Isentress
- Generic Name: raltegravir tablets
- Brand Name: Isentress
- Drug Class: HIV, Integrase Inhibitors
Isentress (Raltegravir Tablets) side effects drug center
Isentress Side Effects Center
What Is Isentress?
Isentress (raltegravir) is an antiviral medication used to treat HIV, which causes acquired immunodeficiency syndrome (AIDS). Isentress is not a cure for HIV or AIDS.
What Are Side Effects of Isentress?
Common side effects of Isentress include:
- nausea,
- vomiting,
- diarrhea,
- stomach pain,
- headache,
- tired feeling,
- dizziness,
- sleep problems (insomnia), or
- changes in the shape or location of body fat (especially in arms, legs, face, neck, breasts, and trunk).
Tell your doctor if you have serious side effects of Isentress including:
- pale skin,
- easy bruising or bleeding,
- signs of a new infection (such as fever or chills, cough, or flu symptoms),
- drowsiness,
- confusion,
- increased thirst,
- lower back pain,
- urinating less than usual or not at all,
- depression,
- thoughts about hurting yourself,
- itching,
- loss of appetite,
- dark urine,
- clay-colored stools,
- yellowing of the skin or eyes,
- muscle pain,
- tenderness,
- weakness with fever or flu symptoms and
- dark colored urine, or
- a severe skin reaction.
Dosage for Isentress
For the treatment of adult patients with HIV-1 infection, the dosage of Isentress is one 400 mg film-coated tablet administered orally, twice daily. Consult your doctor for pediatric dosing.
What Drugs, Substances, or Supplements Interact with Isentress?
Isentress may interact with rifampin, phenobarbital, or cholesterol medications. Tell your doctor all medications and supplements you use.
Isentress During Pregnancy and Breastfeeding
During pregnancy, Isentress should be used only when prescribed. It is unknown if this medication passes into breast milk. Because breast milk can transmit HIV, do not breastfeed.
Additional Information
Our Isentress (raltegravir) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
Isentress Consumer Information
Stop taking this medicine and get emergency medical help if you have signs of an allergic reaction: fever, general ill feeling, tiredness, joint or muscle pain, trouble breathing; upper stomach pain, vomiting, loss of appetite, dark urine, yellowing of the skin or eyes; burning eyes, blisters or mouth sores; rash, hives, blistering or peeling skin; swelling of your face, lips, tongue, or throat.
In rare cases, raltegravir can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, or dark colored urine.
Raltegravir affects your immune system, which may cause certain side effects (even weeks or months after you've taken this medicine). Tell your doctor if you have:
- signs of a new infection--fever, night sweats, swollen glands, cold sores, cough, wheezing, diarrhea, weight loss;
- trouble speaking or swallowing, problems with balance or eye movement, weakness or prickly feeling; or
- swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence.
Common side effects may include:
- nausea;
- headache, dizziness;
- tired feeling; or
- sleep problems (insomnia).
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Read the entire detailed patient monograph for Isentress (Raltegravir Tablets)
Isentress Professional Information
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-Naive Adults
The safety of ISENTRESS was evaluated in HIV-infected treatment-naive subjects in 2 Phase III studies: STARTMRK evaluated ISENTRESS 400 mg twice daily versus efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate (TDF), and ONCEMRK evaluated ISENTRESS HD 1200 mg (2 x 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. Safety data from these two studies are presented side-by-side in Tables 6 and 7 to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up and study design.
STARTMRK (ISENTRESS 400 mg twice daily)
In STARTMRK, subjects received ISENTRESS 400 mg twice daily (N=281) or efavirenz (EFV) 600 mg at bedtime (N=282) both in combination with emtricitabine (+) tenofovir disoproxil fumarate, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir disoproxil fumarate was 1104 patient-years and 1036 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disoproxil fumarate.
In STARTMRK, the rate of discontinuation of therapy due to adverse events through Week 240 was 5% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate.
