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

Adult Patients:

ISENTRESS^® and ISENTRESS^® HD are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.

Storage and Handling

PRINCIPAL DISPLAY PANEL - 100 mg Packet Carton

NDC 0006-3603-61

Isentress ^®

(raltegravir)

For Oral Suspension

100 mg

For Pediatric Use

For Oral Administration Only

Each packet contains 108.6 mg raltegravir potassium, equivalent to 100 mg raltegravir.

Rx only

60 packets

Multi-Dose Kit

DIRECTIONS FOR USE:

See instructions for use

booklet and package insert

for additional information.

Bring this booklet to your child's appointments.

ISENTRESS (raltegravir)

for oral suspension

Instructions for Use

for babies and toddlers

Before You Start

• Be sure you understand these instructions before you start. Call your doctor if you have any questions.
• It is very important that you measure the water and ISENTRESS carefully using the correct syringe.
• Before you give ISENTRESS to your child, check the expiration date. The expiration date is printed on the box and the ISENTRESS packets.
• Do not open the ISENTRESS packets until you are ready to mix a dose.
• The amount of ISENTRESS depends on your child's age and weight, so it will change over time.
  
  Your doctor will tell you the right dose at each check-up after weighing your child.
  
  Be sure to keep your doctor's appointments so you get new dosing information as your child grows.
  
  During your child's first week of life, you will give ISENTRESS 1 time a day. After the first week of life, you will give it 2 times a day.
• This booklet tells you how to:
  • Mix ISENTRESS into a liquid form
  • Measure the right dose using a syringe
  • Give mixed ISENTRESS to your child
  • Clean up

Kit Contents

The kit has an extra cup and set of syringes in case one is lost or damaged.

Do not use any damaged cups or syringes.

Step 1. Get ready

• Put your child in a safe place. You will need both hands to prepare ISENTRESS.
• Wash your hands with soap and water.
• Take out what you need from the kit as shown below to make 1 dose and place on a clean surface:

Step 2. Fill a clean glass with water

Step 3. Fill the blue syringe with water

Step 4. Check for air bubbles

Step 5. Add the 10mL of water to the mixing cup

Add the 10 mL of water from the syringe to the mixing cup by pushing all the way down on the plunger.

Step 6. Add ISENTRESS to the mixing cup

Step 7. Mix ISENTRESS and water

Step 8. Check your prescription

Find the dose amount in 'mL' prescribed by your doctor. This is written on the prescription label on the box from your pharmacy.

Remember that the dose may change each time you go to the doctor, so make sure you check the prescribed dose each time. Be sure to go to all of your doctor's appointments so your child gets the right dose!

Step 9. Choose the syringe you need

Your doctor will prescribe the dose in milliliters (mL). Choose the right syringe for your child's dose:

Then find the mL mark on the syringe that matches your child's dose.

Step 10. Measure ISENTRESS

Step 11. Check for air bubbles

Step 12. Give ISENTRESS to your child

Slowly push in the plunger to give the dose of mixed ISENTRESS to your child. If your child fusses, take the tip of the syringe out of the mouth and try again. It is important that your child takes all of the prescribed dose (a little left in the syringe tip is OK).

Step 13. Clean up

Pour the leftover mixed ISENTRESS into the trash.

Do not pour it into the sink.

Pull the plungers out of any syringes you used.

Hand wash the syringes, plungers, and mixing cup with warm water and dish soap. Do not wash in the dishwasher.

How should I store ISENTRESS?

Store the ISENTRESS for oral suspension kit at room temperature between 68°F to 77°F (20°C to 25°C).

Store in the original container.

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

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

The recommended adult dosage of ISENTRESS film-coated tablets is displayed in Table 1. ISENTRESS and ISENTRESS HD should be taken by mouth and may be taken with or without food [see Clinical Pharmacology (12.3)].

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 C₂₀H₂₀FKN₆O₅ 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 600 mg film-coated tablet of ISENTRESS HD for oral administration contains 651.6 mg of raltegravir (as potassium salt), equivalent to 600 mg of raltegravir free phenol and the following inactive ingredients: croscarmellose sodium, hypromellose 2910, magnesium stearate, microcrystalline cellulose. The film coating contains the following inactive ingredients: ferrosoferric oxide, hypromellose 2910, iron oxide yellow, lactose monohydrate, triacetin and titanium dioxide. The tablet may also contain trace amount of carnauba wax.

