Nutrilipid

Description

Nutrilipid® 20% is a sterile, nonpyrogenic fat emulsion prepared for intravenous administration.

Each 100 mL of Nutrilipid® 20% contains: Soybean Oil 20 g; Egg Yolk Phospholipid 1.2 g; Glycerin USP (glycerol) 2.5 g; Sodium Oleate 0.03 g; Water for Injection USP qs.

pH adjusted with Sodium Hydroxide NF.

pH: 6.8 (6.0-8.9); Osmolality: 390 mOsmolKg (actual). Contains emulsified fat particles averaging approximately 0.26 micron in diameter, similar to naturally occurring chylomicrons. The total caloric value, including fat, phospholipid, and glycerol is 2.0 Kcal per mL.

Soybean oil is a refined natural product consisting of a mixture of neutral triglycerides of predominantly unsaturated fatty acids with the following structure:

 

 

are saturated and unsaturated fatty acid residues. The major component fatty acids are linoleic (48% – 58%), oleic (17% – 30%), palmitic (9% -13%), linolenic (4% – 11%), and stearic (2.5% – 5.0%). These fatty acids have the folIowing chemical and structural formulas:

 

 

Egg yolk phospholipids are a mixture of naturally occurring phospholipids isolated from egg yolk.

Glycerol is chemically designated C₃H₈0₃ and is a clear colorless, hygroscopic syrupy liquid. It is added to adjust tonicity.

Not made with natural rubber latex, PVC or DEHP.

Drug product contains no more than 25 mcg/L of aluminum.

Indications

Nutrilipid® 20% is indicated as a source of calories and essential fatty acids for parenteral nutrition and as a source of essential fatty acids when a deficiency occurs when oral or enteral nutrition is not possible, insufficient, or contraindicated.

Dosage And Administration

Administration Instructions

• Nutrilipid® 20% Pharmacy Bulk Package is not intended for direct intravenous administration.
• Nutrilipid® 20% is for intravenous infusion only through a peripheral or central line. When administered with dextrose and amino acids, the choice of a central or peripheral venous route should depend on the osmolarity of the final infusate.
• Use a non-vented infusion set or close the air vent on a vented set. Use of a vented intravenous administration set with the vent in the open position could result in air embolism.
• Use a dedicated line without any connections. Multiple connections could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.
• Use a 1.2 micron in-line filter.
• Nutrilipid® 20% can be infused concurrently into the same vein as carbohydrate-amino acid solutions by means of a Y-connector located near the infusion site; flow rates of each solution should be controlled separately by infusion pumps.
• Do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP). Conventional administration sets contain polyvinyl chloride (PVC) components that have DEHP as a plasticizer.

Preparation Instructions For Nutrilipid® 20% Bags For Direct Infusion

Caution

Nutrilipid® 20% Pharmacy Bulk Package is not intended for direct intravenous administration.

 

 

Step 1: Inspect infusion bag overwrap and primary bag and do not use if damaged. Inspect oxygen indicator and do not use if oxygen indicator is pink or dark pink. Use only if container and seals are intact.

Step 2: To open, tear overwrap starting from the tear notches (Figure 1). Remove Nutrilipid® 20% bag from overwrap and discard oxygen indicator, oxygen absorber and overwrap.

 

 

Step 3: Inspect Nutrilipid® 20% bag visually (Figure 2). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect Nutrilipid® 20% to ensure that the emulsion has not separated. Discard the bag if any particulates or discoloration are observed.

 

 

Step 4: Remove aluminum foil of outlet port at the bottom of the bag (Figure 3a) and attach administration set (Figure 3b).

 

 

Step 5: Hang bag on IV Pole (Figure 4). If infusion pumps are used, flow rates of each parenteral fluid should be controlled with a separate pump.

 

 

Do not connect flexible bags in series to avoid air embolism due to possible residual gas contained in the primary bag.

Air embolism can result if residual gas in the bag is not fully evacuated prior to administration if the flexible bag is pressurized to increase flow rates.

If administration is controlled by a pumping device, discontinue pumping action before the bag runs dry to avoid air embolism.

Use Of Admixtures In Nutrilipid® Infusion Bags For Direct Infusion

• Some additives may be incompatible and should not be used. If it is deemed advisable to introduce additives, prepare the admixture using strict aseptic techniques to avoid microbial contamination. Compatible supplemental medication (e.g., fat-soluble vitamins) may be added with a 19 to 22 gauge needle through the medication port. Additions to the bag should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to B. Braun Medical Inc., Medical Affairs.
• The prime destabilizers of emulsions are excessive acidity (such as pH below 5) and inappropriate electrolyte content. Give careful consideration to additions of divalent cations (Ca++ and Mg++), which have been shown to cause emulsion instability.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect Nutrilipid® 20% to ensure that:
  • precipitates have not formed during the addition of additives and
  • the emulsion has not separated during the addition of additives.
• Discard the admixture if precipitates or discoloration are observed.

Step 1: Prepare the medication port by removal of aluminum foil (Figure 5a).

Step 2: Puncture the resealable medication port by using a 19 to 22 gauge needle and inject additive(s) (Figure 5b).

 

 

Step 3: Mix thoroughly when additives have been introduced (Figure 6).

 

 

Step 4: The medication port may be swabbed with disinfection agent (e.g., iso-propanol or chlorhexidine) before re-puncturing.

Step 5: Inspect emulsion bag visually for particulates or separation of the emulsion. Discard the bag if any particulates or discoloration are observed.

Do not store solutions containing additives.

Preparation Instructions For Admixing Using Total Parenteral Nutrition Pooling Bags

• Prepare the admixture into pooling bags using strict aseptic techniques to avoid microbial contamination.
• Do not add additives directly to Nutrilipid® 20% Pharmacy Bulk Package.
  • Some additives may be incompatible and should not be used. If it is deemed advisable to introduce additives, prepare the admixture using strict aseptic techniques to avoid microbial contamination. Additions to the pooling bag should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to B. Braun Medical Inc., Medical Affairs.
• Do not add Nutrilipid® 20% to the pooling bag first; destabilization of the lipid may occur from such an admixture.
• The following proper mixing sequence must be followed to minimize pH related problems by ensuring that typically acidic Dextrose Injections are not mixed with lipid emulsions alone:

Manual Admixing

1. Manually transfer Dextrose Injection to the Total Parental Nutrition Admixture Container
2. Manually transfer Amino Acid Injection
3. Manually transfer Nutrilipid® 20%

Use gentle agitation during admixing to minimize localized concentration effects; shake bags gently after each addition.

