Isentress

Isentress

raltegravir

Manufacturer:

MSD

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Raltegravir.
Description
Each film-coated tablet of ISENTRESS (raltegravir, MSD) contains 434.4 mg of raltegravir potassium (as salt), equivalent to 400 mg of raltegravir (free phenol).
Action
Pharmacotherapeutic Class: ISENTRESS (raltegravir) is an HIV integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1).
Pharmacology: Pharmacodynamics:
Drug Resistance: The mutations observed in HIV-1 integrase that contributed to raltegravir resistance (evolved either in vitro or in patients treated with raltegravir) generally included a substitution at either Y143 (changed to C, H or R) or Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional mutations (e.g., L74I/M, E92Q, E138A/K, G140A/S, or V151I).
Recombinant viruses containing a single primary mutation (Q148H, K or R, or N155H) displayed decreased replication capacity and reduced susceptibility to raltegravir in vitro. Secondary mutations further decreased susceptibility to raltegravir and sometimes acted as compensatory mutations for viral replication capacity.
Mutations conferring resistance to raltegravir generally also confer resistance to the integrase strand transfer inhibitor elvitegravir. Mutations at amino acid 143 confer greater resistance to raltegravir than to elvitegravir, and the E92Q mutation confers greater resistance to elvitegravir than to raltegravir. Viruses harboring a mutation at amino acid 148, along with one or more other raltegravir resistance mutations, may also have clinically significant resistance to dolutegravir.
Cardiac Electrophysiology: In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. There was no effect on the QTc interval. Peak raltegravir plasma concentrations were approximately 4 fold higher than the peak concentrations following a 400 mg dose.
Pharmacokinetics: Absorption: As demonstrated in healthy volunteers administered single oral doses of raltegravir (400 mg film coated tablet) in the fasted state, raltegravir 400 mg twice daily is rapidly absorbed with a Tmax of approximately 3 hours postdose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C12hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. In patients on 400 mg twice daily monotherapy, raltegravir drug exposures were characterized by a geometric mean AUC0-12hr of 14.3 μM• hr and C12hr of 142 nM. With twice daily dosing, pharmacokinetic steady state is achieved rapidly, within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax and evidence of slight accumulation in C12hr. The absolute bioavailability of raltegravir has not been established.
Effect of Food on Oral Absorption: ISENTRESS may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-infected patients.
The effect of consumption of low-, moderate- and high-fat meals on steady state raltegravir pharmacokinetics was assessed in healthy volunteers. Administration of multiple doses of 400 mg twice daily raltegravir following a moderate-fat meal did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of 400 mg twice daily raltegravir following a high-fat meal increased AUC and Cmax by approximately 2 fold and increased C12hr by 4.1 fold. Administration of 400 mg twice daily raltegravir following a low-fat meal decreased AUC and Cmax by 46% and 52%, respectively; C12hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.
Distribution: Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM.
Raltegravir readily crossed the placenta in rats, but did not penetrate the brain to any appreciable extent.
In two studies of HIV-1 infected subjects who received raltegravir 400 mg twice daily, raltegravir was readily detected in the cerebrospinal fluid. In the first study (n=18), the median cerebrospinal fluid concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. In the second study (n=16), the median cerebrospinal fluid concentration was 3% (range 1 to 61%) of the corresponding plasma concentration. The median proportions are approximately 3- to 6-fold lower than the free fraction of raltegravir in plasma.
Metabolism and Excretion: The apparent terminal half life of raltegravir is approximately 9 hours, with a shorter α-phase half life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.
Characteristics in Patients: Gender: A study of the pharmacokinetics of raltegravir was performed in young healthy males and females. Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy subjects and 28 HIV patients receiving raltegravir monotherapy with fasted administration. The effect of gender was also evaluated in a population pharmacokinetic (PK) analysis of concentration data from 80 healthy subjects and HIV patients receiving raltegravir alone or in combination with other drugs and in fasted and fed conditions. There were no clinically important pharmacokinetic differences due to gender. No dosage adjustment is necessary.
