RALTEGRAVIR TABLETS

Raltegravir is an antiretroviral drug produced by Merck & Co., used to treat HIV infection.

It received approval by the

U.S. Food and Drug Administration (FDA) on 12 October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval.

For the treatment of

HIV-1 infection in conjunction with other antiretrovirals.

Mechanism of Action Raltegravir is an

HIV-1 antiviral drug. 12.2 Pharmacodynamics 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 and 019, antiviral responses were similar among subjects regardless of dose.

In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo.

Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400 mg dose.

ISENTRESS did not appear to prolong the QTc interval for 12 hours postdose.

After baseline and placebo adjustment, the maximum mean QTc change was -0.4 msec (1-sided 95% upper Cl: 3.1 msec). 12.3 Pharmacokinetics Adults Absorption Raltegravir (film-coated tablet) is absorbed with a T max of approximately 3 hours postdose in the fasted state.

Raltegravir AUC and

C max increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C 12hr increases dose proportionally over the dose range of to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. With twice-daily dosing, pharmacokinetic steady state is achieved within approximately the first 2 days of dosing.

There is little to no accumulation in AUC and C max.

The average accumulation ratio for

C 12hr ranged from approximately 1.2 to 1.6.

The absolute bioavailability of raltegravir has not been established.

Based on a formulation comparison study in healthy adult volunteers, the chewable tablet and oral suspension have higher oral bioavailability compared to the 400 mg film-coated tablet.

In subjects who received 400 mg twice daily alone, raltegravir drug exposures were characterized by a geometric mean AUC 0-12hr of 14.3 µM∙hr and C 12hr of 142 nM.

Considerable variability was observed in the pharmacokinetics of raltegravir.

For observed

C 12hr in Protocols and 019, the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%.

ISENTRESS may be administered with or without food.

Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-1-infected patients.

The effect of consumption of low-, moderate.

• and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers administered the 400 mg film-coated tablet.

Administration of multiple doses of raltegravir following a moderate-fat meal (600 Kcal, 21 g fat) did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting.

C 12hr was 66% higher and C max was 5% higher following a moderate-fat meal compared to fasting.

Administration of raltegravir following a high-fat meal (825 Kcal, 52 g fat) increased AUC and C max by approximately 2-fold and increased C 12hr by 4.1-fold.

Administration of raltegravir following a low-fat meal (300 Kcal, 2.5 g fat) decreased AUC and C max by 46% and 52%, respectively; C 12hr was essentially unchanged.

Food appears to increase pharmacokinetic variability relative to fasting.

Administration of the chewable tablet with a high fat meal led to an average 6% decrease in AUC, 62% decrease in C max, and 188% increase in C 12hr compared to administration in the fasted state.

Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food.

The effect of food on the formulation for oral suspension was not studied.

Raltegravir is approximately 83% bound to human plasma protein over the concentration range of to 10 µM. In one study of HIV-1 infected subjects who received raltegravir 400 mg twice daily, raltegravir was measured in the cerebrospinal fluid.

In the study (n=18), the median cerebrospinal fluid concentration was 5.8% (range to 53.5%) of the corresponding plasma concentration.

This median proportion was approximately 3-fold lower than the free fraction of raltegravir in plasma.

The clinical relevance of this finding is unknown.

The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC.

Following administration of an oral dose of radiolabeled raltegravir, approximately and 32% of the dose was excreted in feces and urine, respectively.

In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species.

Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately and 23% of the dose, respectively.

The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide.

Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide.

Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

Two pediatric formulations were evaluated in healthy adult volunteers, where the chewable tablet and oral suspension were compared to the 400 mg tablet.

The chewable tablet and oral suspension demonstrated higher oral bioavailability, thus higher AUC, compared to the 400 mg tablet.

In the same study, the oral suspension resulted in higher oral bioavailability compared to the chewable tablet.

These observations resulted in proposed pediatric doses targeting 6 mg/kg/dose for the chewable tablets and oral suspension.

As displayed in

Table 9, the doses recommended for HIV-infected infants, children and adolescents 4 weeks to 18 years of age resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily.

