These Highlights Do Not Include All The Information Needed To Use Isentress Safely And Effectively. See Full Prescribing Information For Isentress.

ISENTRESS ^® (eye sen tris )

(raltegravir)

film-coated tablets

ISENTRESS ^® (eye sen tris )

(raltegravir)

chewable tablets

ISENTRESS ^® (eye sen tris )

(raltegravir)

for oral suspension

Read this Patient Information before you start taking ISENTRESS and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is ISENTRESS?

ISENTRESS is a prescription HIV medicine used with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in people 4 weeks of age and older. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

It is not known if ISENTRESS is safe and effective in babies under 4 weeks of age.

When used with other HIV medicines to treat HIV-1 infection, ISENTRESS may help:

• reduce the amount of HIV in your blood. This is called "viral load".
• increase the number of white blood cells called CD4+ (T) cells in your blood, which help fight off other infections.
• reduce the amount of HIV-1 and increase the CD4+ (T) cells in your blood, which may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

ISENTRESS does not cure HIV-1 infection or AIDS.

You must stay on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV-1 infection to others.

• Do not share or re-use needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

Ask your doctor if you have any questions on how to prevent passing HIV to other people.

What should I tell my doctor before taking ISENTRESS?

Before you take ISENTRESS, tell your doctor if you:

• have liver problems
• have a history of a muscle disorder called rhabdomyolysis or myopathy
• have increased levels of creatine kinase in your blood
• have phenylketonuria (PKU). ISENTRESS chewable tablets contain phenylalanine as part of the artificial sweetener, aspartame. The artificial sweetener may be harmful to people with PKU.
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if ISENTRESS can harm your unborn baby.
  
  Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you take ISENTRESS.
  • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • Talk with your doctor about the best way to feed your baby.

Tell your doctor about all the medicines you take, including, prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with ISENTRESS. Keep a list of your medicines to show your doctor and pharmacist.

• You can ask your doctor or pharmacist for a list of medicines that interact with ISENTRESS.
• Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take ISENTRESS with other medicines.

How should I take ISENTRESS?

• Take ISENTRESS exactly as prescribed by your doctor.
• Do not change your dose of ISENTRESS or stop your treatment without talking with your doctor first.
• Stay under the care of your doctor while taking ISENTRESS.
• ISENTRESS film-coated tablets must be swallowed whole.
• ISENTRESS chewable tablets may be chewed or swallowed whole.
• ISENTRESS for oral suspension should be given to your child within 30 minutes of mixing. See the detailed Instructions for Use that comes with ISENTRESS for oral suspension , for information about the correct way to mix and give a dose of ISENTRESS for oral suspension. If you have questions about how to mix or give ISENTRESS for oral suspension, talk to your doctor or pharmacist.
• Do not switch between the film-coated tablet, the chewable tablet, or the oral suspension without talking with your doctor first.
• Do not run out of ISENTRESS. Get a refill of your ISENTRESS from your doctor or pharmacy before you run out.
• If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not double your next dose or take more ISENTRESS than prescribed.
• If you take too much ISENTRESS, call your doctor or go to the nearest hospital emergency room right away.

What are the possible side effects of ISENTRESS?

ISENTRESS can cause serious side effects including:

• Serious skin reactions and allergic reactions. Some people who take ISENTRESS develop serious skin reactions and allergic reactions that can be severe, and may be life-threatening or lead to death. If you develop a rash with any of the following symptoms, stop using ISENTRESS and call your doctor right away:
  • fever
  • generally ill feeling
  • extreme tiredness
  • muscle or joint aches
  • blisters or sores in mouth
  • blisters or peeling of the skin
  • redness or swelling of the eyes
  • swelling of the mouth or face
  • problems breathing

Sometimes allergic reactions can affect body organs, such as your liver. Call your doctor right away if you have any of the following signs or symptoms of liver problems:

• • yellowing of your skin or whites of your eyes
  • dark or tea colored urine
  • pale colored stools (bowel movements)
  • nausea or vomiting
  • loss of appetite
  • pain, aching, or tenderness on the right side of your stomach area

• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor right away if you start having new symptoms after starting your HIV-1 medicine.

