Isentress Side Effects

Generic Name: raltegravir

Please note - some side effects for Isentress may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Isentress - for the Consumer

Isentress

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Isentress:

Diarrhea; dizziness; headache; nausea; tiredness; trouble sleeping; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Isentress:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); change in the amount of urine produced; clumsiness; decreased coordination; eye inflammation; fever, chills, or sore throat; general feeling of being unwell; joint aches; mental or mood changes (eg, anxiety, paranoia, depression); mouth sores; muscle aches, pain, tenderness, or weakness; red, swollen, blistered, or peeling skin; severe or persistent dizziness; severe or persistent tiredness or weakness; shortness of breath; suicidal thoughts or actions; symptoms of liver problems (eg, dark urine, loss of appetite, pale stools, severe or persistent nausea or vomiting, stomach pain, yellowing of the skin or eyes); unusual bruising or bleeding.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Isentress Side Effects - for the Professional

Isentress

Clinical Trials Experience

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.

Treatment-Naïve Studies

The following safety assessment of Isentress in treatment-naïve subjects is based on the randomized double-blind active controlled study of treatment-naïve 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 480 patient-years and 463 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir.

In Protocol 021, the rate of discontinuation of therapy due to adverse reactions was 4% in subjects receiving Isentress + emtricitabine (+) tenofovir and 7% 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-naïve subjects treated with Isentress and occurring at a higher rate than efavirenz are presented in Table 1.

Table 1: Adverse Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Naïve Adult Subjects Receiving Isentress and at a Higher Rate Compared to Efavirenz (96 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)‡ %
* 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
Psychiatric Disorders
Insomnia	4	3

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 2.

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

		Randomized Study Protocol 021
Laboratory Parameter Preferred Term (Unit)	Limit	Isentress 400 mg Twice Daily + Emtricitabine (+) Tenofovir (N = 281)	Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir (N = 282)
ULN = Upper limit of normal range
Hematology
Absolute neutrophil count (103/μL)
Grade 2	0.75 - 0.999	3%	4%
Grade 3	0.50 - 0.749	2%	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	2%	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	3%	4%
Grade 3	251 - 500	1%	0%
Grade 4	>500	0%	0%
Total serum bilirubin
Grade 2	1.6 - 2.5 x ULN	4%	0%
Grade 3	2.6 - 5.0 x ULN	1%	0%
Grade 4	>5.0 x ULN	0%	0%
Serum aspartate aminotransferase
Grade 2	2.6 - 5.0 x ULN	4%	5%
Grade 3	5.1 - 10.0 x ULN	2%	2%
Grade 4	>10.0 x ULN	1%	<1%
Serum alanine aminotransferase
Grade 2	2.6 - 5.0 x ULN	6%	9%
Grade 3	5.1 - 10.0 x ULN	1%	2%
Grade 4	>10.0 x ULN	1%	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	0%	<1%

Lipids, Change from Baseline

Changes from baseline in fasting lipids are shown in Table 3.

Table 3: Lipid Values, Mean Change from Baseline, Protocol 021

Laboratory Parameter Preferred Term	Isentress 400 mg Twice Daily + Emtricitabine (+) Tenofovir N = 281			Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir N = 282
			Change from Baseline at Week 96			Change from Baseline at Week 96
	Baseline Mean(mg/dL)	Week 96 Mean(mg/dL)	Mean Change (mg/dL)	Baseline Mean(mg/dL)	Week 96 Mean(mg/dL)	Mean Change (mg/dL)
Notes:
N = Number of subjects in the treatment group. 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 96, serum lipid-reducing agents were used in 7% of subjects in the group receiving Isentress and 9% in the efavirenz group.
* Fasting (non-random) laboratory tests.
LDL-Cholesterol*	96	103	7	93	115	21
HDL-Cholesterol*	39	42	3	38	48	10
Total Cholesterol*	159	169	10	156	194	38
Triglyceride*	125	121	-4	137	177	40

Treatment-Experienced Studies

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 4.

Table 4: 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)‡
* 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.
Nervous System Disorders
Headache	2	<1

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 5.

Table 5: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (96 Week Analysis)

		Randomized Studies Protocol 018 and 019
Laboratory Parameter Preferred Term (Unit)	Limit	Isentress 400 mg Twice Daily + OBT (N = 462)	Placebo + OBT (N = 237)
ULN = Upper limit of normal range
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%

Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Studies

The following ADRs occurred in <2% of treatment-naïve 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, nausea

General Disorders and Administration Site Conditions: fatigue, asthenia

Hepatobiliary Disorders: hepatitis

Immune System Disorders: hypersensitivity

Infections and Infestations: genital herpes, herpes zoster

Nervous System Disorders: dizziness

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

Cancers were reported in treatment-experienced subjects who initiated Isentress or placebo, both with OBT, and in treatment-naïve 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. 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.

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

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-naïve 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. 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. In treatment-naïve subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 17%, 28% and 17%, respectively, of co-infected subjects treated with Isentress as compared to 6%, 6% and 3% of all other subjects treated with Isentress.