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.

The recommended pediatric dosage of ISENTRESS is displayed in Table 2. ISENTRESS film-coated tablets, chewable tablets and for oral suspension should be taken by mouth and may be taken with or without food [see Clinical Pharmacology (12.3)].

• For full-term neonates (birth to 4 weeks [28 days] of age): Weight-based dosing of the oral suspension as specified in Table 5.
• No data are available in pre-term neonates. The use of ISENTRESS is not recommended in pre-term neonates.

Clinical studies of ISENTRESS/ISENTRESS HD 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 or ISENTRESS HD 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 or ISENTRESS HD with drugs that are strong inducers of UGT1A1, such as rifampin, may result in reduced plasma concentrations of raltegravir (2.1, 7.1).

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.

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.

Adult Patients:

ISENTRESS and ISENTRESS HD are human immunodeficiency virus integrase strand transfer inhibitors (HIV-1 INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients (1).

Pediatric Patients:

ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 2 kg (1).

ISENTRESS HD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg (1).

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 or ISENTRESS HD 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 and ISENTRESS HD 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 or 600 mg film-coated tablet.

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

Adults

• Treatment-naïve patients or patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily:
  • 1200 mg (2 × 600 mg) film-coated tablet orally, once daily or
  • 400 mg film-coated tablet orally, twice daily (2.2).
• Treatment-experienced patients:
  • 400 mg film-coated tablet orally, twice daily (2.2).
• During coadministration with rifampin in adults, 800 mg (2 × 400 mg) twice daily (2.2).

Pediatrics

• If weighing at least 40 kg, and either
  • treatment-naïve patients or
  • patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily:
    • 1200 mg (2 × 600 mg) film-coated tablet orally, once daily or
    • 400 mg film-coated tablet orally, twice daily or
    • 300 mg (3 × 100 mg) chewable tablets, twice daily (2.3).
• If weighing 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 2 (2.3).
• If weighing at least 3 kg to less than 25 kg: Weight-based dosing using the chewable tablet or oral suspension, as specified in Table 4 (2.3).
• For neonates (birth to 4 weeks [28 days] of age): Weight-based dosing of the oral suspension as specified in Table 5 (2.3).

• Film-coated Tablets
  • 400 mg pink, oval-shaped, film-coated tablets with "227" on one side (ISENTRESS).
  • 600 mg yellow, oval-shaped, film-coated tablets with corporate logo and "242" on one side and plain on the other side (ISENTRESS HD).
• Chewable Tablets
  • 100 mg pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the corporate logo and "477" on opposite sides of the score.
  • 25 mg pale yellow, round, orange-banana flavored, chewable tablets with the corporate 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

Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission (8.2).

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

• Because the formulations have different pharmacokinetic profiles, do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet or the ISENTRESS HD 600 mg film-coated tablet. See specific dosing guidance for chewable tablets and the formulation for oral suspension.
• Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided [see Clinical Pharmacology (12.3)].
• ISENTRESS film-coated tablets must be swallowed whole.
• ISENTRESS chewable tablets may be chewed or swallowed whole. Maximum daily dose is 300 mg taken by mouth twice daily.
• For children who have difficulty chewing the 25 mg chewable tablet, the tablet may be crushed.
  • Preparation of the crushed 25 mg chewable tablet:
    • Place the tablet(s) in a small, clean cup. For each tablet, add a teaspoonful (~5 mL) of liquid (for example, water, juice, or breast milk).
    • Within 2 minutes, the tablet(s) will absorb the liquid and fall apart.
    • Using a spoon, crush any remaining pieces of the tablet(s). Immediately administer the entire dose orally.
    • If any portion of the dose is left in the cup, add another teaspoonful (~5 mL) of liquid, swirl and administer immediately.
• ISENTRESS for oral suspension:
  • See Instructions for Use for details on preparation and administration of ISENTRESS for oral suspension.
  • Using the provided mixing cup, combine 10 mL of water and the entire contents of one packet of ISENTRESS for oral suspension and mix. Each single-use packet for oral suspension contains 100 mg of raltegravir which is suspended in 10 mL of water giving a final concentration of 10 mg per mL. Maximum daily dose is 100 mg taken by mouth twice daily.
  • Gently swirl the mixing cup for 45 seconds in a circular motion to mix the powder into a uniform suspension. Do not shake.
  • Once mixed, measure the prescribed dose volume of suspension with a syringe and administer the dose orally. The dose should be administered orally within 30 minutes of mixing.
  • Discard any remaining suspension into the trash.

