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.

6 ADVERSE REACTIONS

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.

6.1 Clinical Trials Experience

Treatment-Naïve Adults

The safety of ISENTRESS was evaluated in HIV-infected treatment-naïve subjects in 2 Phase III studies: STARTMRK evaluated ISENTRESS 400 mg twice daily versus efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate (TDF), and ONCEMRK evaluated ISENTRESS HD 1200 mg (2 × 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. Safety data from these two studies are presented side-by-side in Tables 6 and 7 to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up and study design.

STARTMRK (ISENTRESS 400 mg twice daily)

In STARTMRK, subjects received ISENTRESS 400 mg twice daily (N=281) or efavirenz (EFV) 600 mg at bedtime (N=282) both in combination with emtricitabine (+) tenofovir disoproxil fumarate, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir disoproxil fumarate was 1104 patient-years and 1036 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disoproxil fumarate.

In STARTMRK, the rate of discontinuation of therapy due to adverse events through Week 240 was 5% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate.

ONCEMRK (ISENTRESS HD 1200 mg [2 × 600 mg] once daily)

In ONCEMRK, subjects received ISENTRESS HD 1200 mg once daily (n=531) or ISENTRESS 400 mg twice daily (n=266) both in combination with emtricitabine (+) tenofovir disoproxil fumarate. During double-blind treatment, the total follow-up for subjects with ISENTRESS HD 1200 mg once daily was 913 patient- years and for ISENTRESS 400 mg twice daily was 450 patient-years.

In ONCEMRK, the rate of discontinuation of therapy due to adverse events through Week 96 was 1% in subjects receiving ISENTRESS HD 1200 mg (2 × 600 mg) once daily and 2% in subjects receiving ISENTRESS 400 mg twice daily.

Clinical adverse reactions of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK through Week 240 or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK through Week 96 are presented in Table 6.

In STARTMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS 400 mg twice daily through Week 240 also include diarrhea, flatulence, asthenia, decreased appetite, abnormal dreams, depression and nightmare. In ONCEMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS HD or ISENTRESS 400 mg twice daily through Week 96 also include abdominal pain, diarrhea, vomiting, and decreased appetite.

Table 6: Adverse Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Naïve Adult Subjects Receiving ISENTRESS and ISENTRESS HD

System Organ Class, Preferred Term	STARTMRK Week 240	ONCEMRK Week 96
ISENTRESS 400 mg Twice Daily (N= 281)	Efavirenz 600 mg At Bedtime (N= 282)	ISENTRESS HD 1200 mg Once Daily (N=531)	ISENTRESS 400 mg Twice Daily (N=266)
Note: ISENTRESS BID, ISENTRESS HD and efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate
N= total number of subjects per treatment group
Includes adverse experiences considered by investigators to be at least possibly, probably, or definitely related to the drug. † Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).
Headache	4%	5%	1%	<1%
Insomnia	4%	4%	<1%	<1%
Nausea	3%	4%	1%	0%
Dizziness	2%	6%	<1%	0%
Fatigue	2%	3%	0%	0%

Laboratory Abnormalities

The percentages of adult subjects with selected Grade 2 to 4 laboratory abnormalities (that represent a worsening Grade from baseline) who were treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK are presented in Table 7.

