be dose-related.
    2) In a phase I/II clinical trial, somnolence and/or fatigue occurred in 63% of patients receiving nevirapine 12.5 to 200 mg daily as monotherapy. Dose reduction was necessary in 2% of these patients (Cheeseman et al, 1995).
    b) EFAVIRENZ
    1) In efavirenz pre-marketing clinical trials, 53% of patients reported central nervous system effects, including somnolence, dizziness, confusion, abnormal dreaming, agitation, amnesia, agitation, hallucinations, and euphoria (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2007). Elevated efavirenz plasma levels (greater than 4000 mcg/L) have been associated with an increased frequency of CNS adverse effects (light-headedness, confusion, hallucinations, dizziness, faintness, drunkenness, and restlessness) (Nijhawan et al, 2008; Marzolini et al, 2001).
    c) DELAVIRDINE
    1) Headache and fatigue occurred in approximately 11% to 16% of HIV-infected patients administered delavirdine in trials using combination therapy (Prod Info RESCRIPTOR(R) oral tablets, 2006).
    B) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) EFAVIRENZ
    1) CASE REPORT: An intentional overdose of 90 efavirenz tablets resulted in a manic syndrome, with psychomotor agitation, irritability, expansiveness, disinhibition, and aggressiveness in a 33-year-old woman with asymptomatic HIV infection. Antiretroviral medication (abacavir, nelfinavir, and efavirenz) had been started just 3 days prior to the overdose. Following discontinuation of efavirenz along with antipsychotic therapy with risperidone, the patient had a rapid recovery within 48 hours and full remission of symptoms within 5 days (Blanch et al, 2001).
    2) CASE REPORT: A 17-year-old woman ingested 15.6 grams efavirenz and 3.9 grams lamivudine. She developed agitation, somnolence, and described feeling "high, alienated, with artificial visual impressions" but denied hallucinations. Gait was clumsy. She had wild, bizarre dreams that persisted for 5 days(Boscacci et al, 2006).
    b) LACK OF EFFECT
    1) NEVIRAPINE does not produce muscarinic or benzodiazepine-like effects (Merluzzi et al, 1990).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) EFAVIRENZ
    1) CASE REPORT: A 45-year-old woman, with a history of HIV and cirrhosis, experienced generalized weakness, confusion, and generalized tonic-clonic seizures that progressed to status epilepticus approximately 4 months after beginning an anti-retroviral drug regimen that included tenofovir, emtricitabine, efavirenz, ritonavir-boosted tipranavir, and enfuvirtide. At this time, the patient was also experiencing dysphagia, dysarthria, insomnia, hallucinations, and paranoia. Laboratory analysis, obtained approximately 12 hours post-dose, revealed a plasma efavirenz concentration of 29,440 mg/L (reference range 1200 to 7000 mg/L). The antiretroviral regimen was discontinued and her mental status improved. Several days after restarting the drug regimen, with the dosage of efavirenz lowered, the hallucinations and insomnia recurred. Cessation of the efavirenz again resolved the patient's symptoms, including the seizures, confusion, and hallucinations (Nijhawan et al, 2008).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) DELAVIRDINE: Nausea, diarrhea, and vomiting have frequently occurred with delavirdine therapy during clinical trials (Prod Info RESCRIPTOR(R) oral tablets, 2006)
    b) EFAVIRENZ: Nausea, vomiting and diarrhea are commonly reported adverse effects of efavirenz in clinical trials (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2007).
    c) ETRAVIRINE: Nausea was one of the most commonly reported adverse events occurring in 13.9% of etravirine-treated patients (n=599) compared with 11.1% in placebo (n=604), according to pooled data from 2 randomized, double-blind, placebo-controlled, phase 3 clinical trials of HIV-1 infected patients. Patients received either etravirine 200 mg orally twice daily plus background regimen (darunavir/ritonavir plus 2 others antiretroviral drugs) for a median duration of 30 weeks, or placebo plus background regimen for a median duration of 29.1 weeks (Prod Info INTELENCE(TM) oral tablets, 2008).
    d) NEVIRAPINE: Nausea and diarrhea have been reported during clinical trials in 37% and 20% of nevirapine-treated patients, respectively, and were not dose-related (Cheeseman et al, 1995). .
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old developed lower abdominal pain and then began vomiting 5 hours after ingesting lamivudine 3.9 grams and efavirenz 15.6 grams. The following day she developed diarrhea (Boscacci et al, 2006).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) NEVIRAPINE
    1) Increases in serum GGT levels have been reported more frequently in nevirapine-treated patients than in controls. 10% of HIV-infected patients treated with nevirapine have been reported to experience significant elevations (5 times the upper limit of normal) of gamma-glutamyl transferase (GGT) in the absence of other liver function abnormalities. This was more prevalent at higher doses (Cheeseman et al, 1995). Piroth et al (2000) reported cholestatic toxic hepatitis in a patient 5 weeks after nevirapine was started (Piroth et al, 2000). Prakash et al (2001) reported 4 patients with reversible icteric hepatitis, which occurred 4-6 weeks after starting nevirapine therapy; liver function tests returned to normal 4-6 weeks after discontinuation of nevirapine (Prakash et al, 2001).
    a) Thirty non-HIV infected individuals developed hepatotoxicity a median of 20.5 days following initiation of single-agent nevirapine therapy (n=8) or a nevirapine-containing postexposure prophylaxis (PEP) regimen (n=22). After discontinuation of therapy, all but 2 improved in 14 to 60 days. Hepatotoxicity persisted for 2 months in 1 health care worker who had received a nevirapine-containing PEP. The hepatotoxicity resolved 2 months after a course of corticosteroids was initiated. Fulminant hepatic necrosis and coma developed in 1 health care worker. This individual required a liver transplant 14 days after discontinuation of a nevirapine-containing PEP. None of the 30 patients developed hepatitis C infection or a positive serologic test for HIV (Patel et al, 2004).
    b) Higher nevirapine plasma levels and hepatitis C virus infection have been found to be independent predictors of liver toxicity, with nevirapine plasma concentrations >6 mcg/mL associated with a 92% risk of liver toxicity in patients with chronic hepatitis C (Gonzalez de Requena et al, 2002).
    c) The manufacturer of nevirapine has issued a warning in its product information concerning severe, life-threatening, and in some cases fatal hepatotoxicity, in patients treated with nevirapine. Liver toxicity has included fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure (Anon, 2001; (Prod Info VIRAMUNE(R) oral tablets, suspension, 2007). In 10 patients treated with nevirapine, the median time from initiation of therapy to first abnormal liver function tests was 21 days (Anon, 2001).
    2) CASE REPORT: Severe hepatic failure was reported in a 61-year-old HIV-infected male 15 days after the addition of nevirapine to his antiretroviral therapy. Serum liver enzymes and prothrombin time were elevated, ascites and rash were present, and eosinophilia was reported. Within 2 weeks of drug discontinuation, symptoms abated (Cattelan et al, 1999).
    3) CASE SERIES: Severe hepatotoxicity occurred in 9 of 82 patients who were co-infected with human immunodeficiency virus/hepatitis C virus (HIV/HCV) and who were taking nelfinavir as part of their antiretroviral regimen. Four of the 9 patients who developed severe hepatotoxicity while on the nelfinavir-containing regimen were also taking nevirapine. Concomitant administration of other antiretroviral drugs was not associated with severe hepatotoxicity. The median time from beginning nelfinavir to the hepatotoxicity diagnosis was 6 months; however, the median time from beginning nevirapine therapy to the hepatotoxicity diagnosis was 3.4 months. The serum ALT levels improved in 2 patients following discontinuation of nevirapine therapy. A multivariate analysis demonstrated that only nevirapine use was independently associated with an increase risk for severe hepatotoxicity during nelfinavir therapy (adjusted odds ratio 8.9; 95% CI 1.4-54.1; p=0.01) (Mira et al, 2006).
    4) CASE REPORT: A case of nevirapine-induced prolonged hepatotoxicity 5 months after starting HAART therapy has been reported. Laboratory tests showed parenchymal damage; biopsy showed profound cholestasis and mild sinusoidal fibrosis. Liver function returned to normal following 3 months of supportive therapy (Clarke et al, 2000).
    b) EFAVIRENZ
    1) Elevated AST and ALT levels, 5 times the upper limit of normal, have ranged in clinical trials from 5% to 8% and 2% to 8% of patients, respectively (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2007). Piroth et al (2000) reported efavirenz-induced hepatotoxicity within 2 weeks of starting therapy in an adult. Liver function returned to normal within 2 months of stopping therapy (Piroth et al, 2000).
    c) DELAVIRDINE
    1) Elevated ALT and AST levels were reported with delavirdine therapy in combination with administration of other antiretroviral agents during clinical trials, ranging from 4% to 5% and 2% to 3% of patients, respectively (Prod Info RESCRIPTOR(R) oral tablets, 2006). Delavirdine is metabolized primarily by the liver, thus caution should be exercised when administering this drug to a patient with impaired hepatic function.
    B) ACUTE HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) EFAVIRENZ