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.

The evidence of durable efficacy of ISENTRESS 400 mg twice daily is based on the analyses of 240-week data from a randomized, double-blind, active-controlled trial, STARTMRK evaluating ISENTRESS 400 mg twice daily in antiretroviral treatment-naïve HIV-1 infected adult subjects, the analysis of 96-week data from a randomized, double-blind, active-control trial, ONCEMRK evaluating ISENTRESS HD 1200 mg (2 × 600 mg) once daily in treatment-naïve adult subjects, and 96-week data from 2 randomized, double-blind, placebo-controlled studies, BENCHMRK 1 and BENCHMRK 2, evaluating ISENTRESS 400 mg twice daily in antiretroviral treatment-experienced HIV-1 infected adult subjects. See Table 18.

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.

ISENTRESS HD tablets 600 mg are yellow, oval-shaped, film-coated tablets with corporate logo and "242" on one side and plain on the other side. They are supplied as follows:

•  
  NDC 0006-3080-01 unit-of-use bottles of 60.

ISENTRESS tablets 100 mg are pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the corporate logo and "477" on opposite sides of the score. They are supplied as follows:

•  
  NDC 0006-0477-61 unit-of-use bottles of 60.

ISENTRESS tablets 25 mg are pale yellow, round, orange-banana flavored, chewable tablets with the corporate logo on one side and "473" on the other side. They are supplied as follows:

•  
  NDC 0006-0473-61 unit-of-use bottles of 60.

ISENTRESS for oral suspension 100 mg is a white to off-white granular powder that may contain yellow or beige to tan particles, in child resistant single-use foil packets, packaged as

A kit with two 1 mL syringes, two 3 mL syringes, two 10 mL syringes and two mixing cups. It is supplied as follows:

•  
  NDC 0006-3603-61 unit of use carton with 60 packets.
•  
  NDC 0006-3603-01 individual packet.

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 20 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the placebo group.

Table 21 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 22.

The mean changes in CD4 count from baseline were 118 cells/mm³ in the group receiving ISENTRESS 400 mg twice daily and 47 cells/mm³ 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 23.

No dosage adjustment of ISENTRESS or ISENTRESS HD is necessary in patients with any degree of renal impairment [see Clinical Pharmacology (12.3)]. The extent to which ISENTRESS may be dialyzable is unknown; therefore, dosing before a dialysis session should be avoided.

No dosage adjustment of ISENTRESS is necessary for patients with mild to moderate (Child-Pugh A and B) hepatic impairment. No hepatic impairment study has been conducted with ISENTRESS HD and therefore administration in subjects with hepatic impairment is not recommended. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied [see Clinical Pharmacology (12.3)].

NDC 0006-3080-01

Isentress ^® HD

(raltegravir) tablets

600 mg

RECOMMENDED DOSAGE: Two tablets once daily.

See Package Insert.

Each tablet contains 651.6 mg raltegravir

potassium, equivalent to

600 mg raltegravir.

Rx only

60 Tablets

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 or ISENTRESS HD 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 or ISENTRESS HD treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

NDC 0006-0473-61

Isentress^®

(raltegravir) CHEWABLE Tablets

25 mg

For Pediatric Use

Phenylketonurics: contains phenylalanine (a component

of aspartame) 0.05 mg per 25 mg chewable tablet.

Rx only

60 Tablets

NDC 0006-0477-61

Isentress^®

(raltegravir) CHEWABLE Tablets

100 mg

For Pediatric Use

Phenylketonurics: contains phenylalanine (a component

of aspartame) 0.10 mg per 100 mg chewable tablet.

Rx only

60 Tablets

NDC 0006-0227-61

Isentress^®

(raltegravir) tablets

400 mg

Each tablet contains 434.4 mg raltegravir

potassium, equivalent to 400 mg raltegravir.

USUAL DOSAGE: See Package Insert.

Rx only

60 Tablets

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 is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir and coadministration of ISENTRESS with drugs that induce UGT1A1, such as rifampin, may reduce plasma levels of raltegravir (see Table 11).

Selected drug interactions are presented in Table 11 [see Clinical Pharmacology (12.3)]. In some cases, recommendations differ for ISENTRESS versus ISENTRESS HD.