ONCEMRK (ISENTRESS HD 1200 mg [2 x 600 mg] once daily)
In ONCEMRK, subjects received ISENTRESS HD 1200 mg once daily (n=531) or ISENTRESS 400 mg twice daily (n=266) both in combination with emtricitabine (+) tenofovir disoproxil fumarate. During double-blind treatment, the total follow-up for subjects with ISENTRESS HD 1200 mg once daily was 913 patient-years and for ISENTRESS 400 mg twice daily was 450 patient-years.
In ONCEMRK, the rate of discontinuation of therapy due to adverse events through Week 96 was 1% in subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily and 2% in subjects receiving ISENTRESS 400 mg twice daily.
Clinical adverse reactions of moderate to severe intensity occurring in ≥2% of treatment-naive subjects treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK through Week 240 or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK through Week 96 are presented in Table 6.
In STARTMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS 400 mg twice daily through Week 240 also include diarrhea, flatulence, asthenia, decreased appetite, abnormal dreams, depression and nightmare. In ONCEMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS HD or ISENTRESS 400 mg twice daily through Week 96 also include abdominal pain, diarrhea, vomiting, and decreased appetite.
Table 6: Adverse Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Naive Adult Subjects Receiving ISENTRESS and ISENTRESS HD
| System OrganClass, Preferred Term | STARTMRK Week 240 |
ONCEMRK Week 96 |
||
| ISENTRESS 400 mg Twice Daily (N= 281) |
Efavirenz 600 mg At Bedtime (N= 282) |
ISENTRESS HD 1200 mg Once Daily (N=531) |
ISENTRESS 400 mg Twice Daily (N=266) |
|
| Headache | 4% | 5% | 1% | <1% |
| Insomnia | 4% | 4% | <1% | <1% |
| Nausea | 3% | 4% | 1% | 0% |
| Dizziness | 2% | 6% | <1% | 0% |
| Fatigue | 2% | 3% | 0% | 0% |
| Note: ISENTRESS BID, ISENTRESS HD and efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate *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 |
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Laboratory Abnormalities
The percentages of adult subjects with selected Grade 2 to 4 laboratory abnormalities (that represent a worsening Grade from baseline) who were treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK are presented in Table 7.
Table 7: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Naive Subjects
| STARTMRK Week 240 |
ONCEMRK Week 96 |
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| LaboratoryParameter Preferred Term (Unit) |
Limit | ISENTRESS 400 mg Twice Daily (N = 281) |
Efavirenz 600 mg At Bedtime (N = 282) |
ISENTRESS HD 1200 mg Once Daily (N=531) |
ISENTRESS 400 mg Twice Daily (N=266) |
| Hematology | |||||
| Absolute neutrophil count (103/μL) | |||||
| Grade 2 | 0.75 -0.999 | 3% | 5% | 2% | 1% |
| Grade 3 | 0.50 -0.749 | 3% | 1% | 1% | 1% |
| Grade 4 | <0.50 | 1% | 1% | <1% | 0% |
| Hemoglobin (gm/dL) | |||||
| Grade 2 | 7.5 -8.4 | 1% | 1% | 0% | 0% |
| Grade 3 | 6.5 -7.4 | 1% | 1% | 0% | 0% |
| Grade 4 | <6.5 | <1% | 0% | 0% | 0% |
| Platelet count (103/μL) | |||||
| Grade 2 | 50 -99.999 | 1% | 0% | 1% | <1% |
| Grade 3 | 25 -49.999 | <1% | <1% | 0% | 0% |
| Grade 4 | <25 | 0% | 0% | 0% | <1% |
| 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% | 3% | 2% |
| Grade 3 | 2.6 -5.0 x ULN | 1% | 0% | 1% | <1% |
| Grade 4 | >5.0 x ULN | <1% | 0% | <1% | 0% |
| Creatinine | |||||
| Grade 2 | 1.4-1.8 x ULN | 1% | 1% | 0% | <1% |
| Grade 3 | 1.9-3.4 x ULN | 0% | <1% | 0% | 0% |
| Grade 4 | ≥3.5 x ULN | 0% | 0% | 0% | 0% |
| Serum aspartate aminotransferase | |||||
| Grade 2 | 2.6 -5.0 x ULN | 8% | 10% | 5% | 3% |
| Grade 3 | 5.1 -10.0 x ULN | 5% | 3% | 2% | <1% |
| Grade 4 | >10.0 x ULN | 1% | <1% | 1% | <1% |
| Serum alanine aminotransferase | |||||