    1) CASE REPORT: A 9-year-old boy with HIV developed acute liver failure, requiring liver transplantation, approximately 13 weeks after beginning antiretroviral therapy (ART) that included zidovudine, lamivudine, and efavirenz. Efavirenz trough level was 2.43 mg/L (therapeutic range 1 to 4 mg/L). ART was discontinued and the patient underwent his first liver transplantation. Approximately 19 days later, a second transplantation was performed due to chronic rejection and severe liver dysfunction. Following exclusion of all common causes of acute liver failure, efavirenz was suspected of being the causative agent. Approximately 6 months after transplantation, the patient's ART was restarted, with raltegravir substituted for efavirenz. The patient's condition was stable with persistent elevated liver enzyme concentrations due to mild graft dysfunction (Turkova et al, 2009).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDEMIA
    1) WITH POISONING/EXPOSURE
    a) NEVIRAPINE
    1) CASE REPORT: An 8-day-old infant, born to a mother with HIV, developed mild transient neutropenia (nadir 1705/mm(3)) and hyperlactatemia (2.4 mmol/L) after inadvertently receiving 200 mg of nevirapine (40 times the recommended dose of 2 mg/kg/day) instead of the prescribed 200 mg of nelfinavir. Thirty hours after administration, the patient's plasma nevirapine level was 11.2 mcg/mL (therapeutic adult level: 3 to 8 mcg/mL). Within 1 week following intoxication, the patient spontaneously recovered without sequelae (Brasme et al, 2008).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BONE MARROW FINDING
    1) WITH POISONING/EXPOSURE
    a) LACK OF EFFECT
    1) NEVIRAPINE has been shown to be less toxic to progenitor cells than zidovudine or didanosine. It is not immunosuppressive. At concentrations up to 37.5 mcmol/L, nevirapine was not cytotoxic to human bone marrow progenitors including erythroid burst-forming colonies and colony-forming units of granulocyte, macrophage megakaryocyte, erythroid and granulocyte macrophage (Merluzzi et al, 1990a).
    B) NEUTROPENIA
    1) WITH POISONING/EXPOSURE
    a) NEVIRAPINE
    1) CASE REPORT: An 8-day-old infant, born to a mother with HIV, developed mild transient neutropenia (nadir 1705/mm(3)) and hyperlactatemia (2.4 mmol/L) after inadvertently receiving 200 mg of nevirapine (40 times the recommended dose of 2 mg/kg/day) instead of the prescribed 200 mg of nelfinavir. Thirty hours after administration, the patient's plasma nevirapine level was 11.2 mcg/mL (therapeutic adult level: 3 to 8 mcg/mL). Within 1 week following intoxication, the patient spontaneously recovered without sequelae (Brasme et al, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) DELAVIRDINE
    1) Skin rash due to delavirdine therapy is common. In combination therapies in pre-marketing clinical trials, 35% of patients who received delavirdine 400 mg 3 times daily experienced rashes. Typically, the rash was diffuse, maculopapular, erythematous, and often pruritic. Patients with lower CD4 cell counts developed rash more commonly, with rash usually occurring within 1 to 3 weeks of treatment. Generally, the rash duration was less than 2 weeks and did not require dose reduction or discontinuation (Prod Info RESCRIPTOR(R) oral tablets, 2006).
    b) EFAVIRENZ
    1) Maculopapular skin eruptions, occurring within the first 2 weeks of efavirenz therapy, have been reported as a common adverse effect in clinical trials (26% of patients). Rashes in children appear more frequently and are more severe. The rash generally resolves within 1 month while continuing efavirenz therapy (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2007).
    c) ETRAVIRINE
    1) Rash of any type was one of the most commonly reported adverse events occurring in 16.9% of etravirine-treated patients (n=599) compared with 9.3% in placebo (n=604), according to pooled data from 2 randomized, double-blind, placebo-controlled, phase 3 clinical trials of HIV-1 infected patients. Patients received either etravirine 200 mg orally twice daily plus background regimen (darunavir/ritonavir plus 2 others antiretroviral drugs) for a median duration of 30 weeks, or placebo plus background regimen for a median duration of 29.1 weeks. Rash was generally mild to moderate occurring mostly during the second week of therapy (infrequent after week 4) and in most cases resolved within 1 to 2 weeks on continued therapy. In the etravirine group, rash was seen in higher incidences in female patients compared with men. A history of non-nucleoside reverse transcriptase inhibitor (NNRTI)-induced rash did not increase the risk of rash in patients receiving etravirine. Discontinuation of etravirine therapy due to rash during the phase 3 trials occurred in 2% of patients (Prod Info INTELENCE(TM) oral tablets, 2008).
    d) NEVIRAPINE
    1) Cheeseman et al (1995) reported a 27% incidence of skin rashes in patients receiving nevirapine monotherapy (12.5 to 200 mg daily) (Cheeseman et al, 1995). Mirochnick et al (2000) reported an incidence of nevirapine-induced rashes of 17% in adults, which usually develops within 6 weeks of starting therapy. The rash is generally an erythematous maculopapular eruption of mild to moderate severity (Mirochnick et al, 2000).
    2) In a study of 199 patients receiving combination therapy of nevirapine, zidovudine and didanosine, significant rashes developed in 17 (9%) of patients, after a median of 4 weeks of therapy. In 6 of these patients, the rashes were considered to be severe or life-threatening, warranting discontinuation of therapy (D'Aquila et al, 1996). In a group of 199 patients receiving zidovudine/didanosine therapy alone, rash developed in 3 (2%) patients.
    3) A significantly higher incidence of rash (48%) was reported with doses of 400 mg once daily as monotherapy in clinical trials (Cheeseman et al, 1995).
    4) Most of the nevirapine-induced rashes are mild to moderate and are maculopapular erythematous cutaneous eruptions occurring over the trunk, face and extremities. Several cases of Stevens Johnson Syndrome have been reported (Prod Info VIRAMUNE(R) oral tablets, suspension, 2007). Median onset of rash due to nevirapine therapy in 14 cases was 9 days following initiation of therapy (Anon, 2001).
    5) Twelve non-HIV infected individuals developed nevirapine-associated grade 3 or 4 cutaneous toxicity without hepatic involvement a median of 9 days after initiation of a nevirapine-containing postexposure regimen. Three developed Stevens-Johnson syndrome; 4 patients were hospitalized. All rapidly improved after discontinuation of nevirapine (Patel et al, 2004).
    2) WITH POISONING/EXPOSURE
    a) EFAVIRENZ
    1) CASE REPORT: A 17-year-old developed a generalized, pruritic, maculopapular rash 1 day after ingesting lamivudine 3.9 grams and efavirenz 15.6 grams (Boscacci et al, 2006).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) NEVIRAPINE
    1) Stevens-Johnson syndrome has been reported with nevirapine, efavirenz, and delavirdine therapies, but is an uncommon adverse effect. Out of 14 reports of skin rash due to nevirapine, 1 documented and 2 possible cases of Stevens-Johnson syndrome were reported (Anon, 2001). A case-crossover analysis of patients on antiretroviral showed nevirapine to be the only antiretroviral agent significantly associated with an increased risk of Stevens-Johnson syndrome or toxic epidermal necrolysis (Fagot et al, 2001).
    2) CASE REPORT: A case of probable nevirapine-associated Stevens Johnson syndrome was reported in a 30-year-old male 10 days after starting zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and nevirapine 200 mg per day. The patient presented with oral ulcers, subconjunctival hemorrhages, and tender, erythematous, target-like lesions on his trunk, palms and soles. All medications were stopped. He was discharged 12 days after admission, and no re-challenge with any of the drugs was attempted (Warren et al, 1998).
    3) CASE REPORT: Weiterwald et al (1999) reported 2 cases of nevirapine-induced overlapped Stevens-Johnson syndrome and toxic epidermal necrolysis, occurring 13 and 25 days, respectively, after starting nevirapine therapy. The patients recovered in 2 weeks and 1 month, respectively, following discontinuation of nevirapine. Skin biopsies confirmed the diagnoses (Weiterwald et al, 1999).
    4) CASE REPORTS: Three non-HIV infected individuals who received a nevirapine-containing postexposure prophylaxis regimen developed Stevens-Johnson syndrome at a median of 9 days after initiation of therapy. All 3 rapidly improved after discontinuation of therapy (Patel et al, 2004).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) ETRAVIRINE
    1) Elevated glucose levels, grades 2 and 3 were reported in 13.1% (grade 2), 2.5% (grade 3) and 0% (grade 4) of etravirine-treated patients (n=599) compared with 10.8% (grade 2), 1.8% (grade 3), and 0.2% (grade 4) in placebo (n=604), according to pooled data from 2 randomized, double-blind, placebo-controlled, phase 3 clinical trials of HIV-1 infected patients. Patients received either etravirine 200 mg orally twice daily plus background regimen (darunavir/ritonavir plus 2 others antiretroviral drugs) for a median duration of 30 weeks, or placebo plus background regimen for a median duration of 29.1 weeks (Prod Info INTELENCE(TM) oral tablets, 2008).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) NEVIRAPINE
    1) Hypersensitivity syndrome (HHS) has been described approximately 4 weeks following the therapeutic use of nevirapine. Generalized maculopapular rash, eosinophilia, enlarged lymph nodes, fever, and hepatosplenomegaly developed. Following symptomatic therapy and discontinuation of nevirapine, symptoms resolved (Bourezane et al, 1998). Soriano et al (2000) report that cross-sensitivity between nevirapine and efavirenz is minor since their molecular structure is not related. Thus, efavirenz can be safely administered to patients with a past history of hypersensitivity reactions to nevirapine (Soriano et al, 2000).

