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Isentress

Isentress

SIDE EFFECTS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience

Treatment-Na´ve Adults

The following safety assessment of ISENTRESS in treatment-na´ve subjects is based on the randomized double-blind active controlled study of treatment-na´ve subjects, STARTMRK (Protocol 021) with ISENTRESS 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 300 mg, (N=281) versus efavirenz (EFV) 600 mg at bedtime in combination with emtricitabine (+) tenofovir, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir was 1104 patient-years and 1036 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir.

In Protocol 021, the rate of discontinuation of therapy due to adverse events was 5% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir.

The clinical adverse drug reactions (ADRs) listed below were considered by investigators to be causally related to ISENTRESS + emtricitabine (+) tenofovir or efavirenz + emtricitabine (+) tenofovir. Clinical ADRs of moderate to severe intensity occurring in ≥ 2% of treatment-na´ve subjects treated with ISENTRESS are presented in Table 3.

Table 3: Adverse Drug Reactions* of Moderate to Severe Intensity† Occurring in ≥ 2% of Treatment-Na´ve Adult Subjects Receiving ISENTRESS (240 Week Analysis)

System Organ Class, Preferred Term Randomized Study Protocol 021
ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir
(n = 281)
Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir
(n = 282)
Gastrointestinal Disorders
Nausea 3% 4%
General Disorders and Administration
Fatigue 2% 3%
Nervous System Disorders
Headache 4% 5%
Dizziness 2% 6%
Psychiatric Disorders
Insomnia 1 4% 1 4%
*Includes adverse experiences considered by investigators to be at least possibly, probably, or definitely related to the drug.
†Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).
n = total number of subjects per treatment group

Laboratory Abnormalities

The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or efavirenz in Protocol 021 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 4.

Table 4: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Na´ve Subjects (240 Week Analysis)

Laboratory Parameter Preferred Term (Unit) Limit Randomized Study Protocol 021
ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir
(N = 281)
Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir
(N = 282)
Hematology
Absolute neutrophil coun (103/μL)
  Grade 2 0.75 - 0.999 3% 5%
  Grade 3 0.50 - 0.749 3% 1%
  Grade 4 < 0.50 1% 1%
Hemoglobin (gm/dL) 
  Grade 2 7.5 -8.4 1% 1%
  Grade 3 6.5 -7.4 1% 1%
  Grade 4 < 6.5 < 1% 0%
Platelet count (103/μL)
  Grade 2 50 - 99.999 1% 0%
  Grade 3 25 - 49.999 < 1% < 1%
  Grade 4 < 25 0% 0%
Blood chemistry
Fasting (non-random) serum glucose test (mg/dL)
  Grade 2 126 -250 7% 6%
  Grade 3 251 - 500 2% 1%
  Grade 4 > 500 0% 0%
Total serum bilirubin
  Grade 2 1.6 -2.5 x ULN 5% < 1%
  Grade 3 2.6 -5.0 x ULN 1% 0%
  Grade 4 > 5.0 x ULN < 1% 0%
Serum aspartate aminotransferase
  Grade 2 2.6 -5.0 x ULN 8% 10%
  Grade 3 5.1 -10.0 x ULN 5% 3%
  Grade 4 > 10.0 x ULN 1% < 1%
Serum alanine aminotransferase
  Grade 2 2.6 -5.0 x ULN 11% 12%
  Grade 3 5.1 -10.0 x ULN 2% 2%
  Grade 4 > 10.0 x ULN 2% 1%
Serum alkaline phosphatase
  Grade 2 2.6 -5.0 x ULN 1% 3%
  Grade 3 5.1 -10.0 x ULN 0% 1%
  Grade 4 > 10.0 x ULN < 1% < 1%
ULN = Upper limit of normal range

Lipids, Change from Baseline

Changes from baseline in fasting lipids are shown in Table 5.

Table 5: Lipid Values, Mean Change from Baseline, Protocol 021

Laboratory Parameter Preferred Term ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir
N = 207
Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir
N = 187
  Change from Baseline at Week 240   Change from Baseline at Week 240
Baseline Mean (mg/dL) Week 240 Mean (mg/dL) Mean Change (mg/dL) Baseline Mean (mg/dL) Week 240 Mean (mg/dL) Mean Change (mg/dL)
LDL-Cholesterol* 96 106 10 93 118 25
HDL-Cholesterol* 38 44 6 38 51 13
Total Cholesterol* 159 175 16 157 201 44
Triglyceride* 128 130 2 141 178 37
*Fasting (non-random) laboratory tests at Week 240.
Notes:
N = total number of subjects per treatment group with at least one lipid test result available. The analysis is based on all available data.
If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis. If the missing data was due to other reasons, subjects were censored thereafter for the analysis. At baseline, serum lipid-reducing agents were used in 5% of subjects in the group receiving ISENTRESS and 3% in the efavirenz group. Through Week 240, serum lipid-reducing agents were used in 9% of subjects in the group receiving ISENTRESS and 15% in the efavirenz group.