Automated Device Admixing

When admixing parenteral nutrition using an automated device, the Nutrilipid 20% must be separated from the dextrose product by an amino acid product or other non-acidic products.

• • The prime destabilizers of emulsions are excessive acidity (such as pH below 5) and inappropriate electrolyte content. Give careful consideration to additions of divalent cations (Ca++ and Mg++), which have been shown to cause emulsion instability. Amino acid solutions exert buffering effects that protect the emulsion.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect Nutrilipid® 20% to ensure that:
  • precipitates have not formed during the mixing or addition of additives and
  • the emulsion has not separated. Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the admixed emulsion.

Discard the admixture if any of the above are observed.

• If using an Automated Device, follow the manufacturer instructions.
• Use of the Pharmacy Bulk Package for admixing should be limited to up to four hours after opening.
• Admixtures should be used promptly with storage under refrigeration (2-8°C) not to exceed 24 hours and must be completely used within 24 hours after removal from refrigeration.
• Do not connect flexible bags in series to avoid air embolism due to possible residual gas contained in the primary bag.
• Air embolism can result if residual gas in the bag is not fully evacuated prior to administration if the flexible bag is pressurized to increase flow rates.
• If administration is controlled by a pumping device, discontinue pumping action before the bag runs dry to avoid air embolism.

Dosing Considerations

The dosing of Nutrilipid® 20% depends on the patient’s individual energy requirements, influenced by body weight, tolerance, clinical status, age-related growth rate in pediatric patients and the ability to eliminate and metabolize fat.

For partial parenteral nutrition, energy supply by oral or enteral nutrition has to be taken into account. For complete parenteral nutrition, concomitant supplementation with amino acids, carbohydrates, electrolytes, vitamins, and trace elements is necessary.

Prior to administration of Nutrilipid® 20%, correct severe water and electrolyte disorders, severe fluid overload states, and severe metabolic disorders. Before starting the infusion, obtain serum triglyceride levels to establish the baseline value.

Recommended Adult And Pediatric Dosing

The recommended nutritional requirements of fat and recommended dosages of Nutrilipid® 20% to be administered to meet those requirements for adults and pediatric patients are provided in Table 1, along with recommendations for the initial and maximum infusion rates. The recommended duration of infusion for Nutrilipid® 20% is between 12 and 24 hours, depending on the clinical situation. Adjust the administration flow rate by taking into account the dose being administered, the daily volume/intake, and the duration of the infusion [see OVERDOSAGE].

Treatment with parenteral nutrition may be continued for as long as is required by the patient’s condition.

In patients with elevated triglyceride levels, initiate Nutrilipid® 20% injection at a lower dose, and advance in smaller increments, monitoring the triglyceride levels with each adjustment [see WARNINGS AND PRECAUTIONS].

When Nutrilipid® 20% is administered to correct essential fatty acid deficiency, 8% to 10% of the caloric input should be supplied by Nutrilipid® 20% in order to provide adequate amounts of linoleic and linolenic acids.

Table 1: Adult and Pediatric Nutritional Requirements^1,2 as Provided by Nutrilipid® 20% and Infusion Rate for Direct Infusion Only

Age	Nutritional Requirements	Direct Infusion Rate*
	Recommended Initial Dosage and Maximum Dosage	Initial	Maximum
Preterm and term infants (less than 1 year of age) [see Warnings and Precautions (5.1)]	Initial 1 to 2 g/kg/day not to exceed 3 g/kg/day**	0.05 mL/min for the first 10 to 15 minutes; gradually increase to the required rate after 15 minutes	0.75 mL/kg/hour
Pediatrics patients 1 to 10 years of age	Initial 1 to 2 g/kg/day not to exceed 3 g/kg/day**		0.75 mL/kg/hour
Pediatric patients 11 to <17 years of age	Initial 1 g/kg/day not to exceed 2.5 g/kg/day**		0.5 mL/kg/hour
Adults	1 to 1.5 g/kg/day not to exceed 2.5 g/kg/day**	0.5 mL/min for the first 15 to 30 min; gradually increase to the required rate after 30 minutes	0.5 mL/kg/hour
* Nutrilipid® 20% Pharmacy Bulk Package is not intended for direct intravenous administration. ** Daily dose should also not exceed a maximum of 60% of total energy requirements [see OVERDOSAGE].

 

How Supplied

Dosage Forms And Strengths

Nutrilipid® 20% is a lipid injectable emulsion:

• Lipid content of 0.2 grams/mL in 250 mL and 500 mL
• Lipid content of 0.2 grams/mL in 1000 mL Pharmacy Bulk Package

Storage And Handling

Nutrilipid® 20% is supplied as a sterile emulsion in the following fill sizes:

 

NDC	REF	Volume
0264-4460-00	S4600	1000 mL in Pharmacy Bulk Pack container
0264-4460-10	S4601	500 mL
0264-4460-30	S4603	250 mL

 

Do not freeze. If accidentally frozen, discard the container. Store below 25°C (77°F).

Use of the Pharmacy Bulk Package for admixing should be limited to up to four hours after opening. Admixtures should be used promptly with storage under refrigeration (2-8°C) not to exceed 24 hours and must be completely used within 24 hours after removal from refrigeration.

REFERENCES

1. Carney LN, Nepa A, Cohen SS, Dean A, Yanni C, Markowitz G. Chapter 34. Parenteral and enteral nutrition support: Determining the best way to feed. IN: The A.S.P.E.N. Pediatric Nutrition Support Core Curriculum. Corkins MR (editor in chief). American Society for Parenteral and Enteral Nutrition, Silver Spring, MD: 2010, pages 433-447.

2. Mirtallo J, Canada T, Johnson D, Kumpf V, Petersen C, Sacks G, et al. Task Force for the Revision of Safe Practices for Parenteral Nutrition, Special Report: safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr: 2004, 28 (6 Suppl).

Manufactured for: B. Braun Medical Inc., Bethlehem, PA 18018-3524 USA, 1-800-227-2862. Revised: Jul 2020

Adverse Reactions described elsewhere in labeling:

• Death in Preterm Infants [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Infections [see WARNINGS AND PRECAUTIONS]
• Fat Overload Syndrome [see WARNINGS AND PRECAUTIONS]
• Refeeding Syndrome [see WARNINGS AND PRECAUTIONS]
• Aluminum Toxicity [see WARNINGS AND PRECAUTIONS]
• Risk of Parenteral Nutrition Associated Liver Disease [see WARNINGS AND PRECAUTIONS]
• Hypertriglyceridemia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions reported with other intravenous lipid emulsions include hyperlipidemia, hypercoagulability, thrombophlebitis, and thrombocytopenia.