Age: The effect of age on the pharmacokinetics of raltegravir was evaluated in the composite analysis and the population PK analysis. There was no clinically meaningful effect of age on raltegravir pharmacokinetics. No dosage adjustment is necessary.
Pediatric: The pharmacokinetics of ISENTRESS 400 mg twice daily in pediatric patients less than 4 weeks of age has not been established.
Race and Ethnicity: The effect of race on the pharmacokinetics of raltegravir was evaluated in the composite analysis for ISENTRESS 400 mg twice daily, and no clinical meaningful effect of race on raltegravir pharmacokinetics was concluded. No dosage adjustment is necessary.
Body Mass Index (BMI) and Body weight: The composite analysis assessed the effect of BMI on the pharmacokinetics of raltegravir in adults. There was no clinically meaningful effect of BMI on raltegravir pharmacokinetics. Additionally, no clinically meaningful effect of body weight on raltegravir pharmacokinetics was identified in the population PK analysis. No dosage adjustment is necessary.
Hepatic Insufficiency: Raltegravir is eliminated primarily by glucuronidation in the liver. A study of the pharmacokinetics of raltegravir was performed in adult patients with moderate hepatic insufficiency. Additionally, hepatic insufficiency was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between patients with moderate hepatic insufficiency and healthy subjects. No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency. The effect of severe hepatic insufficiency on the pharmacokinetics of raltegravir has not been studied.
Renal Insufficiency:Renal clearance of unchanged drug is a minor pathway of elimination. A study of the pharmacokinetics of raltegravir was performed in adult patients with severe renal insufficiency. Additionally, renal insufficiency was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy subjects. No dosage adjustment is necessary. Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided.
UGT1A1 Polymorphism: There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinical meaningful extent. In a comparison of 30 adult subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 subjects with wild type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09).
Microbiology: Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (IC95) of viral spread (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir at concentrations of 6 to 50 nM resulted in 95% inhibition of viral spread in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with IC50 values ranging from 5 to 12 nM. Raltegravir also inhibited replication of an HIV 2 isolate when tested in CEMx174 cells (IC95 = 6 nM). Additive to synergistic antiretroviral activity was observed when human T lymphoid cells infected with the H9IIIB variant of HIV 1 were incubated with raltegravir in combination with nucleoside analog reverse transcriptase inhibitors (zidovudine, zalcitabine, stavudine, abacavir, tenofovir, didanosine, or lamivudine); non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine, or delavirdine); protease inhibitors (indinavir, saquinavir, ritonavir, amprenavir, lopinavir, nelfinavir, or atazanavir); or the entry inhibitor enfuvirtide.
Indications/Uses
ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.
Dosage/Direction for Use
For the treatment of patients with HIV-1 infection, the dosage of ISENTRESS (raltegravir) is 400 mg administered orally, twice daily with or without food. Raltegravir is to be given in a combination regimen with other antiretroviral agents.
Overdosage
No specific information is available on the treatment of overdosage with ISENTRESS. Doses as high as 1600 mg single dose and 800 mg b.i.d. multiple doses were studied in Phase I without evidence of toxicity. Occasional doses of 1800 mg per day were taken in Phase II/III studies without evidence of toxicity. Based upon available data, raltegravir appears to be well tolerated at doses up to 800 mg b.i.d. and when administered with drugs that increase exposure by 50-70% (such as tenofovir and atazanavir). Raltegravir had a wide therapeutic margin; thus the potential for toxicity as a result of overdose is limited.
In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. The extent to which ISENTRESS may be dialyzable is unknown.
Contraindications
ISENTRESS is contraindicated in patients who are hypersensitive to any component of this medicine.
Special Precautions
Severe Skin and Hypersensitivity Reactions: Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking ISENTRESS concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping raltegravir treatment or other suspect agents after the onset of severe rash may result in a life threatening reaction.
Drug Interactions: Antacids: Coadministration of ISENTRESS 400 mg twice daily with aluminum and magnesium antacids resulted in reduced raltegravir plasma levels. Coadministration of ISENTRESS 400 mg twice daily with aluminum and/or magnesium antacids is not recommended. (See Interactions.)