| Grade 2 | 2.6 -5.0 x ULN | 11% | 12% | 4% | 2% |
| Grade 3 | 5.1 -10.0 x ULN | 2% | 2% | 1% | <1% |
| Grade 4 | >10.0 x ULN | 2% | 1% | 1% | <1% |
| Serum alkaline phosphatase | |||||
| Grade 2 | 2.6 -5.0 x ULN | 1% | 3% | 1% | 0% |
| Grade 3 | 5.1 -10.0 x ULN | 0% | 1% | <1% | 0% |
| Grade 4 | >10.0 x ULN | <1% | <1% | 0% | 0% |
| Lipase* | |||||
| Grade 2 | 1.6-3.0 x ULN | - | - | 7% | 5% |
| Grade 3 | 3.1-5.0 x ULN | - | - | 2% | 1% |
| Grade 4 | >5.0 x ULN | - | - | 2% | 1% |
| Creatine kinase* | |||||
| Grade 2 | 6.0-9.9 x ULN | - | - | 4% | 5% |
| Grade 3 | 10.0-19.9 x ULN | - | - | 3% | 3% |
| Grade 4 | ≥20.0 x ULN | - | - | 3% | 2% |
| ULN = Upper limit of normal range Notes: ISENTRESS BID, ISENTRESS HD and Efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate * Test not done in STARTMRK †Test not done in ONCEMRK |
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Lipids, Change from Baseline
Changes from baseline in fasting lipids are shown in Table 8.
Table 8: Lipid Values, Mean Change from Baseline, STARTMRK Study
| Laboratory Parameter Preferred Term | ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir Disoproxil Fumarate N = 207 |
Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir Disoproxil Fumarate N = 187 |
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| 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. |
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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 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 9.
Table 9: Adverse Drug Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Experienced Adult Subjects Receiving ISENTRESSand at a Higher Rate Compared to Placebo (96 Week Analysis)
| System Organ Class, Adverse Reactions | Randomized Studies BENCHMRK 1 and BENCHMRK 2 | |
| 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. |
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Laboratory Abnormalities
The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Studies BENCHMRK 1 and BENCHMRK 2 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 10.
Table 10: Selected Grade 2 to 4 Laboratory Abnormalities Reported inTreatment-Experienced Subjects (96 Week Analysis)
| Randomized Studies BENCHMRK 1 and BENCHMRK 2 | |||
| Laboratory Parameter Preferred Term (Unit) |
Limit | ISENTRESS 400 mgTwice 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-Naive and Treatment-Experienced Studies
The following ADRs occurred in <2% of treatment-naive or treatment-experienced subjects receiving ISENTRESS or ISENTRESS HD in a combination regimen. These events have been included because of their seriousness, increased frequency 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
In studies of ISENTRESS 400 mg twice daily, cancers were reported in treatment-experienced subjects who initiated ISENTRESS or placebo, both with OBT, and in treatment-naive subjects who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir disoproxil fumarate; 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 and ISENTRESS HD (see Tables 6 and 8). Myopathy and rhabdomyolysis have been reported with ISENTRESS. 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 Phase III studies of ISENTRESS, patients 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 the treatment-experienced studies, BENCHMRK 1 and BENCHMRK 2, 16% of all patients (114/699) were co-infected; in the treatment-naive studies, STARTMRK and ONCEMRK, 6% (34/563) and 3% (23/797), respectively, were co-infected. 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 receiving ISENTRESS 400 mg twice daily, 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 treatmentnaive subjects receiving ISENTRESS 400 mg twice daily, 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.
