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AIDS ANTIVIRAL INTEGRASE INHIBITORS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dolutegravir, elvitegravir, and raltegravir are human immunodeficiency virus (HIV) integrase strand transfer inhibitors, used in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Specific Substances

    A) DOLUTEGRAVIR (synonym)
    1) S/GSK1349572
    2) Dolutegravir sodium (synonym)
    3) CAS 1051375-16-6
    ELVITEGRAVIR (synonym)
    1) GS-9137
    2) JTK-303
    3) CAS 697761-98-1
    RALTEGRAVIR (synonym)
    1) MK-0518
    2) Raltegravir potassium (synonym)
    3) CAS 871038-72-1
    GENERAL TERMS
    1) HIV-1 INSTI
    2) HIV-1 integrase inhibitor
    3) Integrase inhibitor

    1.2.1) MOLECULAR FORMULA
    1) DOLUTEGRAVIR: C20H18F2N3NaO5
    2) ELVITEGRAVIR: C23H23ClFNO5
    3) RALTEGRAVIR: C20H20FKN6O5

Available Forms Sources

    A) FORMS
    1) DOLUTEGRAVIR is available as 50 mg film-coated tablets (Prod Info TIVICAY(R) oral tablets, 2013).
    2) ELVITEGRAVIR is available as 85 mg and 150 mg film-coated tablets (Prod Info VITEKTA(R) oral tablets, 2014).
    3) RALTEGRAVIR is available as 400 mg film-coated tablets, and as 25 mg and 100 mg (scored) chewable tablets (Prod Info ISENTRESS(R) oral film-coated tablets, oral chewable tablets, 2013).
    B) USES
    1) DOLUTEGRAVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children 12 years of age and older and who weigh at least 40 kg (Prod Info TIVICAY(R) oral tablets, 2013).
    2) ELVITEGRAVIR is indicated in combination with an HIV protease inhibitor and coadministered with ritonavir and other antiretroviral agents for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults (Prod Info VITEKTA(R) oral tablets, 2014).
    3) RALTEGRAVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in children and adolescents 2 years of age and older who weigh at least 10 kg (Prod Info ISENTRESS(R) oral film-coated tablets, oral chewable tablets, 2013).

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: Dolutegravir, elvitegravir, and raltegravir are human immunodeficiency virus (HIV) integrase strand transfer inhibitors, used in combination with other antiretroviral agents for the treatment of HIV infection.
    B) PHARMACOLOGY: HIV integrase inhibitors bind to the integrase active site and block the strand transfer step of retroviral DNA integration which is an essential part of the HIV replication cycle.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects following therapeutic administration, with an incidence of 2% or greater, and that are moderate to severe in intensity, are insomnia and headache.
    2) DOLUTEGRAVIR: Elevated hepatic enzymes (6% to 8%), elevated serum cholesterol levels (8%), hyperglycemia (12%), elevated serum lipase levels (8%).
    3) ELVITEGRAVIR: Diarrhea (7%), nausea (4%).
    4) RALTEGRAVIR: Hyperglycemia (10%), nausea (7%), vomiting (7%), diarrhea (16%), elevated serum lipase levels (5%), dizziness (11%), fatigue (9%). Elevated serum creatine kinase concentrations, myopathy, and rhabdomyolysis have been reported rarely.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there are no acute overdose data available. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Raltegravir alone and abacavir/dolutegravir/lamivudine combination therapy have been classified as FDA pregnancy category C.. Dolutegrevir, elvitegravir alone, and elvitegravir/cobicistat/emtricitabine/tenofovir combination have been classified as FDA pregnancy category B. In a case report and in animal studies, no effects on embryonic/fetal survival or fetal weight have been reported with raltegravir. In animal studies, there was no evidence of teratogenicity with elvitegravir. Lactation studies with raltegravir or elvitegravir have not been conducted in humans. In animal studies, raltegravir and elvitegravir were secreted in the milk of lactating rats.

Laboratory Monitoring

    A) Monitor vital signs and liver enzyme levels after significant overdose.
    B) Monitor fluids and serum electrolytes, pancreatic enzymes, glucose levels, and CPK after significant overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. As these agents are generally given in conjunction with other HIV antiretroviral agents, it would be advisable to monitor for overdoses from these agents as well.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None
    F) RHABDOMYOLYSIS
    1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
    G) ENHANCED ELIMINATION
    1) Dolutegravir is at least 98% protein-bound and raltegravir is approximately 83% protein-bound; hemodialysis may not be useful as a method of enhanced elimination.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home. There is no data to support a safe dose for home management in pediatric exposures.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    J) PHARMACOKINETICS
    1) DOLUTEGRAVIR: at least 98.9% protein-bound; apparent volume of distribution is 17.4 L after oral administration of 50 mg once daily; primarily metabolized in liver via UGT1A1; terminal half-life is approximately 14 hours. RALTEGRAVIR: Approximately 83% protein-bound; elimination-half life is approximately 9 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Other AIDS agents; symptoms from AIDS.

Range Of Toxicity

    A) TOXICITY: DOLUTEGRAVIR: Oral doses up to 250 mg in healthy subjects have been well-tolerated without evidence of specific toxicity. RALTEGRAVIR: Limited data available. Healthy volunteers did not experience any toxicity after receiving doses as high as 1600-mg single dose and 800-mg twice-daily multiple doses. In several studies, patients did not experience any toxicity after receiving occasional doses of up to 1800 mg daily.
    B) THERAPEUTIC DOSE: DOLUTEGRAVIR: 50 mg orally once or twice daily in patients 12 years of age and older and who weigh at least 40 kg. RALTEGRAVIR: Adults: 400 mg orally twice daily. Children: 12 years and older, (film-coated tablet) 400 mg orally twice daily; 2 to 11 years, (chewable tablet) doses range from 75 mg twice daily to 300 mg twice daily depending on patient's weight.