Table 7: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Naïve Subjects

	STARTMRK Week 240	ONCEMRK Week 96
Laboratory Parameter Preferred Term (Unit)	Limit	ISENTRESS 400 mg Twice Daily (N = 281)	Efavirenz 600 mg At Bedtime (N = 282)	ISENTRESS HD 1200 mg Once Daily (N=531)	ISENTRESS 400 mg Twice Daily (N=266)
ULN = Upper limit of normal range
Notes: ISENTRESS BID, ISENTRESS HD and Efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate
Test not done in ONCEMRK † Test not done in STARTMRK
Hematology
Absolute neutrophil count (103/µL)
Grade 2	0.75 - 0.999	3%	5%	2%	1%
Grade 3	0.50 - 0.749	3%	1%	1%	1%
Grade 4	<0.50	1%	1%	<1%	0%
Hemoglobin (gm/dL)
Grade 2	7.5 - 8.4	1%	1%	0%	0%
Grade 3	6.5 - 7.4	1%	1%	0%	0%
Grade 4	<6.5	<1%	0%	0%	0%
Platelet count (103/µL)
Grade 2	50 - 99.999	1%	0%	1%	<1%
Grade 3	25 - 49.999	<1%	<1%	0%	0%
Grade 4	<25	0%	0%	0%	<1%
Blood chemistry
Fasting (non-random) serum glucose test (mg/dL)*
Grade 2	126 - 250	7%	6%
Grade 3	251 - 500	2%	1%
Grade 4	500	0%	0%
Total serum bilirubin
Grade 2	1.6 - 2.5 × ULN	5%	<1%	3%	2%
Grade 3	2.6 - 5.0 × ULN	1%	0%	1%	<1%
Grade 4	5.0 × ULN	<1%	0%	<1%	0%
Creatinine
Grade 2	1.4-1.8 × ULN	1%	1%	0%	<1%
Grade 3	1.9-3.4 × ULN	0%	<1%	0%	0%
Grade 4	≥3.5 × ULN	0%	0%	0%	0%
Serum aspartate aminotransferase
Grade 2	2.6 - 5.0 × ULN	8%	10%	5%	3%
Grade 3	5.1 - 10.0 × ULN	5%	3%	2%	<1%
Grade 4	10.0 × ULN	1%	<1%	1%	<1%
Serum alanine aminotransferase
Grade 2	2.6 - 5.0 × ULN	11%	12%	4%	2%
Grade 3	5.1 - 10.0 × ULN	2%	2%	1%	<1%
Grade 4	10.0 × ULN	2%	1%	1%	<1%
Serum alkaline phosphatase
Grade 2	2.6 - 5.0 × ULN	1%	3%	1%	0%
Grade 3	5.1 - 10.0 × ULN	0%	1%	<1%	0%
Grade 4	10.0 × ULN	<1%	<1%	0%	0%
Lipase†
Grade 2	1.6-3.0 x ULN			7%	5%
Grade 3	3.1-5.0 × ULN			2%	1%
Grade 4	5.0 × ULN			2%	1%
Creatine kinase†
Grade 2	6.0-9.9 × ULN			4%	5%
Grade 3	10.0-19.9 × ULN			3%	3%
Grade 4	≥20.0 × ULN			3%	2%

Lipids, Change from Baseline

Changes from baseline in fasting lipids are shown in Table 8.

Table 8: Lipid Values, Mean Change from Baseline, STARTMRK Study

Laboratory Parameter Preferred Term	ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir Disoproxil Fumarate N = 207	Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir Disoproxil Fumarate N = 187
		Change from Baseline at Week 240		Change from Baseline at Week 240
Baseline Mean	Week 240 Mean	Mean Change	Baseline Mean	Week 240 Mean	Mean Change
(mg/dL)	(mg/dL)	(mg/dL)	(mg/dL)	(mg/dL)	(mg/dL)
Notes: N = total number of subjects per treatment group with at least one lipid test result available. The analysis is based on all available data. If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis. If the missing data was due to other reasons, subjects were censored thereafter for the analysis. At baseline, serum lipid-reducing agents were used in 5% of subjects in the group receiving ISENTRESS and 3% in the efavirenz group. Through Week 240, serum lipid-reducing agents were used in 9% of subjects in the group receiving ISENTRESS and 15% in the efavirenz group.
Fasting (non-random) laboratory tests at Week 240.
LDL-Cholesterol*	96	106	10	93	118	25
HDL-Cholesterol*	38	44	6	38	51	13
Total Cholesterol*	159	175	16	157	201	44
Triglyceride*	128	130	2	141	178	37

Treatment-Experienced Adults

The safety assessment of ISENTRESS in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo- controlled trials, BENCHMRK 1 and BENCHMRK 2 in antiretroviral treatment- experienced HIV-1 infected adult subjects. A total of 462 subjects received the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) compared to 237 subjects taking placebo in combination with OBT. The median duration of therapy in these trials was 96 weeks for subjects receiving ISENTRESS and 38 weeks for subjects receiving placebo. The total exposure to ISENTRESS was 708 patient-years versus 244 patient-years on placebo. The rates of discontinuation due to adverse events were 4% in subjects receiving ISENTRESS and 5% in subjects receiving placebo.