Adverse reactions reported in long-term use with other intravenous lipid emulsions include hepatomegaly, jaundice due to central lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia, abnormalities in liver function tests, brown pigmentation of the liver and overloading syndrome (focal seizures, fever, leukocytosis, hepatomegaly, splenomegaly and shock).

Drug Interactions

Coumarin And Coumarin Derivatives

The soybean oil present in Nutrilipid® 20% has vitamin K1. Vitamin K can reverse the anticoagulant activity of coumarin and coumarin derivatives, including warfarin, which work by blocking recycling of vitamin K. Monitor laboratory parameters for anticoagulant activity in patients who are on both Nutrilipid® 20% and coumarin or coumarin derivatives.

Included as part of the PRECAUTIONS section.

Precautions

Death In Preterm Infants

Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported. Autopsy findings included intravascular lipid accumulation in the lungs.

Base the decision to treat preterm and small for gestational age infants with intravenous lipid emulsion upon careful benefit-risk assessment. Strictly adhere to the recommended total daily dose; hourly infusion rate should be as slow as possible and should not exceed 0.75 mL/kg/hour [see DOSAGE AND ADMINISTRATION]

Preterm and small for gestational age infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion; therefore, seriously consider administration of less than the maximum recommended doses in these patients in order to decrease the likelihood of intravenous fat overload.

Carefully monitor the infant’s ability to eliminate the infused lipids from the circulation (such as serum triglycerides and/or plasma free fatty acid levels) [see WARNINGS AND PRECAUTIONS].

Because of the risk of thrombocytopenia, monitor platelet counts frequently in neonatal patients receiving parenteral nutrition with Nutrilipid® 20%.

Hypersensitivity Reactions

Stop infusion immediately and treat patient accordingly if signs or symptoms of a hypersensitivity or allergic reaction develop. Signs or symptoms may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia and chills.

Infections

Patients who require parenteral nutrition are at high risk of infections due to malnutrition and their underlying disease state.

Infection and sepsis may occur as a result of the use of intravenous catheters to administer parenteral nutrition, poor maintenance of catheters, or immunosuppressive effects of illness, drugs, and parenteral formulations.

Decrease the risk of septic complications with heightened emphasis on aseptic technique in catheter placement and maintenance, as well as aseptic technique in the preparation of the nutritional formula.

Carefully monitor for signs and symptoms (including fever and chills) of early infections, including laboratory test results (including leukocytosis and hyperglycemia) and frequent checks of the parenteral access device.

Fat Overload Syndrome

Fat overload syndrome is a rare condition that has been reported with intravenous lipid formulations. A reduced or limited ability to metabolize the lipids contained in Nutrilipid® 20% accompanied by prolonged plasma clearance may result in a syndrome characterized by a sudden deterioration in the patient’s condition accompanied by fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, liver fatty infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g., coma). The cause of the fat overload syndrome is unclear. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped. Although it has been most frequently observed when the recommended lipid dose was exceeded, cases have also been described where the lipid formulation was administered according to instructions.

Refeeding Syndrome

Refeeding severely undernourished patients with parenteral nutrition may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. Carefully monitor severely undernourished patients and slowly increase their nutrient intakes, while avoiding overfeeding, to prevent these complications.

Monitoring / Laboratory Tests

Monitor fluid status closely in patients with pulmonary edema or heart failure.

Monitor serum triglycerides [see WARNINGS AND PRECAUTIONS], fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count (including platelets), and coagulation parameters throughout treatment.

Interference With Laboratory Tests

Content of Vitamin K may counteract anticoagulant activity [see DRUG INTERACTIONS].

The lipids contained in this emulsion may interfere with the results of certain laboratory tests if the blood sample is taken before the lipids are eliminated from the serum (these are generally eliminated after a period of 5 to 6 hours without receiving lipids).

Aluminum Toxicity

Nutrilipid® 20% contains no more than 25 mcg/L of aluminum.

The aluminum contained in Nutrilipid® 20% may reach toxic levels with prolonged administration in patients with impaired kidney function. Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions that contain aluminum.

Patients with impaired kidney function, including preterm infants, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day, accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of total parenteral nutrition products.

Risk Of Parenteral Nutrition Associated Liver Disease

Parenteral Nutrition Associated Liver Disease (PNALD) has been reported in patients who receive parenteral nutrition for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD although a causal relationship has not been clearly established.

If Nutrilipid® 20% treated patients develop liver test abnormalities consider discontinuation or dose reduction.

Hypertriglyceridemia

To evaluate the patient’s capacity to eliminate and metabolize the infused lipid emulsion, measure serum triglycerides before the start of infusion (baseline value), with each increase in dosage, and regularly throughout treatment.

Reduce dose of Nutrilipid® 20% and monitor serum triglyceride levels in patients with serum triglyceride concentrations above 400 mg/dL to avoid the clinical consequences associated with hypertriglyceridemia. Serum triglyceride levels above 1000 mg/dL have been associated with an increased risk of pancreatitis.

Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. In these cases, increased triglycerides can also be increased by glucose and/or overfeeding. Monitor overall energy intake and other sources of fat and glucose, as well as drugs that may interfere with lipid and glucose metabolism.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of Nutrilipid® 20%, or its effects on fertility. Genotoxic studies have not been conducted with Nutrilipid® 20% to assess its mutagenic potential.

Use In Specific Populations

Pregnancy

Risk Summary

There are no adequate or well controlled studies with Nutrilipid® 20% in pregnant women. Additionally, animal reproduction studies have not been conducted with Nutrilipid® 20%. It is not known whether Nutrilipid® 20% can cause fetal harm when administered to a pregnant woman. Nutrilipid® 20% should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Nutrilipid® 20% is present in human milk. Because many drugs are present in human milk, caution should be exercised when Nutrilipid® 20% is administered to a nursing woman.

Pediatric Use

The evidence for safety and efficacy in pediatric patients of Nutrilipid® 20% as a source of calories and essential fatty acids for parenteral nutrition and as a source of essential fatty acids when a deficiency occurs when oral or enteral nutrition is not possible, insufficient, or contraindicated is derived from the published literature and clinical experience with similar soybean oil-based intravenous lipid emulsions.