Clinical Effects

Summary Of Exposure

    A) USES: Dolutegravir, elvitegravir, and raltegravir are human immunodeficiency virus (HIV) integrase strand transfer inhibitors, used in combination with other antiretroviral agents for the treatment of HIV infection.
    B) PHARMACOLOGY: HIV integrase inhibitors bind to the integrase active site and block the strand transfer step of retroviral DNA integration which is an essential part of the HIV replication cycle.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects following therapeutic administration, with an incidence of 2% or greater, and that are moderate to severe in intensity, are insomnia and headache.
    2) DOLUTEGRAVIR: Elevated hepatic enzymes (6% to 8%), elevated serum cholesterol levels (8%), hyperglycemia (12%), elevated serum lipase levels (8%).
    3) ELVITEGRAVIR: Diarrhea (7%), nausea (4%).
    4) RALTEGRAVIR: Hyperglycemia (10%), nausea (7%), vomiting (7%), diarrhea (16%), elevated serum lipase levels (5%), dizziness (11%), fatigue (9%). Elevated serum creatine kinase concentrations, myopathy, and rhabdomyolysis have been reported rarely.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there are no acute overdose data available. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) DOLUTEGRAVIR
    1) In multicenter trials of treatment-naive patients with HIV evaluated at 48 weeks, moderate to severe headache occurred in less than 1% of patients treated with dolutegravir 50 mg/day plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) (n=403) as well as patients treated with raltegravir 400 mg twice daily plus 2 NRTIs (n=405). Moderate to severe headache was seen in 2% of patients treated with dolutegravir and abacavir/lamivudine once daily (n=414) and in 2% of patients treated with fixed-dose efavirenz/emtricitabine/tenofovir once daily (n=419) (Prod Info TIVICAY(R) oral tablets, 2013).
    b) ELVITEGRAVIR
    1) Headaches were reported in 3% of HIV-1 infected treatment-experienced patients who received elvitegravir (n=354) during clinical trials (Prod Info VITEKTA(R) oral tablets, 2014).
    c) RALTEGRAVIR
    1) Moderate-to-severe headache occurred in 2% of treatment-experienced HIV-1-infected patients, 16 years of age and older, who received raltegravir 400 mg twice daily in combination with optimized background therapy and in less than 1% of patients who received placebo with optimized background therapy, based on pooled data (96-week analysis) from 2 randomized, double-blind, phase 3 trials (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    2) Headache was reported in 4 of 43 patients (9.3%) on 200 milligrams (mg) of raltegravir, 0 of 45 patients (0%) on 400 mg of raltegravir, 2 of 45 patients (4.4%) on 600 mg of raltegravir, and 3 of 45 patients (6.7%) on placebo, in a phase II, double-blind, randomized, placebo-controlled, 24-week trial. All patients received treatment twice daily. In addition, all patients received an optimized background antiviral regimen (Grinsztejn et al, 2007).
    3) Headache was reported in 2 of 28 patients (7%) on raltegravir (100 mg, 200 mg, 400 mg or 600 mg) compared with 1 of 7 patients (14%) on placebo in a multicenter, double-blind, randomized, placebo-controlled, study of 35 HIV-infected treatment-naive patients. Patients received treatment twice daily as monotherapy for 10 days (Markowitz et al, 2006).
    B) CEREBELLAR ATAXIA
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR
    1) Cerebellar ataxia has been reported during postmarketing use of raltegravir; however, it is not always possible to reliably estimate the frequency of postmarketing reaction or establish a causal relationship to product exposure (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    2) A 56-year-old HIV-infected woman with moderately severe COPD developed cerebellar ataxia following treatment with raltegravir. The patient's suppressive antiretroviral regimen was changed recently, replacing atazanavir/ritonavir with raltegravir and etravirine (in combination with tenofovir/emtricitabine). Within 3 days of this change, the patient developed bilateral hand and foot tremors, accompanied by severe dysmetria and ataxia. Etravirine and bupropion (a long-term medication) were discontinued without symptom improvement. She was hospitalized 6 days later with profound bilateral dysmetria, ataxia, and tremor, and the inability to walk heel to toe without falling to the right. Physical, neurological, laboratory, and diagnostic findings were all normal. On day 2 of hospitalization, therapy with raltegravir was switched back to atazanavir/ritonavir. Within 48 hours, her physical and neurological symptoms had resolved. At discharge, she was rechallenged with raltegravir and, within several days, she again developed significant tremor and ataxia. Raltegravir was replaced by etravirine and her symptoms resolved (Reiss et al, 2010).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR: Dizziness was reported in 3 of 28 patients (11%) on raltegravir (100 mg, 200 mg, 400 mg or 600 mg) compared with 1 of 7 patients (14%) on placebo in a multicenter, double-blind, randomized, placebo-controlled, study of 35 HIV-infected treatment-naive patients. Patients received treatment twice daily as monotherapy for 10 days (Markowitz et al, 2006).
    D) DISORIENTATED
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR: Disorientation was reported in 1 of 28 patients (4%) on raltegravir (100 mg, 200 mg, 400 mg or 600 mg) compared with 0 of 7 patients (0%) on placebo in a multicenter, double-blind, randomized, placebo-controlled, study of 35 HIV-infected treatment-naive patients. Patients received treatment twice daily as monotherapy for 10 days (Markowitz et al, 2006).
    E) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) DOLUTEGRAVIR
    1) In multicenter trials of treatment-naive patients with HIV evaluated at 48 weeks, grade 1 insomnia occurred in 1% of patients treated with dolutegravir 50 mg/day in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) (n=403) compared with less than 1% of patients treated with raltegravir 400 mg twice daily in combination with 2 NRTIs (n=405). Grade 2 to 4 insomnia occurred in less than 1% of patients in both treatment groups. Grade 1 insomnia was seen in 7% of patients treated with dolutegravir plus abacavir/lamivudine once daily (n=414) compared with 3% of patients treated with fixed-dose efavirenz/emtricitabine/tenofovir once daily (n=419), Incidence of moderate to severe insomnia was 3% and 2% in the dolutegravir and efavirenz/emtricitabine/tenofovir treatment groups, respectively (Prod Info TIVICAY(R) oral tablets, 2013).
    b) RALTEGRAVIR
    1) Moderate to severe insomnia was reported in 4% of patients taking raltegravir compared with 4% of patients taking active control. In this randomized, double-blind, phase 3 study (analysis of 156 weeks of data), 563 treatment-naive adults with HIV received either raltegravir 400 mg twice daily in combination with fixed dose emtricitabine 200 mg/tenofovir 300 mg (n=281) or active control with efavirenz 600 mg in combination with emtricitabine/tenofovir (n=282) (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    2) PEDIATRIC: Insomnia, psychomotor hyperactivity, and abnormal behavior were reported in 1 pediatric patient during a 24-week, open-label, phase 1/2 study of raltegravir in combination with other antiretroviral agents in HIV infected children 2 to 18 years of age (n=126). Of the 126 patients, 96 received the recommended dose of raltegravir including this case (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    F) FATIGUE
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR
    1) Fatigue was reported in 4 of 43 patients (9.3%) on 200 milligrams (mg) of raltegravir, 0 of 45 patients (0%) on 400 mg of raltegravir, 2 of 45 patients (4.4%) on 600 mg of raltegravir, and 1 of 45 patients (2.2%) on placebo, in a phase II, double-blind, randomized, placebo-controlled, 24-week trial. All patients received treatment twice daily. In addition, all patients received an optimized background antiviral regimen (Grinsztejn et al, 2007).
    2) Fatigue was reported in 2 out of 28 patients (7%) on raltegravir (100 mg, 200 mg, 400 mg or 600 mg) compared with 0 out of 7 patients (0%) on placebo in a multicenter, double-blind, randomized, placebo-controlled, study of 35 HIV-infected treatment-naive patients. Patients received treatment twice daily as monotherapy for 10 days (Markowitz et al, 2006).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) ELVITEGRAVIR