Treatment-Experienced Adults

The safety assessment of ISENTRESS in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult subjects. A total of 462 subjects received the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) compared to 237 subjects taking placebo in combination with OBT. The median duration of therapy in these trials was 96 weeks for subjects receiving ISENTRESS and 38 weeks for subjects receiving placebo. The total exposure to ISENTRESS was 708 patient-years versus 244 patient-years on placebo. The rates of discontinuation due to adverse events were 4% in subjects receiving ISENTRESS and 5% in subjects receiving placebo.

Clinical ADRs were considered by investigators to be causally related to ISENTRESS + OBT or placebo + OBT. Clinical ADRs of moderate to severe intensity occurring in ≥ 2% of subjects treated with ISENTRESS and occurring at a higher rate compared to placebo are presented in Table 6.

Table 6: Adverse Drug Reactions* of Moderate to Severe Intensity† Occurring in ≥ 2% of Treatment-Experienced Adult Subjects Receiving ISENTRESS and at a Higher Rate Compared to Placebo (96 Week Analysis)

System Organ Class, Adverse Reactions Randomized Studies Protocol 018 and 019
ISENTRESS 400 mg Twice Daily + OBT
(n = 462)
Placebo + OBT
(n = 237)
Nervous System Disorders
Headache 2% < 1 %
*Includes adverse reactions at least possibly, probably, or definitely related to the drug.
†Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).
n=total number of subjects per treatment group.

Laboratory Abnormalities

The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Protocols 018 and 019 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 7.

Table 7: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (96 Week Analysis)

Laboratory Parameter Preferred Term (Unit) Limit Randomized Studies Protocol 018 and 019
ISENTRESS 400 mg Twice Daily + OBT
(N = 462)
Placebo + OBT
(N = 237)
Hematology
Absolute neutrophil count (103/μL)
  Grade 2 0.75 - 0.999 4% 5%
  Grade 3 0.50 - 0.749 3% 3%
  Grade 4 < 0.50 1% < 1%
Hemoglobin (gm/dL)
  Grade 2 7.5 -8.4 1% 3%
  Grade 3 6.5 -7.4 1% 1%
  Grade 4 < 6.5 < 1% 0%
Platelet count (103/μL)
  Grade 2 50 - 99.999 3% 5%
  Grade 3 25 - 49.999 1% < 1%
  Grade 4 < 25 1% < 1%
Blood chemistry
Fasting (non-random) serum glucose test (mg/dL)
  Grade 2 126 -250 10% 7%
  Grade 3 251 - 500 3% 1%
  Grade 4 > 500 0% 0%
Total serum bilirubin
  Grade 2 1.6 -2.5 x ULN 6% 3%
  Grade 3 2.6 -5.0 x ULN 3% 3%
  Grade 4 > 5.0 x ULN 1% 0%
Serum aspartate aminotransferase
  Grade 2 2.6 -5.0 x ULN 9% 7%
  Grade 3 5.1 -10.0 x ULN 4% 3%
  Grade 4 > 10.0 x ULN 1% 1%
Serum alanine aminotransferase
  Grade 2 2.6 -5.0 x ULN 9% 9%
  Grade 3 5.1 -10.0 x ULN 4% 2%
  Grade 4 > 10.0 x ULN 1% 2%
Serum alkaline phosphatase
  Grade 2 2.6 -5.0 x ULN 2% < 1%
  Grade 3 5.1 -10.0 x ULN < 1% 1%
  Grade 4 > 10.0 x ULN 1% < 1%
Serum pancreatic amylase test
  Grade 2 1.6 -2.0 x ULN 2% 1%
  Grade 3 2.1 -5.0 x ULN 4% 3%
  Grade 4 > 5.0 x ULN < 1% < 1%
Serum lipase test
  Grade 2 1.6 -3.0 x ULN 5% 4%
  Grade 3 3.1 -5.0 x ULN 2% 1%
  Grade 4 > 5.0 x ULN 0% 0%
Serum creatine kinase
  Grade 2 6.0 -9.9 x ULN 2% 2%
  Grade 3 10.0 - 19.9 x ULN 4% 3%
  Grade 4 > 20.0 x ULN 3% 1%
ULN = Upper limit of normal range

Less Common Adverse Reactions Observed in Treatment-Na´ve and Treatment-Experienced Studies

The following ADRs occurred in < 2% of treatment-na´ve or treatment-experienced subjects receiving ISENTRESS in a combination regimen. These events have been included because of their seriousness, increased frequency on ISENTRESS compared with efavirenz or placebo, or investigator's assessment of potential causal relationship.