Deaths in preterm infants after infusion of intravenous lipid emulsion have been reported [see WARNINGS AND PRECAUTIONS]. Patients, particularly preterm infants, are at risk for aluminum toxicity [see WARNINGS AND PRECAUTIONS]. Patients, including pediatric patients, may be at risk for PNALD [see WARNINGS AND PRECAUTIONS]. In clinical trials of a pure soybean oil based intravenous lipid emulsion product, thrombocytopenia in neonates occurred (less than 1%).

Geriatric Use

Clinical studies of Nutrilipid® 20% 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 patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

Parenteral nutrition should be used with caution in patients with hepatic impairment. Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive parenteral nutrition, including cholestasis, hepatic steatosis, fibrosis and cirrhosis (parenteral nutrition associated liver disease), possibly leading to hepatic failure. Cholecystitis and cholelithiasis have also been observed. The etiology of these disorders is thought to be multifactorial and may differ between patients.

Monitor liver function parameters closely. Patients developing signs of hepatobiliary disorders should be assessed early by a clinician knowledgeable in liver diseases in order to identify causative and contributory factors, and possible therapeutic and prophylactic interventions.

In the event of overdose, fat overload syndrome may result [see WARNINGS AND PRECAUTIONS]. Stop the infusion to allow lipids to clear from serum. The effects are usually reversible after the lipid infusion is stopped. If medically appropriate, further intervention may be indicated. The lipid administered and fatty acids produced are not dialyzable.

Contraindications

Nutrilipid® 20% injection is contraindicated in patients who have:

• Known hypersensitivity to egg or soybean proteins or to any of the ingredients, including excipients, or
• Severe hyperlipidemia (serum triglyceride concentrations above 1000 mg/dL) or severe disorders of lipid metabolism characterized by hypertriglyceridemia.

Mechanism Of Action

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

Pharmacodynamics

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

Cardiac Electrophysiology

At a dose 1.33 times the maximum approved recommended dose (and peak concentrations 1.25-fold higher than the maximum approved dose), raltegravir does not prolong the QT interval or PR interval to any clinically relevant extent.

Pharmacokinetics

Adults

Absorption

Raltegravir, given 400 mg twice daily, is absorbed with a Tmax of approximately 3 hours postdose in the fasted state in healthy subjects. Raltegravir 1200 mg once daily is rapidly absorbed with median Tmax of ~1.5 to 2 hours in the fasted state.

Raltegravir increases dose proportionally (AUC and Cmax) or slightly less than dose proportionally (C12hr) over the dose range 100 mg to 1600 mg.

The absolute bioavailability of raltegravir has not been established. The chewable tablet and oral suspension have higher oral bioavailability compared to the 400 mg film-coated tablet.

Relative to the raltegravir 400 mg formulation, the raltegravir 600 mg formulation has higher relative bioavailability.

Steady-state is generally reached in 2 days, with little to no accumulation with multiple dose administration for the 400 mg twice daily and 1200 once daily formulation.

Effect Of Food On Oral Absorption

The food effect of various formulations are presented in Table 12.

Table 12: Effect of Food on the Pharmacokinetics of Raltegravir Formulations

Formulation	Meal Type	PK parameter ratio (fed/fasted)
		AUC Ratio (90% CI)	Cmax Ratio (90% CI)	Cmin Ratio (90% CI)
400 mg twice daily	Low Fat	0.54 (0.41-0.71)	0.48 (0.35-0.67)	0.86 (0.54-1.36)
	Moderate Fat	1.13 (0.85-1.49)	1.05 (0.75-1.46)	1.66 (1.04-2.64)
	High Fat	2.11 (1.60-2.80)	1.96 (1.41-2.73)	4.13 (2.60-6.57)
1200 mg once daily	Low Fat	0.58 (0.46-0.74)	0.48 (0.37-0.62)	0.84 (0.63-1.10)
	High Fat	1.02 (0.86-1.21)	0.72 (0.58-0.90)	0.88 (0.66-1.18)
Chewable tablet	High Fat	0.94 (0.78-1.14)	0.38 (0.28-0.52)	2.88 (2.21-3.75)
Low-fat meal: 300 Kcal, 2.5 g fat Moderate-fat meal: 600 Kcal, 21 g fat High-fat meal: 825 Kcal, 52 g fat

 

Distribution

Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 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 1 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.

Metabolism And Excretion

The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravirglucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. The major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

Table 13: Multiple-Dose Pharmacokinetic Parameters of Raltegravir Following the Administration of 400 mg Twice Daily and 1200 mg Once Daily in HIV-infected Subjects

Parameter	400 mg BID Geometric Mean (%CV) N=6	1200 mg QD Geometric Mean (%CV) N=524
AUC (μM•hr)	AUCq-12= 14.3 (88.6)	AUC0-24 = 55.3 (41.5)
Cmax (μM)	4.5 (128)	15.7 (45.8)
Cmin (nM)	C12 = 142 (63.8)	C24 = 107 (97.5)

 

Special Populations

Pediatric

ISENTRESS

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 13, the doses recommended for HIV-infected infants, children and adolescents 4 weeks to 18 years of age [see DOSAGE AND ADMINISTRATION] 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 (Ctrough) 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) [see Clinical Studies]. 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 [see DOSAGE AND ADMINISTRATION]. In addition, pediatric patients weighing 11 to 25 kg who were administered the chewable tablets had the lowest trough concentrations (82 nM) compared to all other pediatric subgroups.

Table 14: Raltegravir Steady State Pharmacokinetic Parameters in Pediatric Patients Following Administration of Recommended Twice-Daily Doses

Body Weight	Formulation	Dose	N*	Geometric Mean (%CV†) AUC0-12hr (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 3	9	22.1 (36%)	113 (80%)
11 to less than 25 kg	Chewable tablet	Weight-based dosing, see Table 4	13	18.6 (68%)	82 (123%)
3 to less than 20 kg	Oral suspension	Weight-based dosing, see Table 4	19	24.5 (43%)	113 (69%)
*Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose. †Geometric coefficient of variation.

 

Elimination of raltegravir in vivo in human is primarily through the UGT1A1-mediated glucuronidation pathway. UGT1A1 catalytic activity is negligible at birth and matures after birth. The dose recommended for neonates less than 4 weeks of age takes into consideration the rapidly increasing UGT1A1 activity and drug clearance from birth to 4 weeks of age. Table 15 displays pharmacokinetic parameters for neonates receiving the granules for oral suspension at the recommended dose [see DOSAGE AND ADMINISTRATION].