    1) Diarrhea was reported in 7% of HIV-1 infected treatment-experienced patients who received elvitegravir (n=354) during clinical trials (Prod Info VITEKTA(R) oral tablets, 2014).
    b) RALTEGRAVIR
    1) Diarrhea occurred in 16.6% of treatment-experienced HIV-1-infected patients receiving raltegravir 400 mg twice daily in combination with optimized background therapy (n=507) compared to 19.5% of patients receiving placebo (n=282) based on pooled data from randomized, double-blind, placebo-controlled trials (Prod Info ISENTRESS oral tablets, 2007).
    2) Based on pooled data from randomized, double-blind, placebo-controlled trials, moderate to severe diarrhea occurred in 3.7% of treatment-experienced HIV-1-infected patients receiving raltegravir 400 mg twice daily in combination with optimized background therapy (n=507) compared to 4.6% of patients receiving placebo (n=282) (Prod Info ISENTRESS oral tablets, 2007).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) ELVITEGRAVIR
    1) Nausea was reported in 4% of HIV-1 infected treatment-experienced patients who received elvitegravir (n=354) during clinical trials (Prod Info VITEKTA(R) oral tablets, 2014).
    b) RALTEGRAVIR
    1) Moderate to severe nausea was reported in 3% of patients taking raltegravir compared with 4% of patients taking active control. In this randomized, double-blind, phase 3 study (analysis of 156 weeks of data), 563 treatment-naive adults with HIV received either raltegravir 400 mg twice daily in combination with fixed dose emtricitabine 200 mg/tenofovir 300 mg (n=281) or active control with efavirenz 600 mg in combination with emtricitabine/tenofovir (n=282) (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    2) Nausea was reported in 3 of 43 patients (7%) on 200 milligrams (mg) of raltegravir, 2 of 45 patients (4.4%) on 400 mg of raltegravir, 5 of 45 patients (11.1%) on 600 mg of raltegravir, and 5 of 45 patients (11.1%) on placebo, in a phase II, double-blind, randomized, placebo-controlled, 24-week trial. All patients received treatment twice daily. In addition, all patients received an optimized background antiviral regimen (Grinsztejn et al, 2007).
    C) VOMITING
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR: Vomiting was reported in 3 of 43 patients (7%) on 200 milligrams (mg) of raltegravir, 2 of 45 patients (4.4%) on 400 mg of raltegravir, 1 of 45 patients (2.2%) on 600 mg of raltegravir, and 1 of 45 patients (2.2%) on placebo, in a phase II, double-blind, randomized, placebo-controlled, 24-week trial. All patients received treatment twice daily. In addition, all patients received an optimized background antiviral regimen (Grinsztejn et al, 2007).
    D) SERUM AMYLASE RAISED
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR: Based on pooled data (96-week analysis) from 2 randomized, double-blind, placebo-controlled, phase 3 trials, grade 2 to 4 increases in serum pancreatic amylase levels were reported in a higher percentage of treatment-experienced HIV-1-infected patients who received raltegravir 400 mg twice daily in combination with optimized background therapy (n=462) than in patients who received placebo and optimized background therapy (n=237). Grade 2 (1.6 to 2 times the ULN increases occurred in 2% of raltegravir-treated patients versus 1% of placebo-treated patients. Grade 3 (2.1 to 5 times the ULN) increases occurred in 4% of raltegravir-treated patients and in 3% of placebo-treated patients; grade 4 (greater than 5 times the ULN) increases occurred in less than 1% of both raltegravir-treated patients and placebo-treated patients (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    E) HIGH LIPASE LEVEL IN SERUM
    1) WITH THERAPEUTIC USE
    a) DOLUTEGRAVIR
    1) In multicenter trials of treatment-naive HIV infected patients evaluated at 48 weeks, grade 2 lipase elevations (more than 1.5 to 3 times the ULN) occurred in 5% of patients treated with dolutegravir 50 mg/day in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) (n=403) compared with 6% of patients treated with raltegravir 400 mg twice daily in combination with 2 NRTIs (n=405). Grade 3 to 4 lipase elevations (more than 251 mg/dL) occurred in 1% and 3% of dolutegravir- and raltegravir-treated patients, respectively. Grade 2 lipase elevations developed in 8% of patients treated with dolutegravir 50 mg/day in combination with abacavir/lamivudine (n=414) compared with 7% of patients treated with fixed-dose efavirenz/emtricitabine/tenofovir once daily (n=419); grade 3 to 4 lipase elevations occurred in 3% of patients treated with dolutegravir and 2% of patients treated with efavirenz/emtricitabine/tenofovir (Prod Info TIVICAY(R) oral tablets, 2013).
    2) PEDIATRIC: Grade 3 lipase elevations were reported with dolutegravir 35 mg/day or 50 mg/day combination therapy in 1 patient (mean age, 14 years) in a 48-week, multicenter, open-label trial of treatment-experienced pediatric patients with HIV infection (n=23) (Prod Info TIVICAY(R) oral tablets, 2013).
    b) RALTEGRAVIR
    1) Based on pooled data (96-week analysis) from 2 randomized, double-blind, placebo-controlled, phase 3 trials, grade 2 to 4 increases in serum lipase levels were reported in a higher percentage of treatment-experienced HIV-1-infected patients who received raltegravir 400 mg twice daily in combination with optimized background therapy (n=462) than in patients who received placebo and optimized background therapy (n=237). Grade 2 (1.6 to 3 times the ULN) increases occurred in 5% of raltegravir-treated patients and 4% of placebo-treated patients. Grade 3 (3.1 to 5 times the ULN) increases occurred in 2% of raltegravir-treated patients and 1% of placebo-treated patients; grade 4 (greater than 5 times the ULN) increases occurred in 0% of both raltegravir-treated patients and placebo-treated patients (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    F) PERITONITIS
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR
    1) CASE REPORT: A 49-year-old man coinfected with HIV and hepatitis C developed peritonitis following raltegravir therapy. For more than 5 years, the patient was taking a combination antiretroviral regimen of abacavir, nevirapine, and lopinavir/ritonavir. Due to bleeding tendencies, lopinavir/ritonavir was replaced by raltegravir. All other drugs remained unchanged. On day 18 of raltegravir treatment, the patient presented with worsening pain in his right upper abdomen and lower chest for the past 3 days. Eleven days after onset of symptoms, a CT scan revealed contrast enhancement of his liver surface and fatty standing of the greater omentum. With the initiation of oral prednisone (60 mg/day for 3 days, then tapering to 30 mg/day for 3 days), all symptoms immediately resolved. However, abdominal symptoms resurfaced once prednisone treatment was discontinued. Prednisone was reinitiated on day 31 at a dose of 30 mg/day. Tapering the dose again led to abdominal discomfort and the development of stomatitis. A dose of prednisone 20 mg/day was continued and raltegravir treatment was changed back to lopinavir/ritonavir 11 weeks after the onset of abdominal symptoms. All antiretroviral drugs were discontinued 4 days later due to diarrhea and bleeding related to lopinavir/ritonavir. The patient's symptoms improved, and prednisone was tapered to 10 mg/day within 2 weeks. A CT scan 10 days after the discontinuation of his antiretroviral regimen showed perihepatic improvement (Tsukada et al, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) SERUM BILIRUBIN LEVEL - FINDING
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR: Based on pooled data (96-week analysis) from 2 randomized, double-blind, placebo-controlled, phase 3 trials, grade 2 (1.6 to 2.5 times the ULN) increases in total serum bilirubin levels were reported in 6% of treatment-experienced, HIV-1-infected patients who received raltegravir 400 mg twice daily in combination with optimized background therapy (n=462) and in 3% of patients who received optimized background therapy and placebo (n=237). Grade 3 (2.6 to 5 times the ULN) increases in total serum bilirubin levels were reported in 3% of both raltegravir-treated patients and placebo-treated patients; grade 4 (greater than 5 times the ULN) increases occurred in 1% and 0%, respectively (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    B) INCREASED LIVER AMINOTRANSFERASE LEVEL