Strong inducers of drug metabolizing enzymes: Caution should be used when coadministering ISENTRESS 400 mg twice daily with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of raltegravir (see Interactions).
Immune Reconstitution Syndrome: During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis, or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Use in Children: The safety, tolerability, pharmacokinetic profile, and efficacy of twice daily ISENTRESS were evaluated in HIV-1 infected infants, children and adolescents 4 weeks to 18 years of age in an open-label, multicenter clinical trial, IMPAACT P1066. The safety profile was comparable to that observed in adults (see Side Effects).
Use in the Elderly: Clinical studies of ISENTRESS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Use In Pregnancy & Lactation
Use in Pregnancy: Developmental toxicity studies were performed in rabbits (at doses up to 1000 mg/kg/day) and rats (at doses up to 600 mg/kg/day). The highest doses in these studies produced systemic exposures in these species approximately 3 to 4 fold above the exposure at the recommended human dose. No treatment-related external, visceral, or skeletal changes were observed in rabbits. Treatment-related increases over controls in the incidence of supernumerary ribs were seen in rats at 600 mg/kg/day (exposures 4.4 fold above the exposure at the recommended human dose). In both rabbits and rats, no treatment related effects on embryonic/fetal survival or fetal weights were observed.
In rats, at a maternal dose of 600 mg/kg/day, mean drug concentrations in fetal plasma were approximately 1.5- to 2.5-fold greater than in maternal plasma at 1 hour and 24 hours postdose, respectively. In rabbits, at a maternal dose of 1000 mg/kg/day, mean drug concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose. Toxicokinetic studies demonstrated placental transfer of drug in both species.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an International Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients via email at SM_APR@INCResearch.com or via facsimile at +1-910-256-0637 (in the U.S. and in Canada, call 1-800-258-4263).
Antiretroviral Pregnancy Registry (APR) Data: Based on prospective reports from the APR of over 550 exposures to raltegravir during pregnancy resulting in live births (including over 300 exposures in the first trimester), there was no difference between the overall risk of birth defects for raltegravir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).
The use of ISENTRESS 400 mg twice daily may be considered during pregnancy, if clinically needed. Existing post-marketing data suggest that tolerability and safety of ISENTRESS 400 mg twice daily in pregnant women is consistent with that observed in other populations.
Use in Lactation: It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. In rats, at a maternal dose of 600 mg/kg/day, mean drug concentrations in milk were approximately 3-fold greater than in maternal plasma. Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
Side Effects
Treatment-Experienced Adverse Experiences: The safety assessment of ISENTRESS in treatment experienced patients is based on the pooled safety data from the randomized clinical studies, P018 and P019 reported using the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) in 462 patients, in comparison to 237 patients taking placebo in combination with OBT. During double blind treatment, the total follow-up was 1051 patient years in the group receiving ISENTRESS 400 mg b.i.d. and 322 patient years in the group receiving placebo.
For patients in the group receiving ISENTRESS 400 mg twice daily + OBT (mean follow up 118.7 weeks) and the comparator group receiving placebo + OBT (mean follow up 71.0 weeks) in the pooled analysis for studies P018 and P019, the most commonly reported clinical adverse experiences (>10% in either group), of all intensities and regardless of causality were: diarrhea in 26.6% and 24.9%, nausea in 13.6% and 16.0%, headache in 12.1% and 13.5%, nasopharyngitis in 14.3% and 8.9%, fatigue in 12.1% and 5.9%, upper respiratory tract infection in 15.8% and 10.1%, bronchitis in 12.1% and 6.8%, pyrexia in 9.7% and 13.9%, vomiting in 8.9% and 11.0% of patients, respectively. In this pooled analysis, the rates of discontinuation of therapy due to adverse experiences (clinical and laboratory) were 4.5% in patients receiving raltegravir + OBT and 5.5% in patients receiving placebo + OBT.
Drug Related Adverse Experiences: The clinical adverse experiences listed below were considered by investigators to be of moderate to severe intensity and causally related to ISENTRESS or placebo alone or in combination with OBT. Drug-related clinical adverse experiences of moderate to severe intensity occurring in ≥2% of treatment experienced adult patients in either treatment group are presented in Table 1. (See Table 1.)