Table 15: Raltegravir Pharmacokinetic Parameters from IMPAACT P1110 Following Age and Weight-Based Dosing of Oral Suspension

Age (hours/days) at PK Sampling	Dose (See Table 5)	N*	Geometric Mean (%CV†) AUC (μM•hr )	Geometric Mean (%CV† Ctrough (nM)
Birth – 48 hours	1.5 mg/kg once daily	25	85.9 (38.4%)‡	2132.9 (64.2%)‡
15 to 18 days	3.0 mg/kg twice daily	23	32.2 (43.3%)§	1255.5 (83.7%)§
*Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose. †Geometric coefficient of variation. ‡ AUC0-24hr (N = 24) and C24hr §AUC0-12hr and C12hr

 

ISENTRESS HD

ISENTRESS HD 1200 mg (2 x 600 mg) was not evaluated in a pediatric clinical study. Exposures for pediatric subjects weighing at least 40 kg administered ISENTRESS HD are predicted to be comparable to adult exposures observed from Phase III ONCEMRK.

Age/Race/Gender

There is no clinically meaningful effect of age (18 years and older), race, or gender on the pharmacokinetics of raltegravir. Hepatic Impairment

Raltegravir is eliminated primarily by glucuronidation in the liver. The pharmacokinetics of a single 400mg dose of raltegravir were not altered in patients with moderate (Child-Pugh Score 7 to 9) hepatic impairment.

No hepatic impairment study has been conducted with ISENTRESS HD 1200 mg (2 x 600 mg) once daily.

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

Renal Impairment

Renal clearance of unchanged drug is a minor pathway of elimination. The pharmacokinetics of a single 400-mg dose of raltegravir were not altered in patients with severe (24-hour creatinine clearance of <30 mL/min/1.73 m²) renal impairment.

No renal impairment study was conducted with ISENTRESS HD 1200 mg (2 x 600 mg) once daily.

The extent to which ISENTRESS may be dialyzable is unknown.

Drug Interactions

In vitro, raltegravir does not inhibit (IC50>100 μM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A. In vivo, raltegravir does not inhibit CYP3A4. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Similarly, raltegravir is not an inhibitor (IC50>50 μM) of UGT1A1 or UGT2B7, and raltegravir does not inhibit P-glycoprotein-mediated transport.

Raltegravir drug interaction study results are shown in Tables 16 and 17. For information regarding clinical recommendations [see DRUG INTERACTIONS].

Table 16: 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	Cmax	AUC	Cmin
aluminum and magnesium hydroxide antacid*	20 mL single dose given with raltegravir	400 mg twice daily	25	0.56 (0.42, 0.73)	0.51 (0.40, 0.65)	0.37 (0.29, 0.48)
	20 mL single dose given 2 hours before raltegravir		23	0.49 (0.33, 0.71)	0.49 (0.35, 0.67)	0.44 (0.34, 0.55)
	20 mL single dose given 2 hours after raltegravir		23	0.78 (0.53, 1.13)	0.70 (0.50, 0.96)	0.43 (0.34, 0.55)
	20 mL single dose given 4 hours before raltegravir		17	0.78 (0.55, 1.10)	0.81 (0.63, 1.05)	0.40 (0.31, 0.52)
	20 mL single dose given 4 hours after raltegravir		18	0.70 (0.48, 1.04)	0.68 (0.50, 0.92)	0.38 (0.30, 0.49)
	20 mL single dose given 6 hours before raltegravir		16	0.90 (0.58, 1.40)	0.87 (0.64, 1.18)	0.50 (0.39, 0.65)
	20 mL single dose given 6 hours after raltegravir		16	0.90 (0.58, 1.41)	0.89 (0.64, 1.22)	0.51 (0.40, 0.64)
aluminum and magnesium hydroxide antacid*	20 mL single dose given 12 hours after raltegravir	1200 mg single dose	19	0.86 (0.65, 1.15)	0.86 (0.73, 1.03)	0.42 (0.34, 0.52)
atazanavir	400 mg daily	100 mg single dose	10	1.53 (1.11, 2.12)	1.72 (1.47, 2.02)	1.95 (1.30, 2.92)
atazanavir	400 mg daily	1200 mg single dose	14	1.16 (1.01, 1.33)	1.67 (1.34, 2.10)	1.26 (1.08, 1.46)
atazanavir/ritonavir	300 mg/100 mg daily	400 mg twice daily	10	1.24 (0.87, 1.77)	1.41 (1.12, 1.78)	1.77 (1.39, 2.25)
boceprevir	800 mg three times daily	400 mg single dose	22	1.11 (0.91, 1.36)	1.04 (0.88, 1.22)	0.75 (0.45, 1.23)
calcium carbonate antacid*	3000 mg single dose given with raltegravir	400 mg twice daily	24	0.48 (0.36, 0.63)	0.45 (0.35, 0.57)	0.68 (0.53, 0.87)
calcium carbonate antacid*	3000 mg single dose given with raltegravir	1200 mg single dose	19	0.26 (0.21, 0.32)	0.28 (0.24, 0.32)	0.52 (0.45, 0.61)
	3000 mg single dose given 12 hours after raltegravir			0.98 (0.81, 1.17)	0.90 (0.80, 1.03)	0.43 (0.36, 0.51)
efavirenz	600 mg daily	400 mg single dose	9	0.64 (0.41, 0.98)	0.64 (0.52, 0.80)	0.79 (0.49, 1.28)
efavirenz	600 mg daily	1200 mg single dose	21	0.91 (0.70, 1.17)	0.86 (0.73, 1.01)	0.94 (0.76, 1.17)
etravirine	200 mg twice daily	400 mg twice daily	19	0.89 (0.68, 1.15)	0.90 (0.68, 1.18)	0.66 (0.34, 1.26)
omeprazole*	20 mg daily	400 mg twice daily	18	1.51 (0.98, 2.35)	1.37 (0.99, 1.89)	1.24 (0.95, 1.62)
rifampin	600 mg daily	400 mg single dose	9	0.62 (0.37, 1.04)	0.60 (0.39, 0.91)	0.39 (0.30, 0.51)
rifampin	600 mg daily	400 mg twice daily when administered alone; 800 mg twice daily when administered with rifampin	14	1.62 (1.12, 2.33)	1.27 (0.94, 1.71)	0.47 (0.36, 0.61)
ritonavir	100 mg twice daily	400 mg single dose	10	0.76 (0.55, 1.04)	0.84 (0.70, 1.01)	0.99 (0.70, 1.40)
tenofovir disoproxil fumarate	300 mg daily	400 mg twice daily	9	1.64 (1.16, 2.32)	1.49 (1.15, 1.94)	1.03 (0.73, 1.45)
tipranavir/ritonavir	500 mg/200 mg twice daily	400 mg twice daily	15 (14 for Cmin)	0.82 (0.46, 1.46)	0.76 (0.49, 1.19)	0.45 (0.31, 0.66)
*Study conducted in HIV-infected subjects.