Clinical ADRs were considered by investigators to be causally related to ISENTRESS + OBT or placebo + OBT. Clinical ADRs of moderate to severe intensity occurring in ≥2% of subjects treated with ISENTRESS and occurring at a higher rate compared to placebo are presented in Table 9.

Table 9: Adverse Drug Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Experienced Adult Subjects Receiving ISENTRESS and at a Higher Rate Compared to Placebo (96 Week Analysis)

System Organ Class, Adverse Reactions	Randomized Studies BENCHMRK 1 and BENCHMRK 2
ISENTRESS 400 mg Twice Daily + OBT (n = 462)	Placebo + OBT (n = 237)
Nervous System Disorders
n=total number of subjects per treatment group.
Includes adverse reactions at least possibly, probably, or definitely related to the drug. † Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).
Headache	2%	<1%

Laboratory Abnormalities

The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Studies BENCHMRK 1 and BENCHMRK 2 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 10.

Table 10: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (96 Week Analysis)

		Randomized Studies BENCHMRK 1 and BENCHMRK 2
Laboratory Parameter Preferred Term (Unit)	Limit	ISENTRESS 400 mg Twice Daily + OBT (N = 462)	Placebo + OBT (N = 237)
ULN = Upper limit of normal range
Hematology
Absolute neutrophil count (103/µL)
Grade 2	0.75 - 0.999	4%	5%
Grade 3	0.50 - 0.749	3%	3%
Grade 4	<0.50	1%	<1%
Hemoglobin (gm/dL)
Grade 2	7.5 - 8.4	1%	3%
Grade 3	6.5 - 7.4	1%	1%
Grade 4	<6.5	<1%	0%
Platelet count (103/µL)
Grade 2	50 - 99.999	3%	5%
Grade 3	25 - 49.999	1%	<1%
Grade 4	<25	1%	<1%
Blood chemistry
Fasting (non-random) serum glucose test (mg/dL)
Grade 2	126 - 250	10%	7%
Grade 3	251 - 500	3%	1%
Grade 4	500	0%	0%
Total serum bilirubin
Grade 2	1.6 - 2.5 × ULN	6%	3%
Grade 3	2.6 - 5.0 × ULN	3%	3%
Grade 4	5.0 × ULN	1%	0%
Serum aspartate aminotransferase
Grade 2	2.6 - 5.0 × ULN	9%	7%
Grade 3	5.1 - 10.0 × ULN	4%	3%
Grade 4	10.0 × ULN	1%	1%
Serum alanine aminotransferase
Grade 2	2.6 - 5.0 × ULN	9%	9%
Grade 3	5.1 - 10.0 × ULN	4%	2%
Grade 4	10.0 × ULN	1%	2%
Serum alkaline phosphatase
Grade 2	2.6 - 5.0 × ULN	2%	<1%
Grade 3	5.1 - 10.0 × ULN	<1%	1%
Grade 4	10.0 × ULN	1%	<1%
Serum pancreatic amylase test
Grade 2	1.6 - 2.0 × ULN	2%	1%
Grade 3	2.1 - 5.0 × ULN	4%	3%
Grade 4	5.0 × ULN	<1%	<1%
Serum lipase test
Grade 2	1.6 - 3.0 × ULN	5%	4%
Grade 3	3.1 - 5.0 × ULN	2%	1%
Grade 4	5.0 × ULN	0%	0%
Serum creatine kinase
Grade 2	6.0 - 9.9 × ULN	2%	2%
Grade 3	10.0 - 19.9 × ULN	4%	3%
Grade 4	≥20.0 × ULN	3%	1%

Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment- Experienced Studies

The following ADRs occurred in <2% of treatment-naïve or treatment-experienced subjects receiving ISENTRESS or ISENTRESS HD in a combination regimen. These events have been included because of their seriousness, increased frequency compared with efavirenz or placebo, or investigator's assessment of potential causal relationship.