Reproductive

    3.20.1) SUMMARY
    A) Etravirine, nevirapine, rilpivirine, and emtricitabine/rilpivirine/tenofovir are classified as FDA pregnancy category B, delavirdine is classified as FDA pregnancy category C, and efavirenz and efavirenz/emtricitabine/tenofovir are classified as FDA pregnancy category D. In animal studies, teratogenicity was not observed with etravirine, nevirapine, or rilpivirine; however, malformations (anencephaly, unilateral anophthalmia, microphthalmia, and cleft palate) have been demonstrated with efavirenz use in monkeys and ventricular septal defects have been reported with delavirdine use in rats. In humans, there have been reports of neural tube defects, one report of ventricular septal defect, placental transfer, maternal hepatotoxicity, and ectopic pregnancies with some of these agents. In animal studies, delavirdine and efavirenz were secreted into the milk of lactating rats. Nevirapine is considered the preferred NNRTI in pregnant women receiving combination antiretroviral therapy (ART). However, initiation of nevirapine therapy in pregnant women with CD4 cell counts greater than 250 cells/mm(3) should be considered only if the benefits clearly outweigh the risks for potentially life-threatening hepatotoxicity and nevirapine has been shown to be excreted in human breast milk.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) EFAVIRENZ
    a) In a meta-analysis of 19 studies involving 1437 live-born infants to women with first trimester exposure to efavirenz, the prevalence of birth defects (primary outcome) ranged from 0% to 22.6%, with a pooled prevalence of 2%. One case of neural tube defect (myelomeningocele) was reported, yielding an incidence of 0.07%. There were 11 studies that reported 38 birth defects among 1290 live births in women receiving first trimester efavirenz compared with 316 defects reported among 8122 live births in women receiving non-efavirenz-containing regimens. Among secondary outcomes, the prevalence of spontaneous abortion was 0% to 16.05% and the prevalence of stillbirths was 0% to 13.3% (data from 8 studies) (Ford et al, 2011).
    b) As of January 2012, the Antiretroviral Pregnancy Registry has received reports of birth defects in 18 of the 679 live births with first-trimester exposure to efavirenz. First-trimester exposure resulted in a neural tube defect in 1 case and anophthalmia, including severe oblique facial clefts and amniotic banding, in another case. CNS defects, including meningomyelocele, were reported in 6 retrospective cases; all were cases of first-trimester exposure (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
    c) In a retrospective, population-based study of children born to mothers with HIV, first-trimester efavirenz exposure was associated with an increased prevalence of birth defects. Overall, 15.6% of infants with first-trimester exposure to efavirenz (5 of 32) were diagnosed with a birth defect in the first year of life (1 case each for laryngomalacia, meningomyelocele with Arnold-Chiari Malformation Type II, hypospadias, varus feet and hypertonicity of extremities, and cleft palate). All 5 mothers were also receiving lamivudine plus other antiretroviral agents. However, birth defect prevalence was not associated with overall antiretroviral exposure or HIV infection status. The one case of neural tube defect was reported to the US Antiretroviral Pregnancy Registry (Brogly et al, 2010).
    2) NEVIRAPINE
    a) Two case reports describe HIV-positive women treated with combination antiretroviral therapy who unexpectedly conceived and whose fetuses progressively developed spinal malformations. The first woman's regimen included zidovudine, zalcitabine, and cotrimoxazole. At week 32 of gestation, a fetal ultrasound revealed hemivertebrae in the lumbar spine. A viable infant was delivered at term with a bony mass present in the lumbar spine but no neurological abnormalities. The second woman's medications included didanosine, stavudine, nevirapine, and cotrimoxazole. A fetal ultrasound performed at week 19 of gestation was significant for spina bifida and ventriculomegaly and the pregnancy was electively terminated (Richardson et al, 2000).
    B) VENTRICULAR SEPTAL DEFECTS
    1) DELAVIRDINE
    a) In premarketing clinical trials and postmarketing surveillance of delavirdine, 8 out of 10 infants (including 1 set of twins) born from 9 pregnancies were healthy. Of the remaining 2 infants, one was HIV-positive, but had no congenital anomalies and was otherwise healthy. The other infant was premature (at 34 to 35 weeks of gestation) and had a small muscular ventricular septal defect, which spontaneously resolved. In this case, the mother had been exposed to delavirdine and zidovudine for about 6 weeks early in the pregnancy (Prod Info RESCRIPTOR(R) oral tablets, 2008).
    C) LACK OF EFFECT
    1) EFAVIRENZ
    a) A systematic review comparing the risk of congenital anomalies with efavirenz exposure with other antiretroviral exposure during the first trimester of pregnancy reported congenital anomalies and neural tube defects in 1.63% and 0.05% of infants, respectively. The Antiretroviral Pregnancy Registry reports a 2.3% congenital anomaly rate, which is not considered to be statistically significant from the efavirenz population. In a meta-analysis of 12 studies comparing efavirenz and non-efavirenz exposure, there was no significant risk of congenital anomalies observed between the two groups (Ford et al, 2014).
    2) ETRAVIRINE
    a) A case study report describes the pregnancy and births of 4 infants free of maternal, fetal, or neonatal toxicity to 4 HIV-1-infected women, 19 to 42 years of age, receiving antiretroviral therapy, including etravirine, through the third trimester of pregnancy. In addition to etravirine 200 mg twice daily, the women received darunavir/ritonavir and nucleoside reverse transcriptase inhibitors or enfuvirtide. A small accessory auricle on the right ear (polyotia) was observed in one infant who was otherwise normal at birth. Etravirine plasma concentrations for one mother during the third trimester and for her infant at the time of delivery (postpartum cord blood) were 339 and 112 ng/mL respectively. Data available only for 2 mothers and 1 infant showed undetectable viral loads at the time of delivery (Izurieta et al, 2011).
    b) Two case reports described HIV-positive women treated with combination antiretroviral therapy (including etravirine 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).
    3) NEVIRAPINE
    a) There have been sufficient numbers of first trimester exposures to nevirapine to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of birth defects in the more common classes, cardiovascular, and genitourinary systems. 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 nevirapine use was 2.7% (28 of 1020 births; 95% confidence interval, 1.8% to 4%) 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 phase 1 study designed to evaluate the safety and pharmacokinetics of nevirapine reported no adverse effects in the infected women or their infants. A single 200-mg dose was administered at the onset of labor and as a single 2-mg/kg dose to the infant 48 to 72 hours after birth (Mirochnick et al, 1998).
    D) ANIMAL STUDIES
    1) DELAVIRDINE
    a) In animals treated with delavirdine doses of at least 50 mg/kg/day during the period of organogenesis, ventricular septal defects were reported (Prod Info RESCRIPTOR(R) oral tablets, 2008).
    b) In animals administered delavirdine doses approximately 6-fold higher than the recommended human exposure during the period of organogenesis, malformations were not evident. However, as a result of maternal and embryo death, only a limited number of fetuses were available for analysis (Prod Info RESCRIPTOR(R) oral tablets, 2008).
    2) EFAVIRENZ
    a) In animals treated with efavirenz approximately 1.3 times the recommended human dose compared with those in a control group (n=20), malformations, including anencephaly and unilateral anophthalmia in one fetus, microphthalmia in another, and cleft palate in a third fetus, were observed in 3 of the efavirenz-treated animals compared with none of the control group monkeys (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2015).
    3) ETRAVIRINE
    a) In studies in animals, systemic exposures equivalent to those achieved with the recommended human dose of 400 mg/day showed no evidence of fetal harm (Prod Info INTELENCE(R) oral tablets, 2010).
    4) NEVIRAPINE
    a) In animals treated with nevirapine at doses up to approximately 50% higher than the recommended human daily dose, no teratogenicity was observed (Prod Info Viramune(R) oral tablets oral suspension, 2010).
    5) RILPIVIRINE
    a) In animal studies, no adverse effects were observed at rilpivirine doses up to 70 times the recommended daily dose for humans (Prod Info ODEFSEY(R) oral tablets, 2016; Prod Info EDURANT(R) oral tablets, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) EFAVIRENZ
    1) RISK SUMMARY
    a) Efavirenz should not be used during the first trimester of pregnancy (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2015).
    b) PREGNANCY REGISTRY
    1) Physicians may register patients inadvertently exposed to efavirenz during pregnancy in an Antiretroviral Pregnancy Registry to monitor maternal-fetal outcomes (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2015).
    2) MATERNAL ADVERSE REACTION
    a) CASE REPORT: A case of 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 5 months after delivery of a viable infant (Hill et al, 2001).
    B) PREGNANCY CATEGORY
    1) DELAVIRDINE
    a) Delavirdine has been classified as FDA pregnancy category C (Prod Info RESCRIPTOR(R) oral tablets, 2008).
    2) EFAVIRENZ/EMTRICITABINE/TENOFOVIR
    a) Efavirenz/emtricitabine/tenofovir has been classified as FDA pregnancy category D (Prod Info ATRIPLA(R) oral tablets, 2010).
    3) EMTRICITABINE/RILPIVIRINE/TENOFOVIR
    a) Emtricitabine/rilpivirine/tenofovir has been classified as FDA pregnancy category B (Prod Info COMPLERA(TM) oral tablets, 2011).
    4) ETRAVIRINE
    a) Etravirine has been classified as FDA pregnancy category B (Prod Info INTELENCE(R) oral tablets, 2010).
    5) NEVIRAPINE
    a) Nevirapine has been classified as FDA pregnancy category B (Prod Info Viramune(R) oral tablets oral suspension, 2010).
    6) RILPIVIRINE
    a) Rilpivirine has been classified as FDA pregnancy category B (Prod Info EDURANT(R) oral tablets, 2011).
    7) There are no adequate and well-controlled studies with delavirdine, efavirenz/emtricitabine/tenofovir, emtricitabine/rilpivirine/tenofovir etravirine, nevirapine, or rilpivirine in pregnant women. An Antiretroviral Pregnancy Registry has been established, and prescribers can register patients by calling 1-800-258-4263 (Prod Info ODEFSEY(R) oral tablets, 2016; Prod Info SUSTIVA(R) oral capsules, tablets, 2011; Prod Info ATRIPLA(R) oral tablets, 2010; Prod Info INTELENCE(R) oral tablets, 2010; Prod Info RESCRIPTOR(R) oral tablets, 2008; Prod Info Viramune(R) oral tablets oral suspension, 2010; Prod Info EDURANT(R) oral tablets, 2011). Delavirdine is no longer available in the United States. Efavirenz may cause fetal harm when given to pregnant women during the first trimester and should therefore be avoided in the first trimester. However, in general, women who are receiving combination ART for HIV infection when pregnancy is discovered should continue their regimen while being monitored for complications and toxicities (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