The most common side effects of ISENTRESS include:

• trouble sleeping
• headache
• dizziness
• nausea
• tiredness

Less common side effects of ISENTRESS include:

• depression
• hepatitis
• genital herpes
• herpes zoster including shingles
• kidney failure
• kidney stones
• indigestion or stomach area pain
• vomiting
• suicidal thoughts and actions
• weakness

Tell your doctor right away if you get unexplained muscle pain, tenderness, or weakness while taking ISENTRESS. These may be signs of a rare serious muscle problem that can lead to kidney problems.

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

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

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ISENTRESS?

Film-Coated Tablets:

• Store ISENTRESS film-coated tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Chewable Tablets:

• Store ISENTRESS chewable tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store ISENTRESS chewable tablets in the original package with the bottle tightly closed.
• Keep the drying agent (desiccant) in the bottle to protect from moisture.

For Oral Suspension:

• Store ISENTRESS for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
• Store in the original container. Do not open the foil packet until ready for use.

Keep ISENTRESS and all medicines out of the reach of children.

General information about ISENTRESS

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use ISENTRESS for a condition for which it was not prescribed. Do not give ISENTRESS to other people, even if they have the same symptoms you have. It may harm them.

You can ask your doctor or pharmacist for information about ISENTRESS that is written for health professionals.

For more information go to www.ISENTRESS.com or call 1-800-622-4477.

What are the ingredients in ISENTRESS?

ISENTRESS film-coated tablets:

Active ingredient: raltegravir

Inactive ingredients: calcium phosphate dibasic anhydrous, hypromellose 2208, lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate.

The film coating contains: black iron oxide, polyethylene glycol 3350, polyvinyl alcohol, red iron oxide, talc and titanium dioxide.

ISENTRESS chewable tablets:

Active ingredient: raltegravir

Inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide. The 100 mg chewable tablet also contains red iron oxide.

ISENTRESS for oral suspension:

Active ingredient: raltegravir

Inactive ingredients: ammonium hydroxide, banana with other natural flavors, carboxymethylcellulose sodium, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, macrogol/PEG 400, magnesium stearate, maltodextrin, mannitol, medium chain triglycerides, microcrystalline cellulose, monoammonium glycyrrhizinate, oleic acid, sorbitol, sucralose and sucrose.

This Patient Information has been approved by the U.S. Food and Drug Administration.

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.

ISENTRESS Film-Coated Tablets

• Film-Coated Tablets must be swallowed whole

Storage and Handling

400 mg Film-coated Tablets, Chewable Tablets and For Oral Suspension

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

For the treatment of adult patients with HIV-1 infection, the dosage of ISENTRESS is one 400 mg film-coated tablet administered orally, twice daily.

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 up to 1800 mg per day were taken in the clinical studies of HIV-1 infected subjects 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.

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 C ₂₀H ₂₀FKN ₆O ₅ and the molecular weight is 482.51. The structural formula is:

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

Each 100 mg chewable tablet of ISENTRESS for oral administration contains 108.6 mg of raltegravir (as potassium salt), equivalent to 100 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, red iron oxide, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide.

Each 25 mg chewable tablet of ISENTRESS for oral administration contains 27.16 mg of raltegravir (as potassium salt), equivalent to 25 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide.

Each packet of ISENTRESS for oral suspension 100 mg, contains 108.6 mg of raltegravir (as potassium salt), equivalent to 100 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, banana with other natural flavors, carboxymethylcellulose sodium, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, macrogol/PEG 400, magnesium stearate, maltodextrin, mannitol, medium chain triglycerides, microcrystalline cellulose, monoammonium glycyrrhizinate, oleic acid, sorbitol, sucralose and sucrose.