    1) WITH THERAPEUTIC USE
    a) DOLUTEGRAVIR
    1) In multicenter trials of treatment-experienced, integrase strand transfer inhibitor-experienced patients with HIV-1, grade 2 to 4 ALT elevations occurred in 8% of patients treated with dolutegravir 50 mg/day in combination with a background regimen (n=183) (Prod Info TIVICAY(R) oral tablets, 2013).
    2) In multicenter trials of treatment-experienced, integrase strand transfer inhibitor-experienced patients with HIV-1, grade 2 to 4 AST elevations occurred in 6% of patients treated with dolutegravir 50 mg/day in combination with a background regimen (n=183) (Prod Info TIVICAY(R) oral tablets, 2013).
    3) In multicenter trials of treatment-naive HIV infected patients evaluated at 48 weeks, Grade 2 ALT elevations (more than 2.5 to 5 times the ULN) occurred in 2% of patients treated with dolutegravir 50 mg/day in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) (n=403) compared with 3% of patients treated with raltegravir 400 mg twice daily in combination with 2 NRTIs (n=405). Grade 3 to 4 ALT elevations (more than 5.1 times the ULN) occurred in 2% and 1% of dolutegravir- and raltegravir-treated patients, respectively. Grade 2 ALT elevations developed in 2% of patients treated with dolutegravir 50 mg/day in combination with abacavir/lamivudine (n=414) compared with 5% of patients treated with fixed-dose efavirenz/emtricitabine/tenofovir once daily (n=419); grade 3 to 4 elevations occurred in less than 1% of patients treated with either dolutegravir or efavirenz/emtricitabine/tenofovir (Prod Info TIVICAY(R) oral tablets, 2013).
    4) In multicenter trials of treatment-naive HIV infected patients evaluated at 48 weeks, Grade 2 AST elevations (more than 2.5 to 5 times the ULN) occurred in 3% of patients treated with dolutegravir 50 mg/day in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) (n=403) compared with 3% of patients treated with raltegravir 400 mg twice daily in combination with 2 NRTIs (n=405). Grade 3 to 4 AST elevations (more than 5.1 times the ULN) occurred in 2% and 2% of dolutegravir- and raltegravir-treated patients, respectively. Grade 2 AST elevations developed in 2% of patients treated with dolutegravir 50 mg/day in combination with abacavir/lamivudine (n=414) compared with 3% of patients treated with fixed-dose efavirenz/emtricitabine/tenofovir once daily (n=419); grade 3 to 4 elevations occurred in 0% of patients treated with dolutegravir and 2% of patients treated with efavirenz/emtricitabine/tenofovir (Prod Info TIVICAY(R) oral tablets, 2013).
    b) RALTEGRAVIR
    1) Based on pooled data (96-week analysis) from 2 randomized, double-blind, placebo-controlled, phase 3 trials, grade 2 (2.6 to 5 times the ULN) increases in serum AST levels were reported in 9% of treatment-experienced HIV-1-infected patients who received raltegravir 400 mg twice daily in combination with optimized background therapy (n=462) and in 7% of patients who received optimized background therapy and placebo (n=237). Grade 3 (5.1 to 10 times the ULN) increases in AST levels occurred in 4% of raltegravir-treated patients and in 3% of placebo-treated patients; grade 4 (greater than 10 times the ULN) increases in AST levels occurred in 1% of both raltegravir-treated and placebo-treated patients (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    2) Based on pooled data (96-week analysis) from 2 randomized, double-blind, placebo-controlled, phase 3 trials, grade 2 (2.6 to 5 times the ULN) increases in serum ALT levels were reported in 9% of treatment-experienced HIV-1-infected patients who received raltegravir 400 mg twice daily in combination with optimized background therapy (n=462) and in 9% of patients who received optimized background therapy and placebo (n=237). Grade 3 (5.1 to 10 times the ULN) increases in ALT levels occurred in 4% of raltegravir-treated patients and 2% of placebo-treated patients; grade 4 (greater than 10 times the ULN) increases in ALT levels occurred in 1% of raltegravir-treated patients and 2% of placebo-treated patients (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    3) One patient on raltegravir 200 mg twice daily experienced increased liver aminotransferase levels in a phase II, double-blind, randomized, placebo-controlled, 24-week trial. Patients were randomized to placebo (n=45), raltegravir 200 mg (n=43) , 400 mg (n=45), or 600 mg (n=45) twice daily. In addition, all patients received an optimized background antiviral regimen (Grinsztejn et al, 2007).
    4) PEDIATRIC: Grade 4 elevation of AST and grade 3 elevation of ALT was reported in 1 pediatric patient during a 24-week, open-label study of raltegravir in combination with other antiretroviral agents in HIV infected children 2 to 18 years of age (n=126) (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR: Pruritus was reported in 1 of 43 patients (2.3%) on 200 milligrams (mg) of raltegravir, 2 of 45 patients (4.4%) on 400 mg of raltegravir, 3 of 45 patients (6.7%) on 600 mg of raltegravir, and 0 of 45 patients (0%) on placebo, in a phase II, double-blind, randomized, placebo-controlled, 24-week trial. All patients received treatment twice daily. In addition, all patients received an optimized background antiviral regimen (Grinsztejn et al, 2007).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) INCREASED CREATINE KINASE LEVEL
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR: Based on pooled data (96-week analysis) from 2 randomized, double-blind, placebo-controlled, phase 3 trials, grade 2 to 4 increases in serum creatine kinase levels were reported in equal or slightly higher percentages of treatment-experienced HIV-1-infected patients who received raltegravir 400 mg twice daily in combination with optimized background therapy (n=462) as compared with patients who received optimized background therapy and placebo (n=237). Grade 2 (6 to 9.9 times the ULN) increases occurred in 2% of raltegravir-treated patients and placebo-treated patients. Grade 3 (10 to 19.9 times the ULN) increases occurred in 4% of raltegravir-treated and in 3% of placebo-treated patients; grade 4 (greater than or equal to 20 times the ULN) increases occurred in 3% of raltegravir-treated patients and 1% of placebo-treated patients. Myopathy and rhabdomyolysis have been reported with raltegravir use (Prod Info ISENTRESS(R) oral film-coated tablets, oral chewable tablets, 2013a).
    B) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR
    1) Myopathy and rhabdomyolysis have been reported with raltegravir use, and rhabdomyolysis has also been reported during postmarketing use of raltegravir, although a causal relationship has not been established (Prod Info ISENTRESS(R) oral film-coated tablets, oral chewable tablets, 2013a).
    2) A 44-year-old man coinfected with HIV and hepatitis C developed rhabdomyolysis with severe acute renal failure while on raltegravir therapy. The patient, who had a past history of IV drug abuse, was receiving antiretroviral therapy with raltegravir and tenofovir/emtricitabine for the past 2 years (HIV-RNA undetectable; CD4 greater than 500 cells/mcL). He presented with signs and symptoms of acute renal failure, along with complaints of muscular pain in his dorsolumbar area, neck, and abdomen. Blood tests revealed significantly elevated serum creatinine (13.2 mg/dL), creatine kinase (8947 units/L), AST (177 units/L), and ALT (196 units/L) levels. Antiretroviral therapy was discontinued and hemodialysis was initiated. Subsequently, diuresis increased and renal function improved. Dialysis was discontinued following his sixth session. Within a week, his CK level had returned to normal, and blood and urine cultures were negative. On day 16 following admission, his serum creatinine had decreased to 1.88 mg/dL, which decreased further to 1.1 mg/dL by day 21 (Masia et al, 2010).
    C) DISORDER OF SKELETAL MUSCLE