    8) Nevirapine is considered the preferred NNRTI in pregnant women receiving combination antiretroviral therapy (ART). However, initiation of nevirapine therapy in pregnant women with CD4 cell counts greater than 250 cells/mm(3) should be considered only if the benefits clearly outweigh the risks for potentially life-threatening hepatotoxicity (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
    9) A meta-analysis of 2123 pregnant women infected with HIV 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 untreated women; 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, 2002).
    C) PLACENTAL BARRIER
    1) ETRAVIRINE
    a) Transplacental transfer of etravirine was documented in a 38-year-old HIV-1-positive African woman with multi-class HIV resistance who received a change in antiretroviral therapy (ART) at 6 weeks of a twin pregnancy. To minimize the risk of mother-to-child transmission, her current ART of tenofovir/emtricitabine and boosted atazanavir was changed at 25 weeks' gestation to darunavir 600 mg twice daily plus ritonavir 100 mg twice daily along with etravirine 200 mg twice daily and enfuvirtide 90 mg subQ twice daily with tenofovir 245 mg/emtricitabine 200 mg once daily as optimized background therapy. At 34 weeks' gestation, a healthy baby boy and girl were delivered via Caesarean section; notably, instead of standard prophylaxis with zidovudine or nevirapine, the mother was administered an extra dose of antiretrovirals 2.5 hours before the C-section. Cord blood analysis from twin 1 and twin 2 revealed significant levels of darunavir (577 and 1020 nanograms (ng)/mL, respectively) and etravirine (414 and 345 ng/mL, respectively), but not enfuvirtide (undetectable in both); ritonavir cord levels were 25.7 and 123 ng/mL, respectively. The twins were HIV-negative at 4 months of age (Furco et al, 2009).
    2) NEVIRAPINE
    a) When the pregnant mother is treated with a single oral nevirapine dose once labor has been established, the drug rapidly crosses the placenta. Nevirapine has a lengthened half-life in the neonate, with therapeutic plasma concentrations sustained for 7 days and only one additional oral dose given to the neonate after 48 to 72 hours (Taylor et al, 2000; Mirochnick et al, 2000).
    D) HEPATOCELLULAR DAMAGE
    1) NEVIRAPINE
    a) Severe hepatic events, including fatalities, have been reported in pregnant women treated with chronic nevirapine therapy as part of HIV infection combination treatment, particularly in those with CD4 cell counts greater than 250 cells/mm(3). It is not known if pregnancy enhances the risk of hepatotoxicity that is observed in women who are not pregnant (Prod Info Viramune(R) oral tablets oral suspension, 2010; Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
    E) ANIMAL STUDIES
    1) DELAVIRDINE
    a) In animals treated with delavirdine doses of 5 times the recommended human doses, maternal toxicity, embryotoxicity, fetal developmental delay, and reduced pup survival were reported. In animals exposed to delavirdine approximately equal to the expected human exposure on postpartum day 0, reduced pup survival was observed (Prod Info RESCRIPTOR(R) oral tablets, 2008).
    b) In animals administered delavirdine doses approximately 6-fold higher than the recommended human exposure during the period of organogenesis, maternal toxicity, embryotoxicity and abortions were observed. The no-observed-adverse effect dose in pregnant animals was 100 mg/kg/day; systemic exposures were lower in pregnant animals at this dose compared with those expected in humans at the recommended dose. Various malformations were observed at this dose; however, none showed statistical significance (Prod Info RESCRIPTOR(R) oral tablets, 2008).
    2) EFAVIRENZ
    a) 3 malformed fetuses (n=20) that exhibited anencephaly and unilateral anophthalmia (n=1), microophthalmia (n=1), and cleft palate (n=1) developed with efavirenz doses that produced AUC values equal to 1.3 times the human exposure, while no defects developed in the offspring of placebo-treated animals (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2015)
    b) Efavirenz administered during organogenesis or from organogenesis through lactation produced early resorptions and early neonatal mortality. No reproductive toxicity was observed in animals (Prod Info SUSTIVA(R) oral capsules, tablets, 2011).
    3) ETRAVIRINE
    a) In animals treated with doses up to those achieved with the recommended human dose of 400 mg/day showed no effects on embryonic development (Prod Info INTELENCE(R) oral tablets, 2010).
    4) NEVIRAPINE
    a) In animals treated with nevirapine at exposures approximately 50% higher than that seen at the recommended human clinical dose, decreased fetal body weights were observed (Prod Info VIRAMUNE XR oral extended-release tablets, 2012; Prod Info Viramune(R) oral tablets oral suspension, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) EFAVIRENZ
    1) RISK SUMMARY
    a) Breastfeeding should be avoided (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2015).
    B) EMTRICITABINE/RILPIVIRINE/TENOFOVIR ALAFENAMIDE
    1) RISK SUMMARY
    a) Mothers should not breastfeed while taking emtricitabine/rilpivirine/tenofovir alafenamide (Prod Info ODEFSEY(R) oral tablets, 2016).
    C) BREAST MILK
    1) At the time of this review, no data were available to assess the potential effects of exposure to delavirdine, efavirenz, etravirine, or rilpivirine during lactation in humans (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2014; Prod Info ATRIPLA(R) oral tablets, 2010; Prod Info RESCRIPTOR(R) oral tablets, 2008; Prod Info INTELENCE(R) oral tablets, 2010; Prod Info EDURANT(R) oral tablets, 2011). However, due to the risk of postnatal transmission of HIV, the Centers for Disease Control and Prevention does not recommend breastfeeding for HIV-infected mothers, including those who are receiving combination antiretroviral therapy or prophylaxis (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
    2) NEVIRAPINE
    a) Four breast milk samples obtained from 3 nursing mothers during the first postpartum week contained a median concentration of 76% (range, 54% to 104%) of serum concentrations of nevirapine (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012).
    b) In a study of HIV-positive Ugandan pregnant women (n=62), participating in an intervention for the prevention of mother-to-child transmission (PMTCT) of HIV, nevirapine was detectable in breast milk and plasma of mothers and children for 2 to 3 weeks. All women received a 200-mg nevirapine oral tablet within 48 hours prior to delivery; neonates received 2 mg/kg nevirapine syrup within 72 hours of birth. The median CD4 count at delivery was 516 cells/mm(3) and the median HIV-1 viral load was 7433 copies/mL. Breast milk and plasma samples of mothers and children were collected at delivery and 1,2, and 6 weeks after maternal nevirapine intake. Mean nevirapine concentrations at week 1 were 164 nanograms (ng)/mL (maternal plasma), 114 ng/mL (breast milk), and 183 ng/mL (child plasma). The simulations, using a population pharmacokinetic model, predicted total nevirapine concentrations of greater than 10 ng/mL in 80% of the samples for 2 to 3 weeks (13 days in breast milk; 14 days in maternal plasma, and 18 days in child plasma); however, the slowly decreasing concentrations of nevirapine could precipitate the resistance formation. The most recent PMTCT guidelines recommend the additional postnatal treatment of zidovudine/lamivudine for one week to prevent resistance formation. However, because of the long presence of nevirapine concentrations shown in this study, the duration of zidovudine/lamivudine treatment would have to be extended considerably longer that one week. This extension of treatment could increase the risk of nucleoside reverse transcriptase inhibitor-resistant virus selection (Kunz et al, 2009).
    c) In 21 women treated with a 200-mg single dose of nevirapine during labor, the median colostrum/breast milk to maternal plasma nevirapine concentration was 60.5% (range, 25% to 122%) during the first week of life, and the median concentration in breast milk was 103 nanograms (ng)/mL (range, 25 to 309 ng/mL) one week post-delivery (Musoke et al, 1999).
    d) The median breast milk-to-plasma ratio for nevirapine was 0.75 and nevirapine concentrations in infant dried blood spots were 303 nanograms (ng)/mL to 1032 ng/mL in a substudy (n=67 infant-mother pairs) of an open-label clinical trial of pregnant HIV-infected women and their nursing infants. Women received lamivudine 150 mg twice daily, zidovudine 300 mg twice daily, and nevirapine 200 mg once daily for 14 days followed by 200 mg twice daily starting at 34 to 36 weeks of gestation, continuing through labor, and for 6 months postpartum. Mothers were instructed to exclusively breastfeed until 5.5 months at which time they were to start weaning. The median concentration (interquartile range) of nevirapine in infants dried blood spots were 987 ng/mL (790 to 1269 ng/mL), 1032 ng/mL (811 to 1375 ng/mL), 734 ng/mL (560 to 1017 ng/mL), and 303 ng/mL (below the lower limit of quantitation (LLQ) to 444 ng/mL) at 2, 6, 14, and 24-weeks postpartum. The median (interquartile ranges) maternal plasma and breast milk concentrations were 6087 ng/mL (4895 to 7518 ng/mL) and 4546 ng/mL (3480 to 5715 ng/mL), respectively. The breast milk to plasma ratio was 0.75 (0.64 to 0.89). If an infant's intake of breast milk was 150 mL/kg/day, then the median estimated infant dose of nevirapine was 682 micrograms/kg per day (Mirochnick et al, 2009).
    e) Nevirapine has been shown to readily enter breast milk in humans. The amount of drug provided to the nursing infant is small, approximately 0.06 mg/kg on day 2 of life and 0.02 mg/kg on day 7 following administration during labor (Mirochnick et al, 2000).
    D) ANIMAL STUDIES
    1) DELAVIRDINE
    a) In studies of lactating animals, delavirdine was excreted into the breast milk at a concentration of 3 to 5 times that of rat plasma (Prod Info RESCRIPTOR(R) oral tablets, 2008).
    2) EFAVIRENZ
    a) In animal studies, efavirenz was excreted into the breast milk (Prod Info SUSTIVA(R) oral capsules, tablets, 2011).
    3) RILPIVIRINE
    a) In animal studies, rilpivirine was excreted into the breast milk (Prod Info EDURANT(R) oral tablets, 2011). no adverse effects were observed at rilpivirine lactation doses up to 63 times the recommended daily dose for humans (Prod Info ODEFSEY(R) oral tablets, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) DELAVIRDINE
    a) In animals treated with delavirdine doses up to 200 mg/kg/day, fertility was not impaired in male or females treated for 70 days and 14 days prior to mating, respectively (Prod Info RESCRIPTOR(R) oral tablets, 2008).
    2) EFAVIRENZ
    a) In male and female animals, mating and fertility were not impaired and sperm was not affected. Reproductive performance of offspring born to females treated with efavirenz was not affected. Systemic drug exposures achieved in animals were equivalent to or below those achieved in humans given therapeutic efavirenz doses, due to the rapid clearance of efavirenz in animals (Prod Info SUSTIVA(R) oral capsules, tablets, 2011).
    3) ETRAVIRINE
    a) There were no effects on fertility when animals were administered doses up to those achieved with the recommended human dose of 400 mg/day (Prod Info INTELENCE(R) oral tablets, 2010).
    4) NEVIRAPINE
    a) In an animal study, evidence of impaired fertility was seen in females at doses providing systemic exposure approximately equivalent to that attained with the recommended human nevirapine dose based on AUC (Prod Info Viramune(R) oral tablets oral suspension, 2010).
    5) RILPIVIRINE
    a) In animal studies, fertility was unaffected at rilpivirine doses approximately 40 times the recommended daily dose for humans (Prod Info ODEFSEY(R) oral tablets, 2016; Prod Info EDURANT(R) oral tablets, 2011).