Gastrointestinal Disorders: abdominal pain, gastritis, dyspepsia, vomiting

General Disorders and Administration Site Conditions: asthenia

Hepatobiliary Disorders: hepatitis

Immune System Disorders: hypersensitivity

Infections and Infestations: genital herpes, herpes zoster

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

Renal and Urinary Disorders: nephrolithiasis, renal failure

Selected Adverse Events - Adults

In studies of ISENTRESS 400 mg twice daily, cancers were reported in treatment-experienced subjects who initiated ISENTRESS or placebo, both with OBT, and in treatment-naïve subjects who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir disoproxil fumarate; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm3 and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving ISENTRESS and the group receiving the comparator.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS and ISENTRESS HD (see Tables 6 and 8). Myopathy and rhabdomyolysis have been reported with ISENTRESS. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS + darunavir/ritonavir compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

Patients with Co-existing Conditions - Adults

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

In Phase III studies of ISENTRESS, patients with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In the treatment-experienced studies, BENCHMRK 1 and BENCHMRK 2, 16% of all patients (114/699) were co-infected; in the treatment-naïve studies, STARTMRK and ONCEMRK, 6% (34/563) and 3% (23/797), respectively, were co-infected. In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that in subjects without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups.

At 96 weeks, in treatment-experienced subjects receiving ISENTRESS 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29%, 34% and 13%, respectively, of co-infected subjects treated with ISENTRESS as compared to 11%, 10% and 9% of all other subjects treated with ISENTRESS. At 240 weeks, in treatment-naïve subjects receiving ISENTRESS 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22%, 44% and 17%, respectively, of co-infected subjects treated with ISENTRESS as compared to 13%, 13% and 5% of all other subjects treated with ISENTRESS.

At 96 weeks, in treatment-naïve subjects receiving ISENTRESS HD 1200 mg (2 × 600 mg) once daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 27%, 40% and 13%, respectively, of co-infected subjects treated with ISENTRESS HD 1200 mg once daily as compared to 7%, 5% and 3% of all other subjects treated with ISENTRESS HD 1200 mg once daily.

Pediatrics

2 to 18 Years of Age

ISENTRESS has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see Use in Specific Populations (8.4) and Clinical Studies (14.4)]. Of the 126 patients, 96 received the recommended dose of ISENTRESS.

In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 24 were comparable to those observed in adults.

One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.

One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.

4 Weeks to Less than 2 Years of Age

ISENTRESS has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see Use in Specific Populations (8.4) and Clinical Studies (14.4)].

In these 26 infants and toddlers, the frequency, type and severity of drug related adverse reactions through Week 48 were comparable to those observed in adults.

One patient experienced a Grade 3 serious drug related allergic rash that resulted in treatment discontinuation.

HIV-1 Exposed Neonates

Forty-two neonates were treated with ISENTRESS for up to 6 weeks from birth, and followed for a total of 24 weeks in IMPAACT P1110 [see Use in Specific Populations (8.4)]. There were no drug related clinical adverse reactions and three drug related laboratory adverse reactions (one case of transient Grade 4 neutropenia in a subject receiving zidovudine-containing regimen for prevention of mother to child transmission (PMTCT), and two bilirubin elevations (one each, Grade 1 and Grade 2) considered non-serious and not requiring specific therapy). The safety profile in neonates was generally similar to that observed in older patients treated with ISENTRESS. No clinically meaningful differences in the adverse event profile of neonates were observed when compared to adults.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ISENTRESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

11 DESCRIPTION

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

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

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Bring this booklet to your child's appointments.