At 96 weeks, in treatment-naive subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 27%, 40% and 13%, respectively, of co-infected subjects treated with ISENTRESS HD 1200 mg once daily as compared to 7%, 5% and 3% of all other subjects treated with ISENTRESS HD 1200 mg once daily.
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 Week 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 Week 48 were comparable to those observed in adults.
One patient experienced a Grade 3 serious drug-related allergic rash that resulted in treatment discontinuation.
HIV-1 Exposed Neonates
Forty-two neonates were treated with ISENTRESS for up to 6 weeks from birth, and followed for a total of 24 weeks in IMPAACT P1110 [see Use In Specific Populations]. There were no drug related clinical adverse reactions and three drug-related laboratory adverse reactions (one case of transient Grade 4 neutropenia in a subject receiving zidovudine-containing regimen for prevention of mother to child transmission (PMTCT), and two bilirubin elevations (one each, Grade 1 and Grade 2) considered non-serious and not requiring specific therapy). The safety profile in neonates was generally similar to that observed in older patients treated with ISENTRESS. No clinically meaningful differences in the adverse event profile of neonates were observed when compared to adults.
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
DRUG INTERACTIONS
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. Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir and coadministration of ISENTRESS with drugs that induce UGT1A1, such as rifampin, may reduce plasma levels of raltegravir (see Table 11).
Selected drug interactions are presented in Table 11 [see CLINICAL PHARMACOLOGY]. In some cases, recommendations differ for ISENTRESS versus ISENTRESS HD.
Table 11: Selected Drug Interactions in Adults
| Concomitant Drug Class: Drug Name | Effect on Concentration of Raltegravir | Clinical Comment for ISENTRESS | Clinical Comment for ISENTRESS HD |
| Metal-Containing Antacids | |||
| Aluminum and/or magnesium-containing antacids | ↓ | Coadministration or staggered administration is not recommended. | |
| Calcium carbonate antacid | ↓ | No dose adjustment | Co-administration is not recommended |
| Other Agents | |||
| Rifampin | ↓ | The recommended dosage is 800 mg twice daily 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]. | Co-administration is not recommended |
| Tipranavir/ritonavir | No dose adjustment | Co-administration is not recommended | |
| Etravirine | ↓ | No dose adjustment | Co-administration is not recommended |
| Strong inducers of drug metabolizing enzymes not mentioned above e.g., Carbamazepine Phenobarbital Phenytoin | ↓↔ | The impact of other strong inducers of drug metabolizing enzymes on raltegravir is unknown. Coadministration is not recommended. | |
Drugs Without Clinically Significant Interactions With ISENTRESS Or ISENTRESS HD
ISENTRESS
In drug interaction studies performed using ISENTRESS film-coated tablets 400 mg twice daily dose, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: ethinyl estradiol/norgestimate, methadone, midazolam, lamivudine, tenofovir disoproxil fumarate, etravirine, darunavir/ritonavir, or boceprevir. Moreover, atazanavir, atazanavir/ritonavir, boceprevir, calcium carbonate antacids, darunavir/ritonavir, efavirenz, etravirine, omeprazole, or tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of 400 mg twice daily raltegravir. No dose adjustment is required when ISENTRESS 400 mg twice daily is coadministered with these drugs.
There is no predicted pharmacokinetic drug interaction between ISENTRESS and tenofovir alafenamide.
ISENTRESS HD
In drug interaction studies, efavirenz did not have a clinically meaningful effect on the pharmacokinetics of ISENTRESS HD 1200 mg (2 x 600 mg) once daily. No dose adjustment is recommended when ISENTRESS HD 1200 mg once daily is coadministered with atazanavir, atazanavir/ritonavir, hormonal contraceptives, methadone, lamivudine, tenofovir disoproxil fumarate, darunavir/ritonavir, boceprevir, efavirenz and omeprazole.
There is no predicted pharmacokinetic drug interaction between ISENTRESS HD and tenofovir alafenamide.
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