Dutrebis

Dosage Forms And Strengths

• Tablets
  150 mg lamivudine and 325.8 mg raltegravir potassium, equivalent to 300 mg raltegravir, green, oval-shaped, film-coated tablets with “144” on one side.

DUTREBIS tablets (150 mg lamivudine/300 mg raltegravir) are green, oval-shaped, film-coated tablets with “144” on one side. They are supplied as follows:

NDC 0006-3054-60 unit-of-use bottles of 60.
No. 3054

Storage And Handling

150 mg lamivudine/300 mg raltegravir tablets

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

Store in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.

Distributed by: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Whitehouse Station, NJ 08889, USA. Issued February 2015

DUTREBIS™ is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.

Recommended Dosage

DUTREBIS is a fixed-dose combination product containing 150 mg of lamivudine and 300 mg of raltegravir. The recommended dosage of DUTREBIS in adults, adolescents (16 years of age and older), and pediatric patients (6 through 16 years of age and weighing at least 30 kg) is one tablet taken twice daily orally with or without food.

Administer DUTREBIS in conjunction with other antiretroviral agents. The maximum dose of DUTREBIS is one tablet (150 mg lamivudine/300 mg raltegravir) taken twice daily.

Patients With Renal Impairment

DUTREBIS is not recommended in patients with a creatinine clearance of < 50 mL/min. If creatinine clearance decreases to < 50 mL/min, DUTREBIS should be switched to the individual components (lamivudine and raltegravir) to allow for lamivudine dose reduction. Please refer to the full prescribing information for lamivudine and raltegravir for dosing instructions.

DUTREBIS is contraindicated in patients with hypersensitivity to lamivudine, raltegravir, or any component of this medicine.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Lactic Acidosis/Severe Hepatomegaly With Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of NRTIs alone or in combination, including lamivudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering DUTREBIS to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. Treatment with DUTREBIS should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Post-treatment Exacerbations Of Hepatitis In Patients With HIV-1 And Hepatitis B Virus Coinfection

In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of post-treatment exacerbations of hepatitis. Safety and efficacy of DUTREBIS have not been established for treatment of chronic hepatitis B in patients co-infected with HIV1 and HBV.

Pancreatitis

In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, DUTREBIS should be used with caution. Treatment with DUTREBIS should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.

Hepatic Decompensation When Used With Interferon-And Ribavirin-Based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine NRTIs such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients , hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and DUTREBIS should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of DUTREBIS should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6). See the complete prescribing information for interferon and ribavirin.

Severe Skin And Hypersensitivity Reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking raltegravir. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue DUTREBIS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping DUTREBIS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Immune Reconstitution Syndrome

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

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

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Antiretrovirals Not Recommended

DUTREBIS is not recommended in combination with products containing the individual components of DUTREBIS (lamivudine and raltegravir) or emtricitabine.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

General Information

Instruct patients to reread patient labeling each time the prescription is renewed.

Inform patients they should remain under the care of a physician when using DUTREBIS. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

Inform patients that DUTREBIS is not a cure for HIV-1 infection and they may continue to experience illnesses associated with HIV-1 infection such as opportunistic infections. Inform patients that sustained decreases in plasma HIV RNA are associated with a reduced risk of progression to AIDS and death. Instruct patients to remain on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses.

Advise patients to avoid doing things that can spread HIV-1 infection to others.

• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• Do not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Lamivudine is excreted in human breast milk; however it is unknown if raltegravir can be passed to the baby through breast milk and whether it could harm the baby.

General Dosing Instructions

Advise patients not to miss a dose of DUTREBIS. Instruct patients that if they miss a dose of DUTREBIS, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double the next dose or take more than the prescribed dose.

Severe and Potentially Life-threatening Rash

Inform patients that severe and potentially life-threatening rash has been reported. Advise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking DUTREBIS and other suspect agents, and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or severe hypersensitivity: fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver problems. Tell patients that if severe rash occurs, they will be closely monitored, laboratory tests will be ordered and appropriate therapy will be initiated.

Lactic Acidosis/Hepatomegaly

Inform patients that some HIV medicines, including DUTREBIS, can cause a rare, but serious condition called lactic acidosis with liver enlargement and inform patients of the signs and symptoms of lactic acidosis.

Rhabdomyolysis

Instruct patients to immediately report to their healthcare provider any unexplained muscle pain, tenderness, or weakness while taking DUTREBIS.

Drug Interactions

Instruct patients not to take DUTREBIS with aluminum and/or magnesium containing antacids.

HIV-1/HBV Co-infection

Inform patients co-infected with HIV-1 and HBV that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician.

Risk of Pancreatitis

Advise parents or guardians to monitor pediatric patients for signs and symptoms of pancreatitis.

Nonclinical Toxicology

No animal studies have been conducted with DUTREBIS. The following data are based on findings in separate studies with the individual components of DUTREBIS (lamivudine and raltegravir).

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lamivudine

Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose for HIV-1 infection. Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

Raltegravir

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.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant patients exposed to DUTREBIS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1800-258-4263.