ISENTRESS (raltegravir)
for oral suspension

Instructions for Use

for babies and toddlers

Before You Start

Note: Make sure your doctor shows you how to prepare and give ISENTRESS for oral suspension.

• 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

Prescription (on box)		2 mixing cups
Instructions for Use (this booklet) Prescribing Information 6 syringes		60 packets of ISENTRESS

2blue (10mL) syringes	2green (3mL) syringes	2white (1mL) syringes

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:

1 mixing cup (Using the tab on the mixing cup, pull open the lid)	1 packet of ISENTRESS	a clean glass	3 syringes (Have one of each size ready, but you will only need 1 or 2, depending on the prescribed dose)

Step 2. Fill a clean glass with water

Fill a clean glass with room-temperature drinking water from your sink or use bottled water.

Step 3. Fill theblue**** syringe with water

Push the plunger of theblue syringe into the syringe as far as it goes.
Put the tip of the syringe into the glass of water. Pull back the plunger to draw up water into the syringe. Stop when you get to the 10mL mark.

Step 4. Check for air bubbles

Hold the syringe with tip up. Tap it with your finger to move any air bubbles up towards the tip. Slowly push up on the plunger to make the air come out. You may see some drops of water come out.
	Re-check the amount of water in the syringe. If it is less than 10mL, put the tip back into the water and pull back on the plunger until you get to the 10mL mark.

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

Note before adding ISENTRESS: Make sure you and your child are ready! After mixing ISENTRESS,use it within 30 minutes. Throw away any leftover ISENTRESS after you have given the dose to your child.

	Take 1 packet of ISENTRESS and shake the powder to the bottom of the packet.
Tear or cut open the packet at the dotted line and add all of the powder to the water in the mixing cup. Make sure the packet is completely empty.

Step 7. Mix ISENTRESS and water

Snap the lid of the mixing cup shut. Gently swirl the mixing cup for 45 seconds in a circular motion to mix the powder and water. Use a clock or timer to time for 45 seconds.Do not shake the mixture.
	Check to make sure the powder is mixed. If it is not mixed, swirl it some more. The mixture should look cloudy.

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:

WHITE (1mL) for1mL or less

GREEN (3mL) for1.5mL to3mL

BLUE (10mL) for3.5mL to10mL

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

Step 10. Measure ISENTRESS

Push the plunger into the barrel of the syringe as far as it goes.
Put the tip of the syringe into the cup of the mixed ISENTRESS and pull back on the plunger. Stop when you get to the line that matches your child's prescribed dose.

IMPORTANT: Your child's dose may be different from the one shown in this figure. There will usually be some leftover mixed ISENTRESS in the mixing cup.

Step 11. Check for air bubbles

Hold the syringe with tip up. Tap it with your finger to move any air bubbles up towards the tip. Slowly push the plunger to make the air come out. You may see some drops of medicine come out.
	Re-check the amount of ISENTRESS in the syringe. If it is less than the prescribed dose, put the tip back into the cup of mixed ISENTRESS and pull back on the plunger until you get to the right dose mark.

Step 12. Give ISENTRESS to your child

Place the tip of the syringe inside your child's mouth so that it touches either the right or left cheek.

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).

IMPORTANT: If your child does not take all of the prescribed dose or spits some of it out, call your doctor to find out what to do.

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.

Rinse with water and let air dry. Put everything in a clean, dry place.

How should I store ISENTRESS?

Store theISENTRESS 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.

Be sure to keep your doctor's appointments so you always know how much ISENTRESS to give to your child.

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

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Recommendations

• 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:
  • SeeInstructions 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.

2.2 Adults

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)].

Table 1: Dosing Recommendations for ISENTRESS and ISENTRESS HD in Adult Patients

Population	Recommended Dose
Treatment-naïve patients or patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily	1200 mg (2 × 600 mg) once daily or 400 mg twice daily
Treatment-experienced	400 mg twice daily
Treatment-naïve or treatment-experienced when coadministered with rifampin [see Drug Interactions (7.1)]	800 mg (2 × 400 mg) twice daily

2.3 Pediatrics

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)].