Adult Patients:

ISENTRESS^® and ISENTRESS^® HD are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.

Storage and Handling

PRINCIPAL DISPLAY PANEL - 100 mg Packet Carton

NDC 0006-3603-61

Isentress ^®

(raltegravir)

For Oral Suspension

100 mg

For Pediatric Use

For Oral Administration Only

Each packet contains 108.6 mg raltegravir potassium, equivalent to 100 mg raltegravir.

Rx only

60 packets

Multi-Dose Kit

DIRECTIONS FOR USE:

See instructions for use

booklet and package insert

for additional information.

Bring this booklet to your child's appointments.

ISENTRESS (raltegravir)

for oral suspension

Instructions for Use

for babies and toddlers

Before You Start

• Be sure you understand these instructions before you start. Call your doctor if you have any questions.
• It is very important that you measure the water and ISENTRESS carefully using the correct syringe.
• Before you give ISENTRESS to your child, check the expiration date. The expiration date is printed on the box and the ISENTRESS packets.
• Do not open the ISENTRESS packets until you are ready to mix a dose.
• The amount of ISENTRESS depends on your child's age and weight, so it will change over time.
  
  Your doctor will tell you the right dose at each check-up after weighing your child.
  
  Be sure to keep your doctor's appointments so you get new dosing information as your child grows.
  
  During your child's first week of life, you will give ISENTRESS 1 time a day. After the first week of life, you will give it 2 times a day.
• This booklet tells you how to:
  • Mix ISENTRESS into a liquid form
  • Measure the right dose using a syringe
  • Give mixed ISENTRESS to your child
  • Clean up

Kit Contents

The kit has an extra cup and set of syringes in case one is lost or damaged.

Do not use any damaged cups or syringes.

Step 1. Get ready

• Put your child in a safe place. You will need both hands to prepare ISENTRESS.
• Wash your hands with soap and water.
• Take out what you need from the kit as shown below to make 1 dose and place on a clean surface:

Step 2. Fill a clean glass with water

Step 3. Fill the blue syringe with water

Step 4. Check for air bubbles

Step 5. Add the 10mL of water to the mixing cup

Add the 10 mL of water from the syringe to the mixing cup by pushing all the way down on the plunger.

Step 6. Add ISENTRESS to the mixing cup

Step 7. Mix ISENTRESS and water

Step 8. Check your prescription

Find the dose amount in 'mL' prescribed by your doctor. This is written on the prescription label on the box from your pharmacy.

Remember that the dose may change each time you go to the doctor, so make sure you check the prescribed dose each time. Be sure to go to all of your doctor's appointments so your child gets the right dose!

Step 9. Choose the syringe you need

Your doctor will prescribe the dose in milliliters (mL). Choose the right syringe for your child's dose:

Then find the mL mark on the syringe that matches your child's dose.

Step 10. Measure ISENTRESS

Step 11. Check for air bubbles

Step 12. Give ISENTRESS to your child

Slowly push in the plunger to give the dose of mixed ISENTRESS to your child. If your child fusses, take the tip of the syringe out of the mouth and try again. It is important that your child takes all of the prescribed dose (a little left in the syringe tip is OK).

Step 13. Clean up

Pour the leftover mixed ISENTRESS into the trash.

Do not pour it into the sink.

Pull the plungers out of any syringes you used.

Hand wash the syringes, plungers, and mixing cup with warm water and dish soap. Do not wash in the dishwasher.

How should I store ISENTRESS?

Store the ISENTRESS for oral suspension kit at room temperature between 68°F to 77°F (20°C to 25°C).

Store in the original container.

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

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

The recommended adult dosage of ISENTRESS film-coated tablets is displayed in Table 1. ISENTRESS and ISENTRESS HD should be taken by mouth and may be taken with or without food [see Clinical Pharmacology (12.3)].

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 C₂₀H₂₀FKN₆O₅ 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 600 mg film-coated tablet of ISENTRESS HD for oral administration contains 651.6 mg of raltegravir (as potassium salt), equivalent to 600 mg of raltegravir free phenol and the following inactive ingredients: croscarmellose sodium, hypromellose 2910, magnesium stearate, microcrystalline cellulose. The film coating contains the following inactive ingredients: ferrosoferric oxide, hypromellose 2910, iron oxide yellow, lactose monohydrate, triacetin and titanium dioxide. The tablet may also contain trace amount of carnauba wax.