Genotoxicity

    A) Nevirapine has not demonstrated mutagenic or clastogenic activity in a number of in vitro and in vivo assays including microbial assays for gene mutation, mammalian cell gene mutation assays, cytogenetic assays using Chinese hamster ovary cell lines and a mouse bone marrow micronucleus assay following oral administration (Prod Info Viramune(R), nevirapine, 2000).
    B) Delavirdine was shown NOT to be mutagenic in the Ames assay, in vitro unscheduled DNA synthesis (UDS) assay, an in vitro cytogenetics (chromosome aberration) assay in human peripheral lymphocytes, a mammalian mutation assay in Chinese hamster ovary cells, and the micronucleus test in mice (Prod Info Rescriptor(R), delavirdine mesylate, 1999).
    C) Efavirenz was NOT mutagenic or genotoxic in both in vitro and in vivo genotoxicity assays which included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese Hamster Ovary cells, chromosomal aberration assays in human peripheral blood lymphocytes or Chinese Hamster Ovary cells, and an in vivo mouse bone marrow micronucleus assay (Prod Info Sustiva(TM), efavirenz, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Measurement of a basic metabolic panel, complete blood count, and liver enzymes should be performed in cases where adverse effects or overdose are suspected.
    B) Right upper quadrant ultrasound should be considered to evaluate for alternative etiologies of transaminitis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum electrolytes should be monitored in all HIV non-nucleoside overdose cases due to possible dehydration from extensive diarrhea.
    2) These agents may cause hepatotoxicity. Monitor liver function tests in patients with significant exposures.
    4.1.3) URINE
    A) SPECIFIC AGENT
    1) Efavirenz has been reported to result in false positive urine cannabinoid test results with the CEDIA DAU Multi-Level THC assay in human volunteers (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2007).
    4.1.4) OTHER
    A) OTHER
    1) DERMAL
    a) These agents may cause skin toxicities, including Stevens Johnson Syndrome. Monitor for skin reactions such as a maculopapular rash.
    2) ULTRASOUND
    a) Right upper quadrant ultrasound should be considered to evaluate for alternative etiologies of transaminitis.

Methods

    A) CHROMATOGRAPHY
    1) Cheeseman et al (1993) describe a high-pressure liquid chromatography (HPLC) method to measure plasma concentrations of nevirapine for pharmacokinetic studies and Fiske et al (1998) describe HPLC for measurement of efavirenz in serum (Cheeseman et al, 1993a).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe toxicity should be admitted. Patients with Stevens-Johnson syndrome or hepatic failure should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Suicidal patients should be referred to a health care facility. Asymptomatic patients with inadvertent ingestions of NNRTIs can be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Infectious disease should be consulted if a change to anti-retroviral therapy is indicated. Hepatic failure should prompt consultation with a transplant center.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Asymptomatic or mildly symptomatic patients should be observed for 4 to 6 hours, primarily monitoring signs of coingestant toxicity.

Monitoring

    A) Measurement of a basic metabolic panel, complete blood count, and liver enzymes should be performed in cases where adverse effects or overdose are suspected.
    B) Right upper quadrant ultrasound should be considered to evaluate for alternative etiologies of transaminitis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) No prehospital decontamination is indicated. Prehospital care should focus on assessment of vital signs and general supportive care.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    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.
    2) CHARCOAL DOSE
    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).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. As these agents are generally given in conjunction with HIV nucleoside antiretrovirals, such as zidovudine, it would be advisable to monitor for overdoses from these agents also, particularly if the overdose involves a combination of drugs.
    B) MONITORING OF PATIENT
    1) Measurement of a basic metabolic panel, complete blood count, and liver enzymes should be performed in cases where adverse effects or overdose are suspected.
    2) Right upper quadrant ultrasound should be considered to evaluate for alternative etiologies of transaminitis.
    C) NEUTROPENIA
    1) Granulocyte colony stimulating factor (GCSF) should be considered for neutropenia complicated by infection felt to be secondary to nevirapine.
    2) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    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.
    D) CONSULTATION
    1) HOTLINE: Health and Human Services (HHS) has launched the National Clinicians' Post-Exposure Prophylaxis Hotline (PEPline), a national toll-free hotline for assisting health care providers counsel and treat health care workers with job-related exposure to blood-borne diseases and infections, including hepatitis and HIV infection. The toll free number is: 1-888-448-4911 (Anon, 1997).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is NOT LIKELY to be of benefit in treatment of overdose from nevirapine, efavirenz or delavirdine due to their significant protein binding.