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Drug related clinical adverse experiences, occurring in less than 2% of treatment experienced patients (n=462) receiving raltegravir + OBT and of moderate to severe intensity are listed below by System Organ Class.
[Common (≥1/100, <1/10), Uncommon (≥1/1,000, <1/100)]:Cardiac Disorders: Uncommon: Ventricular extrasystoles.
Ear and Labyrinth Disorders:Uncommon: Vertigo.
Eye Disorders: Uncommon: Visual disturbance.
Gastrointestinal Disorders: Common: Diarrhea, nausea. Uncommon: Abdominal pain, abdominal distension, abdominal pain upper, vomiting, constipation, abdominal discomfort, dyspepsia, flatulence, gastritis, gastroesophageal reflux disease, dry mouth, eructation.
General Disorders and Administration Site Conditions: Common: Asthenia, fatigue. Uncommon: Pyrexia, chills, face edema, peripheral edema.
Hepatobiliary Disorders: Uncommon: Hepatitis.
Immune System Disorders: Uncommon: Drug hypersensitivity.
Infections and Infestations: Uncommon: Herpes simplex, genital herpes, gastroenteritis.
Investigations: Uncommon: weight increased, weight decreased.
Metabolism and Nutrition Disorders: Uncommon: Diabetes mellitus, dyslipidaemia, increased appetite, decrease appetite.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Arthralgia, myalgia, back pain, musculoskeletal pain, osteoporosis, polyarthritis.
Nervous System Disorders: Uncommon: Dizziness, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremor.
Psychiatric disorders: Uncommon: Depression, insomnia, anxiety.
Renal and urinary disorders: Uncommon: Nephritis, nephrolithiasis, nocturia, renal failure, tubulointerstitial nephritis.
Reproductive System and Breast Disorders: Uncommon: Gynecomastia.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Epistaxis.
Skin and Subcutaneous Tissue Disorders: Uncommon: Lipodystrophy acquired, rash, hyperhidrosis, dermatitis acneiform, erythema, lipohypertrophy, night sweats, rash macular, rash maculopapular, rash pruritic, xeroderma, prurigo, lipoatrophy, pruritus.
Serious Events: Investigations: Uncommon: weight increased, weight decreased.
The following serious drug related clinical adverse experiences were reported in clinical studies: Gastritis, hepatitis, renal failure, genital herpes, accidental overdose.
TREATMENT NAÏVE ADVERSE EXPERIENCES: STARTMRK (Protocol 021; ISENTRESS 400 mg twice daily): The following safety assessment of ISENTRESS in treatment naïve patients is based on the randomized double blind active controlled study of treatment naïve patients, protocol 021 (STARTMRK) with ISENTRESS 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir disproxil fumarate 245 mg, (N=281) versus efavirenz (EFV) 600 mg at bedtime in combination with emtricitabine (+) tenofovir disproxil fumarate (N=282). During double blind treatment, the total follow-up for patients with raltegravir 400 mg twice daily + emtricitabine (+) tenofovir disproxil fumarate was 1104 patient years and 1036 patient years for patients with efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disproxil fumarate.
Numbers (%) of patients with clinical adverse experiences and with drug-related adverse experiences in the group receiving ISENTRESS, were less frequent than in the group receiving efavirenz based on the nominal p-values (0.325 and <0.001, respectively). In this study, the rates of discontinuation of therapy due to adverse experiences (clinical and laboratory) were 5.0% in patients receiving ISENTRESS + emtricitabine (+) tenofovir disproxil fumarate and 10.0% in patients receiving efavirenz + emtricitabine (+) tenofovir disproxil fumarate.
For patients in the group receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir and the group receiving the comparator, efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disproxil fumarate, the most commonly reported clinical adverse experiences (>10% in either group), of all intensities and regardless of causality are shown in Table 2. (See Table 2.)