Risk Summary

There are no adequate and well-controlled studies with DUTREBIS, lamivudine, or raltegravir in pregnant women. Lamivudine caused increased early embryolethality in rabbits at exposure levels similar to those in humans. Raltegravir induced treatment-related increases in the incidence of supernumerary ribs in rats at 3-fold the exposure at the recommended human dose. DUTREBIS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human Data

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples, while amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels. It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients. There have been no pharmacokinetic studies conducted with raltegravir in pregnant patients.

Animal Data

Lamivudine

Lamivudine is not teratogenic at oral doses up to 4000 mg/kg/day (130 times human exposures) in rats and 1000 mg/kg/day (60 times human exposures) in rabbits. Evidence of increased early embryolethality was seen in rabbits at exposure levels similar to those in humans but there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

Raltegravir

Developmental toxicity studies were performed in rabbits (at oral doses up to 1000 mg/kg/day) and rats (at oral doses up to 600 mg/kg/day). The reproductive toxicity study in rats was performed with pre-, peri-, and postnatal evaluation. The highest doses in these studies produced systemic exposures in these species approximately 3-to 4-fold the exposure at the recommended human dose. In both rabbits and rats, no treatment-related effects on embryonic/fetal survival or fetal weights were observed. In addition, no treatment-related external, visceral, or skeletal changes were observed in rabbits. However, treatment-related increases over controls in the incidence of supernumerary ribs were seen in rats at 600 mg/kg/day (exposures 3-fold the exposure at the recommended human dose).

Placenta transfer of drug was demonstrated in both rats and rabbits. At a maternal dose of 600 mg/kg/day in rats, mean drug concentrations in fetal plasma were approximately 1.5-to 2.5-fold greater than in maternal plasma at 1 hour and 24 hours postdose, respectively. Mean drug concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.

Nursing Mothers

DUTREBIS

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

Lamivudine

Lamivudine is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.

Raltegravir

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 raltegravir through the milk.

Pediatric Use

DUTREBIS

DUTREBIS is indicated in pediatric patients 6 through 16 years of age and weighing at least 30 kg. DUTREBIS should not be used in children below 6 years of age or in patients weighing less than 30 kg due to weight based dosing requirements in this patient population.

Geriatric Use

Separate clinical trials of each component of DUTREBIS (lamivudine and raltegravir) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. Because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored. A reduction in renal function may necessitate switching DUTREBIS to a regimen of lamivudine and raltegravir. Please refer to the full prescribing information for lamivudine and raltegravir for dosing instructions.

Use In Patients With Hepatic Impairment

No dose adjustment for DUTREBIS is required for patients with mild to moderate hepatic insufficiency.

Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.

Use In Patients With Renal Impairment

DUTREBIS should not be given in patients with a creatinine clearance of < 50 mL/min.

DUTREBIS

One drug interaction study was conducted for DUTREBIS and etravirine. In addition, drug interaction studies were conducted with lamivudine or raltegravir coadministered with other commonly used drugs. The results of the drug interaction studies are summarized in Tables 2, 3 and 4. For information regarding clinical recommendations, see DRUG INTERACTIONS).

Table 2: Effect of Etravirine on the Pharmacokinetics of Lamivudine/Raltegravir in Adults

Lamivudine

Interferon Alfa

There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.

Ribavirin

In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.

Trimethoprim/Sulfamethoxazole

Table 3: Effect of Trimethoprim/Sulfamethoxazole on the Pharmacokinetics of Lamivudine

Zidovudine

No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).

Raltegravir

The results of the drug interaction studies represented in the following table were conducted with raltegravir.

Table 4: Effect of Other Agents on the Pharmacokinetics of Raltegravir in Adults

Pregnancy Category C

Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant patients exposed to DUTREBIS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1800-258-4263.

Risk Summary

There are no adequate and well-controlled studies with DUTREBIS, lamivudine, or raltegravir in pregnant women. Lamivudine caused increased early embryolethality in rabbits at exposure levels similar to those in humans. Raltegravir induced treatment-related increases in the incidence of supernumerary ribs in rats at 3-fold the exposure at the recommended human dose. DUTREBIS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human Data

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples, while amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels. It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients. There have been no pharmacokinetic studies conducted with raltegravir in pregnant patients.

Animal Data

Lamivudine

Lamivudine is not teratogenic at oral doses up to 4000 mg/kg/day (130 times human exposures) in rats and 1000 mg/kg/day (60 times human exposures) in rabbits. Evidence of increased early embryolethality was seen in rabbits at exposure levels similar to those in humans but there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

Raltegravir

Developmental toxicity studies were performed in rabbits (at oral doses up to 1000 mg/kg/day) and rats (at oral doses up to 600 mg/kg/day). The reproductive toxicity study in rats was performed with pre-, peri-, and postnatal evaluation. The highest doses in these studies produced systemic exposures in these species approximately 3-to 4-fold the exposure at the recommended human dose. In both rabbits and rats, no treatment-related effects on embryonic/fetal survival or fetal weights were observed. In addition, no treatment-related external, visceral, or skeletal changes were observed in rabbits. However, treatment-related increases over controls in the incidence of supernumerary ribs were seen in rats at 600 mg/kg/day (exposures 3-fold the exposure at the recommended human dose).

