ISENTRESS® (raltegravir) Tablets

ISENTRESS - raltegravir tablet, film coated 
Merck & Co., Inc.

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ISENTRESS® (raltegravir) Tablets

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ISENTRESS safely and effectively. See full prescribing information for ISENTRESS.
ISENTRESS (raltegravir) tablet, film coated for oral use
Initial U.S. Approval: 2007

INDICATIONS AND USAGE

ISENTRESS® is a human immunodeficiency virus integrase strand transfer inhibitor (HIV-1 INSTI) indicated:

  • In combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents (1).

The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients (1).


DOSAGE AND ADMINISTRATION

  • 400 mg administered orally, twice daily with or without food (2.1).

DOSAGE FORMS AND STRENGTHS

Tablets: 400 mg (3).


CONTRAINDICATIONS

None


WARNINGS AND PRECAUTIONS

Monitor for Immune Reconstitution Syndrome (5.1)

Drug Interactions

  • Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of raltegravir (5.2).

ADVERSE REACTIONS

  • The most common adverse reactions (>10%) of all intensities, reported in subjects in either the ISENTRESS or the placebo treatment group, regardless of causality were: nausea, headache, diarrhea and pyrexia (6.1).
  • Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions (6.1).


To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc. at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


USE IN SPECIFIC POPULATIONS

Pregnancy:

  • ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Physicians are encouraged to register pregnant women exposed to ISENTRESS by calling 1-800-258-4263 so that Merck can monitor maternal and fetal outcomes (8.1).

Nursing Mothers:

  • Breast-feeding is not recommended while taking ISENTRESS (8.3).


See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 11/2008

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

1. INDICATIONS AND USAGE

2. DOSAGE AND ADMINISTRATION

2.1 Dosing Information

3. DOSAGE FORMS AND STRENGTHS

4. CONTRAINDICATIONS

5. WARNINGS AND PRECAUTIONS

5.1 Immune Reconstitution Syndrome

5.2 Drug Interactions

6. ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7. DRUG INTERACTIONS

7.1 Effect of Raltegravir on the Pharmacokinetics of Other Agents

7.2 Effect of Other Agents on the Pharmacokinetics of Raltegravir

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Use in Patients with Hepatic Impairment

8.7 Use in Patients with Renal Impairment

10. OVERDOSAGE

11. DESCRIPTION

12. CLINICAL PHARMACOLOGY

12.1 Mechanism Of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

14. CLINICAL STUDIES

16. HOW SUPPLIED/STORAGE AND HANDLING

17. PATIENT COUNSELING INFORMATION


FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

ISENTRESS1 in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of ISENTRESS. These studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults.

The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response [see Clinical Studies (14)].

The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients.

There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.


1

Trademark of MERCK & CO., Inc.
COPYRIGHT © 2007 MERCK & CO., Inc.
All rights reserved

2. DOSAGE AND ADMINISTRATION

2.1 Dosing Information

For the treatment of patients with HIV-1 infection, the dosage of ISENTRESS is 400 mg administered orally, twice daily with or without food.

3. DOSAGE FORMS AND STRENGTHS

400 mg pink, oval shaped, film-coated tablets with "227" on one side.

4. CONTRAINDICATIONS

None

5. WARNINGS AND PRECAUTIONS

5.1 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, Mycobacterium tuberculosis, or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.

5.2 Drug Interactions

Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of raltegravir [see Drug Interactions (7)].

6. ADVERSE REACTIONS

6.1 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-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), and the randomized, double-blind, placebo-controlled, dose-ranging trial (Protocol 005) in antiretroviral treatment-experienced HIV-1 infected adult subjects reported using the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) in 507 subjects, in comparison to 282 subjects taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 332.2 patient-years in the ISENTRESS 400 mg twice daily group and 150.2 patient-years in the placebo group.

The most commonly (>10%) reported adverse reactions, of all intensities, regardless of causality in subjects treated with ISENTRESS and OBT versus placebo and OBT are presented in Table 1.