• If at least 25 kg: One 400 mg film-coated tablet orally, twice daily.
• If unable to swallow a tablet, consider the chewable tablet, as specified in Table 1.

• If at least 4 weeks of age and weighing at least 3 kg to less than 25 kg: Weight based dosing, as specified in Table 2.
• For patients weighing between 11 and 20 kg, either the chewable tablet or oral suspension can be used, as specified in Table 2. Patients can remain on the oral suspension as long as their weight is below 20 kg. Refer to Table 2 for appropriate dosing [see Clinical Studies (14.3)] .

The safety, tolerability, pharmacokinetic profile, and efficacy of 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 [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)] . The safety profile was comparable to that observed in adults [see Adverse Reactions (6.1)] . See Dosage and Administration (2.3) for dosing recommendations for children 4 weeks of age and older. The safety and dosing information for ISENTRESS have not been established in infants less than 4 weeks of age.

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.

None

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.

• Coadministration of ISENTRESS and other drugs may alter the plasma concentration of raltegravir. The potential for drug-drug interactions must be considered prior to and during therapy ( 7).
• Coadministration of ISENTRESS with drugs that are strong inducers of UGT1A1, such as rifampin, may result in reduced plasma concentrations of raltegravir ( 2.1, 7.2).

Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.

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.

ISENTRESS Chewable Tablets contain phenylalanine, a component of aspartame. Each 25 mg ISENTRESS Chewable Tablet contains approximately 0.05 mg phenylalanine. Each 100 mg ISENTRESS Chewable Tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

ISENTRESS ^® (eye sen tris)

(raltegravir)

for oral suspension

Read this Instructions for Use before you mix and give a dose of ISENTRESS for oral suspension to your child for the first time, and each time you get a refill. There may be new information. These instructions will help you to correctly mix and give a dose of ISENTRESS for oral suspension to your child.

See the Patient Information leaflet that comes with ISENTRESS for oral suspension for more information about ISENTRESS.

Your doctor will decide the right dose based on your child's weight.

Ask your doctor or pharmacist if you have any questions about how to mix or give ISENTRESS for oral suspension to your child.

How should I store ISENTRESS for oral suspension?

• Store ISENTRESS for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
• Store in the original container. Do not open the foil packets until ready for use.

Keep ISENTRESS for oral suspension and all medicines out of the reach of children.

For more information go to www.ISENTRESS.com or call 1-800-622-4477.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

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

In the randomized, double-blind, placebo-controlled, dose-ranging trial, Protocol 005, and Protocols 018 and 019, antiviral responses were similar among subjects regardless of dose.

ISENTRESS® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in patients 4 weeks of age and older.

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

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

• Severe, potentially life-threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis. Immediately discontinue treatment with ISENTRESS and other suspect agents if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransferase elevations develops and monitor clinical status, including liver aminotransferases closely ( 5.1).
• Monitor for Immune Reconstitution Syndrome ( 5.2).
• Inform patients with phenylketonuria that the 100 mg and 25 mg chewable tablets contain phenylalanine ( 5.3).

ISENTRESS can be administered with or without food ( 2.1).

Do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet.

See specific dosing guidance for chewable tablets and the formulation for oral suspension ( 2.1).

Adults

• 400 mg film-coated tablet orally, twice daily ( 2.2).
• During coadministration with rifampin in adults, 800 mg twice daily ( 2.1).

Children and Adolescents

• If at least 25 kg: One 400 mg film-coated tablet orally, twice daily. If unable to swallow a tablet, consider the chewable tablet, as specified in Table 1 ( 2.3).
• If at least 3 kg to less than 25 kg: Weight based dosing, as specified in Table 2. For patients weighing between 11 and 20 kg, either the chewable tablet or the formulation for oral suspension can be used, as specified in Table 2 ( 2.3).