Placenta transfer of drug was demonstrated in both rats and rabbits. At a maternal dose of 600 mg/kg/day in rats, mean drug concentrations in fetal plasma were approximately 1.5-to 2.5-fold greater than in maternal plasma at 1 hour and 24 hours postdose, respectively. Mean drug concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.

The following adverse reactions are discussed in other sections of the labeling:

• Lactic acidosis and severe hepatomegaly with steatosis.
• Severe acute exacerbations of hepatitis B.
• Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C.
• Pancreatitis.

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.

Clinical trials in patients have not been specifically performed with DUTREBIS. Common adverse reactions to each individual component (lamivudine and raltegravir) are summarized below.

Adult Subjects

Lamivudine

See the lamivudine full prescribing information for complete clinical trial information.

In four controlled clinical trials with lamivudine coadministered with zidovudine in adults, the most common reported adverse reactions (incidence greater than or equal to 15%, all grades) were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

Raltegravir

See the raltegravir full prescribing information for complete clinical trial information.

In Phase 3 clinical trials with raltegravir in treatment-naive or treatment-experienced adults, the most common reported adverse reactions (incidence greater than or equal to 2%) of at least moderate intensity (greater than or equal to Grade 2) were insomnia, headache, dizziness, nausea, and fatigue.

Creatine kinase elevations were observed in subjects who received raltegravir. Myopathy and rhabdomyolysis have been reported. Monitor 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.

Pediatric Subjects

Lamivudine

See the lamivudine full prescribing information for complete clinical trial information.

In controlled clinical trials with lamivudine oral solution coadministered with zidovudine in pediatric subjects 3 months to 18 years of age, the most common reported adverse reactions (incidence greater than or equal to 15%, all grades) were fever and cough.

Raltegravir

See the raltegravir full prescribing information for complete clinical trial information.

Raltegravir 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. Of the 126 patients, 96 received the recommended dose of raltegravir.

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

Postmarketing Experience

See the full prescribing information for lamivudine and raltegravir for postmarketing information.

DUTREBIS

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 DUTREBIS may be dialyzable is unknown.

Lamivudine

Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

Cardiac Electrophysiology

DUTREBIS

No cardiac physiology studies were performed with DUTREBIS.

Raltegravir

The effect of raltegravir 1600 mg (4 times the recommended dose) on QTc interval was evaluated in a randomized, single-dose, placebo-controlled, crossover study in 31 healthy subjects. At a dose 4 times the recommended dose, raltegravir did not prolong the QTc interval to any clinically relevant extent.

Lamivudine

No cardiac physiology studies have been performed with lamivudine.

DUTREBIS

In an open-label, single-dose, randomized, two-period, crossover study in healthy subjects (n=108), one DUTREBIS (150 mg lamivudine/300 mg raltegravir) fixed-dose combination tablet was shown to provide comparable lamivudine and raltegravir exposures to one EPIVIR 150 mg tablet plus one ISENTRESS 400 mg tablet.

Due to the higher bioavailability of raltegravir contained in DUTREBIS, the exposures provided by the 300 mg dose of raltegravir are comparable to 400 mg of raltegravir given as the raltegravir poloxamer formulation (ISENTRESS), which accounts for the difference in raltegravir dose.

Please refer to the full prescribing information for raltegravir and lamivudine for additional pharmacokinetic information.

Adults - Absorption

DUTREBIS

When DUTREBIS is administered in the fasted state, raltegravir is absorbed with a T max of approximately 1 hour. The bioavailability of the raltegravir component of DUTREBIS in the fasted state is approximately 60%. Once absorbed, lamivudine and raltegravir distribution, metabolism, and excretion are similar to those of the reference components administered individually as described in the full prescribing information for lamivudine and raltegravir.

Effect of Food on Oral Absorption

An open-label, single-dose, randomized, two-period crossover study assessed the effect of a high fat meal on DUTREBIS administered to 20 healthy male and female subjects. Similar AUC values for fed vs. fasted and somewhat lower C max values (23% for raltegravir and 21% for lamivudine) were observed with DUTREBIS. In addition, higher C 12h levels (20% for raltegravir and 53% for lamivudine) were observed.

These changes are not considered clinically meaningful and DUTREBIS can be taken without regard to a meal.

Distribution

Lamivudine

Binding of lamivudine to human plasma proteins is low ( < 36%). In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.

Raltegravir

Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 μM.

Metabolism and Excretion

Lamivudine

Metabolism of lamivudine is a minor route of elimination. Within 12 hours after a single oral dose of lamivudine in 6 HIV-1-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the transsulfoxide metabolite in the urine.

Raltegravir

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

Elimination

Lamivudine

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion.

In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t ½) ranged from 5 to 7 hours.

Raltegravir

Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, 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 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.