Table 1: Percentage of Subjects with the Most Commonly Reported (>10%) Adverse Reactions of All Intensities* and Regardless of Causality  Occurring in Treatment-Experienced Adult Subjects
System Organ Class, Adverse ReactionsRandomized Studies P005, P018 and P019

ISENTRESS 400 mg

twice daily + OBT

(n=507) 

%

Placebo + OBT

(n=282) 

%
*
Intensities are defined as follows: Mild (awareness of sign or symptom, but easily tolerated); 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.
Gastrointestinal Disorders
Diarrhea16.619.5
Nausea9.914.2
Nervous System Disorders
Headache9.711.7
General Disorders and Administration Site Conditions
Pyrexia4.910.3

The clinical adverse reactions listed below were considered by investigators to be of moderate to severe intensity and causally related to any drug in the combination regimen (ISENTRESS/placebo alone or in combination with OBT, or OBT alone):

Common Adverse Reactions

Drug-related clinical adverse reactions of moderate to severe intensity occurring in ≥2% of subjects treated with ISENTRESS + OBT are presented in Table 2.

Table 2: Percentage of Subjects with Drug-Related*Adverse Reactions of Moderate to Severe Intensity Occurring in ≥2% of Treatment-Experienced Adult Subjects
System Organ Class, Adverse ReactionsRandomized Studies P005, P018 and P019
ISENTRESS 400 mg twice daily
+ OBT
(n = 507)
%
Placebo + OBT
(n = 282)
%
*
Includes adverse reactions at least possibly, probably, or very likely 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.
Gastrointestinal Disorders
Diarrhea3.74.6
Nausea2.23.2
Nervous System Disorders
Headache2.41.4

Less Common Adverse Reactions

Drug-related adverse reactions occurring in at least 1% but less than 2% of treatment-experienced subjects (n=507) receiving ISENTRESS + OBT and of moderate (discomfort enough to cause interference with usual activity) to severe (incapacitating with inability to work or do usual activity) intensity are listed below by system organ class:

Gastrointestinal Disorders: abdominal pain, vomiting

General Disorders and Administration Site Conditions: asthenia, fatigue

Nervous System Disorders: dizziness

Skin and Subcutaneous Tissue Disorders: lipodystrophy acquired

Discontinuations

In the pooled analyses for studies P005, P018 and P019, the rates of discontinuation of therapy due to adverse reactions were 2.0% in subjects receiving ISENTRESS + OBT and 1.4% in subjects receiving placebo + OBT.

Serious Events

Drug Related

The following serious drug-related reactions were reported in the clinical studies, P005, P018 and P019: hypersensitivity (hypersensitivity was seen in 2 subjects with ISENTRESS; therapy was interrupted and upon rechallenge the subjects were able to resume drug), anemia, neutropenia, myocardial infarction, gastritis, hepatitis, herpes simplex, toxic nephropathy, renal failure, chronic renal failure and renal tubular necrosis.

Regardless of Drug Relationship

Cancers were reported in treatment-experienced subjects who initiated ISENTRESS with OBT; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ cell counts below 50 cells/mm3 and most had prior AIDS diagnoses). The cancers included Kaposi’s sarcoma, lymphoma, squamous cell carcinoma, hepatocellular carcinoma and anal cancer. Most subjects 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 ISENTRESS use.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS (see Table 3). Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.

Patients with Co-existing Conditions

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

In the clinical studies, P018 and P019, subjects with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection (N = 113/699 or 16.2%) were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). The rates of AST and ALT abnormalities were somewhat higher in the subgroup of subjects with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to subjects without hepatitis B and/or hepatitis C virus co-infection. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 26%, 27% and 12%, respectively, of raltegravir-treated coinfected subjects as compared to 9%, 8% and 7% of all other raltegravir-treated subjects.

Laboratory Abnormalities

The percentages of adult subjects treated with ISENTRESS 400 mg twice daily in P005, P018 and P019 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening from baseline are presented in Table 3.

Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects
Randomized Studies P005, P018
and P019
Laboratory
Parameter
Preferred Term
(Unit)
LimitISENTRESS
400 mg Twice Daily +
OBT

(N = 507)
Placebo
+
OBT

(N = 282)
ULN = Upper limit of normal range
Hematology
Absolute neutrophil count (103/μL)
Grade 20.75 - 0.9993.7%7.4%
Grade 30.50 - 0.7492.4%2.5%
Grade 4<0.501.0%1.1%
Hemoglobin (gm/dL)
Grade 27.5 - 8.41.0%2.8%
Grade 36.5 - 7.41.0%0.4%
Grade 4<6.50.0%0.0%
Platelet count (103/μL)
Grade 250 - 99.9993.7%5.7%
Grade 325 - 49.9990.4%0.4%
Grade 4<250.8%0.4%
Blood chemistry
Fasting (non-random) serum glucose test (mg/dL)
Grade 2126 – 250 9.3%6.8%
Grade 3251 – 500 1.4%1.4%
Grade 4>500 0.0%0.0%
Total serum bilirubin
Grade 21.6 - 2.5 x ULN5.3%6.7%
Grade 32.6 - 5.0 x ULN 3.2%2.5%
Grade 4>5.0 x ULN 0.8%0.0%
Serum aspartate aminotransferase
Grade 22.6 - 5.0 x ULN 9.1%5.7%
Grade 35.1 - 10.0 x ULN 2.2%2.1%
Grade 4>10.0 x ULN0.4%0.7%
Serum alanine aminotransferase
Grade 22.6 - 5.0 x ULN 6.9%7.8%
Grade 35.1 - 10.0 x ULN3.0%1.4%
Grade 4>10.0 x ULN0.6%1.1%
Serum alkaline phosphatase
Grade 22.6 - 5.0 x ULN 2.0%0.4%
Grade 35.1 - 10.0 x ULN0.4%1.1%
Grade 4>10.0 x ULN0.4%0.4%
Serum pancreatic amylase test
Grade 21.6 - 2.0 x ULN1.4%0.7%
Grade 32.1 - 5.0 x ULN3.6%2.1%
Grade 4>5.0 x ULN0.2%0.0%
Serum lipase test
Grade 21.6 - 3.0 x ULN3.4%1.8%
Grade 33.1 - 5.0 x ULN0.6%0.4%
Grade 4>5.0 x ULN0.2%0.0%
Serum creatine kinase
Grade 26.0 - 9.9 x ULN2.2%1.4%
Grade 310.0 - 19.9 x ULN2.4%1.8%
Grade 4>10.0 x ULN2.2%0.7%

6.2 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.

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

Skin and Subcutaneous Tissue Disorders: rash, Stevens-Johnson syndrome

7. DRUG INTERACTIONS

7.1 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 effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC50>50 µM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, methadone, opioid analgesics, statins, azole antifungals, proton pump inhibitors, oral contraceptives, and anti-erectile dysfunction agents).

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: lamivudine, tenofovir.

7.2 Effect of Other Agents on the Pharmacokinetics of Raltegravir

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

Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, caution should be used when coadministering ISENTRESS with rifampin or other strong inducers of UGT1A1 [see Warnings and Precautions (5.2)]. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Other less strong inducers (e.g., efavirenz, nevirapine, rifabutin, St. John's wort) may be used with the recommended dose of ISENTRESS.

Similar to rifampin, tipranavir/ritonavir reduces plasma concentrations of ISENTRESS. However, approximately 100 subjects received raltegravir in combination with tipranavir/ritonavir in Protocols 018 and 019. Comparable efficacy was observed in this subgroup relative to subjects not receiving tipranavir/ritonavir. Based on these data, tipranavir/ritonavir may be coadministered with ISENTRESS without dose adjustment of ISENTRESS.

Atazanavir, a strong inhibitor of UGT1A1, and atazanavir/ritonavir increase plasma concentrations of raltegravir. However, concomitant use of ISENTRESS and atazanavir/ritonavir did not result in a unique safety signal in Protocol 005 and Protocols 018 and 019. Based on these data, atazanavir/ritonavir may be coadministered with ISENTRESS without dose adjustment of ISENTRESS.

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

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women. In addition, there have been no pharmacokinetic studies conducted in pregnant patients.

Developmental toxicity studies were performed in rabbits (at oral doses up to 1000 mg/kg/day) and rats (at oral doses up to 600 mg/kg/day). The reproductive toxicity study in rats was performed with pre-, peri-, and postnatal evaluation. The highest doses in these studies produced systemic exposures in these species approximately 3- to 4-fold 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 addition, no treatment-related external, visceral, or skeletal changes were observed in rabbits. However, treatment-related increases over controls in the incidence of supernumerary ribs were seen in rats at 600 mg/kg/day (exposures 3-fold the exposure at the recommended human dose).