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR: Skeletal muscle toxicity (a composite of isolated creatine kinase [CK] elevation, myalgia, proximal myopathy on examination, and rhabdomyolysis) was reported in 37% of HIV-infected patients treated with raltegravir (n=159) compared with 19% of patients in the control group (n=159) in a cross-sectional, prevalence study of 318 adults (98% male; 89% white; median age, 51 years) receiving combination antiretroviral therapy (cART). Close to 91% of HIV patients had HIV RNA load of less than 50 copies/mL. The mean duration of raltegravir therapy was 28 months (SD, 17.2). Analysis of individual composite components showed a significant difference between the raltegravir and control groups in incidence of myalgia (19% vs 3%, respectively) and proximal myopathy (4% vs 0%) but not isolated CK elevation (14% vs 16%). No patient in either group developed rhabdomyolysis. While a multivariate analysis showed that both raltegravir therapy and strenuous exercise were both independently associated with overall muscle toxicity, the duration of cART or raltegravir therapy and raltegravir trough level were not associated with any individual component. Overall, it appears that raltegravir-based therapy is associated with symptomatic muscle toxicity, which is not time or concentration dependent (Lee et al, 2013).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) INCREASED GLUCOSE LEVEL
    1) WITH THERAPEUTIC USE
    a) DOLUTEGRAVIR
    1) In multicenter trials of treatment-experienced, integrase strand transfer inhibitor-experienced patients with HIV-1, grade 2 to 4 hyperglycemia occurred in 12% of patients treated with dolutegravir 50 mg/day in combination with a background regimen (n=183) (Prod Info TIVICAY(R) oral tablets, 2013).
    2) In multicenter trials of treatment-naive HIV infected patients evaluated at 48 weeks, Grade 2 hyperglycemia (blood glucose 126 to 250 mg/dL) occurred in 5% of patients treated with dolutegravir 50 mg/day in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) (n=403) and in 5% of patients treated with raltegravir 400 mg twice daily in combination with 2 NRTIs (n=405). Grade 3 hyperglycemia (blood glucose greater than 251 mg/dL) occurred in less than 1% of dolutegravir-treated patients and in 1% of raltegravir-treated patients. Grade 2 hyperglycemia developed in 7% of patients treated with dolutegravir 50 mg/day in combination with abacavir/lamivudine (n=414) compared with 4% of patients treated with fixed-dose efavirenz/emtricitabine/tenofovir once daily (n=419); grade 3 hyperglycemia occurred in 1% of patients treated with dolutegravir and less than 1% of patients treated with efavirenz/emtricitabine/tenofovir (Prod Info TIVICAY(R) oral tablets, 2013).
    b) RALTEGRAVIR
    1) Based on pooled data (96-week analysis) from 2 randomized, double-blind, placebo-controlled, phase 3 trials, grade 2 (126 to 250 mg/dL) increases in fasting serum blood glucose levels were reported in 10% of treatment-experienced HIV-1-infected patients who received raltegravir 400 mg twice daily in combination with optimized background therapy (n=462) and in 7% of patients who received placebo with optimized background therapy (n=237). Grade 3 (251 to 500 mg/dL) increases in fasting serum blood glucose levels were reported in 3% of raltegravir-treated patients and 1% of placebo-treated patients; grade 4 (greater than 500 mg/dL) increases in fasting serum blood glucose levels were not reported in either group (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012).
    B) SERUM CHOLESTEROL RAISED
    1) WITH THERAPEUTIC USE
    a) DOLUTEGRAVIR
    1) In multicenter trials of treatment-experienced, integrase strand transfer inhibitor-experienced patients with HIV-1, grade 2 to 4 cholesterol elevations occurred in 8% of patients treated with dolutegravir 50 mg/day in combination with a background regimen (n=183) (Prod Info TIVICAY(R) oral tablets, 2013).
    2) In multicenter trials of treatment-naive HIV infected patients evaluated at 48 weeks, the mean increase in fasted cholesterol levels from baseline was 6.7 mg/dL patients treated with dolutegravir 50 mg/day in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) (n=403) compared with 8.3 mg/dL in patients treated with raltegravir 400 mg twice daily in combination with 2 NRTIs (n=405). Mean increases in fasted cholesterol levels from baseline were in 17.1 mg/dL in patients treated with dolutegravir 50 mg/day in combination with abacavir/ lamivudine (n=414) compared with 24 mg/dL in patients treated with fixed-dose efavirenz/emtricitabine/tenofovir once daily (n=419) (Prod Info TIVICAY(R) oral tablets, 2013).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) RALTEGRAVIR: Hypersensitivity occurred in less than 2% of patients who received raltegravir in a combination regimen. Severe hypersensitivity reactions, manifested as rash, constitutional findings, and sometimes organ dysfunction including hepatic failure, have also been reported (Prod Info ISENTRESS(R) oral film-coated tablets, chewable tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Raltegravir alone and abacavir/dolutegravir/lamivudine combination therapy have been classified as FDA pregnancy category C.. Dolutegrevir, elvitegravir alone, and elvitegravir/cobicistat/emtricitabine/tenofovir combination have been classified as FDA pregnancy category B. In a case report and in animal studies, no effects on embryonic/fetal survival or fetal weight have been reported with raltegravir. In animal studies, there was no evidence of teratogenicity with elvitegravir. Lactation studies with raltegravir or elvitegravir have not been conducted in humans. In animal studies, raltegravir and elvitegravir were secreted in the milk of lactating rats.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) RALTEGRAVIR
    a) A case report described a 19-year-old, HIV-positive woman treated with combination antiretroviral therapy that included raltegravir during pregnancy who delivered healthy, normal baby at term. Her regimen, initiated 21 weeks before conception, included etravirine 200 mg twice daily, darunavir 600 mg twice daily, 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. Cord serum drug levels were not collected from the infant (Jaworsky et al, 2010).
    B) ANIMAL STUDIES
    1) DOLUTEGRAVIR
    a) RATS, RABBITS: During animal studies, administration of oral dolutegravir up to 1000 mg/kg/day (approximately 27 times the human clinical exposure based on AUC) in rats during gestation days 6 through 17, did not result in maternal or developmental toxicity or teratogenicity. Similarly, administration of dolutegravir up to 1000 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC) in rabbits during gestation days 6 through 18, did not result in teratogenic or developmentally toxic effects. Maternal toxicity, including decreased food consumption and suppressed body weight gain, was observed in rabbits administered dolutegravir up to 1000 mg/kg/day (Prod Info TIVICAY(R) oral tablets, 2013).
    2) ELVITEGRAVIR
    a) RABBITS, RATS: In animal studies, there was no evidence of teratogenicity with elvitegravir. The exposures at the embryo-fetal no observed adverse effects levels (NOAELs) in rats and rabbits treated with elvitegravir during pregnancy were 23 and 0.2 times higher, respectively, than the exposure in humans at the recommended daily dose of 150 mg (Prod Info VITEKTA(R) oral tablets, 2014; Prod Info STRIBILD(TM) oral tablets, 2012).
    3) ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR ALAFENAMIDE
    a) During animal studies with single-agent administration, there were no reports of teratogenicity or adverse effects on reproductive function with elvitegravir at doses up to 23 times the recommended human dose RHD) or with cobicistat at doses up to 3.8 times the RHD. There was no reported increase in fetal variations or malformations with administration of emtricitabine at doses up to approximately 108 times the RHD. Similarly, there was no evidence of impaired fertility or fetal harm due to administration of tenofovir alafenamide at doses approximately 53 times greater than the RHD (Prod Info GENVOYA(R) oral tablets, 2015).
    4) RALTEGRAVIR
    a) RABBITS, RATS: Oral doses of raltegravir in rabbits up to 3- to 4-fold the recommended human dose (up to 1000 mg/kg/day), did not produce any treatment-related external, visceral, or skeletal changes. However, in rats, there were increases in the incidence of supernumerary ribs compared with controls at doses that were 3-fold the recommended human dose (600 mg/kg/day). There were no effects on embryonic/fetal survival or fetal weights in either rabbits or rats (Prod Info ISENTRESS(R) oral tablets, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) ABACAVIR/DOLUTEGRAVIR/LAMIVUDINE