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

• Chewable Tablets
  
  100 mg pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score.
  
  25 mg pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side.

• For Oral Suspension
  
  100 mg white to off-white, banana flavored, granular powder that may contain yellow or beige to tan particles in a child resistant single-use foil packet.

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

Pregnancy:

• ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus ( 8.1).

Nursing Mothers:

• Breastfeeding is not recommended while taking ISENTRESS ( 8.3).

Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• ISENTRESS Film-Coated Tablets, Chewable Tablets and For Oral Suspension can be administered with or without food [see Clinical Pharmacology (12.3)] .
• Because the formulations are not bioequivalent, do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet. See specific dosing guidance for chewable tablets and the formulation for oral suspension.
• During coadministration of ISENTRESS 400 mg film-coated tablets with rifampin, the recommended dosage of ISENTRESS is 800 mg twice daily in adults. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Drug Interactions (7.2)] .
• Maximum dose of chewable tablets is 300 mg twice daily.
• Maximum dose of oral suspension is 100 mg twice daily.
• Each single-use packet for oral suspension contains 100 mg of raltegravir which is suspended in 5 mL of water giving a final concentration of 20 mg/mL.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ISENTRESS. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

STARTMRK (Protocol 021) is a Phase 3 study to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir versus efavirenz 600 mg at bedtime plus emtricitabine (+) tenofovir in treatment-naïve HIV-1-infected subjects with HIV-1 RNA >5000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤50,000 copies/mL; and >50,000 copies/mL) and by hepatitis status.

Table 11 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the comparator group.

Week 240 outcomes from Protocol 021 are shown in Table 12.

The mean changes in CD4 count from baseline were 295 cells/mm ³ in the group receiving ISENTRESS 400 mg twice daily and 236 cells/mm ³ in the group receiving Efavirenz 600 mg at bedtime.

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

• NDC 68071-2113-6 bottles of 6

BENCHMRK 1 and BENCHMRK 2 are Phase 3 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-1-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 13 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the placebo group.

Table 14 compares the characteristics of optimized background therapy at baseline in the group receiving ISENTRESS 400 mg twice daily and subjects in the control group.

Week 96 outcomes for the 699 subjects randomized and treated with the recommended dose of ISENTRESS 400 mg twice daily or placebo in the pooled BENCHMRK 1 and 2 studies are shown in Table 15.

The mean changes in CD4 count from baseline were 118 cells/mm ³ in the group receiving ISENTRESS 400 mg twice daily and 47 cells/mm ³ for the control group.

Treatment-emergent CDC Category C events occurred in 4% of the group receiving ISENTRESS 400 mg twice daily and 5% of the control group.

Virologic responses at Week 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 16.

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)].

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)].

Severe, potentially life-threatening, and fatal skin reactions have been reported. 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 ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was 1.8-fold (females) or 1.2-fold (males) greater than the AUC (54 µM∙hr) at the 400-mg twice daily human dose. Treatment-related squamous cell carcinoma of nose/nasopharynx was observed in female rats dosed with 600 mg/kg/day raltegravir for 104 weeks. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats dosed with 150 mg/kg/day (males) and 50 mg/kg/day (females) and the systemic exposure in rats was 1.7-fold (males) to 1.4-fold (females) greater than the AUC (54 μM∙hr) at the 400-mg twice daily human dose.

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 a 3-fold exposure above the exposure at the recommended human dose.

Raltegravir does not inhibit (IC ₅₀>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or 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 (IC ₅₀>50 µM) of UGT1A1 or 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, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).

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.

The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.

Selected drug interactions are presented in Table 8 [see Clinical Pharmacology (12.3)] .

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine, darunavir/ritonavir, or boceprevir. Moreover, atazanavir, atazanavir/ritonavir, boceprevir, calcium carbonate antacids, darunavir/ritonavir, efavirenz, etravirine, omeprazole, or tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of raltegravir. No dose adjustment is required when ISENTRESS is coadministered with these drugs.