Placenta transfer of drug was demonstrated in both rats and rabbits. At a maternal dose of 600 mg/kg/day in rats, 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. Mean drug concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers

Breast-feeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.

It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. Mean drug concentrations in milk were approximately 3-fold greater than those in maternal plasma at a maternal dose of 600 mg/kg/day in rats. There were no effects in rat offspring attributable to exposure of ISENTRESS through the milk.

8.4 Pediatric Use

Safety and effectiveness of ISENTRESS in pediatric patients less than 16 years of age have not been established.

8.5 Geriatric Use

Clinical studies of ISENTRESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. 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.

8.6 Use in Patients with Hepatic Impairment

No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied [see Clinical Pharmacology (12.3)].

8.7 Use in Patients with Renal Impairment

No clinically important pharmacokinetic differences between subjects with severe renal impairment and healthy subjects were observed. No dosage adjustment is necessary [see Clinical Pharmacology (12.3)].

10. OVERDOSAGE

No specific information is available on the treatment of overdosage with ISENTRESS. Doses as high as 1600-mg single dose and 800-mg twice-daily multiple doses were studied in healthy volunteers without evidence of toxicity. Occasional doses of 1800 mg per day were taken in the P005/P018 & P019 studies without evidence of toxicity.

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.

11. DESCRIPTION

ISENTRESS contains raltegravir potassium, a human immunodeficiency virus integrase strand transfer inhibitor. The chemical name for raltegravir potassium is N-[(4-Fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt.

The empirical formula is C20H20FKN6O5 and the molecular weight is 482.51. The structural formula is:

Image from Drug Label Content

Raltegravir potassium is a white to off-white powder. It is soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile and insoluble in isopropanol.

Each film-coated tablet of ISENTRESS for oral administration contains 434.4 mg of raltegravir potassium (as salt), equivalent to 400 mg of raltegravir (free phenol) and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism Of Action

Raltegravir is an HIV-1 antiviral drug [see Clinical Pharmacology (12.4)].

12.2 Pharmacodynamics

In a monotherapy study raltegravir (400 mg twice daily) demonstrated rapid antiviral activity with mean viral load reduction of 1.66 log10 copies/mL by Day 10.

In Protocol 005 and Protocols 018 and 019, antiviral responses were similar among subjects regardless of dose.

Effects on Electrocardiogram

In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400 mg dose. ISENTRESS did not appear to prolong the QTc interval for 12 hours postdose. After baseline and placebo adjustment, the maximum mean QTc change was -0.4 msec (1-sided 95% upper Cl: 3.1 msec).

12.3 Pharmacokinetics

Absorption

Raltegravir is 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. With twice-daily dosing, pharmacokinetic steady state is achieved within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax. The average accumulation ratio for C12hr ranged from approximately 1.2 to 1.6.

The absolute bioavailability of raltegravir has not been established.

In subjects who received 400 mg twice daily alone, raltegravir drug exposures were characterized by a geometric mean AUC0-12hr of 14.3 μM●hr and C12hr of 142 nM.

Considerable variability was observed in the pharmacokinetics of raltegravir. For observed C12hr in Protocols 018 and 019, the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%.

Effect of Food on Oral Absorption

ISENTRESS may be administered without regard to food. Administration of raltegravir following a high-fat meal increased raltegravir AUC by approximately 19%. A high-fat meal slowed the rate of absorption resulting in an approximately 34% decrease in Cmax, an 8.5-fold increase in C12hr, and a delay in Tmax following a single 400 mg dose. The effect of consumption of a range of food types on steady-state pharmacokinetics is not known. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-1 positive subjects.

Distribution

Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM.

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.

Special Populations

Pediatric

The pharmacokinetics of raltegravir in pediatric patients has not been established.

Age

The effect of age on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.

Race

The effect of race on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.

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-1 infected subjects receiving raltegravir monotherapy with fasted administration. No dosage adjustment is necessary.