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CNS Events: In treatment naïve patients (P021) central nervous system (CNS) adverse experiences, as measured by proportion of patients with 1 or more CNS symptoms (described below), were reported significantly less frequently in the group receiving ISENTRESS + emtricitabine (+) tenofovir disproxil fumarate as compared with the group receiving efavirenz + emtricitabine (+) tenofovir, p <0.001, <0.001 and <0.001 for cumulative events through Weeks 8, 48 and 96, respectively. In the group receiving ISENTRESS, the percentage of patients with 1 or more CNS symptoms was 20.3% compared to 52.1% in the group receiving efavirenz by Week 8, 26.3% compared to 58.5% by Week 48 and 28.8% compared to 60.6% by Week 96. CNS adverse experiences for this analysis were dizziness, insomnia, concentration impaired, somnolence, depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, auditory hallucination, completed suicide and major depression.
Drug Related Adverse Experiences: The clinical adverse reactions listed below were considered by investigators to be of moderate to severe intensity and causally related to raltegravir or efavirenz alone or in combination with emtricitabine (+) tenofovir disproxil fumarate.
Drug-related clinical adverse reactions of moderate to severe intensity occurring in ≥2% of treatment naïve adult patients in either treatment group are presented in Table 3 (see Table 3).

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Drug related clinical adverse experiences, occurring in less than 2% of treatment naïve patients (n=281) receiving ISENTRESS + emtricitabine (+) tenofovir disproxil fumarate and of moderate to severe intensity are listed below by System Organ Class.
[Common (≥1/100, <1/10), Uncommon (≥1/1,000, <1/100)]: Blood and Lymphatic System Disorders: Uncommon: Lymph node pain, neutropenia, anemia, lymphadenopathy.
Ear and Labyrinth Disorders: Uncommon: Tinnitus, vertigo.
Gastrointestinal Disorders: Common: Diarrhea, abdominal pain. Uncommon: Vomiting, abdominal pain upper, dyspepsia, erosive duodenitis, gastroesophageal reflux disease, abdominal distension.
General Disorders and Administration Site Conditions: Common: Fatigue, asthenia. Uncommon: Submandibular mass.
Hepatobiliary Disorders: Uncommon: Hepatitis alcoholic.
Immune System Disorders: Uncommon: Immune reconstitution syndrome.
Infections and Infestations: Uncommon: Herpes zoster, gastroenteritis, folliculitis, lymph node abscess.
Metabolism and Nutrition Disorders: Uncommon: Decreased appetite, hypercholesterolemia, body fat disorder.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Arthritis, neck pain.
Nervous System Disorders: Common: Dizziness. Uncommon: Hypersomnia, somnolence, memory impairment.
Psychiatric disorders: Common: Abnormal dreams, nightmare, depression. Uncommon: Anxiety, mental disorder, confusional state, major depression, suicide attempt.
Renal and Urinary Disorders: Common: Nephrolithiasis.
Reproductive System and Breast Disorders: Uncommon: Erectile dysfunction.
Skin and Subcutaneous Tissue Disorders: Uncommon: Acne, alopecia, skin lesion, lipoatrophy.
Serious Events: The following serious drug related adverse experiences were reported in the clinical study, P021 in treatment-naïve patients receiving ISENTRESS + emtricitabine (+) tenofovir disproxil fumarate: Anemia, immune reconstitution syndrome, mental disorder, suicide attempt, depression.
Selected Adverse Experiences: In studies of ISENTRESS 400 mg twice daily, cancers were observed in treatment experienced patients who initiated ISENTRESS or placebo, both with OBT, and in treatment naïve patients who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir disproxil 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 raltegravir (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.
Rash occurred more commonly in treatment experienced patients receiving regimens containing raltegravir + darunavir compared to patients receiving raltegravir without darunavir or darunavir without raltegravir. 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 limited therapy; there were no discontinuations due to rash. Rash occurred less commonly in treatment naïve patients receiving raltegravir compared with efavirenz, each in combination with emtricitabine (+) tenofovir disproxil fumarate.
Patients with Co-Existing Conditions: Patients Co-infected with hepatitis B and/or hepatitis C virus: In Phase III studies, treatment experienced patients (N=114/699 or 16%) and treatment naïve patients (N=34/563 or 6%) with chronic (but not acute) active hepatitis B and/or hepatitis C coinfection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal. In general the safety profile of raltegravir in patients with hepatitis B and/or hepatitis C co-infection was similar to that in patients without hepatitis B and/or hepatitis C co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup with hepatitis B and/or hepatitis C co infection for both treatment groups.
Postmarketing Experience: The following additional adverse experiences have been reported in a postmarketed experience without regard to causality: Blood and Lymphatic System Disorders: Thrombocytopenia.
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: Depression (particularly in patients with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS).
Laboratory Test Findings: Laboratory Abnormalities: Treatment-Experienced: The percentages of treatment experienced adult patients receiving either ISENTRESS 400 mg twice daily or placebo (both with OBT), in P018 and P019 with selected Grade 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 4 (see Table 4).

