Abacavir; dolutegravir; lamivudine is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients at least 3 months of age and weighing 6 kg or more. This combination product consists of 1 integrase strand transfer inhibitor (INSTI) and 2 nucleoside analog reverse transcriptase inhibitors (NRTIs). The product is available as Triumeq (oral tablet containing 600 mg abacavir, 50 mg dolutegravir, 300 mg lamivudine) for use in patients weighing at least 25 kg and as Triumeq PD (tablet for oral suspension containing 60 mg abacavir, 5 mg dolutegravir, 30 mg lamivudine) for use in pediatric patients weighing 6 to 24 kg. Due to differing pharmacokinetic profiles of the dolutegravir component, Triumeq and Triumeq PD cannot be interchanged on a mg-per-mg basis. The FDA approved package labeling contains Black Box Warnings for fatal hypersensitivity reactions associated with abacavir and exacerbations of hepatitis B associated with discontinuation of lamivudine in patients with both hepatitis B and HIV.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Screen for HLA-B*5701 before initiating treatment to reduce the risk of hypersensitivity reaction. HLA-B*5701-positive patients MUST not receive abacavir.
Hazardous Drugs Classification
-Abacavir is classified as a hazardous drug.
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.
Route-Specific Administration
Oral Administration
-Available as 2 dosage forms:
--Triumeq oral tablet (600 mg abacavir, 50 mg dolutegravir, 300 mg lamivudine)
-Triumeq PD tablet for oral suspension (60 mg abacavir, 5 mg dolutegravir, 30 mg lamivudine)
-Triumeq and Triumeq PD cannot be interchanged on a mg-per-mg basis because of differing pharmacokinetic profiles of the dolutegravir component. If a pediatric patient switches from Triumeq PD to Triumeq, the dosage must be adjusted. Incorrect dosing of a given formulation may result in loss of therapeutic effect, development of resistance, or adverse reactions.
Oral Solid Formulations
Tablet (Triumeq)
-Administer with or without food.
-DO NOT chew, cut, or crush the tablets.
-Administer at least 2 hours before or 6 hours after taking cation-containing antacids or laxatives (i.e., magnesium, aluminum), sucralfate, oral calcium supplements, oral iron supplements, or buffered medications. Alternatively, may administer oral calcium and iron supplements concurrently if administered with food.
Oral Liquid Formulations
Tablet for oral suspension (Triumeq PD)
-DO NOT swallow the tablets whole. DO NOT chew, cut, or crush the tablets.
-Fully disperse the tablets for oral suspension in 20 mL of drinking water (if using 4, 5, or 6 tablets) or 15 mL of drinking water (if using 3 tablets) in the supplied cup.
-Swirl the suspension so that no lumps remain.
-Once fully dispersed, administer the oral suspension within 30 minutes of mixing.
-For those unable to use the supplied cup, an appropriately-sized syringe may be used to administer the oral suspension.
-Administer with or without food.
-Administer at least 2 hours before or 6 hours after taking cation-containing antacids or laxatives (i.e., magnesium, aluminum), sucralfate, oral calcium supplements, oral iron supplements, or buffered medications. Alternatively, may administer oral calcium and iron supplements concurrently if administered with food.
This section discusses adverse reactions reported with the combination products Triumeq and Triumeq PD. Refer to the individual monographs of abacavir, dolutegravir or lamivudine for specific information concerning adverse events related to the individual agents.
Neurologic adverse events that have been reported with treatment with abacavir; dolutegravir; lamivudine during clinical trials include abnormal dreams or nightmares (less than 1%), depression (1%), dizziness (less than 1%), fatigue (2%), headache (2%), insomnia (3%), lethargy (less than 2%), and somnolence (less than 2%). Suicidal ideation, attempt, behavior, or completion was reported in less than 2% of patients. These events were observed primarily in patients with a pre-existing history of depression or other psychiatric illness. Paresthesias, peripheral neuropathy, seizures, and anxiety have been reported with one or more of the individual components in postmarketing use. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Gastrointestinal adverse events experienced by less than 2% of abacavir; dolutegravir; lamivudine-treated patients during clinical trials included abdominal pain, distention, or discomfort, anorexia, dyspepsia, flatulence, gastroesophageal reflux, and vomiting. Diarrhea and nausea were reported in less than 1% of patients. Stomatitis and weight gain have been reported in postmarketing surveillance. Data from postmarketing trials found treatment-naive patients who started an integrase inhibitor-containing regimen (such as abacavir; dolutegravir; lamivudine) gained more weight than patients who began a protease inhibitor- or NNRTI-based regimen. Among agents within the integrase inhibitor class, the mean increase in weight from baseline was similar for dolutegravir and bictegravir (approximately 3.5 kg) and lower for elvitegravir. It is unknown whether the increase in weight is reversible upon treatment discontinuation.