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.

ISENTRESS Film-Coated Tablets

• Film-Coated Tablets must be swallowed whole

Storage and Handling

400 mg Film-coated Tablets, Chewable Tablets and For Oral Suspension

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

For the treatment of adult patients with HIV-1 infection, the dosage of ISENTRESS is one 400 mg film-coated tablet administered orally, twice daily.

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 up to 1800 mg per day were taken in the clinical studies of HIV-1 infected subjects 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.

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 C ₂₀H ₂₀FKN ₆O ₅ and the molecular weight is 482.51. The structural formula is:

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

Each 100 mg chewable tablet of ISENTRESS for oral administration contains 108.6 mg of raltegravir (as potassium salt), equivalent to 100 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, red iron oxide, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide.

Each 25 mg chewable tablet of ISENTRESS for oral administration contains 27.16 mg of raltegravir (as potassium salt), equivalent to 25 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide.

Each packet of ISENTRESS for oral suspension 100 mg, contains 108.6 mg of raltegravir (as potassium salt), equivalent to 100 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, banana with other natural flavors, carboxymethylcellulose sodium, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, macrogol/PEG 400, magnesium stearate, maltodextrin, mannitol, medium chain triglycerides, microcrystalline cellulose, monoammonium glycyrrhizinate, oleic acid, sorbitol, sucralose and sucrose.

• If at least 25 kg: One 400 mg film-coated tablet orally, twice daily.
• If unable to swallow a tablet, consider the chewable tablet, as specified in Table 1.

• If at least 4 weeks of age and weighing at least 3 kg to less than 25 kg: Weight based dosing, as specified in Table 2.
• For patients weighing between 11 and 20 kg, either the chewable tablet or oral suspension can be used, as specified in Table 2. Patients can remain on the oral suspension as long as their weight is below 20 kg. Refer to Table 2 for appropriate dosing [see Clinical Studies (14.3)] .

The safety, tolerability, pharmacokinetic profile, and efficacy of 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 [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)] . The safety profile was comparable to that observed in adults [see Adverse Reactions (6.1)] . See Dosage and Administration (2.3) for dosing recommendations for children 4 weeks of age and older. The safety and dosing information for ISENTRESS have not been established in infants less than 4 weeks of age.

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.

None

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.

• Coadministration of ISENTRESS and other drugs may alter the plasma concentration of raltegravir. The potential for drug-drug interactions must be considered prior to and during therapy ( 7).
• Coadministration of ISENTRESS with drugs that are strong inducers of UGT1A1, such as rifampin, may result in reduced plasma concentrations of raltegravir ( 2.1, 7.2).

Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.

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.

ISENTRESS ^® (eye sen tris )

(raltegravir)

film-coated tablets

ISENTRESS ^® (eye sen tris )

(raltegravir)

chewable tablets

ISENTRESS ^® (eye sen tris )

(raltegravir)

for oral suspension

Read this Patient Information before you start taking ISENTRESS and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is ISENTRESS?

ISENTRESS is a prescription HIV medicine used with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in people 4 weeks of age and older. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

It is not known if ISENTRESS is safe and effective in babies under 4 weeks of age.

When used with other HIV medicines to treat HIV-1 infection, ISENTRESS may help:

• reduce the amount of HIV in your blood. This is called "viral load".
• increase the number of white blood cells called CD4+ (T) cells in your blood, which help fight off other infections.
• reduce the amount of HIV-1 and increase the CD4+ (T) cells in your blood, which may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

ISENTRESS does not cure HIV-1 infection or AIDS.

You must stay on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV-1 infection to others.

• Do not share or re-use needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

Ask your doctor if you have any questions on how to prevent passing HIV to other people.

What should I tell my doctor before taking ISENTRESS?