 

Table 17: Effect of Raltegravir on the Pharmacokinetics of Other Agents in Adults

Substrate Drug	Raltegravir Dose/Schedule	Ratio (90% Confidence Interval) of Substrate Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00
		n	Cmax	AUC	Cmin
Tenofovir disoproxil fumarate 300 mg	400 mg	9	0.77 (0.69, 0.85)	0.90 (0.82, 0.99)	C24hr 0.87 (0.74, 1.02)
Etravirine 200 mg	400 mg	19	1.04 (0.97, 1.12)	1.10 (1.03, 1.16)	1.17 (1.10, 1.26)

 

In drug interaction studies, there was no effect of raltegravir on the PK of ethinyl estradiol, methadone, midazolam or boceprevir.

Microbiology

Mechanism Of Action

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

Antiviral Activity In Cell Culture

Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (EC95) of viral spread (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, 5 clinical isolates of HIV-1 subtype B had EC95 values ranging from 9 to 19 nM in cultures of mitogen-activated human peripheral blood mononuclear cells. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV-1 isolates representing 5 non-B subtypes (A, C, D, F, and G) and 5 circulating recombinant forms (AE, AG, BF, BG, and cpx) with EC50 values ranging from 5 to 12 nM. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 value = 6 nM). No antagonism was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine); protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir); or the entry inhibitor enfuvirtide.

Resistance

The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Y143 (changed to C, H, or R) or Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M, E92Q, Q95K/R, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R, and D232N). E92Q, T97A, and F121C are occasionally seen in the absence of substitutions at Y143, Q148, or N155 in raltegravir-treatment failure subjects.

Treatment-Naive Adult Subjects

By Week 240 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 4 (2 with Y143H/R and 2 with Q148H/R) of the 12 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. By Week 96 in the ONCEMRK trial, primary raltegravir resistance substitutions were observed in on treatment isolates obtained from 4 (3 with N155H and 1 with E92Q) of 14 virologic failure subjects with evaluable genotypic data in the 1,200 mg QD arm and 2 (1 with N155H and 1 with T97A) of 6 virologic failure subjects in the 400 mg BID arm. Additional integrase substitutions observed included L74M, Q95K, V151I, E170A, I203M and D232N. These resistant isolates exhibited 6.2-to 19-fold reductions in susceptibility to raltegravir. Overall, at Week 96, detection of raltegravir resistance was not different between the QD and BID arms in subjects who were failing treatment and had resistance data evaluable (28.6% versus 33.3%, respectively).

Treatment-Experienced Adult Subjects

By Week 96 in the BENCHMRK trials, at least one of the primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 76 of the 112 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. The emergence of the primary raltegravir resistance-associated substitutions was observed cumulatively in 70 subjects by Week 48 and 78 subjects by Week 96, 15.2% and 17% of the raltegravir recipients, respectively. Some (n=58) of those HIV-1 isolates harboring one or more of the primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 26.3-fold (mean 48.9 ± 44.8-fold decrease, ranging from 0.8-to 159-fold) compared to the wild-type reference.

Cross Resistance

Cross resistance has been observed among HIV-1 integrase strand transfer inhibitors (INSTIs). Amino acid substitutions in HIV-1 integrase conferring resistance to raltegravir generally also confer resistance to elvitegravir. Substitutions at amino acid Y143 confer greater reductions in susceptibility to raltegravir than to elvitegravir, and the E92Q substitution confers greater reductions in susceptibility to elvitegravir than to raltegravir. Viruses harboring a substitution at amino acid Q148, along with one or more other raltegravir resistance substitutions, may also have clinically significant resistance to dolutegravir.

Pharmacogenomics

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 (0.96, 2.09).

In the neonatal study IMPAACT P1110, there was no association between apparent clearance (CL/F) of raltegravir and UGT 1A1 genotype polymorphisms.

Clinical Studies

Description Of Clinical Studies

The evidence of durable efficacy of ISENTRESS 400 mg twice daily is based on the analyses of 240week data from a randomized, double-blind, active-controlled trial, STARTMRK evaluating ISENTRESS 400 mg twice daily in antiretroviral treatment-naive 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 x 600 mg) once daily in treatment-naive 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.

Table 18: Trials Conducted with ISENTRESS and ISENTRESS HD in Subjects with HIV-1 Infection

Trial	Study Type	Population	Study Arms (N)	Dose/ Formulation	Timepoint
STARTMRK	Randomized, doubleblind, active-controlled	Treatment-Naive Adults	ISENTRESS 400 mg Twice Daily (281) Efavirenz 600 mg At Bedtime (282) Both in combination with emtricitabine (+) tenofovir disoproxil fumarate	400 mg film-coated tablet	Week 240
ONCEMRK	Randomized, doubleblind, active-controlled	Treatment-Naive Adults	ISENTRESS HD 1200 mg Once Daily (531) ISENTRESS 400 mg Twice Daily (266) Both in combination with emtricitabine (+) tenofovir disoproxil fumarate	600 mg film-coated tablet 400 mg film-coated tablet	Week 96
BENCHMRK1	Randomized, doubleblind, placebo-controlled	Treatment- Experienced Adults	ISENTRESS 400 mg Twice Daily (232) Placebo (118) Both in combination with optimized background therapy	400 mg film-coated tablet	Week 240 (Week 156 on double-blind plus Week 84 on open-label)
BENCHMRK2	Randomized, doubleblind, placebo-controlled	Treatment- Experienced Adults	ISENTRESS 400 mg Twice Daily (230) Placebo (119) Both in combination with optimized background therapy	400 mg film-coated tablet	Week 240 (Week 156 on double-blind plus Week 84 on open-label)
IMPAACT P1066	Open-label, noncomparative	Pediatric Patients – 4 weeks to 18 years of age (Treatment-Experienced or Failed Prior PMTCT)	ISENTRESS 400 mg tablet Twice Daily – 12 to 18 years or 6 to <12 years and ≥25 kg (87) ISENTRESS chewable tablet- Weight-Based Dose to Approximate 6 mg/kg Twice Daily – 2 to <12 years (39) ISENTRESS for oral suspension- Weight-Based Dose to Approximate 6 mg/kg Twice Daily – 4 weeks to <2 years (26) In combination with optimized background therapy	400 mg film-coated tablet 25 mg and 100 mg chewable tablet 100 mg sachet for oral suspension	Week 240