Hepatic Impairment

Raltegravir is eliminated primarily by glucuronidation in the liver. A study of the pharmacokinetics of raltegravir was performed in subjects with moderate hepatic impairment. Additionally, hepatic impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.

Renal Impairment

Renal clearance of unchanged drug is a minor pathway of elimination. A study of the pharmacokinetics of raltegravir was performed in subjects with severe renal impairment. Additionally, renal impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with severe renal impairment 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

Data currently available are not sufficient to determine the impact of UGT1A1 polymorphism on raltegravir pharmacokinetics.

Drug Interactions [see Drug Interactions (7)].

Table 4: Effect of Other Agents on the Pharmacokinetics of Raltegravir
Coadministered
Drug
Coadministered
Drug Dose/Schedule
Raltegravir
Dose/Schedule
Ratio (90% Confidence Interval) of
Raltegravir Pharmacokinetic Parameters
with/without Coadministered Drug;

No Effect = 1.00
nCmaxAUCCmin
atazanavir400 mg daily100 mg single
dose
101.53
(1.11, 2.12)
1.72
(1.47, 2.02)
1.95
(1.30, 2.92)
atazanavir/ritonavir300 mg/100 mg daily400 mg twice
daily
101.24
(0.87, 1.77)
1.41
(1.12, 1.78)
1.77
(1.39, 2.25)
efavirenz600 mg daily400 mg single dose90.64
(0.41, 0.98)
0.64
(0.52, 0.80)
0.79
(0.49, 1.28)
rifampin 600 mg daily400 mg single
dose
90.62
(0.37, 1.04)
0.60
(0.39, 0.91)
0.39
(0.30, 0.51)
ritonavir100 mg twice daily400 mg single
dose
100.76
(0.55, 1.04)
0.84
(0.70, 1.01)
0.99
(0.70 1.40)
tenofovir300 mg daily400 mg twice daily91.64
(1.16, 2.32)
1.49
(1.15, 1.94)
1.03
(0.73, 1.45)
tipranavir/ritonavir 500 mg/200 mg twice
daily
400 mg twice
daily
15
(14 for Cmin)
0.82
(0.46, 1.46)
0.76
(0.49, 1.19)
0.45
(0.31, 0.66)

12.4 Microbiology

Mechanism of Action

Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ.

Antiviral Activity in Cell Culture

Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (EC95) 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 resistant to reverse transcriptase inhibitors and protease inhibitors. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 value = 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 non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine); protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir); or the entry inhibitor enfuvirtide.

Resistance

The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M/R, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226D/F/H, S230R and D232N). Amino acid substitution at Y143C/H/R is another pathway to raltegravir resistance.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term (2-year) carcinogenicity studies of raltegravir in rodents are ongoing.

No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage and in vitro and in vivo chromosomal aberration studies.

No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day which resulted in 4.8-fold exposure above the exposure at the recommended human dose.

14. CLINICAL STUDIES

Description of Clinical Studies

The evidence of efficacy of ISENTRESS is based on the analyses of 24-week data from 2 ongoing, randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019), in antiretroviral treatment-experienced HIV-1 infected adult subjects. These efficacy results were supported by the 48-week analysis of a randomized, double-blind, controlled, dose-ranging trial, Protocol 005, in antiretroviral treatment-experienced HIV-1 infected adult subjects.

Treatment-Experienced Subjects

BENCHMRK 1 and BENCHMRK 2 are Phase III studies to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily in combination with an optimized background therapy (OBT), versus OBT alone, in HIV-infected subjects, 16 years or older, with documented resistance to at least 1 drug in each of 3 Classes (NNRTIs, NRTIs, PIs) of antiretroviral therapies. Randomization was stratified by degree of resistance to PI (1PI vs. >1PI) and the use of enfuvirtide in the OBT. Prior to randomization, OBT was selected by the investigator based on genotypic/phenotypic resistance testing and prior ART history.

Table 5 shows the demographic characteristics of subjects in the ISENTRESS 400 mg twice daily arm and subjects in the placebo arm.