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Treatment-Naïve: STARTMRK (Protocol 021; ISENTRESS 400 mg twice daily): The percentages of treatment naïve adult patients receiving either ISENTRESS 400 mg twice daily or efavirenz (both with emtricitabine (+) tenofovir disproxil fumarate), in P021 with selected Grade 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 5 (see Table 5).

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Lipids, Change from Baseline: For P021, changes from baseline in fasting lipids are shown in Table 6 (see Table 6).

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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 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 meaningful 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 (UGTs) 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, methadone, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).
In drug interaction studies performed using the 400 mg twice daily dose, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, maraviroc, tenofovir, midazolam, lamivudine, etravirine, darunavir/ritonavir and boceprevir. In a multiple-dose drug interaction study, ethinyl estradiol and norelgestromin AUC values were 98% and 114%, respectively, when coadministered with raltegravir as compared to when administered without raltegravir. In a multiple-dose drug interaction study, tenofovir AUC and trough concentrations when coadministered with raltegravir were 90% and 87% of values obtained with tenofovir disproxil fumarate monotherapy. In another drug interaction study, midazolam AUC from coadministration was 92% of the value obtained with midazolam alone. In a Phase II study, lamivudine pharmacokinetics were similar in patients receiving combinations with raltegravir versus with efavirenz. The effect of raltegravir on coadministered drugs is presented in Table 7 (see Table 7).
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.
Inducers of Drug Metabolizing Enzymes: Coadministration of ISENTRESS 400 mg twice daily with drugs that are potent inducers of UGT1A1, such as rifampin (an inducer of numerous drug metabolizing enzymes), reduces plasma concentrations of raltegravir. Caution should be used when coadministering ISENTRESS 400 mg twice daily with rifampin or other strong inducers of UGT1A1 (see Precautions). The impact of other potent inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Other less potent inducers (e.g., efavirenz, nevirapine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of ISENTRESS 400 mg twice daily.
Inhibitors of UGT1A1: Coadministration of ISENTRESS 400 mg twice daily with drugs that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) increases plasma levels of raltegravir. However, the degree of increase is modest and combination therapy with these inhibitors was well tolerated in the clinical studies such that no dose adjustment is required for ISENTRESS 400 mg twice daily.
Antacids: Coadministration of ISENTRESS 400 mg twice daily 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 6 hours of ISENTRESS administration significantly decreased raltegravir plasma levels. Therefore, coadministration of ISENTRESS 400 mg twice daily with aluminum and/or magnesium containing antacids is not recommended. Coadministration of ISENTRESS 400 mg twice daily with a calcium carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when ISENTRESS 400 mg twice daily is coadministered with calcium carbonate containing antacids, no dose adjustment is recommended.
Agents that Increase Gastric pH: Coadministration of ISENTRESS 400 mg twice daily with drugs that are known to increase gastric pH (e.g., omeprazole) may increase raltegravir plasma levels based on increased solubility of ISENTRESS at higher pH. In subjects who received ISENTRESS 400 mg twice daily in combination with proton pump inhibitors (PPIs) or H2 blockers in Protocols 018 and 019, comparable safety profiles were observed in this subgroup relative to subjects not receiving proton pump inhibitors or H2 blockers. Based on these data, proton pump inhibitors and H2 blockers may be coadministered with ISENTRESS 400 mg twice daily without dose adjustment.
Additional Considerations: In drug interaction studies of ISENTRESS 400 mg twice daily, atazanavir, efavirenz, ritonavir, tenofovir, and tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of raltegravir. Rifampin, which is a strong inducer of drug metabolizing enzymes, caused a decrease in trough levels of raltegravir (see subsections Inducers of Drug Metabolizing Enzymes and Inhibitors of UGT1A1 in the previous text).
All interaction studies were performed in adults. Drug interactions are further described below in Table 7 (see Table 7).

Click on icon to see table/diagram/image
Storage
Store at or below 30°C (86°F).
MIMS Class
ATC Classification
J05AJ01 - raltegravir ; Belongs to the class of integrase inhibitors. Used as direct acting antiviral in the systemic treatment of viral infections.
Presentation/Packing
FC tab 400 mg (gray, oval, biconvex, debossed with "227" and Merck logo on one side and plain on the other) x 60's.
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