Range Of Toxicity

Summary

    A) OVERDOSE: A full month supply of many of these agents has been ingested in overdose without clinical effects, although toxicity can occur at therapeutic doses with all non-nucleoside reverse transcriptase inhibitors (NNRTIs). ADULT: Psychomotor agitation developed after 15.6 grams and 54 grams efavirenz in adults. PEDIATRIC: An ingestion of 200 mg of nevirapine (40 times the recommended dose of 2 mg/kg/day) instead of the prescribed 200 mg of nelfinavir in an 8-day-old infant resulted in mild transient neutropenia and hyperlactatemia.
    B) THERAPEUTIC DOSE: DELAVIRDINE: ADULT: 400 mg three times daily. PEDIATRIC (age 16 years or older): 400 mg three times daily. EFAVIRENZ: ADULT: 600 mg/day. PEDIATRIC: 10 kg to less than 15 kg: 200 mg/day; 15 kg to less than 20 kg: 250 mg/day; 20 kg to less than 25 kg: 300 mg/day; 25 kg to less than 32.5 kg: 350 mg/day; 32.5 kg to less than 40 kg: 400 mg/day; 40 kg or more: 600 mg/day. ETRAVIRINE: ADULT: 200 mg twice daily. NEVIRAPINE: ADULT: 200 mg twice daily. PEDIATRIC: 150 mg/m(2) twice daily (Max: 400 mg/day).

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) DELAVIRDINE: Adult recommended dose is 400 mg 3 times daily; it is recommended to give in combination with other appropriate retroviral therapy (Prod Info RESCRIPTOR(R) oral tablets, 2006).
    2) EFAVIRENZ: Recommended adult oral dose is 600 mg daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitor (Prod Info SUSTIVA(R) oral capsules, tablets, 2013).
    3) EMTRICITABINE/RILPIVIRINE/TENOFOVIR ALAFENAMIDE: 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).
    4) EMTRICITABINE/RILPIVIRINE/TENOFOVIR DISOPROXIL FUMARATE: 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).
    5) ETRAVIRINE: The recommended adult dose is 200 mg orally twice daily taken after meals (Prod Info INTELENCE(R) oral tablets, 2012).
    6) NEVIRAPINE: Recommended adult starting dose is 200 mg/day for 2 weeks, followed by 200 mg twice daily, in combination with other antiretroviral agents (Prod Info Viramune(R) oral tablets oral suspension, 2010).
    7) RILPIVIRINE: Recommended adult oral dose is 25 mg once daily, in combination with other antiretroviral agents (Prod Info EDURANT(R) oral tablets, 2015).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) DELAVIRDINE
    a) Safety and efficacy in pediatric patients younger than 16 years of age have not been established (Prod Info RESCRIPTOR(R) oral tablets, 2006).
    2) EFAVIRENZ
    a) The following table presents recommended daily dosages for pediatric patients 3 months of age or older in combination with a protease inhibitor and/or nucleoside reverse transcriptase inhibitors (Prod Info SUSTIVA(R) oral capsules, tablets, 2013):
    BODY WEIGHT (Kg)EFAVIRENZ DOSE
    3.5 to less than 5100 mg
    5 to less than 7.5150 mg
    7.5 to less than 15200 mg
    15 to less than 20250 mg
    20 to less than 25300 mg
    25 to less than 32.5350 mg
    32.5 to less than 40400 mg
    40 or greater600 mg

    3) EMTRICITABINE/RILPIVIRINE/TENOFOVIR ALAFENAMIDE
    a) 12 YEARS AND OLDER WEIGHING AT LEAST 35 KG: 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).
    b) YOUNGER THAN 12 YEARS OF AGE OR WEIGHING LESS THAN 35 KG: Safety and efficacy have not been established (Prod Info ODEFSEY(R) oral tablets, 2016).
    4) EMTRICITABINE/RILPIVIRINE/TENOFOVIR DISOPROXIL FUMARATE
    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).
    5) ETRAVIRINE
    a) LESS THAN 6 YEARS OF AGE: Safety and efficacy have not been established (Prod Info INTELENCE(R) oral tablets, 2012).
    b) 6 TO LESS THAN 18 YEARS OF AGE: The recommended dose is based on weight. MAXIMUM, 400 mg/day (Prod Info INTELENCE(R) oral tablets, 2012):
    BODY WEIGHT (Kg)ETRAVIRINE DOSE
    16 to less than 20100 mg twice daily
    20 to less than 25125 mg twice daily
    25 to less than 30150 mg twice daily
    30 or greater200 mg twice daily

    6) NEVIRAPINE
    a) 15 DAYS OLD AND OLDER: Initially, 150 mg/m(2) (MAXIMUM 200 mg/dose) orally once daily for the first 14 days. If no rash develops, increase to 150 mg/m(2) orally twice daily (MAXIMUM 200 mg twice daily) (Prod Info VIRAMUNE(R) oral suspension, oral tablets, 2011). Younger children (8 years and younger) may need a higher dose of 200 mg/m(2) orally twice daily (MAXIMUM 200 mg twice daily) (Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2009).
    7) RILPIVIRINE
    a) 12 YEARS AND OLDER: The recommended dose is 25 mg once daily, in combination with other antiretroviral agents (Prod Info EDURANT(R) oral tablets, 2015).
    b) LESS THAN 12 YEARS OF AGE: Safety and efficacy have not been established (Prod Info EDURANT(R) oral tablets, 2015).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) NEVIRAPINE
    a) According to the manufacturer, overdose ingestions of nevirapine, ranging from 800 to 1600 mg daily for up to 15 days, have resulted in a variety of adverse effects, including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea and vomiting, pulmonary infiltrates, rash, vertigo, and weight loss (Prod Info VIRAMUNE(R) oral tablets, suspension, 2007).
    b) No adverse signs or symptoms were noted following an intentional overdose of 6 grams of nevirapine in a 26-year-old non-HIV-positive woman (Sigg et al, 2001). There were also no significant toxic effects in a 35-year-old man with HIV following an intentional overdose ingestion of 6 grams of nevirapine (Elens et al, 2009).
    c) CASE REPORT (INFANT): An 8-day-old infant, born to a mother with HIV, developed mild transient neutropenia (nadir 1,705/mm(3)) and hyperlactatemia (2.4 mmol/L) after inadvertently receiving 200 mg of nevirapine (40 times the recommended dose of 2 mg/kg/day) instead of the prescribed 200 mg of nelfinavir. Thirty hours after administration, the patient's plasma nevirapine level was 11.2 mcg/mL (therapeutic adult level: 3 to 8 mcg/mL). Within 1 week following intoxication, the patient spontaneously recovered without sequelae (Brasme et al, 2008).
    2) EFAVIRENZ
    a) Accidental overdose in adults of 600 milligrams twice daily resulted in increased nervous system symptoms. Involuntary muscle contractions occurred in one patient (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2007).
    b) An intentional overdose of 90 efavirenz tablets in a 33-year-old woman, who had just started antiretroviral therapy (abacavir, nelfinavir and efavirenz) just 3 days prior, resulted in a manic syndrome, with psychomotor agitation, irritability, expansiveness, disinhibition, and aggressiveness. Manic syndrome resolved within 5 days of stopping efavirenz and starting risperidone therapy (Blanch et al, 2001).
    c) A 17-year-old woman ingested 3.9 grams lamivudine and 15.6 grams 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 (Boscacci et al, 2006).
    3) DELAVIRDINE
    a) Adult doses as high as 850 milligrams 3 times daily for up to 6 months have been taken with no serious drug-related adverse events (Prod Info Rescriptor(R), delavirdine mesylate, 1999).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) EFAVIRENZ
    a) CASE REPORT: An efavirenz level of 59.4 mg/L (approximately 30-fold more than the normal limit) has been reported in a HIV-infected woman after taking efavirenz 600 mg once daily for 1 month; she was homozygous for the CYP2B6 G516T allele, resulting in slow hepatic metabolism. She developed acute psychosis, confusion, childish behavior, verbal aggressiveness, severe depression, and suicidal thoughts. Following the discontinuation of antiretroviral therapy, her symptoms resolved. A lower dose of efavirenz (200 mg once daily) was restarted; her plasma drug levels were normal during treatment (Hasse et al, 2005).
    2) NEVIRAPINE
    a) CASE REPORT/PEDIATRIC: A plasma nevirapine level of 11.2 mcg/mL (therapeutic adult level: 3 to 8 mcg/mL) was reported in an 8-day-old infant 30 hours after inadvertently receiving 200 mg of nevirapine (40 times the recommended dose of 2 mg/kg/day) instead of the prescribed 200 mg of nelfinavir (Brasme et al, 2008).
    b) CASE REPORT/ADULT: A 35-year-old man, with HIV and on antiretroviral therapy consisting of nevirapine 200 mg and epivir-azidothymidine 150/250 mg twice daily, ingested 30 nevirapine tablets (total of 6 grams) in a suicide attempt. His maximum serum nevirapine concentration at 3 hours post-ingestion was 30.6 mg/L (Elens et al, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nevirapine and delavirdine are dipyridodiazepinone derivatives which are nonnucleoside antiretroviral agents specific for human immunodeficiency virus (HIV) type 1. Nevirapine selectively inhibits reverse transcriptase activity and replication of HIV-1. Its inhibitory mechanism is noncompetitive with regard to both nucleoside and template-primer. Binding sites on HIV-1 reverse transcriptase appear to be the conserved tyrosines (Tyr-181 and Tyr-188) on the p66 subunit (Tramontano & Cheng, 1992; Grob et al, 1992; Merluzzi et al, 1990; Hargrave et al, 1991; Richman et al, 1994; Larder, 1992; Kopp et al, 1991; Koup et al, 1991; Cohen et al, 1991) Wu et al, 1991; (Richman et al, 1991; Spence et al, 1995).
    B) Nevirapine has no activity against reverse transcriptase from other retroviruses, including HIV-2, and is inactive against all four human DNA polymerases (Grob et al, 1992; Merluzzi et al, 1990; Koup et al, 1991; Klunder et al, 1992).
    C) Unlike nucleoside analogues, nevirapine does not require intracellular phosphorylation for antiviral activity. It reacts directly with reverse transcriptase (De Clercq, 1992).