Before you take ISENTRESS, tell your doctor if you:

• have liver problems
• have a history of a muscle disorder called rhabdomyolysis or myopathy
• have increased levels of creatine kinase in your blood
• have phenylketonuria (PKU). ISENTRESS chewable tablets contain phenylalanine as part of the artificial sweetener, aspartame. The artificial sweetener may be harmful to people with PKU.
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if ISENTRESS can harm your unborn baby.
  
  Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you take ISENTRESS.
  • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • Talk with your doctor about the best way to feed your baby.

Tell your doctor about all the medicines you take, including, prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with ISENTRESS. Keep a list of your medicines to show your doctor and pharmacist.

• You can ask your doctor or pharmacist for a list of medicines that interact with ISENTRESS.
• Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take ISENTRESS with other medicines.

How should I take ISENTRESS?

• Take ISENTRESS exactly as prescribed by your doctor.
• Do not change your dose of ISENTRESS or stop your treatment without talking with your doctor first.
• Stay under the care of your doctor while taking ISENTRESS.
• ISENTRESS film-coated tablets must be swallowed whole.
• ISENTRESS chewable tablets may be chewed or swallowed whole.
• ISENTRESS for oral suspension should be given to your child within 30 minutes of mixing. See the detailed Instructions for Use that comes with ISENTRESS for oral suspension , for information about the correct way to mix and give a dose of ISENTRESS for oral suspension. If you have questions about how to mix or give ISENTRESS for oral suspension, talk to your doctor or pharmacist.
• Do not switch between the film-coated tablet, the chewable tablet, or the oral suspension without talking with your doctor first.
• Do not run out of ISENTRESS. Get a refill of your ISENTRESS from your doctor or pharmacy before you run out.
• If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not double your next dose or take more ISENTRESS than prescribed.
• If you take too much ISENTRESS, call your doctor or go to the nearest hospital emergency room right away.

What are the possible side effects of ISENTRESS?

ISENTRESS can cause serious side effects including:

• Serious skin reactions and allergic reactions. Some people who take ISENTRESS develop serious skin reactions and allergic reactions that can be severe, and may be life-threatening or lead to death. If you develop a rash with any of the following symptoms, stop using ISENTRESS and call your doctor right away:
  • fever
  • generally ill feeling
  • extreme tiredness
  • muscle or joint aches
  • blisters or sores in mouth
  • blisters or peeling of the skin
  • redness or swelling of the eyes
  • swelling of the mouth or face
  • problems breathing

Sometimes allergic reactions can affect body organs, such as your liver. Call your doctor right away if you have any of the following signs or symptoms of liver problems:

• • yellowing of your skin or whites of your eyes
  • dark or tea colored urine
  • pale colored stools (bowel movements)
  • nausea or vomiting
  • loss of appetite
  • pain, aching, or tenderness on the right side of your stomach area

• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor right away if you start having new symptoms after starting your HIV-1 medicine.

The most common side effects of ISENTRESS include:

• trouble sleeping
• headache
• dizziness
• nausea
• tiredness

Less common side effects of ISENTRESS include:

• depression
• hepatitis
• genital herpes
• herpes zoster including shingles
• kidney failure
• kidney stones
• indigestion or stomach area pain
• vomiting
• suicidal thoughts and actions
• weakness

Tell your doctor right away if you get unexplained muscle pain, tenderness, or weakness while taking ISENTRESS. These may be signs of a rare serious muscle problem that can lead to kidney problems.

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

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

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ISENTRESS?

Film-Coated Tablets:

• Store ISENTRESS film-coated tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Chewable Tablets:

• Store ISENTRESS chewable tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store ISENTRESS chewable tablets in the original package with the bottle tightly closed.
• Keep the drying agent (desiccant) in the bottle to protect from moisture.

For Oral Suspension:

• Store ISENTRESS for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
• Store in the original container. Do not open the foil packet until ready for use.

Keep ISENTRESS and all medicines out of the reach of children.