    a) Abacavir/dolutegravir/lamivudine combination therapy has been classified as FDA pregnancy category C (Prod Info TRIUMEQ(R) oral tablets, 2014).
    2) DOLUTEGRAVIR
    a) Dolutegravir has been classified as FDA pregnancy category B (Prod Info TIVICAY(R) oral tablets, 2013)
    3) ELVITEGRAVIR
    a) Elvitegravir has been classified as FDA pregnancy category B (Prod Info VITEKTA(R) oral tablets, 2014).
    4) ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR
    a) Elvitegravir/cobicistat/emtricitabine/tenofovir has been classified as FDA pregnancy category B (Prod Info STRIBILD(TM) oral tablets, 2012).
    5) ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR ALAFENAMIDE
    a) The combination substance of elvitegravir/cobicistat//emtricitabine/tenofovir alafenamide has been classified as FDA pregnancy category B (Prod Info GENVOYA(R) oral tablets, 2015).
    b) Use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk. Patients exposed to cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide during pregnancy may register with the Antiretroviral Pregnancy Registry by calling 1-800-258-4263 (Prod Info GENVOYA(R) oral tablets, 2015).
    6) RALTEGRAVIR
    a) The manufacturer has classified raltegravir as FDA pregnancy category C (Prod Info ISENTRESS(R) oral tablets, 2010).
    b) There is limited data on raltegravir use in pregnancy; however, raltegravir can be considered for use in special circumstances when preferred or alternative agents cannot be used. In general, women who are receiving combination antiretroviral therapy (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). An Antiretroviral Pregnancy Registry has been established, and prescribers can register patients by calling 1-800-258-4263 (Prod Info TIVICAY(R) oral tablets, 2013; Prod Info ISENTRESS(R) oral tablets, 2010).
    B) PLACENTAL TRANSFER
    1) Three case reports described placental transfer leading to high raltegravir concentrations in neonates of 3 pregnant women who received the drug during late pregnancy (gestational week 28, 38, and 39, respectively). Neonates 1 and 2 had raltegravir concentrations of 3634 nanograms (ng)/mL (at 3 hours post-delivery) and 209 ng/mL (at 1 hour post-delivery), which were approximately 7 and 9.5 times, respectively, higher than the paired maternal samples. Neonate 3 did not have a paired maternal sample; however, raltegravir concentrations remained high (776 ng/mL) at 2.5 hours post-delivery. High neonatal raltegravir concentrations continued for up to 3 days after delivery. At week 12, all neonates were negative for HIV-1 DNA PCR. There were no neonatal or maternal adverse effects (McKeown et al, 2010)
    C) ANIMAL STUDIES
    1) ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR ALAFENAMIDE
    a) During animal studies with single-agent administration, there were no reports of teratogenicity or adverse effects on reproductive function with elvitegravir at doses up to 23 times the recommended human dose RHD) or with cobicistat at doses up to 3.8 times the RHD. There was no reported increase in fetal variations or malformations with administration of emtricitabine at doses up to approximately 108 times the RHD. Similarly, there was no evidence of impaired fertility or fetal harm due to administration of tenofovir alafenamide at doses approximately 53 times greater than the RHD (Prod Info GENVOYA(R) oral tablets, 2015).
    2) RALTEGRAVIR
    a) RATS, RABBITS: In both rats and rabbits, placental transfer of raltegravir occurred. A maternal dose of 600 mg/kg/day in rats produced mean fetal plasma drug concentrations approximately 1.5- to 2.5-fold greater than maternal plasma at 1 hour and 24 hours post-dose, respectively. In rabbits, a 1000 mg/kg/day dose produced mean fetal plasma drug concentrations approximately 2% of the mean maternal concentration at both 1 hour and 24 hours post-dose (Prod Info ISENTRESS(R) oral tablets, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) BREAST MILK
    a) DOLUTEGRAVIR
    1) It is not known whether dolutegravir is excreted into human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Dolutegravir has been detected in the milk of lactating rats. Due to the risk of postnatal transmission of HIV, the Centers for Disease Control and Prevention does not recommend breastfeeding for HIV-infected mothers. The manufacturer does not recommend the breastfeeding by lactating women receiving dolutegravir (Prod Info TIVICAY(R) oral tablets, 2013).
    b) ELVITEGRAVIR
    1) It is not known whether elvitegravir is excreted into human breast milk (Prod Info VITEKTA(R) oral tablets, 2014; Prod Info STRIBILD(TM) oral tablets, 2012).
    c) RALTEGRAVIR
    1) Lactation studies with raltegravir have not been conducted in humans. It is not known whether raltegravir is excreted into human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. To avoid risking maternal-to-infant transmission of HIV-1, it is recommended that mothers infected with HIV-1 do not breastfeed (Prod Info ISENTRESS(R) oral tablets, 2010).
    B) ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR ALAFENAMIDE
    1) Avoid breastfeeding while taking this drug (Prod Info GENVOYA(R) oral tablets, 2015).
    2) It is unknown whether cobicistat, elvitegravir, or tenofovir are excreted into human breast milk. Emtricitabine was detected samples of breast milk from 5 HIV-1 infected mothers. Breastfeeding infants exposed to emtricitabine may be at risk for developing a viral resistance to emtricitabine. Additional adverse effects are currently unknown (Prod Info GENVOYA(R) oral tablets, 2015).
    3) 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).
    C) ANIMAL STUDIES
    1) RATS: Raltegravir was secreted in the milk of lactating rats at a mean drug concentration approximately 3-fold greater than that of maternal plasma following a 600 mg/kg/day dose. However, raltegravir exposure through milk did not appear to affect the rat offspring (Prod Info ISENTRESS(R) oral tablets, 2010).
    2) RATS: Elvitegravir was secreted in the milk of lactating rats (Prod Info VITEKTA(R) oral tablets, 2014; Prod Info STRIBILD(TM) oral tablets, 2012).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RALTEGRAVIR
    a) RATS: There were no observed effects on rat fertility at raltegravir doses 3-fold above the recommended human dose (600 mg/kg/day) (Prod Info ISENTRESS(R) oral tablets, 2010).
    2) ELVITEGRAVIR
    a) RATS: There was no apparent effect on fertility in male and female rats at approximately 16- and 30-fold exposures, respectively, above the recommended human dose of 150 mg daily (Prod Info VITEKTA(R) oral tablets, 2014; Prod Info STRIBILD(TM) oral tablets, 2012). Rat offspring exposed to elvitegravir daily from before birth (in utero) through sexual maturity at approximately 18-fold exposures higher than the exposure at the recommended human dose had normal fertility (Prod Info VITEKTA(R) oral tablets, 2014).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) RALTEGRAVIR
    a) Long-term (2-year) carcinogenicity studies of raltegravir in animals are being performed at the time of this review (Prod Info ISENTRESS oral tablets, 2007).
    B) LACK OF EFFECT
    1) DOLUTEGRAVIR
    a) No drug related increases in neoplasm incidence were observed in rats and mice administered dolutegravir during two-year carcinogenicity studies. Mice and rats administered doses up to 500 mg/kg and 50 mg/kg, respectively, resulting in dolutegravir AUC approximately 14-fold and 10- to 15-fold the human exposure, respectively, showed no significant increases in drug-related neoplasms (Prod Info TIVICAY(R) oral tablets, 2013).
    2) ELVITEGRAVIR
    a) No drug-related increases in tumor incidence were determined in long-term carcinogenicity studies of elvitegravir. Mice administered doses up to 2000 mg/kg/day alone or in combination with ritonavir 25 mg/kg/day at exposures 3- and 14-fold, respectively, the human systemic exposure at the recommended daily dose of 150 mg were not found to have drug-related increases in tumor incidence at 104 weeks. Rats administered doses up to 2000 mg/kg/day at exposures 12- to 27-fold, respectively, in males and females the human systemic exposure at the recommended daily dose of 150 mg were not found to have drug-related increases in tumor incidence at 88 weeks (males) and 90 weeks (females) (Prod Info GENVOYA(R) oral tablets, 2015; Prod Info STRIBILD(TM) oral tablets, 2012).