Physicochemical

Physical Characteristics

    A) DELAVIRDINE MESYLATE is an odorless, white-to-tan crystalline powder. Delavirdine free base has an aqueous solubility at 23 degrees C of 2942 mcg/mL at pH 1, 295 mcg/mL at pH 2, and 0.81 mcg/mL at pH 7.4 (Prod Info RESCRIPTOR(R) oral tablets, 2012).
    B) EFAVIRENZ is a white to slightly pink crystalline powder that is practically insoluble in water (less than 10 mcg/mL) (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2015).
    C) ETRAVIRINE is a white to slightly yellowish brown powder that is practically insoluble in water over a wide pH range, very slightly soluble in propylene glycol, slightly soluble in ethanol, soluble in polyethylene glycol (PEG) 400, and freely soluble in some organic solvents (ie, N,N-dimethylformamide, tetrahydrofuran) (Prod Info INTELENCE(R) oral tablets, 2014).
    D) NEVIRAPINE is a white to off-white crystalline powder (Prod Info VIRAMUNE(R) oral tablets, oral suspension, 2014).
    E) RILPIVIRINE HYDROCHLORIDE is a white to almost white powder that is practically insoluble in water over a wide pH range (Prod Info ODEFSEY(R) oral tablets, 2016).

Molecular Weight

    A) DELAVIRDINE MESYLATE: 552.68 (Prod Info RESCRIPTOR(R) oral tablets, 2012)
    B) EFAVIRENZ: 315.68 (Prod Info SUSTIVA(R) oral capsules, oral tablets, 2015)
    C) ETRAVIRINE: 435.28 (Prod Info INTELENCE(R) oral tablets, 2014)
    D) NEVIRAPINE: 266.3 (Prod Info VIRAMUNE(R) oral tablets, oral suspension, 2014)
    E) RILPIVIRINE HYDROCHLORIDE: 402.88 (Prod Info ODEFSEY(R) oral tablets, 2016)

