Side Effects of Isentress (raltegravir)

Isentress (raltegravir) is an antiretroviral medicine called an integrase inhibitor used to treat human immunodeficiency virus (HIV) infection.

Isentress slows the spread of HIV infection by blocking the HIV integrase enzyme required for virus multiplication. To improve the chance of fighting HIV-1 infection, Isentress must be taken with other HIV medicines.

Although Isentress does not cure HIV or AIDS, continuous HIV treatment with Isentress can help patients control the infection and decrease their risk of acquiring HIV-related illnesses.

Isentress improves the immune system by increasing the number of white blood cells called CD4+ (T) cells, and consequently reduce the risk of death or getting opportunistic infections that can happen when the immune system is weak. 

Common side effects of Isentress include

• trouble sleeping (insomnia),
• headache,
• dizziness,
• nausea, and
• tiredness.

Serious side effects of Isentress include

• depression,
• hepatitis,
• paranoia,
• blood disorders,
• kidney failure,
• kidney stones,
• indigestion or stomach pain,
• muscle pain,
• muscle destruction (rhabdomyolysis),
• increased bilirubin,
• increased levels of liver enzymes,
• increased blood glucose,
• vomiting,
• suicidal thoughts or actions,
• weakness, and
• serious skin and allergic reactions.

Drug interactions of Isentress include medicines which alter the activity of UGT1A1 enzymes, such as rifampin, which may affect blood levels of Isentress.

Patients should avoid taking Isentress with aluminum or magnesium containing antacids which may reduce blood levels of Isentress.

Use of Isentress in pregnant women has not been adequately evaluated. Due to the lack of conclusive safety data, Isentress should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known if Isentress is excreted into human milk. Breastfeeding is not recommended while taking Isentress. To avoid transmitting the HIV-1 virus to the nursing infant, it is not recommended that HIV-1-infected mothers breastfeed their infants.

The most common side effects of raltegravir include:

• Trouble sleeping insomnia)
• Headache
• Dizziness
• Nausea
• Tiredness

Other potential side effects of raltegravir include:

• Depression
• Hepatitis (a type of viral infection of the liver)
• Paranoia
• Blood disorders
• Kidney failure
• Kidney stones
• Indigestion or stomach pain
• Muscle pain (myopathy)
• Rhabdomyolysis (muscle destruction)
• Increased bilirubin
• Increased levels of liver enzymes
• Increased blood glucose
• Vomiting
• Suicidal thoughts or actions
• Weakness

Some patients taking raltegravir experience serious skin and allergic reactions. These reactions can be severe or life-threatening if not treated promptly. Patients who develop any type of skin rash with other symptoms should call their doctor right away.

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

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-byside in Tables 5 and 6 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

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

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

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 Isentress and at a Higher Rate Compared to Placebo (96 Week Analysis)

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 in Treatment-Experienced Subjects (96 Week Analysis)

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

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 treatment-naive 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

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. 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.

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.

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

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. In some cases, recommendations differ for Isentress versus Isentress HD.

Table 11: Selected Drug Interactions in Adults

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, the following drugs did not have a clinically meaningful effect on the pharmacokinetics of 400 mg twice daily raltegravir:

• atazanavir,
• atazanavir/ritonavir,
• boceprevir,
• calcium carbonate antacids,
• darunavir/ritonavir,
• efavirenz,
• etravirine,
• omeprazole, or
• tipranavir/ritonavir.

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.