General information about ISENTRESS

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use ISENTRESS for a condition for which it was not prescribed. Do not give ISENTRESS to other people, even if they have the same symptoms you have. It may harm them.

You can ask your doctor or pharmacist for information about ISENTRESS that is written for health professionals.

For more information go to www.ISENTRESS.com or call 1-800-622-4477.

What are the ingredients in ISENTRESS?

ISENTRESS film-coated tablets:

Active ingredient: raltegravir

Inactive ingredients: calcium phosphate dibasic anhydrous, hypromellose 2208, lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate.

The film coating contains: black iron oxide, polyethylene glycol 3350, polyvinyl alcohol, red iron oxide, talc and titanium dioxide.

ISENTRESS chewable tablets:

Active ingredient: raltegravir

Inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide. The 100 mg chewable tablet also contains red iron oxide.

ISENTRESS for oral suspension:

Active ingredient: raltegravir

Inactive ingredients: ammonium hydroxide, banana with other natural flavors, carboxymethylcellulose sodium, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, macrogol/PEG 400, magnesium stearate, maltodextrin, mannitol, medium chain triglycerides, microcrystalline cellulose, monoammonium glycyrrhizinate, oleic acid, sorbitol, sucralose and sucrose.

This Patient Information has been approved by the U.S. Food and Drug Administration.

ISENTRESS Chewable Tablets contain phenylalanine, a component of aspartame. Each 25 mg ISENTRESS Chewable Tablet contains approximately 0.05 mg phenylalanine. Each 100 mg ISENTRESS Chewable Tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

ISENTRESS ^® (eye sen tris)

(raltegravir)

for oral suspension

Read this Instructions for Use before you mix and give a dose of ISENTRESS for oral suspension to your child for the first time, and each time you get a refill. There may be new information. These instructions will help you to correctly mix and give a dose of ISENTRESS for oral suspension to your child.

See the Patient Information leaflet that comes with ISENTRESS for oral suspension for more information about ISENTRESS.

Your doctor will decide the right dose based on your child's weight.

Ask your doctor or pharmacist if you have any questions about how to mix or give ISENTRESS for oral suspension to your child.

How should I store ISENTRESS for oral suspension?

• Store ISENTRESS for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
• Store in the original container. Do not open the foil packets until ready for use.

Keep ISENTRESS for oral suspension and all medicines out of the reach of children.

For more information go to www.ISENTRESS.com or call 1-800-622-4477.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

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

In the randomized, double-blind, placebo-controlled, dose-ranging trial, Protocol 005, and Protocols 018 and 019, antiviral responses were similar among subjects regardless of dose.

ISENTRESS® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in patients 4 weeks of age and older.

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

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

• Severe, potentially life-threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis. Immediately discontinue treatment with ISENTRESS and other suspect agents if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransferase elevations develops and monitor clinical status, including liver aminotransferases closely ( 5.1).
• Monitor for Immune Reconstitution Syndrome ( 5.2).
• Inform patients with phenylketonuria that the 100 mg and 25 mg chewable tablets contain phenylalanine ( 5.3).

ISENTRESS can be administered with or without food ( 2.1).

Do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet.

See specific dosing guidance for chewable tablets and the formulation for oral suspension ( 2.1).

Adults

• 400 mg film-coated tablet orally, twice daily ( 2.2).
• During coadministration with rifampin in adults, 800 mg twice daily ( 2.1).

Children and Adolescents

• If at least 25 kg: One 400 mg film-coated tablet orally, twice daily. If unable to swallow a tablet, consider the chewable tablet, as specified in Table 1 ( 2.3).
• If at least 3 kg to less than 25 kg: Weight based dosing, as specified in Table 2. For patients weighing between 11 and 20 kg, either the chewable tablet or the formulation for oral suspension can be used, as specified in Table 2 ( 2.3).

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

• Chewable Tablets
  
  100 mg pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score.
  