References

General Bibliography

    1) Altice FL, Friedland GH, & Cooney EL: Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS 1999; 13:957-962.
    2) Balani SK, Kauffman LR & Lin JH: Pharmacokinetics of L-743,726 (DMP-266), an HIV-1 reverse transcriptase inhibitor, in rats and monkeys (abstract). 7th North American ISSX Meeting, October 20, 1996; 10:268, October 20, 1996.
    3) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    4) Blanch J, Corbella B, & Garcia F: Manic syndrome associated with efavirenz overdose (letter). Clin Infect Dis 2001; 33:270-271.
    5) Boscacci RT, Buclin T, Furrer H, et al: A case of voluntary intoxication with efavirenz and lamivudine. AIDS (London, England) 2006; 20(9):1352-1354.
    6) Bourezane Y, Salard D, & Hoen B: DRESS (drug rash with eosinophilia and systemic symptoms) syndrome associated with nevirapine therapy. Clin Infect Dise 1998; 27:1321-1322.
    7) Brasme JF, Mille F, Benhayoun M, et al: Uncomplicated outcome after an accidental overdose of nevirapine in a newborn. Eur J Pediatr 2008; 167(6):689-690.
    8) Brogly SB , Abzug MJ , Watts DH , et al: Birth Defects Among Children Born to Human Immunodeficiency Virus-Infected Women: Pediatric AIDS Clinical Trials Protocols 219 and 219C. Pediatr Infect Dis J 2010; 29(8):721-727.
    9) Cattelan AM, Erne E, & Salatino A: Severe hepatic failure related to nevirapine treatment. Clin Infect Dis 1999; 29:455-456.
    10) Cheeseman SH, Hattox SE, & McLaughlin MM: Pharmacokinetics of nevirapine: initial single-rising-dose study in humans. Antimicrob Agents Chemother 1993; 37:178-182.
    11) Cheeseman SH, Hattox SE, McLaughlin MM, et al: Pharmacokinetics of nevirapine: initial single-rising-dose study in humans. Antimicrob Agents Chemother 1993a; 37:178-182.
    12) Cheeseman SH, Havlir D, & McLaughlin MM: Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8:141-151.
    13) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    14) Clarke S, Harrington P, & Condon C: Late onset hepatitis and prolonged deterioration in hepatic function associated with nevirapine therapy. Intl J STD AIDS 2000; 11:336-337.
    15) Cohen KA, Hopkins J, & Ingraham RH: Characterization of the binding site for nevirapine (BI-RG-587), a nonnucleoside inhibitor of human immunodeficiency virus. J Biol Chem 1991; 266:14670-14674.
    16) Curi ALL, Kapembwa M, & Pavesio C: Retinal toxicity due to efavirenz. Eye 2001; 15:246-248.
    17) D'Aquila RT, Hughes MD, & Johnson VA: Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. Ann Int Med 1996; 124:1019-1030.
    18) De Clercq E: HIV inhibitors targeted at the reverse transcriptase. Aids Res Hum Retroviruses 1992; 8:119-134.
    19) Elens L, Haufroid V, Doyen C, et al: Acute intoxication with nevirapine in an HIV-1-infected patient: clinical and pharmacokinetic follow up. AIDS 2009; 23(10):1291-1293.
    20) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    21) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    22) Fagot JP, Mockenhaupt M, & Bouwes-Bavinck JN: Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. AIDS 2001; 15:1843-1848.
    23) Figgitt D: Progress with enzyme inhibitors for treating HIV infection. Inpharma 1995; 1007:9-10.
    24) Ford N , Calmy A , & Mofenson L : Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS 2011; 25(18):2301-2304.
    25) Ford N, Mofenson L, Shubber Z, et al: Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS 2014; 28 Suppl 2:S123-S131.
    26) Furco A, Gosrani B, Nicholas S, et al: Successful use of darunavir, etravirine, enfuvirtide and tenofovir/emtricitabine in pregnant woman with multiclass HIV resistance. AIDS 2009; 23(3):434-435.
    27) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    28) Gonzalez de Requena D, Nunez M, & Jimenez-Nacher I: Liver toxicity caused by nevirapine. AIDS 2002; 16:290-291.
    29) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    30) Grob PM, Wu JC, & Cohen KA: Nonnucleoside inhibitors of HIV-1 reverse transcriptase: nevirapine as a prototype drug. Aids Res Hum Retroviruses 1992; 8:145-152.
    31) Hargrave KD, Proudfoot JR, & Grozinger KG: Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiazepinones. J Med Chem 1991; 34:2231-2241.
    32) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    33) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    34) Hasse B, Gunthard HF, Bleiber G, et al: Efavirenz intoxication due to slow hepatic metabolism. Clin Infect Diseases 2005; 40:22e-23e.
    35) Hill JB, Sheffield JS, & Zeeman GG: Hepatotoxicity with antiretroviral treatment of pregnant women. Obstet Gynecol 2001; 98:909-911.
    36) Izurieta P, Kakuda TN, Feys C, et al: Safety and pharmacokinetics of etravirine in pregnant HIV-1-infected women. HIV Med 2011; 12(4):257-258.
    37) Jaworsky D, Thompson C, Yudin MH, et al: Use of newer antiretroviral agents, darunavir and etravirine with or without raltegravir, in pregnancy: a report of two cases. Antivir Ther 2010; 15(4):677-680.
    38) Klunder JM, Hargrave KD, & West M: Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 2. Tricyclic pyridobenzoxazepinones and dibenzoxazepinones. J Med Chem 1992; 35:1887-1897.
    39) Kopp EB, Miglietta JJ, & Shrutkowski AG: Steady state kinetics and inhibition of HIV-1 reverse transcriptase by a non-nucleoside dipyridodiazepinone BI-RG-587, using a heteropolymeric template. Nucleic Acids Res 1991; 19:3035-3039.
    40) Koup RA, Merluzzi VJ, & Hargrave KD: Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepinone BI-RG-587. JID 1991; 163:966-970.
    41) Kunz A, Frank M, Mugenyi K, et al: Persistence of nevirapine in breast milk and plasma of mothers and their children after single-dose administration. J Antimicrob Chemother 2009; 63(1):170-177.
    42) Larder BA: 3-azido-3-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 1992; 36:2664-2669.
    43) Marzolini C, Telenti A, & Decosterd LA: Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001; 15:71-75.
    44) Merluzzi VJ, Hargrave KD, & Labadia M: Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 1990; 250:1411-1413.
    45) Merluzzi VJ, Hargrave KD, Labadia M, et al: Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 1990a; 250:1411-1413.
    46) Mira JA, Macias J, Giron-Gonzalez JA, et al: Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C. J Antimicrob Chemother 2006; 58(1):140-146.
    47) Mirochnick M, Clarke DF, & Dorenbaum A: Nevirapine. Pharmacokinetic considerations in children and pregnant women. Clin Pharmacokinet 2000; 39:281-293.
    48) Mirochnick M, Fenton T, Gagnier P, et al: Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. J Infect Dis 1998; 178(2):368-374.
    49) Mirochnick M, Thomas T, Capparelli E, et al: Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother 2009; 53(3):1170-1176.
    50) Musoke P, Guay LA, Bagenda D, et al: A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS 1999; 13(4):479-86.
    51) Nijhawan AE, Zachary KC, Kwara A, et al: Status epilepticus resulting from severe efavirenz toxicity in an HIV-infected patient. AIDS Read. 2008; 18(7):386-388, C3.
    52) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    53) Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission: Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. AIDSinfo, U.S. Department of Health and Human Services. Rockville, MD. 2012. Available from URL: http://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0/. As accessed 2012-08-02.
    54) Patel SM, Johnson S, Belknap SM, et al: Serious adverse cutaneous and hepatic toxicities associated with nevirapine use by non-HIV-infected individuals. J Acquir Immune Defic Syndr 2004; 35:120-125.
    55) Patel SS & Benfield P: New drug profile: Nevirapine. Clin Immunother 1996; 6(4):307-317.
    56) Piroth L, Grappin M, & Sgro C: Recurrent NNRTI-induced hepatotoxicity in an HIV-HCV-coinfected patient (letter). Ann Pharmacother 2000; 34:534-535.
    57) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    58) Poulsen H & Lublin H: Efavirenz-induced psychosis leading to involuntary detention (letter). AIDS 2003; 17(3):451-452.
    59) Prakash M, Poreddy V, & Tiyyagura L: Jaundice and hepatocellular damage associated with nevirapine therapy. Am J Gastroenterol 2001; 96:1571-1574.
    60) Product Information: ATRIPLA(R) oral tablets, efavirenz/emtricitabine/tenofovir disoproxil fumarate oral tablets. Gilead Sciences and Bristol-Myers Squibb, LLC, Foster City, CA, 2010.
    61) Product Information: COMPLERA(R) oral tablets, emtricitabine, rilpivirine, tenofovir disoproxil fumarate oral tablets. Gilead Sciences, Inc.(per manufacturer), Foster City, CA, 2016.
    62) Product Information: COMPLERA(TM) oral tablets, emtricitabine/rilpivirine/tenofovir disoproxil fumarate oral tablets. Gilead Sciences, Inc. (per Manufacturer), Foster City, CA, 2011.
    63) Product Information: EDURANT(R) oral tablets, rilpivirine oral tablets. Janssen Products (per FDA), Titusville, NJ, 2015.
    64) Product Information: EDURANT(R) oral tablets, rilpivirine oral tablets. Tibotec Therapeutics, Raritan, NJ, 2011.
    65) Product Information: INTELENCE(R) oral tablets, etravirine oral tablets. Janssen Therapeutics (per FDA), Titusville, NJ, 2014.
    66) Product Information: INTELENCE(R) oral tablets, etravirine oral tablets. Janssen Therapeutics (per manufacturer), Titusville, NJ, 2012.
    67) Product Information: INTELENCE(R) oral tablets, etravirine oral tablets. Tibotec, Inc., Raritan, NJ, 2010.
    68) Product Information: INTELENCE(TM) oral tablets, etravirine oral tablets. Tibotec Therapeutics,Inc, Raritan, NJ, 2008.
    69) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    70) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    71) Product Information: ODEFSEY(R) oral tablets, emtricitabine, rilpivirine, tenofovir alafenamide oral tablets. Gilead Sciences Inc (per manufacturer), Foster City, CA, 2016.
    72) Product Information: RESCRIPTOR(R) oral tablets, delavirdine mesylate oral tablets. Pfizer,Inc, New York, NY, 2006.
    73) Product Information: RESCRIPTOR(R) oral tablets, delavirdine mesylate oral tablets. Pharmacia & Upjohn Company, New York, NY, 2008.
    74) Product Information: RESCRIPTOR(R) oral tablets, delavirdine mesylate oral tablets. ViiV Healthcare (per FDA), Research Triangle Park, NC, 2012.
    75) Product Information: Rescriptor(R), delavirdine mesylate. Pharmacia and Upjohn Pharmaceuticals, Kalamazoo, MI, 1999.
    76) Product Information: SUSTIVA(R) oral capsules, oral tablets, efavirenz oral capsules, oral tablets. Bristol-Myers Squibb Company, Princeton, NJ, 2007.
    77) Product Information: SUSTIVA(R) oral capsules, oral tablets, efavirenz oral capsules, oral tablets. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, 2014.
    78) Product Information: SUSTIVA(R) oral capsules, oral tablets, efavirenz oral capsules, oral tablets. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, 2015.
    79) Product Information: SUSTIVA(R) oral capsules, tablets, efavirenz oral capsules, tablets. Bristol-Myers Squibb Company, Princeton, NJ, 2008.
    80) Product Information: SUSTIVA(R) oral capsules, tablets, efavirenz oral capsules, tablets. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, 2011.
    81) Product Information: SUSTIVA(R) oral capsules, tablets, efavirenz oral capsules, tablets. Bristol-Myers Squibb Company, Princeton, NJ, 2013.
    82) Product Information: Sustiva(TM), efavirenz. DuPont Pharmaceuticals, Wilmington, DE, 1998.
    83) Product Information: VIRAMUNE XR oral extended-release tablets, nevirapine oral extended-release tablets. Boehringer Ingelheim Pharmaceuticals, Inc. (per FDA), Ridgefield, CT, 2012.
    84) Product Information: VIRAMUNE XR(R) oral extended release tablets, nevirapine oral extended release tablets. Boehringer Ingelheim Pharmaceuticals, Inc. (per FDA), Ridgefield, CT, 2014.
    85) Product Information: VIRAMUNE(R) oral suspension, oral tablets, nevirapine oral suspension, oral tablets. Boehringer Engelheim Pharmaceuticals, Inc, Ridgefield, CT, 2011.
    86) Product Information: VIRAMUNE(R) oral tablets, oral suspension, nevirapine oral tablets, oral suspension. Boehringer Ingelheim Pharmaceuticals, Inc. (per FDA), Ridgefield, CT, 2014.
    87) Product Information: VIRAMUNE(R) oral tablets, suspension, nevirapine oral tablets, suspension. Boehringer Ingelheim Pharmaceuticals,Inc, Ridgefield, CT, 2008.
    88) Product Information: VIRAMUNE(R) oral tablets, suspension, nevirapine oral tablets, suspension. Boehringer Ingelheim, Ridgefield, CT, 2007.
    89) Product Information: Viramune(R) oral tablets oral suspension, nevirapine oral tablets oral suspension. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, 2010.
    90) Product Information: Viramune(R), nevirapine. Roxane Laboratories, Inc, Columbus, OH, 2000.
    91) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    92) Richardson M, Osrin D, Donaghy S, et al: Spinal malformations in the fetuses of HIV infected women receiving combination antiretroviral therapy and co-trimoxazole. Eu J Obstet Gynecol Reprod Biol 2000; 93:215-217.
    93) Richman D, Shih CK, & Lowy I: Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci 1991; 88:11241-11245.
    94) Richman RD, Havlir D, & Corbeil J: Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994; 68:1660-1666.
    95) Sigg T, Oberg D, & Wahl M: Ingestion of a large quantity of nevirapine in a non-HIV+ patient (abstract). J Toxicol-Clin Toxicol 2001; 39:512.
    96) Soriano V, Dona C, & Barreiro P: Is there cross-toxicity between nevirapine and efavirenz in subjects developing rash?. AIDS 2000; 14:1672-1673.
    97) Spence RA, Kati WM, & Anderson KS: Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science 1995; 267:988-993.
    98) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    99) Taylor GP, Lyall EGH, & Back D: Pharmacological implications of lengthened in-utero exposure to nevirapine (letter). Lancet 2000; 355:2134-2135.
    100) Tramontano E & Cheng YC: HIV-1 reverse transcriptase inhibition by a dipyridodiazepinone derivative: BI-RG-587. Biochem Pharmacol 1992; 43:1371-1376.
    101) Tuomala RE, Shapiro DE, Mofenson LM, et al: Antiretroviral therapy during pregnacy and the risk of an adverse outcome. N Engl J Med 2002; 346(24):1863-1870.
    102) Turkova A, Ball C, Gilmour-White S, et al: A paediatric case of acute liver failure associated with efavirenz-based highly active antiretroviral therapy and effective use of raltegravir in combination antiretroviral treatment after liver transplantation. J Antimicrob Chemother 2009; 63(3):623-625.
    103) Warren KJ, Boxwell DE, & Kim NY: Nevirapine-associated Stevens-Johnson syndrome. Lancet 1998; 351:567.
    104) Weiterwald E, Cleach LL, & Michel C: Nevirapine-induced overlap Stevens- Johnson syndrome/toxic epidermal necrolysis (letter). Br J Dermatol 1999; 140:980-982.
    105) Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children: Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. AIDSinfo. Rockville, MD. 2009. Available from URL: http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf. As accessed 2009-02-25.
    106) Young SD, Britcher SF, Tran LO, et al: L-743,726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficicency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1995; 39:2602-2605.