Table 5: Baseline Characteristics
BENCHMRK 1 and 2 PooledISENTRESS 400 mg Twice Daily
+ OBT
(N = 462)
Placebo
+ OBT
(N = 237)
*
Hepatitis B virus surface antigen positive or hepatitis C virus antibody positive.
Gender n (%)
    Male 405 (87.7) 210 (88.6)
    Female 57 (12.3) 27 (11.4)
Race n (%)
    White 301 (65.2) 173 (73.0)
    Black 66 (14.3) 26 (11.0)
    Asian 16 (3.5) 6 (2.5)
    Hispanic 53 (11.5) 19 (8.0)
    Others 26 (5.6) 13 (5.5)
Age (years)
    Median (min, max) 45.0 (16 to 74) 45.0 (17 to 70)
CD4+ Cell Count
    Median (min, max), cells/mm3 119 (1 to 792) 123 (0 to 759)
    ≤50 cells/mm3, n (%) 146 (31.6) 78 (32.9)
    >50 and ≤200 cells/mm3, n (%) 173 (37.4) 85 (35.9)
Plasma HIV-1 RNA
    Median (min, max), log10 copies/mL 4.8 (2 to 6) 4.7 (2 to 6)
    >100,000 copies/mL, n (%) 164 (35.5) 78 (32.9)
History of AIDS n (%)
    Yes 426 (92.2) 216 (91.1)
Prior Use of ART, Median (1st Quartile, 3rd Quartile)
    Years of ART Use 10.1 (7.4 to 12.1) 10.2 (7.9 to 12.4)
    Number of ART 12.0 (9 to 15) 12.0 (9 to 14)
Hepatitis Co-infection* n (%)
    No Hepatitis B or C virus 385 (83.3) 201 (84.8)
    Hepatitis B virus only 36 (7.8) 7 (3.0)
    Hepatitis C virus only 37 (8.0) 27 (11.4)
    Co-infection of Hepatitis B and C virus 4 (0.9) 2 (0.8)
Stratum n (%)
    Enfuvirtide in OBT 175 (37.9) 89 (37.6)
    Resistant to ≥2 PI 447 (96.8) 226 (95.4)

Table 6 compares the characteristics of optimized background therapy at baseline in the ISENTRESS 400 mg twice daily arm and subjects in the control arm.

Table 6: Characteristics of Optimized Background Therapy at Baseline
BENCHMRK 1 and 2 PooledISENTRESS 400 mg Twice Daily
+ OBT
(N = 462)
Placebo
+ OBT
(N = 237)
*
Darunavir use in OBT in darunavir naïve subjects was counted as one active PI.
The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity Score (GSS) were defined as the total oral ARTs in OBT to which a subject's viral isolate showed phenotypic sensitivity and genotypic sensitivity, respectively, based upon phenotypic and genotypic resistance tests. Enfuvirtide use in OBT in enfuvirtide-naïve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naïve subjects was counted as one active drug in OBT.
             Number of ARTs in OBT
Median (min, max) 4.0 (1 to 7) 4.0 (2 to 7)
       Number of Active PI in OBT by
         Phenotypic Resistance Test* 
0 166 (35.9) 97 (40.9)
1 or more 278 (60.2) 137 (57.8)
    Phenotypic Sensitivity Score (PSS) 
0 67 (14.5) 44 (18.6)
1 145 (31.4) 71 (30.0)
2 142 (30.7) 66 (27.8)
3 or more 85 (18.4) 48 (20.3)
     Genotypic Sensitivity Score (GSS) 
0 115 (24.9) 65 (27.4)
1 178 (38.5) 96 (40.5)
2 111 (24.0) 49 (20.7)
3 or more 51 (11.0) 23 (9.7)

Week 24 outcomes for subjects on the recommended dose of ISENTRESS 400 mg twice daily from the pooled studies BENCHMRK 1 and 2 are shown in Table 7. The efficacy responses were evaluated based upon the 436 subjects from the pooled studies BENCHMRK 1 and 2 who had completed 24 weeks of treatment or discontinued earlier. All other outcomes were based upon the total 699 subjects who were randomized and treated.