Rash and pruritus were reported by less than 1% and less than 2%, respectively, of patient receiving treatment with abacavir; dolutegravir; lamivudine during clinical trials. Other dermatologic adverse events reported with postmarketing use include alopecia, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and urticaria. Due to the voluntary nature of postmarket reports, neither a frequency nor a definitive causal relationship can be established.
During clinical trials, recipients of abacavir; dolutegravir; lamivudine experienced a mean increase in serum creatinine concentrations of 0.14 mg/dL over baseline, and less than 2% developed renal impairment. The change in serum creatinine was observed within the first 4 weeks of treatment and remained stable through 144 weeks. This increase occurs as a result of dolutegravir inhibiting tubular secretion of creatinine without affecting renal glomerular function. Other laboratory abnormalities reported by recipients of abacavir; dolutegravir; lamivudine during clinical trials included elevated hepatic enzymes (2.5- to 5-times ULN, 3%; more than 5-times ULN, 1%), creatine phosphokinase (10-times or more ULN, 7%), and lipase (more than 3-times ULN, 5%), hyperglycemia (more than 250 mg/dL, 2%), and neutropenia (0.75 to 0.99 x109, 4%; less than 0.75 x109, 3%). Drug recipients also experienced a mean increase in total cholesterol and triglycerides over baseline levels of 24 mg/dL and 13.6 mg/dL, respectively; hypertriglyceridemia was reported in less than 2% of patients. In a study of 57 pediatric patients weighing 6 to 39 kg, the overall safety profile of abacavir; dolutegravir; lamivudine was similar to that observed in adults. In this pediatric study, the most common adverse reactions were classified as laboratory abnormalities and included decreased glomerular filtration rate (23%, n = 13), increased blood creatinine (18%, n = 10), and increased ALT (5%, n = 3). Two pediatric patients experienced Grade 3 or 4 adverse reactions. One had Grade 3 increased blood creatinine and Grade 3 decreased glomerular filtration rate, and the other had drug-induced liver injury with Grade 4 increased ALT and AST. Postmarketing cases of muscle weakness, myalgia and rhabdomyolysis (potentially associated with elevated CPK), aplastic anemia, lymphadenopathy, and hyperlactemia have been reported. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
There have been postmarketing reports of severe acute hepatitis B exacerbation in patients with HBV and HIV coinfection following the discontinuation of lamivudine therapy; close monitoring of clinical signs and symptoms, including laboratory monitoring, are recommended for several months following discontinuation. Typically, HBV exacerbation is associated with a return of HBV DNA and increases in ALT concentrations. Usually this exacerbation is self-limited; however, some fatalities have been reported. The casual relationship of discontinuation of lamivudine to the recurrence of HBV infection is not known. There is insufficient evidence to determine whether re-initiation of therapy alters the course of posttreatment exacerbations of hepatitis.
Lactic acidosis and severe hepatotoxicity (i.e., fatal cases of hepatomegaly with steatosis) have been reported with the use of nucleoside reverse transcriptase inhibitors. Many of these cases have occurred in women; additional risk factors included obesity and prolonged nucleoside exposure. Additionally, cases of acute hepatic failure have been reported in patients receiving a dolutegravir-containing regimen who had no preexisting hepatic disease or other identifiable risk factors. Abacavir; dolutegravir; lamivudine should be discontinued if a patient develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, including hepatomegaly and steatosis even in the absence of marked elevated transaminases. Pancreatitis, splenomegaly, and drug-induced liver injury requiring liver transplant have been reported with one or more of the individual components during postmarketing use. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Serious hypersensitivity reactions or anaphylaxis, including fatal reactions, have occurred in recipients of abacavir and dolutegravir containing regimens. Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir in combination with medications known to be associated with SJS and TEN; because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. Signs and symptoms of abacavir hypersensitivity include fatigue, fever, malaise, skin rash, gastrointestinal symptoms such as abdominal pain, diarrhea, nausea or vomiting, and respiratory symptoms including pharyngitis, dyspnea, or cough. Respiratory symptoms occur in approximately 20% of patients with abacavir hypersensitivity reactions. Wheezing occur infrequently during abacavir hypersensitivity reactions. Other signs and symptoms include lethargy, headache, myolysis, myalgia, edema, chest x-ray abnormalities, arthralgia, and paresthesias. Physical findings include lymphadenopathy, mucous membrane lesions (conjunctivitis and oral ulceration), and rash. The rash, if present, usually appears as a maculopapular rash or urticarial rash (urticaria) but may be variable in appearance. There have been reports of erythema multiforme. Laboratory findings include elevated hepatic enzymes, increased creatine phosphokinase, increased creatinine, and lymphopenia. Signs and symptoms associated with