Genotoxicity

    A) Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, and in vivo rodent micronucleus assay (Prod Info TIVICAY(R) oral tablets, 2013). There was no evidence of mutagenicity or genotoxicity in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage and in vitro and in vivo chromosomal aberration studies of raltegravir (Prod Info ISENTRESS oral tablets, 2007). There was no evidence of genotoxicity in the reverse mutation bacterial test (Ames) and the rat micronucleus assay of elvitegravir. In an in vitro chromosomal aberration study, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation (Prod Info GENVOYA(R) oral tablets, 2015; Prod Info STRIBILD(TM) oral tablets, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and liver enzyme levels after significant overdose.
    B) Monitor fluids and serum electrolytes, pancreatic enzymes, glucose levels, and CPK after significant overdose.

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 who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home. There is no data to support a safe dose for home management in pediatric exposures.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs and liver enzyme levels after significant overdose.
    B) Monitor fluids and serum electrolytes, pancreatic enzymes, glucose levels, and CPK after significant overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) 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).
    6.5.2) 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. There is no antidote available. As these agents are generally given in conjunction with other HIV antiretroviral agents, it would be advisable to monitor for overdoses from these agents as well.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and liver enzyme levels after significant overdose.
    2) Monitor fluids and serum electrolytes, pancreatic enzymes, glucose levels, and CPK after significant overdose.
    C) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Dolutegravir is at least 98% protein-bound and raltegravir is approximately 83% protein-bound (Prod Info TIVICAY(R) oral tablets, 2013; Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2012); hemodialysis may not be useful as a method of enhanced elimination.

Range Of Toxicity

Summary

    A) TOXICITY: DOLUTEGRAVIR: Oral doses up to 250 mg in healthy subjects have been well-tolerated without evidence of specific toxicity. RALTEGRAVIR: Limited data available. Healthy volunteers did not experience any toxicity after receiving doses as high as 1600-mg single dose and 800-mg twice-daily multiple doses. In several studies, patients did not experience any toxicity after receiving occasional doses of up to 1800 mg daily.
    B) THERAPEUTIC DOSE: DOLUTEGRAVIR: 50 mg orally once or twice daily in patients 12 years of age and older and who weigh at least 40 kg. RALTEGRAVIR: Adults: 400 mg orally twice daily. Children: 12 years and older, (film-coated tablet) 400 mg orally twice daily; 2 to 11 years, (chewable tablet) doses range from 75 mg twice daily to 300 mg twice daily depending on patient's weight.