Table 7: Outcomes by Treatment Group through Week 24

BENCHMRK 1 and 2 Pooled
n (%)
ISENTRESS 400 mg
Twice Daily
+ OBT
(N = 462)
Placebo
+ OBT
(N = 237)
*
Based upon the 436 subjects with Week 24 data
Virologic failure: defined as non-responders who did not achieve >1.0 log10 HIV-1 RNA reduction or <400 HIV-1 RNA copies/mL by Week 16, or viral rebound, which was defined as: (a) HIV-1 RNA >400 copies/mL (on 2 consecutive measurements at least 1 week apart) after initial response with HIV-1 RNA <400 copies/mL, or (b) >1.0 log10 increase in HIV-1 RNA above nadir level (on 2 consecutive measurements at least 1 week apart).
Based upon the total 699 subjects randomized and treated, not all subjects complete to Week 24
§
Includes available data beyond Week 24
Includes loss to follow-up, subjects withdrew consent, noncompliance, protocol violation and other reasons.
Outcome at Week 24n (%)n (%)
Subjects with Week 24 data
Subjects with HIV-1 RNA less than 400 copies/mL*
Subjects with HIV-1 RNA less than 50 copies/mL*
286
216 (75.5)
179 (62.6)
150
59 (39.3)
50 (33.3)
Virologic Failure (confirmed),
      Non-responder,
      Rebound,
74 (16.0)
13 (2.8)
61 (13.2)
121 (51.1)
78 (32.9)
43 (18.1)
Death,§
Discontinuation due to adverse experiences,§
Discontinuation due to other reasons,§,
6 (1.3)
9 (1.9)
6 (1.3)
3 (1.3)
5 (2.1)
1 (0.4)

The mean changes in plasma HIV-1 RNA from baseline were -1.85 log10 copies/mL in the ISENTRESS 400 mg twice daily arm and -0.84 log10 copies/mL for the control arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving ISENTRESS 400 mg twice daily. (89 cells/mm3) than in the control arm (35 cells/mm3).

Virologic responses at Week 24 by baseline genotypic and phenotypic sensitivity score are shown in Table 8.

Table 8: Virologic Response at Week 24 by Baseline Genotypic/Phenotypic Sensitivity Score
BENCHMRK 1 and 2
Pooled

(Noncompleters as failures approach)
Percent with HIV RNA
<400 copies/mL at
Week 24
Percent with HIV RNA
<50 copies/mL at
Week 24

n
ISENTRESS
400 mg Twice Daily
+ OBT
(N = 286)

n

Placebo

+ OBT

(N = 150)

n
ISENTRESS
400 mg Twice Daily
+ OBT
(N = 286)

n

Placebo

+ OBT

(N = 150)
*
The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity Score (GSS) were defined as the total oral ARTs in OBT to which a subject's viral isolate showed phenotypic sensitivity and genotypic sensitivity, respectively, based upon phenotypic and genotypic resistance tests. Enfuvirtide use in OBT in enfuvirtide-naïve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naïve subjects was counted as one active drug in OBT.
Phenotypic Sensitivity Score (PSS)*
0 44 5026 4 44 4126 4
1 89 7550 34 89 6650 30
2 95 8636 42 95 70 36 36
3 or more 48 7333 67 48 5633 55
Genotypic Sensitivity Score (GSS)*
0 69 5440 8 69 41 405
1 115 82 64 36 115 70 64 33
2 67 88 27 78 67 75 27 63
3 or more 30 70 18 61 30 53 18 50

16. HOW SUPPLIED/STORAGE AND HANDLING

ISENTRESS tablets 400 mg are pink, oval-shaped, film-coated tablets with “227” on one side. They are supplied as follows:

NDC 0006-0227-61 unit-of-use bottles of 60.

No. 3894

Storage and Handling

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F). See USP Controlled Room Temperature.

17. PATIENT COUNSELING INFORMATION

[See FDA-Approved Patient Labeling].

Patients should be informed that ISENTRESS is not a cure for HIV infection or AIDS. They should also be told that people taking ISENTRESS may still get infections or other conditions common in people with HIV (opportunistic infections). In addition, patients should be told that the long-term effects of ISENTRESS are not known at this time. Patients should also be told that it is very important that they stay under a physician's care during treatment with ISENTRESS.