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

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Side Effects by Body System - for Healthcare Professionals

General

The safety report of raltegravir is based on 281 treatment-naive and 462 treatment-experienced HIV-infected patients receiving the indicated twice daily dosing regimen in combination with emtricitabine plus tenofovir and optimized background therapy, respectively. The most common side effect of moderate to severe intensity which occurred in treatment-naive patients at a higher rate compared to efavirenz was insomnia. The most common side effect of moderate to severe intensity which occurred in treatment-experienced patients at a higher rate compared to placebo was headache. The rates of discontinuation due to side effects were 4% and 7% in treatment-naive subjects receiving raltegravir and efavirenz, respectively, and 4% and 5% in treatment-experienced subjects receiving raltegravir and placebo, respectively.

Gastrointestinal

Gastrointestinal side effects have included nausea, abdominal pain, gastritis, dyspepsia, and vomiting in less than 2% of patients. At least one case each of mouth ulceration and peritonitis (including perihepatitis) have been reported. Diarrhea has been reported during postmarketing experience.

Nervous system

Nervous system side effects of moderate to severe intensity have included insomnia (4%) and headache (greater than or equal to 2%). Dizziness has been reported in less than 2% of patients. Cerebellar ataxia has been reported during postmarketing experience.

Metabolic

Metabolic side effects have included acquired lipodystrophy and elevated serum glucose (Grade 2: up to 10%, Grade 3: up to 3%), alkaline phosphatase (Grade 2: up to 2%, Grade 3: less than 1%, Grade 4: up to 1%), pancreatic amylase (Grade 2: 2%, Grade 3: 4%, Grade 4: less than 1%), and lipase (Grade 2: 5%, Grade 3: 2%). Elevated triglycerides, fasting cholesterol, and low density lipoprotein cholesterol have been reported.

Hepatic

Hepatic side effects have included hepatitis (less than 2%) and elevated aspartate transaminase (AST; Grade 2: up to 9%, Grade 3: up to 4%, Grade 4: up to 1%), alanine transaminase (ALT; Grade 2: up to 9%, Grade 3: up to 4%, Grade 4: up to 1%), and total bilirubin (Grade 2: up to 6%, Grade 3: up to 3%, Grade 4: up to 1%). The rates of AST and ALT abnormalities were higher in patients with hepatitis B and/or hepatitis C virus coinfection. Hepatic failure (with and without associated hypersensitivity) has been reported during postmarketing experience in patients with underlying liver disease and/or concomitant medications.

In treatment-naive patients, Grade 2 or higher laboratory abnormalities indicating a worsening Grade from baseline of AST, ALT, or total bilirubin occurred in 17%, 28%, and 17%, respectively, of coinfected patients treated with raltegravir as compared to 6%, 6%, and 3% of all other patients treated with raltegravir. In treatment-experienced patients, Grade 2 or higher laboratory abnormalities indicating a worsening Grade from baseline of AST, ALT, or total bilirubin occurred in 29%, 34%, and 13%, respectively, of coinfected patients treated with raltegravir as compared to 11%, 10%, and 9% of all other patients treated with raltegravir.

Hematologic

Hematologic side effects have included decreased hemoglobin (Grade 2: up to 1%, Grade 3: up to 1%, Grade 4: less than 1%), absolute neutrophil count (Grade 2: up to 4%, Grade 3: up to 3%, Grade 4: up to 1%), and platelet count (Grade 2: up to 3%, Grade 3: up to 1%, Grade 4: up to 1%). Thrombocytopenia has been reported during postmarketing experience.

Other

Other side effects have included asthenia and fatigue in less than 2% of patients. Pyrexia and diaphoresis have been reported.

Musculoskeletal

Musculoskeletal side effects have included myopathy and rhabdomyolysis; however, relationship of raltegravir to these events is unknown. Elevated creatine kinase (Grade 2: 2%, Grade 3: 4%, Grade 4: 3%) has been reported. Rhabdomyolysis has been reported during postmarketing experience.

Cardiovascular

Cardiovascular side effects have included myocardial infarction.

Renal

Renal side effects have included nephrolithiasis (less than 2%), renal failure (less than 2%), toxic nephropathy, chronic renal failure, and renal tubular necrosis.

Hypersensitivity

Hypersensitivity side effects have included hypersensitivity reactions characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure.

Oncologic

Oncologic side effects have included Kaposi's sarcoma, lymphoma, squamous cell carcinoma, skin cancer, hepatocellular carcinoma, rectal adenocarcinoma, and anal cancer, regardless of causality. The types and rates of specified cancers were expected in a highly immunodeficient population and most patients had other risk factors for cancer, including tobacco use, papillomavirus, and active hepatitis B virus infection. It is unknown if these cancer diagnoses were related to raltegravir use.

Immunologic

Immunologic side effects have included hypersensitivity, genital herpes, and herpes zoster in less than 2% of patients.

Dermatologic

Dermatologic side effects have included skin rash and pruritus. Severe, potentially life-threatening, and fatal skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported.

Rashes considered drug related were mild to moderate in severity and did not limit treatment.

Psychiatric

Psychiatric side effects have included depression (particularly in patients with a history of psychiatric illness), including suicidal ideation and behaviors, in less than 2% of patients. Abnormal dreams and exacerbation of depression have been reported. Anxiety and paranoia have been reported during postmarketing experience.

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