Gastrointestinal Disorders: abdominal pain, gastritis, dyspepsia, vomiting

General Disorders and Administration Site Conditions: asthenia

Hepatobiliary Disorders: hepatitis

Immune System Disorders: hypersensitivity

Infections and Infestations: genital herpes, herpes zoster

Psychiatric Disorders: depression (particularly in subjects with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors

Renal and Urinary Disorders: nephrolithiasis, renal failure

Selected Adverse Events -Adults

Cancers were reported in treatment-experienced subjects who initiated ISENTRESS or placebo, both with OBT, and in treatment-na´ve subjects who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm³ and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving ISENTRESS and the group receiving the comparator.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS (see Table 6). Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS + darunavir/ritonavir compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

Patients with Co-existing Conditions -Adults

Patients Co-infected with Hepatitis B and/or Hepatitis C Virus

In the randomized, double-blind, placebo-controlled trials, treatment-experienced subjects (N = 114/699 or 16%) and treatment-na´ve subjects (N = 34/563 or 6%) with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that in subjects without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. At 96 weeks, in treatment-experienced subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29%, 34% and 13%, respectively, of co-infected subjects treated with ISENTRESS as compared to 11%, 10% and 9% of all other subjects treated with ISENTRESS. At 240 weeks, in treatment-na´ve subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22%, 44% and 17%, respectively, of co-infected subjects treated with ISENTRESS as compared to 13%, 13% and 5% of all other subjects treated with ISENTRESS.

Pediatrics

2 to 18 Years of Age

ISENTRESS has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see Use in Specific Populations and Clinical Studies]. Of the 126 patients, 96 received the recommended dose of ISENTRESS.

In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through W eek 24 were comparable to those observed in adults.

One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.

One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.

4 Weeks to less than 2 Years of Age

ISENTRESS has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see Use in Specific Populations and Clinical Studies].

In these 26 infants and toddlers, the frequency, type and severity of drug-related adverse reactions through W eek 48 were comparable to those observed in adults.

One patient experienced a Grade 3 serious drug-related allergic rash that resulted in treatment discontinuation.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ISENTRESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: thrombocytopenia

Gastrointestinal Disorders: diarrhea

Hepatobiliary Disorders: hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Nervous System Disorders: cerebellar ataxia

Psychiatric Disorders: anxiety, paranoia

Read the Isentress (raltegravir tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Effect Of Raltegravir On The Pharmacokinetics Of Other Agents

Raltegravir does not inhibit (IC50 > 100 μM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC50 > 50 μM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine, darunavir/ritonavir, telaprevir, boceprevir.

Effect Of Other Agents On The Pharmacokinetics Of Raltegravir

Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, in adults the dose of ISENTRESS should be increased during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see DOSAGE AND ADMINISTRATION]. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.

Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.

Coadministration of ISENTRESS with antacids containing divalent metal cations may reduce raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminum and magnesium antacid within 2 hours of ISENTRESS administration significantly decreased raltegravir plasma levels. Therefore, coadministration of ISENTRESS with aluminum and/or magnesium-containing antacids is not recommended. Coadministration of ISENTRESS with a calcium carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when ISENTRESS is coadministered with calcium carbonate-containing antacids, no dose adjustment is recommended.

All interaction studies were performed in adults.

Selected drug interactions are presented in Table 8 [see CLINICAL PHARMACOLOGY].

Table 8: Selected Drug Interactions in Adults

Concomitant Drug Class: Drug Name Effect on Concentration of Raltegravir Clinical Comment
HIV-1-Antiviral Agents
atazanavir Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Metal-Containing Antacids
aluminum and/or magnesium-containing antacids Coadministration or staggered administration (by 2 hours) of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended.
calcium carbonate antacids No dose adjustment is recommended when ISENTRESS is coadministered with calcium carbonate-containing antacids.
H2 Blockers and Proton Pump Inhibitors
omeprazole Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
HCV-Antiviral Agents
boceprevir No dose adjustment required for ISENTRESS or boceprevir.
telaprevir No dose adjustment required for ISENTRESS or telaprevir.
Other Agents
rifampin Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

Read the Isentress Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 4/24/2014
This monograph has been modified to include the generic and brand name in many instances.

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