Patients should be informed that ISENTRESS does not reduce the chance of passing HIV to others through sexual contact, sharing needles, or being exposed to blood. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms or other barrier methods to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should also be advised to never re-use or share needles.

Physicians should instruct their patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not take two tablets of ISENTRESS at the same time.

Physicians should instruct their patients to read the Patient Package Insert before starting ISENTRESS therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

Manufactured and Distributed by:
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Printed in USA

9795102

U.S. Patent Nos. US 7,169,780

FDA-Approved Patient Labeling

Patient Information
ISENTRESS® (eye sen tris)
(raltegravir)
Tablets

Read the patient information that comes with ISENTRESS1 before you start taking it and each time you get a refill. There may be new information. This leaflet is a summary of the information for patients. Your doctor or pharmacist can give you additional information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is ISENTRESS?

ISENTRESS must be used with other anti-HIV medicines.

How does ISENTRESS work?

Does ISENTRESS lower the chance of passing HIV to other people?

No. ISENTRESS does not reduce the chance of passing HIV to others through sexual contact, sharing needles, or being exposed to your blood.

Ask your doctor if you have any questions about safer sex or how to prevent passing HIV to other people.

What should I tell my doctor before and during treatment with ISENTRESS?

Tell your doctor about all of your medical conditions. Include any of the following that applies to you:

Tell your doctor about all the medicines you take. Include the following:

Know the medicines you take.

How should I take ISENTRESS?

Take ISENTRESS exactly as your doctor has prescribed. The recommended dose is as follows:

Do not change your dose or stop taking ISENTRESS or your other anti-HIV medicines without first talking with your doctor.

IMPORTANT: Take ISENTRESS exactly as your doctor prescribed and at the right times of day because if you don't:

If you fail to take ISENTRESS the way you should, here's what to do:

Be sure to keep a supply of your anti-HIV medicines.

What are the possible side effects of ISENTRESS?

When ISENTRESS has been given with other anti-HIV drugs, the most common side effects included:

Other side effects include rash, severe skin reactions, depression, suicidal thoughts and actions.

A condition called Immune Reconstitution Syndrome can happen in some patients with advanced HIV infection (AIDS) when combination antiretroviral treatment is started. Signs and symptoms of inflammation from opportunistic infections that a person has or had may occur as the medicines work to control the HIV infection and strengthen the immune system. Call your doctor right away if you notice any signs or symptoms of an infection after starting ISENTRESS with other anti-HIV medicines.

Contact your doctor promptly if you experience unexplained muscle pain, tenderness, or weakness while taking ISENTRESS.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the side effects of ISENTRESS. For more information, ask your doctor or pharmacist.

How should I store ISENTRESS?

General information about the use of ISENTRESS

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

This leaflet gives you the most important information about ISENTRESS.

What are the ingredients in ISENTRESS?

Active ingredient: Each film-coated tablet contains 400 mg of raltegravir.

Inactive ingredients: Microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide.

Manufactured and Distributed by:
MERCK & CO., Inc.
Whitehouse Station, NJ 08889, USA

Revised November 2008

9795102

U.S. Patent Nos. US 7,169,780


ISENTRESS 
raltegravir   tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0006-0227
Route of AdministrationORALDEA Schedule    
INGREDIENTS
Name (Active Moiety)TypeStrength
raltegravir (raltegravir) Active400 MILLIGRAM  In 1 TABLET
black iron oxideInactive 
butylated hydroxytolueneInactive 
calcium phosphate dibasic anhydrousInactive 
hypromellose 2208Inactive 
lactose monohydrateInactive 
magnesium stearateInactive 
microcrystalline celluloseInactive 
poloxamer 407Inactive 
polyethylene glycol 3350Inactive 
polyvinyl alcoholInactive 
red iron oxideInactive 
sodium stearyl fumarateInactive 
talcInactive 
titanium dioxideInactive 
Product Characteristics
Colorpink (pink) Score no score
ShapeOVAL (oval-shaped) Size16mm
FlavorImprint Code 227
Contains    
CoatingtrueSymbolfalse
Packaging
#NDCPackage DescriptionMultilevel Packaging
10006-0227-6160 TABLET In 1 BOTTLENone

Revised: 11/2008Merck & Co., Inc.