 

Treatment-Naive Adult Subjects

STARTMRK (ISENTRESS 400 mg twice daily)

STARTMRK is a Phase 3 randomized, international, double-blind, active-controlled trial to evaluate the safety and efficacy of ISENTRESS 400 mg twice daily versus efavirenz 600 mg at bedtime both with emtricitabine (+) tenofovir disoproxil fumarate in treatment-naive HIV-1-infected subjects with HIV-1 RNA >5000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤50,000 copies/mL; or >50,000 copies/mL) and by hepatitis status. In STARTMRK, 563 subjects were randomized and received at least 1 dose of either raltegravir 400 mg twice daily or efavirenz 600 mg at bedtime, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. There were 563 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 37 years (range 19-71), 19% female, 58% non-white, 6% had hepatitis B and/or C virus co-infection, 20% were CDC Class C (AIDS), 53% had HIV-1 RNA greater than 100,000 copies per mL, and 47% had CD4+ cell count less than 200 cells per mm ; the frequencies of these baseline characteristics were similar between treatment groups.

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

ONCEMRK is a Phase 3 randomized, international, double-blind, active-controlled trial to evaluate the safety and efficacy of ISENTRESS HD 1200 mg (2 x 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naive HIV-1infected subjects with HIV-1 RNA ≥1000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤100,000 or >100,000 copies/mL) and by hepatitis B and C infection status.

In ONCEMRK, 797 subjects were randomized and received at least 1 dose of either raltegravir 1200 mg once daily or raltegravir 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. There were 797 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years (range 18-84), 15% female, 41% non-white, 3% had hepatitis B and/or C virus co-infection, 13% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, and 13% had CD4+ cell count less than 200 cells per mm³; the frequencies of these baseline characteristics were similar between treatment groups.

Table 19 shows the virologic outcomes in both studies. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up.

Table 19: Virologic Outcomes of Randomized Treatment in STARTMRK and ONCEMRK (Snapshot Algorithm) in HIV Treatment-Naive Adults

	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)
HIV RNA < Lower Limit of Quantitation*	66%	60%	82%	80%
Treatment Difference	6.6% (95% CI: -1.4%, 14.5%)		1.4% (95% CI: -4.4%, 7.3%)
HIV RNA ≥ Lower Limit of Quantitation	8%	15%	9%	8%
No Virologic Data at Analysis Timepoint	26%	26%	9%	12%
Reasons
Discontinued trial due to AE or Death†	5%	10%	1%	3%
Discontinued trial for Other Reasons‡	15%	14%	7%	8%
On trial but missing data at timepoint	6%	2%	1%	2%
Notes: ISENTRESS BID, ISENTRESS HD and Efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate *Lower Limit of Quantitation: STARTMRK <50 copies/mL; ONCEMRK < 40 copies/mL. † Includes subjects who discontinued because of adverse event (AE) or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. ‡Other Reasons includes: lost to follow-up, moved, non-compliance with study drug, physician decision, pregnancy, withdrawal by subject.

 

In the ONCEMRK trial, ISENTRESS HD 1200 mg (2 x 600 mg) once daily demonstrated consistent virologic and immunologic efficacy relative to ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, across demographic and baseline prognostic factors, including: baseline HIV RNA levels >100,000 copies/mL and demographic groups (including age, gender, race, ethnicity and region), concomitant proton pump inhibitors/H2 blockers use and viral subtypes (comparing non-clade B as a group to clade B).

Consistent efficacy in subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily was observed across HIV subtypes with 80.6% (270/335) and 83.5% (162/194) of subjects with B and non-B subtypes respectively, achieving HIV RNA <40 copies/mL at week 96 (Snapshot approach).

Treatment-Experienced Adult Subjects

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 20: Trials BENCHMRK 1 and BENCHMRK 2 Baseline Characteristics

Randomized Studies BENCHMRK1 and BENCHMRK2	ISENTRESS 400 mg Twice Daily + OBT (N = 462)	Placebo + OBT (N = 237)
Gender
Male	88%	89%
Female	12%	11%
Race
White	65%	73%
Black	14%	11%
Asian	3%	3%
Hispanic	11%	8%
Others	6%	5%
Age (years)
Median (min, max)	45 (16 to 74)	45 (17 to 70)
CD4+ Cell Count
Median (min, max), cells/mm³	119 (1 to 792)	123 (0 to 759)
≤50 cells/mm³	32%	33%
>50 and ≤200 cells/mm³	37%	36%
Plasma HIV-1 RNA
Median (min, max), log10 copies/mL	4.8 (2 to 6)	4.7 (2 to 6)
>100,000 copies/mL	36%	33%
History of AIDS
Yes	92%	91%
Prior Use of ART, Median (1st Quartile, 3rd Quartile)
Years of ART Use	10 (7 to 12)	10 (8 to 12)
Number of ART	12 (9 to 15)	12 (9 to 14)
Hepatitis Co-infection*
No Hepatitis B or C virus	83%	84%
Hepatitis B virus only	8%	3%
Hepatitis C virus only	8%	12%
Co-infection of Hepatitis B and Cvirus	1%	1%
Stratum
Enfuvirtide in OBT	38%	38%
Resistant to ≥2 PI	97%	95%
*Hepatitis B virus surface antigen positive or hepatitis C virus antibody positive.

 

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.

Table 21: Trials BENCHMRK 1 and BENCHMRK 2 Characteristics of Optimized Background Therapy at Baseline

Randomized Studies BENCHMRK1 and BENCHMRK2	ISENTRESS 400 mg Twice Daily + OBT (N = 462)	Placebo + OBT (N = 237)
Number of ARTs in OBT
Median (min, max)	4 (1 to 7)	4 (2 to 7)
Number of Active PI in OBT by Phenotypic Resistance Test*
0	36%	41%
1 or more	60%	58%
Phenotypic Sensitivity Score (PSS)†
0	15%	18%
1	31%	30%
2	31%	28%
3 or more	18%	20%
Genotypic Sensitivity Score (GSS)†
0	25%	27%
1	38%	40%
2	24%	21%
3 or more	11%	10%
*Darunavir use in OBT in darunavir-naive subjects was counted as one active PI. †The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity Score (GSS) were defined as the total oral ARTs in OBT to which a subject’s viral isolate showed phenotypic sensitivity and genotypic sensitivity, respectively, based upon phenotypic and genotypic resistance tests. Enfuvirtide use in OBT in enfuvirtide-naive subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naive subjects was counted as one active drug in OBT.

