DUTREBIS DUTREBIS is available for oral use as a film-coated tablet containing 150 mg of lamivudine and 325.8 mg of raltegravir potassium, equivalent to 300 mg of raltegravir and the inactive ingredients: croscarmellose sodium, hypromellose (2910), lactose monohydrate, magnesium stearate, microcrystalline cellulose, and silicon dioxide [colloidal]. The film-coating contains: FD&C Blue #2, hypromellose, lactose monohydrate, titanium dioxide, triacetin, and yellow iron oxide. Lamivudine Lamivudine is an HIV-1 nucleoside analogue reverse transcriptase inhibitor. The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2',3'dideoxy, 3'-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3. It has the following structural formula: Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C. Raltegravir Raltegravir potassium is a human immunodeficiency virus integrase strand transfer inhibitor. The chemical name for raltegravir potassium is N-[(4-Fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-2[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt. The empirical formula is C20H20FKN6O5 and the molecular weight is 482.51. The structural formula is: Raltegravir potassium is a white to off-white powder. It is soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile and insoluble in isopropanol. Last reviewed on RxList: 2/19/2015
This monograph has been modified to include the generic and brand name in many instances.

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

• Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
• Severe acute exacerbations of hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
• Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see WARNINGS AND PRECAUTIONS].
• Pancreatitis [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. 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-naïve 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 [see Use in Specific Populations]. 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. Read the Dutrebis (lamivudine and raltegravir film-coated tablets) Side Effects Center for a complete guide to possible side effectsLearn More »

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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.

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Effect Of Lamivudine And Raltegravir on the Pharmacokinetics of Concomitant Drugs DUTREBIS DUTREBIS is not expected to affect the pharmacokinetics of drugs that are substrates of the cytochrome P450 (CYP) enzymes, UGT1A1 or UGT2B7, or P-glycoprotein (e.g., protease inhibitors, NNRTIs, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents). Raltegravir Raltegravir does not inhibit (IC 50 > 100 μM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC 50 > 50 μM) of UGT1A1 or UGT2B7, and raltegravir does not inhibit P-glycoprotein-mediated transport. Effect Of Concomitant Drugs On The Pharmacokinetics Of Lamivudine And Raltegravir Lamivudine Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim). No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine. Raltegravir Raltegravir is not a substrate of CYP enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. Coadministration of DUTREBIS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir and coadministration of DUTREBIS with drugs that induce UGT1A1 may reduce plasma levels of raltegravir. Established And Other Potentially Significant Interactions Lamivudine Interferon-and Ribavirin-Based Regimens Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV coinfected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Trimethoprim/Sulfamethoxazole (TMP/SMX) No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP. Raltegravir The impact of inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Selected drug interactions are presented in Table 1 [see CLINICAL PHARMACOLOGY]. The results of the drug interaction studies represented in the following table were conducted with raltegravir; however, the recommendations are applicable to DUTREBIS as raltegravir is a component of DUTREBIS. Table 1: Selected Drug Interactions in Adults Receiving Raltegravir Concomitant Drug Class: Drug Name Effect on Concentration of Raltegravir Clinical Comment HIV-1-Antiviral Agents Metal-Containing Antacids aluminum and/or magnesium-containing antacids ↓ Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and DUTREBIS is not recommended. Other Agents rifampin ↓ DUTREBIS should not be coadministered with rifampin. If coadministration with rifampin is unavoidable, DUTREBIS may be switched to a regimen of the individual components (lamivudine and raltegravir). Please refer to the full prescribing information for the individual components of DUTREBIS for dosing instructions. Drugs Without Clinically Significant Interactions With Lamivudine And Raltegravir DUTREBIS In a drug interaction study with DUTREBIS and etravirine, there was no clinically meaningful change in raltegravir exposures. No dosage adjustment is necessary when these agents are given together. Lamivudine A drug interaction study showed no clinically significant interaction between lamivudine and zidovudine. Raltegravir In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine, darunavir/ritonavir, telaprevir, or boceprevir. Moreover, atazanavir, atazanavir/ritonavir, boceprevir, calcium carbonate antacids, darunavir/ritonavir, efavirenz, etravirine, omeprazole, or tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of raltegravir. No dose adjustment is required when DUTREBIS is coadministered with these drugs. Last reviewed on RxList: 2/19/2015
This monograph has been modified to include the generic and brand name in many instances.

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

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DUTREBIS is contraindicated in patients with hypersensitivity to lamivudine, raltegravir, or any component of this medicine. Last reviewed on RxList: 2/19/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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.

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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 Last reviewed on RxList: 2/19/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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 [see CLINICAL PHARMACOLOGY], 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 [see WARNINGS AND PRECAUTIONS]. 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 [see DRUG INTERACTIONS]. 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 [see WARNINGS AND PRECAUTIONS]. Risk of Pancreatitis Advise parents or guardians to monitor pediatric patients for signs and symptoms of pancreatitis [see WARNINGS AND PRECAUTIONS]. 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 [see CLINICAL PHARMACOLOGY]. 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 [see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION]. 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 [see DOSAGE AND ADMINISTRATION]. Last reviewed on RxList: 2/19/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com