  25 mg pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side.

• For Oral Suspension
  
  100 mg white to off-white, banana flavored, granular powder that may contain yellow or beige to tan particles in a child resistant single-use foil packet.

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

Pregnancy:

• ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus ( 8.1).

Nursing Mothers:

• Breastfeeding is not recommended while taking ISENTRESS ( 8.3).

Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• ISENTRESS Film-Coated Tablets, Chewable Tablets and For Oral Suspension can be administered with or without food [see Clinical Pharmacology (12.3)] .
• Because the formulations are not bioequivalent, do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet. See specific dosing guidance for chewable tablets and the formulation for oral suspension.
• During coadministration of ISENTRESS 400 mg film-coated tablets with rifampin, the recommended dosage of ISENTRESS is 800 mg twice daily in adults. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Drug Interactions (7.2)] .
• Maximum dose of chewable tablets is 300 mg twice daily.
• Maximum dose of oral suspension is 100 mg twice daily.
• Each single-use packet for oral suspension contains 100 mg of raltegravir which is suspended in 5 mL of water giving a final concentration of 20 mg/mL.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ISENTRESS. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

STARTMRK (Protocol 021) is a Phase 3 study to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir versus efavirenz 600 mg at bedtime plus emtricitabine (+) tenofovir in treatment-naïve HIV-1-infected subjects with HIV-1 RNA >5000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤50,000 copies/mL; and >50,000 copies/mL) and by hepatitis status.

Table 11 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the comparator group.

Week 240 outcomes from Protocol 021 are shown in Table 12.

The mean changes in CD4 count from baseline were 295 cells/mm ³ in the group receiving ISENTRESS 400 mg twice daily and 236 cells/mm ³ in the group receiving Efavirenz 600 mg at bedtime.

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

• NDC 68071-2113-6 bottles of 6

BENCHMRK 1 and BENCHMRK 2 are Phase 3 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-1-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 13 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the placebo group.

Table 14 compares the characteristics of optimized background therapy at baseline in the group receiving ISENTRESS 400 mg twice daily and subjects in the control group.

Week 96 outcomes for the 699 subjects randomized and treated with the recommended dose of ISENTRESS 400 mg twice daily or placebo in the pooled BENCHMRK 1 and 2 studies are shown in Table 15.

The mean changes in CD4 count from baseline were 118 cells/mm ³ in the group receiving ISENTRESS 400 mg twice daily and 47 cells/mm ³ for the control group.

Treatment-emergent CDC Category C events occurred in 4% of the group receiving ISENTRESS 400 mg twice daily and 5% of the control group.

Virologic responses at Week 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 16.

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)].

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)].

Severe, potentially life-threatening, and fatal skin reactions have been reported. 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 ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was 1.8-fold (females) or 1.2-fold (males) greater than the AUC (54 µM∙hr) at the 400-mg twice daily human dose. Treatment-related squamous cell carcinoma of nose/nasopharynx was observed in female rats dosed with 600 mg/kg/day raltegravir for 104 weeks. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats dosed with 150 mg/kg/day (males) and 50 mg/kg/day (females) and the systemic exposure in rats was 1.7-fold (males) to 1.4-fold (females) greater than the AUC (54 μM∙hr) at the 400-mg twice daily human dose.

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 a 3-fold exposure above the exposure at the recommended human dose.

Raltegravir does not inhibit (IC ₅₀>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or 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 (IC ₅₀>50 µM) of UGT1A1 or 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, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).

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.

The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.

Selected drug interactions are presented in Table 8 [see Clinical Pharmacology (12.3)] .

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine, darunavir/ritonavir, or boceprevir. Moreover, atazanavir, atazanavir/ritonavir, boceprevir, calcium carbonate antacids, darunavir/ritonavir, efavirenz, etravirine, omeprazole, or tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of raltegravir. No dose adjustment is required when ISENTRESS is coadministered with these drugs.