Overall, dosing in pediatric patients achieved exposures (C trough ) above 45 nM in the majority of subjects, but some differences in exposures between formulations were observed.

Pediatric patients above 25 kg administered the chewable tablets had lower trough concentrations (113 nM) compared to pediatric patients above 25 kg administered the 400 mg tablet formulation (233 nM) .

As a result, the 400 mg film-coated tablet is the recommended dose in patients weighing at least 25 kg; however, the chewable tablet offers an alternative regimen in patients weighing at least 25 kg who are unable to swallow the film-coated tablet.

In addition, pediatric patients weighing to 25 kg who were administered the chewable tablets had the lowest trough concentrations (82 nM) compared to all other pediatric subgroups.

Table 9: Raltegravir Steady State Pharmacokinetic Parameters in Pediatric Patients Following Administration of Recommended Doses Body Weight Formulation Dose N Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose.

Mean (%CV Geometric coefficient of variation). AUC 0-12hr (µM∙hr) Geometric Mean (%CV ) C 12hr (nM) ≥25 kg Film-coated tablet 400 mg twice daily 18 14.1 (121%) 233 ( 157% ) ≥25 kg Chewable tablet Weight based dosing, see Table 1 9 22.1 ( 36% ) 113 ( 80% ) 11 to less than 25 kg Chewable tablet Weight based dosing, see Table 2 13 18.6 ( 68% ) 82 ( 123%) 3 to less than 20 kg Oral suspension Weight based dosing, see Table 2 19 24.5 ( 43% ) 113 ( 69% ) The pharmacokinetics of raltegravir in infants under 4 weeks of age has not been established.

The effect of age (18 years and older) on the pharmacokinetics of raltegravir was evaluated in the composite analysis.

No dosage adjustment is necessary.

The effect of race on the pharmacokinetics of raltegravir in adults was evaluated in the composite analysis.

A study of the pharmacokinetics of raltegravir was performed in healthy adult males and females.

Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy subjects and 28 HIV-1 infected subjects receiving raltegravir monotherapy with fasted administration.

Raltegravir is eliminated primarily by glucuronidation in the liver.

A study of the pharmacokinetics of raltegravir was performed in adult subjects with moderate hepatic impairment.

Additionally, hepatic impairment was evaluated in the composite pharmacokinetic analysis.

There were no clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects.

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment.

The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.

Renal clearance of unchanged drug is a minor pathway of elimination.

A study of the pharmacokinetics of raltegravir was performed in adult subjects with severe renal impairment.

Additionally, renal impairment was evaluated in the composite pharmacokinetic analysis.

There were no clinically important pharmacokinetic differences between subjects with severe renal impairment and healthy subjects.

Because the extent to which

ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided.

UGT1A1 Polymorphism There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent.

In a comparison of 30 adult subjects with 28/28 genotype (associated with reduced activity of UGT1A1) to 27 adult subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41.

Table 10: Effect of Other Agents on the Pharmacokinetics of Raltegravir in Adults Coadministered Drug Coadministered Drug Dose/Schedule Raltegravir Dose/Schedule Ratio (90% Confidence Interval) of Raltegravir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 n C max AUC C min aluminum and magnesium hydroxide antacid 20 mL single dose given with raltegravir 400 mg twice daily 25 0.56 0.51 0.37 20 mL single dose given 2 hours before raltegravir 23 0.49 0.49 0.44 20 mL single dose given 2 hours after raltegravir 23 0.78 0.70 0.43 20 mL single dose given 4 hours before raltegravir 17 0.78 0.81 0.40 20 mL single dose given 4 hours after raltegravir 18 0.70 0.68 0.38 20 mL single dose given 6 hours before raltegravir 16 0.90 0.87 0.50 20 mL single dose given 6 hours after raltegravir 16 0.90 0.89 0.51 atazanavir 400 mg daily 100 mg single dose 10 1.53 1.72 1.95 atazanavir/ritonavir 300 mg/100 mg daily 400 mg twice daily 10 1.24 1.41 1.77 boceprevir 800 mg three times daily 400 mg single dose 22 1.11 1.04 0.75 calcium carbonate antacid 3000 mg single dose given with raltegravir 400 mg twice daily 24 0.48 0.45 0.68 efav.