Therapeutic Dose

    7.2.1) ADULT
    A) ABACAVIR/DOLUTEGRAVIR/LAMIVUDINE
    1) The recommended dose is one fixed-dose tablet of abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg orally once daily (Prod Info TRIUMEQ(R) oral tablets, 2014)
    B) DOLUTEGRAVIR
    1) The recommended dose is 50 mg once daily, with or without food, in treatment-naive or treatment-experienced INSTI-naive patients. If coadministered with UGT1A/CYP3A inducers, the recommended dose is 50 mg twice daily. In patients with known or suspected INSTI resistance, the recommended dose is 50 mg twice daily (Prod Info TIVICAY(R) oral tablets, 2016).
    C) ELVITEGRAVIR
    1) Elvitegravir must be given with ritonavir and another antiretroviral agent(s), with the recommended dosing regimens as follows (Prod Info VITEKTA(R) oral tablets, 2014):
    a) 85 mg orally once daily coadministered with atazanavir 300 mg and ritonavir 100 mg orally once daily
    b) 85 mg orally once daily coadministered with lopinavir 400 mg and ritonavir 100 mg orally which are given twice daily
    c) 150 mg orally once daily coadministered with darunavir 600 mg and ritonavir 100 mg orally which are given twice daily
    d) 150 mg orally once daily coadministered with fosamprenavir 700 mg and ritonavir 100 mg orally which are given twice daily
    e) 150 mg orally once daily coadministered with tipranavir 500 mg and ritonavir 200 mg orally which are given twice daily
    D) ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR
    a) The recommended dose is 1 tablet (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) orally once a day with food (Prod Info STRIBILD(TM) oral tablets, 2012).
    E) ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR ALAFENAMIDE
    1) The recommended dose is 1 tablet (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg) orally once daily with food (Prod Info GENVOYA(R) oral tablets, 2015)
    F) RALTEGRAVIR
    1) The recommended dose of film-coated tablets is 400 mg orally twice daily, with or without food, for the treatment of HIV-1 infection. If coadministered with rifampin, the recommended dose is 800 mg twice daily (Prod Info ISENTRESS(R) oral film-coated tablets, chewable tablets, suspension, 2013).
    7.2.2) PEDIATRIC
    A) ABACAVIR/DOLUTEGRAVIR/LAMIVUDINE
    1) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info TRIUMEQ(R) oral tablets, 2014)
    B) DOLUTEGRAVIR
    1) 30 KG TO LESS THAN 40 KG: 35 mg once daily (Prod Info TIVICAY(R) oral tablets, 2016)
    2) 30 KG TO LESS THAN 40 KG (COADMINISTERED WITH A UGT1A/CYP3A INDUCER): 35 mg twice daily (Prod Info TIVICAY(R) oral tablets, 2016)
    3) 40 KG OR MORE: 50 mg once daily (Prod Info TIVICAY(R) oral tablets, 2016)
    4) 40 KG OR MORE (COADMINISTERED WITH A UGT1A/CYP3A INDUCER): 50 mg twice daily (Prod Info TIVICAY(R) oral tablets, 2016)
    5) INSTI RESISTANT: Safety and effectiveness have not been established (Prod Info TIVICAY(R) oral tablets, 2016).
    C) ELVITEGRAVIR
    1) 12 YEARS OF AGE AND OLDER: In an open-label, multicenter trial of HIV-1 infected antiretroviral experienced adolescent patients (aged 12 through 17 years), either elvitegravir 150 mg plus darunavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir (n=11) or elvitegravir 85 mg plus lopinavir/ritonavir or atazanavir/ritonavir (n=14) was administered. However, only 9 patients completed the 48-week treatment phase of the trial and 8 of these patients (89%) had undetectable elvitegravir levels during treatment, suggesting poor adherence. Thus, the 48-week treatment phase data were insufficient to establish safety and effectiveness of elvitegravir in adolescent patients (Prod Info VITEKTA(R) oral tablets, 2014)
    2) YOUNGER THAN 12 YEARS OF AGE: Safety and effectiveness have not been evaluated in clinical trials (Prod Info VITEKTA(R) oral tablets, 2014).
    D) ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR
    1) YOUNGER THAN 18 YEARS OF AGE: Safety and efficacy have not been established in pediatric patients (Prod Info STRIBILD(TM) oral tablets, 2012).
    E) ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR ALAFENAMIDE
    1) 12 YEARS OR OLDER, WEIGHING AT LEAST 35 KG: The recommended dose is 1 tablet (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg) orally once daily with food (Prod Info GENVOYA(R) oral tablets, 2015)
    2) LESS THAN 12 YEARS: Safety and effectiveness have not been established in patients less than 12 years of age (Prod Info GENVOYA(R) oral tablets, 2015).
    F) RALTEGRAVIR
    1) 25 KG OR MORE
    a) FILM-COATED TABLET: The recommended dose is 400 mg orally twice daily (Prod Info ISENTRESS(R) oral film-coated tablets, chewable tablets, suspension, 2013), OR
    b) CHEWABLE TABLET: The dose is based on weight of approximately 6 mg/kg/dose twice daily, up to a MAXIMUM DOSE of 300 mg twice daily; (25 kg to less than 28 kg) 150 mg orally twice daily; (28 kg to less than 40 kg) 200 mg orally twice daily; (at least 40 kg) 300 mg orally twice daily (Prod Info ISENTRESS(R) oral film-coated tablets, chewable tablets, suspension, 2013).
    2) 4 WEEKS OR OLDER AND LESS THAN 25 KG
    a) CHEWABLE TABLETS: The dose is based on weight of approximately 6 mg/kg/dose twice daily, up to a MAXIMUM DOSE of 150 mg twice daily; (11 kg to less than 14 kg) 75 mg orally twice daily; (14 kg to less than 20 kg) 100 mg orally twice daily; (20 kg to less than 25 kg) 150 mg orally twice daily (Prod Info ISENTRESS(R) oral film-coated tablets, chewable tablets, suspension, 2013), OR
    b) ORAL SUSPENSION: The dose is based on weight of approximately 6 mg/kg/dose twice daily, up to a MAXIMUM dose of 100 mg twice daily; (3 kg to less than 4 kg) 20 mg (1 mL) orally twice daily; (4 kg to less than 6 kg) 30 mg (1.5 mL) orally twice daily; (6 kg to less than 8 kg) 40 mg (2 mL) orally twice daily; (8 kg to less than 11 kg) 60 mg (3 mL) orally twice daily; (11 kg to less than 14 kg) 80 mg (4 mL) orally twice daily; (14 kg to less than 20 kg) 100 mg (5 mL) orally twice daily (Prod Info ISENTRESS(R) oral film-coated tablets, chewable tablets, suspension, 2013).
    3) YOUNGER THAN 4 WEEKS OF AGE: Safety and efficacy have not been established in this age group (Prod Info ISENTRESS(R) oral film-coated tablets, chewable tablets, suspension, 2013).

Maximum Tolerated Exposure

    A) DOLUTEGRAVIR: Oral doses up to 250 mg in healthy subjects have been well-tolerated without evidence of specific toxicity (Prod Info TIVICAY(R) oral tablets, 2013).
    B) RALTEGRAVIR: Limited data available. Healthy volunteers did not experience any toxicity after receiving doses as high as 1600-mg single dose and 800-mg twice-daily multiple doses. In several studies, patients did not experience any toxicity after receiving occasional doses of up to 1800 mg daily (Prod Info ISENTRESS(R) oral film-coated tablets, oral chewable tablets, 2013).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) DOLUTEGRAVIR
    1) Dolutegravir is an HIV-1 integrase inhibitor. It binds to the integrase active site and blocks the strand transfer step of retroviral DNA integration which is an essential part of the HIV replication cycle (Prod Info TIVICAY(R) oral tablets, 2013).
    B) ELVITEGRAVIR
    1) Elvitegravir is an HIV-1 integrase strand transfer inhibitor. By inhibiting HIV-1 integrase, the HIV virus is unable to integrate viral DNA into the host DNA, further inhibiting HIV-1 provirus and propagation of viral infection. Elvitegravir does not inhibit human topoisomerases I or II (Prod Info VITEKTA(R) oral tablets, 2014).
    C) RALTEGRAVIR
    1) Raltegravir potassium is an HIV-1 integrase inhibitor. It prevents viral replication by inhibiting viral DNA insertion into the host's cellular genome. Specifically, raltegravir prevents integrase insertion essential for endonucleolytic processing of the viral DNA ends, and the subsequent strand transfer or integration of viral and cellular DNA. Humans lack the integrase enzyme and therefore, toxicities due to integrase inhibition are not expected (Palmisano, 2007; Kassahun et al, 2007; Markowitz et al, 2006).

Physicochemical

Physical Characteristics

    A) DOLUTEGRAVIR is a white to light yellow powder that is slightly soluble in water (Prod Info TIVICAY(R) oral tablets, 2013).
    B) ELVITEGRAVIR is a white to pale yellow powder that has a solubility of less than 0.3 mcg/mL in water at a temperature of 20 degrees C (Prod Info GENVOYA(R) oral tablets, 2015; Prod Info VITEKTA(R) oral tablets, 2014).
    C) RALTEGRAVIR is a white to off-white powder that is soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile, and insoluble in isopropanol (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2013).

Molecular Weight

    A) DOLUTEGRAVIR: 441.36 g/mol (Prod Info TIVICAY(R) oral tablets, 2013)
    B) ELVITEGRAVIR: 447.9 (Prod Info GENVOYA(R) oral tablets, 2015; Prod Info VITEKTA(R) oral tablets, 2014)
    C) RALTEGRAVIR: 482.51 (Prod Info ISENTRESS(R) oral film coated tablets, oral chewable tablets, 2013)

References

General Bibliography

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    30) Product Information: ISENTRESS oral tablets, raltegravir oral tablets. Merck & Co,Inc, Whitehouse Station, NJ, 2007.
    31) Product Information: ISENTRESS(R) oral film coated tablets, oral chewable tablets, raltegravir oral film coated tablets, oral chewable tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2012.
    32) Product Information: ISENTRESS(R) oral film coated tablets, oral chewable tablets, raltegravir oral film coated tablets, oral chewable tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2013.
    33) Product Information: ISENTRESS(R) oral film-coated tablets, chewable tablets, raltegravir oral film-coated tablets, chewable tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2012.
    34) Product Information: ISENTRESS(R) oral film-coated tablets, chewable tablets, suspension, raltegravir oral film-coated tablets, chewable tablets, suspension. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2013.
    35) Product Information: ISENTRESS(R) oral film-coated tablets, oral chewable tablets, raltegravir oral film-coated tablets, oral chewable tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2013a.
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