 

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.

Table 22: Virologic Outcomes of Randomized Treatment of BENCHMRK 1 and BENCHMRK 2 Trials at 96 Weeks (Pooled Analysis)

	ISENTRESS 400 mg Twice Daily + OBT (N = 462)	Placebo + OBT (N = 237)
Subjects with HIV-1 RNA less than 50 copies/mL	55%	27%
Virologic Failure*	35%	66%
No virologic data at Week 96 Window
Reasons
Discontinued study due to AE or death†	3%	3%
Discontinued study for other reasons‡	4%	4%
Missing data during window but on study	4%	<1%
*Includes subjects who switched to open-label raltegravir after Week 16 due to the protocol-defined virologic failure, subjects who discontinued prior to Week 96 for lack of efficacy, subjects changed OBT due to lack of efficacy prior to Week 96, or subjects who were ≥50 copies in the 96 week window. †Includes subjects who discontinued due to AE or death at any time point from Day 1 through the Week 96 window if this resulted in no virologic data on treatment during the Week 96 window. ‡Other includes: withdrew consent, loss to follow-up, moved etc., if the viral load at the time of discontinuation was <50 copies/mL.

 

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.

Table 23: Virologic Response at 96 Week Window by Baseline Genotypic/Phenotypic Sensitivity Score

	Percent with HIV-1 RNA <50 copies/mL At Week 96
	n	ISENTRESS400 mg Twice Daily + OBT (N = 462)	n	Placebo+ OBT (N = 237)
Phenotypic Sensitivity Score (PSS)*
0	67	43	43	5
1	144	58	71	23
2	142	61	66	32
3 or more	85	48	48	42
Genotypic Sensitivity Score (GSS)*
0	116	39	65	5
1	177	62	95	26
2	111	61	49	53
3 or more	51	49	23	35
*The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity Score (GSS) were defined as the total oral ARTs in OBT to which a subject’s viral isolate showed phenotypic sensitivity and genotypic sensitivity, respectively, based upon phenotypic and genotypic resistance tests. Enfuvirtide use in OBT in enfuvirtide-naive subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naive subjects was counted as one active drug in OBT.

 

Switch Of Suppressed Subjects From Lopinavir (+) Ritonavir To Raltegravir

The SWITCHMRK 1 & 2 Phase 3 studies evaluated HIV-1 infected subjects receiving suppressive therapy (HIV-1 RNA <50 copies/mL on a stable regimen of lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors for >3 months) and randomized them 1:1 to either continue lopinavir (+) ritonavir (n=174 and n=178, SWITCHMRK 1 & 2, respectively) or replace lopinavir (+) ritonavir with ISENTRESS 400 mg twice daily (n=174 and n=176, respectively). The primary virology endpoint was the proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 24 with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks.

Subjects with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.

These studies were terminated after the primary efficacy analysis at Week 24 because they each failed to demonstrate non-inferiority of switching to ISENTRESS versus continuing on lopinavir (+) ritonavir. In the combined analysis of these studies at Week 24, suppression of HIV-1 RNA to less than 50 copies/mL was maintained in 82.3% of the ISENTRESS group versus 90.3% of the lopinavir (+) ritonavir group. Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups.

Pediatric Subjects

2 To 18 Years Of Age

IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Subjects were stratified by age, enrolling adolescents first and then successively younger children. Subjects were enrolled into cohorts according to age and received the following formulations: Cohort I (12 to less than 18 years old), 400 mg film-coated tablet; Cohort IIa (6 to less than 12 years old), 400 mg film-coated tablet; Cohort IIb (6 to less than 12 years old), chewable tablet; Cohort III (2 to less than 6 years), chewable tablet. Raltegravir was administered with an optimized background regimen.

The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional subjects were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 subjects, 96 received the recommended dose of ISENTRESS [see DOSAGE AND ADMINISTRATION].

These 96 subjects had a median age of 13 (range 2 to 18) years, were 51% Female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log₁₀ copies/mL, median CD4 cell count was 481 cells/mm³ (range: 0 – 2361) and median CD4% was 23.3% (range: 0 – 44). Overall, 8% had baseline plasma HIV-1 RNA >100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most subjects had previously used at least one NNRTI (78%) or one PI (83%).

Ninety-three (97%) subjects 2 to 18 years of age completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 54% achieved HIV RNA <50 copies/mL; 66% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm³ (3.8%).

4 Weeks To Less Than 2 Years Of Age

IMPAACT P1066 also enrolled HIV-infected, infants and toddlers 4 weeks to less than 2 years of age (Cohorts IV and V) who had received prior antiretroviral therapy either as prophylaxis for prevention of mother-to-child transmission (PMTCT) and/or as combination antiretroviral therapy for treatment of HIV infection. Raltegravir was administered as an oral suspension without regard to food in combination with an optimized background regimen.

The 26 subjects had a median age of 28 weeks (range: 4 -100), were 35% female, 85% Black and 8% Caucasian. At baseline, mean plasma HIV-1 RNA was 5.7 log₁₀ copies/mL (range: 3.1 – 7), median CD4 cell count was 1400 cells/mm³ (range: 131 – 3648) and median CD4% was 18.6% (range: 3.3 – 39.3). Overall, 69% had baseline plasma HIV-1 RNA exceeding 100,000 copies/mL and 23% had a CDC HIV clinical classification of category B or C. None of the 26 subjects were completely treatment naive. All infants under 6 months of age had received nevirapine or zidovudine for prevention of mother-to-infant transmission, and 43% of subjects greater than 6 months of age had received two or more antiretrovirals.

Of the 26 treated subjects, 23 subjects were included in the Week 24 and 48 efficacy analyses, respectively. All 26 treated subjects were included for safety analyses.

At Week 24, 39% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 500 cells/mm³ (7.5%).

At Week 48, 44% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 48 was 492 cells/mm³ (7.8%).