Absorbed from the gastrointestinal tract.

Approximately 83% bound to human plasma protein and is minimally distributed into red blood cells (blood-to-plasma partitioning ratio of 0.6).

The major mechanism of clearance of raltegravir in humans is glucuronidation mediated by UGT1A1, the renal clearance of unchanged drug is a minor pathway of elimination of raltegravir (9% of total dose).

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

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.

can be administered with or without food.

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.

Adults 400 mg film-coated tablet orally, twice daily.

During coadministration with rifampin in adults, 800 mg twice daily.

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 3 kg to less than 25 kg: Weight based dosing, as specified in Table 2.

For patients weighing between and 20 kg, either the chewable tablet or the formulation for oral suspension can be used, as specified in Table 2. 2.1 General Dosing Recommendations ISENTRESS Film-Coated Tablets, Chewable Tablets and For Oral Suspension can be administered with or without food.

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.

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.

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. 2.2 Adults 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. 2.3 Pediatrics If at least 25 kg: One 400 mg film-coated tablet orally, twice daily.

Table 1: Alternative Dose The weight-based dosing recommendation for the chewable tablet is based on approximately 6 mg/kg/dose twice daily. with ISENTRESS Chewable Tablets for Pediatric Patients Weighing at Least 25 kg Body Weight (kg) Dose Number of Chewable Tablets to less than 28 150 mg twice daily 1.5 × 100 mg The 100 mg chewable tablet can be divided into equal halves. twice daily 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 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 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 for appropriate dosing.

Table 2: Recommended Dose The weight-based dosing recommendation for the chewable tablet and oral suspension is based on approximately 6 mg/kg/dose twice daily. for ISENTRESS For Oral Suspension and Chewable Tablets in Pediatric Patients Weighing Less than 25 kg Body Weight (kg) Volume (Dose) of Suspension to be Administered Number of Chewable Tablets to less than 4 1 mL (20 mg) twice daily to less than 6 1.5 mL (30 mg) twice daily to less than 8 2 mL (40 mg) twice daily to less than 11 3 mL (60 mg) twice daily to less than For weight between and 20 kg either formulation can be used.

The chewable tablets are available as 25 mg and 100 mg tablets. 4 mL (80 mg) twice daily 3 × 25 mg twice daily to less than 20 5 mL (100 mg) twice daily 1 × 100 mg twice daily to less than 25 1.5 × 100 mg The 100 mg chewable tablet can be divided into equal halves. twice daily 2.4 Method of Administration ISENTRESS Film-Coated Tablets Film-Coated Tablets must be swallowed whole ISENTRESS Chewable Tablets Chewable Tablets may be chewed or swallowed whole ISENTRESS For Oral Suspension Each single-use ISENTRESS packet for oral suspension contains 100 mg of raltegravir which is to be suspended in 5 mL of water giving a final concentration of 20 mg/mL.

Pour packet contents of

ISENTRESS for oral suspension into 5 mL of water and mix Once mixed, measure the recommended volume (dose) of suspension with a syringe and administer the dose orally The volume (dose) of suspension should be administered orally within 30 minutes of mixing Discard any remaining suspension For more details on preparation and administration of the suspension, see Instructions for Use.

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 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).

Store in the original package with the bottle tightly closed.

Keep the desiccant in the bottle to protect from moisture.

Store in the original container.

Do not open foil packet until ready for use.

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).

Store in the original package with the bottle tightly closed.

Keep the desiccant in the bottle to protect from moisture.

Store in the original container.

Do not open foil packet until ready for use.

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 and 24 hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.

To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established.

Physicians are encouraged to register patients by calling 1-800-258-4263.

Breastfeeding is not recommended while taking

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.

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.

The safety profile was comparable to that observed in adults.

See Dosage and

Administration 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 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.