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.

The recommended pediatric dosage of ISENTRESS is displayed in Table 2. ISENTRESS film-coated tablets, chewable tablets and for oral suspension should be taken by mouth and may be taken with or without food [see Clinical Pharmacology (12.3)].

• For full-term neonates (birth to 4 weeks [28 days] of age): Weight-based dosing of the oral suspension as specified in Table 5.
• No data are available in pre-term neonates. The use of ISENTRESS is not recommended in pre-term neonates.

Clinical studies of ISENTRESS/ISENTRESS HD 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 or ISENTRESS HD 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 or ISENTRESS HD with drugs that are strong inducers of UGT1A1, such as rifampin, may result in reduced plasma concentrations of raltegravir (2.1, 7.1).

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.

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.

Adult Patients:

ISENTRESS and ISENTRESS HD are human immunodeficiency virus integrase strand transfer inhibitors (HIV-1 INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients (1).

Pediatric Patients:

ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 2 kg (1).

ISENTRESS HD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg (1).

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 or ISENTRESS HD 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 and ISENTRESS HD 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 or 600 mg film-coated tablet.

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

Adults

• Treatment-naïve patients or patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily:
  • 1200 mg (2 × 600 mg) film-coated tablet orally, once daily or
  • 400 mg film-coated tablet orally, twice daily (2.2).
• Treatment-experienced patients:
  • 400 mg film-coated tablet orally, twice daily (2.2).
• During coadministration with rifampin in adults, 800 mg (2 × 400 mg) twice daily (2.2).

Pediatrics

• If weighing at least 40 kg, and either
  • treatment-naïve patients or
  • patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily:
    • 1200 mg (2 × 600 mg) film-coated tablet orally, once daily or
    • 400 mg film-coated tablet orally, twice daily or
    • 300 mg (3 × 100 mg) chewable tablets, twice daily (2.3).
• If weighing 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 2 (2.3).
• If weighing at least 3 kg to less than 25 kg: Weight-based dosing using the chewable tablet or oral suspension, as specified in Table 4 (2.3).
• For neonates (birth to 4 weeks [28 days] of age): Weight-based dosing of the oral suspension as specified in Table 5 (2.3).

• Film-coated Tablets
  • 400 mg pink, oval-shaped, film-coated tablets with "227" on one side (ISENTRESS).
  • 600 mg yellow, oval-shaped, film-coated tablets with corporate logo and "242" on one side and plain on the other side (ISENTRESS HD).
• Chewable Tablets
  • 100 mg pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the corporate logo and "477" on opposite sides of the score.
  • 25 mg pale yellow, round, orange-banana flavored, chewable tablets with the corporate 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

Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission (8.2).

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

• Because the formulations have different pharmacokinetic profiles, do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet or the ISENTRESS HD 600 mg film-coated tablet. See specific dosing guidance for chewable tablets and the formulation for oral suspension.
• Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided [see Clinical Pharmacology (12.3)].
• ISENTRESS film-coated tablets must be swallowed whole.
• ISENTRESS chewable tablets may be chewed or swallowed whole. Maximum daily dose is 300 mg taken by mouth twice daily.
• For children who have difficulty chewing the 25 mg chewable tablet, the tablet may be crushed.
  • Preparation of the crushed 25 mg chewable tablet:
    • Place the tablet(s) in a small, clean cup. For each tablet, add a teaspoonful (~5 mL) of liquid (for example, water, juice, or breast milk).
    • Within 2 minutes, the tablet(s) will absorb the liquid and fall apart.
    • Using a spoon, crush any remaining pieces of the tablet(s). Immediately administer the entire dose orally.
    • If any portion of the dose is left in the cup, add another teaspoonful (~5 mL) of liquid, swirl and administer immediately.
• ISENTRESS for oral suspension:
  • See Instructions for Use for details on preparation and administration of ISENTRESS for oral suspension.
  • Using the provided mixing cup, combine 10 mL of water and the entire contents of one packet of ISENTRESS for oral suspension and mix. Each single-use packet for oral suspension contains 100 mg of raltegravir which is suspended in 10 mL of water giving a final concentration of 10 mg per mL. Maximum daily dose is 100 mg taken by mouth twice daily.
  • Gently swirl the mixing cup for 45 seconds in a circular motion to mix the powder into a uniform suspension. Do not shake.
  • Once mixed, measure the prescribed dose volume of suspension with a syringe and administer the dose orally. The dose should be administered orally within 30 minutes of mixing.
  • Discard any remaining suspension into the trash.