Table 2: Dosing Recommendations for ISENTRESS and ISENTRESS HD in Pediatric Patients

	Recommended Pediatric Dosage and Formulation
Population/Weight	Film-Coated Tablets 400 mg	Film-Coated Tablets 600 mg	Chewable Tablets 100 mg and 25 mg	For Oral Suspension 100 mg
If able to swallow a tablet
If at least 40 kg and either: treatment-naïve or virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily	400 mg twice daily	1200 mg (2 × 600 mg) once daily	300 mg twice daily (see Table 3)	NA
If at least 25 kg	400 mg twice daily*	NA	Weight-based dosing twice daily (see Table 3)	NA
If at least 4 weeks of age and weighing 3 kg to less than 25 kg	NA	NA	Weight-based dosing twice daily (see Table 4)	Weight-based dosing twice daily up to 20 kg (see Table 4)
From birth to 4 weeks (28 days) weighing at least 2 kg	NA	NA	NA	Weight-based dosing once daily or twice daily (see Table 5)

Table 3: Alternative Dosage* with ISENTRESS Chewable Tablets for Pediatric Patients Weighing at Least 25 kg

Body Weight (kg)	Dose	Number of 100 mg Chewable Tablets
The weight-based dosing recommendation for the chewable tablet is based on approximately 6 mg/kg/dose twice daily [see Clinical Pharmacology (12.3)]. † The 100 mg chewable tablet can be divided into equal halves.
25 to less than 28	150 mg twice daily	1.5 × 100 mg† twice daily
28 to less than 40	200 mg twice daily	2 × 100 mg twice daily
At least 40	300 mg twice daily	3 × 100 mg twice daily

Table 4: Recommended Dosage* for ISENTRESS For Oral Suspension and Chewable Tablets in Pediatric Patients at Least 4 Weeks of Age and Weighing at Least 3 kg and Less than 25 kg

Body Weight (kg)	Volume (Dose) of Suspension to be Administered	Number of Chewable Tablets†
The weight-based dosing recommendation for the chewable tablet and oral suspension is based on approximately 6 mg/kg/dose twice daily [see Clinical Pharmacology (12.3)]. † The chewable tablets are available as 25 mg and 100 mg tablets. ‡ May be administered as a crushed tablet(s); see General Dosing Recommendations (2.1) for guidance. § The 100 mg chewable tablet can be divided into equal halves.
3 to less than 4	2.5 mL (25 mg) twice daily	1 × 25 mg twice daily‡
4 to less than 6	3 mL (30 mg) twice daily
6 to less than 8	4 mL (40 mg) twice daily	2 × 25 mg twice daily‡
8 to less than 10	6 mL (60 mg) twice daily
10 to less than 14	8 mL (80 mg) twice daily	3 × 25 mg twice daily‡
14 to less than 20	10 mL (100 mg) twice daily	1 × 100 mg twice daily
20 to less than 25	Not applicable	1.5 × 100 mg§ twice daily

• 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.

Table 5: Recommended Dose for ISENTRESS For Oral Suspension in Full- Term Neonates (Birth to 4 Weeks [28 days] of Age)

Body Weight (kg)	Volume (Dose) of Suspension to be Administered
Note: If the mother has taken ISENTRESS or ISENTRESS HD 2-24 hours before delivery, the neonate's first dose should be given between 24-48 hours after birth.
The dosing recommendations are based on approximately 1.5 mg/kg/dose. † The dosing recommendations are based on approximately 3 mg/kg/dose.
Birth to 1 Week - Once daily dosing*****
2 to less than 3	0.4 mL (4 mg) once daily
3 to less than 4	0.5 mL (5 mg) once daily
4 to less than 5	0.7 mL (7 mg) once daily
1 to 4 Weeks - Twice daily dosing**†**
2 to less than 3	0.8 mL (8 mg) twice daily
3 to less than 4	1 mL (10 mg) twice daily
4 to less than 5	1.5 mL (15 mg) twice daily