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.

The evidence of durable efficacy of ISENTRESS 400 mg twice daily is based on the analyses of 240-week data from a randomized, double-blind, active-controlled trial, STARTMRK evaluating ISENTRESS 400 mg twice daily in antiretroviral treatment-naïve HIV-1 infected adult subjects, the analysis of 96-week data from a randomized, double-blind, active-control trial, ONCEMRK evaluating ISENTRESS HD 1200 mg (2 × 600 mg) once daily in treatment-naïve adult subjects, and 96-week data from 2 randomized, double-blind, placebo-controlled studies, BENCHMRK 1 and BENCHMRK 2, evaluating ISENTRESS 400 mg twice daily in antiretroviral treatment-experienced HIV-1 infected adult subjects. See Table 18.

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.

ISENTRESS HD tablets 600 mg are yellow, oval-shaped, film-coated tablets with corporate logo and "242" on one side and plain on the other side. They are supplied as follows:

•  
  NDC 0006-3080-01 unit-of-use bottles of 60.

ISENTRESS tablets 100 mg are pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the corporate logo and "477" on opposite sides of the score. They are supplied as follows:

•  
  NDC 0006-0477-61 unit-of-use bottles of 60.

ISENTRESS tablets 25 mg are pale yellow, round, orange-banana flavored, chewable tablets with the corporate logo on one side and "473" on the other side. They are supplied as follows:

•  
  NDC 0006-0473-61 unit-of-use bottles of 60.

ISENTRESS for oral suspension 100 mg is a white to off-white granular powder that may contain yellow or beige to tan particles, in child resistant single-use foil packets, packaged as

A kit with two 1 mL syringes, two 3 mL syringes, two 10 mL syringes and two mixing cups. It is supplied as follows:

•  
  NDC 0006-3603-61 unit of use carton with 60 packets.
•  
  NDC 0006-3603-01 individual packet.

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 20 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the placebo group.

Table 21 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 22.

The mean changes in CD4 count from baseline were 118 cells/mm³ in the group receiving ISENTRESS 400 mg twice daily and 47 cells/mm³ 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 23.

No dosage adjustment of ISENTRESS or ISENTRESS HD is necessary in patients with any degree of renal impairment [see Clinical Pharmacology (12.3)]. The extent to which ISENTRESS may be dialyzable is unknown; therefore, dosing before a dialysis session should be avoided.

No dosage adjustment of ISENTRESS is necessary for patients with mild to moderate (Child-Pugh A and B) hepatic impairment. No hepatic impairment study has been conducted with ISENTRESS HD and therefore administration in subjects with hepatic impairment is not recommended. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied [see Clinical Pharmacology (12.3)].

NDC 0006-3080-01

Isentress ^® HD

(raltegravir) tablets

600 mg

RECOMMENDED DOSAGE: Two tablets once daily.

See Package Insert.

Each tablet contains 651.6 mg raltegravir

potassium, equivalent to

600 mg raltegravir.

Rx only

60 Tablets

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 or ISENTRESS HD 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 or ISENTRESS HD treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

NDC 0006-0473-61

Isentress^®

(raltegravir) CHEWABLE Tablets

25 mg

For Pediatric Use

Phenylketonurics: contains phenylalanine (a component

of aspartame) 0.05 mg per 25 mg chewable tablet.

Rx only

60 Tablets

NDC 0006-0477-61

Isentress^®

(raltegravir) CHEWABLE Tablets

100 mg

For Pediatric Use

Phenylketonurics: contains phenylalanine (a component

of aspartame) 0.10 mg per 100 mg chewable tablet.

Rx only

60 Tablets

NDC 0006-0227-61

Isentress^®

(raltegravir) tablets

400 mg

Each tablet contains 434.4 mg raltegravir

potassium, equivalent to 400 mg raltegravir.

USUAL DOSAGE: See Package Insert.

Rx only

60 Tablets

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 is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir and coadministration of ISENTRESS with drugs that induce UGT1A1, such as rifampin, may reduce plasma levels of raltegravir (see Table 11).

Selected drug interactions are presented in Table 11 [see Clinical Pharmacology (12.3)]. In some cases, recommendations differ for ISENTRESS versus ISENTRESS HD.