dolutegravir hypersensitivity include severe rash, fever, malaise, fatigue, arthralgia, myalgia, oral lesions, conjunctivitis, angioedema, facial edema, hepatitis, eosinophilia, and breathing difficulty or wheezing. Deaths have been reported in patients receiving abacavir who were initially diagnosed with an acute respiratory disease (pneumonia, bronchitis, or flu-like illness) who were later recognized to have had a hypersensitivity reaction to abacavir that included respiratory symptoms. A delay in diagnosis of abacavir or dolutegravir hypersensitivity can result in the drug being continued or reintroduced, leading to more severe hypersensitivity reactions including, life-threatening hypotension, anaphylactoid reactions, hepatic failure, renal failure (unspecified), acute respiratory distress syndrome (ARDS), respiratory arrest, and death. Symptoms usually appear within the first 6 weeks of treatment, although these reactions may occur at any time during therapy. Hypersensitivity reactions have been reported upon reintroduction of abacavir therapy that has been discontinued for other medical reasons. In a minority of these patients, hypersensitivity occurred days or weeks after reintroduction of abacavir treatment. Symptoms worsen with continued therapy but often resolve upon discontinuation of the drug. Patients developing signs or symptoms of hypersensitivity should discontinue use of abacavir; dolutegravir; lamivudine as soon as a hypersensitivity reaction is suspected. In patients presenting with symptoms of acute respiratory disease and other symptoms listed above, a hypersensitivity reaction should be suspected even if alternative respiratory diagnoses (i.e., pneumonia, bronchitis, pharyngitis, or flu-like illness) are possible. If the clinical presentation of an acute illness cannot be clearly differentiated from a hypersensitivity reaction, the drug should be permanently discontinued. Patients should never be restarted on any abacavir or dolutegravir containing product following a hypersensitivity reaction because more severe symptoms will recur within hours of administration and may include life-threatening hypotension and death. To facilitate reporting of hypersensitivity reactions and collection of information on each case, healthcare professionals should report all hypersensitivity reactions to the FDA MedWatch program at (800) FDA-1088.
Abacavir treatment was linked with the development of myocardial infarction (MI) in several prospective, observational, epidemiologic trial. In contrast to these observational trials, a sponsor-conducted, pooled analysis of clinical trials showed no excess risk of MI in abacavir-treated subjects as compared with control subjects. A meta-analysis of 26 randomized clinical trials conducted by the FDA failed to reveal an association between treatment with abacavir-containing regimens and development of MI (OR = 1.02; 95% CI: 0.56 to 1.84). In light of the conflicting data, caution is advised when prescribing abacavir to patients with pre-existing coronary heart disease. Healthcare providers are encouraged to minimize a patient's modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking) prior to prescribing.
Preliminary data from an ongoing observational study found an increased incidence of teratogenesis (specifically, neural tube birth defects involving the brain, spine and spinal cord) in infants born to mothers who received dolutegravir at the time of becoming pregnant or early in the first trimester. No cases have been identified in babies born to women starting dolutegravir later in pregnancy; however, the FDA continues to investigate the safety risk and will update the public when more information is available. The FDA advises healthcare providers and patients to report all side effects involving dolutegravir, or other medicines, to the FDA MedWatch Program.
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U. Instruct patients to achieve sustained viral suppression (i.e., 2 recorded measurements of plasma viral loads that are below the limits of detection and taken at least 3 months apart) before attempting to conceive a child in order to maximize their health, prevent HIV sexual transmission, and minimize the risk of HIV transmission to the infant once conception occurs. For partners with different HIV status when the person with HIV is on antiretroviral therapy and has achieved sustained viral suppression, sexual intercourse without a condom allows conception without sexual HIV transmission to the person without HIV. Expert consultation is recommended.
Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Healthcare providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.
Administration is contraindicated in patients with a history of dolutegravir, lamivudine, or abacavir hypersensitivity. Abacavir has been associated with serious hypersensitivity reactions or anaphylaxis (some cases have been fatal); to reduce the risk, perform HLA-B*5701 testing on all patients before initiating treatment. Do not prescribe or administer abacavir to an HLA-B*5701-positive patient; clearly record the positive status as an abacavir allergy in the patients' medical record. According to the manufacturer, the estimated incidence of hypersensitivity to abacavir was 8% when HLA-B*5701 screening was not performed; the incidence was 1% when HLA-B*5701-positive patients were excluded. Racial background may help identify those at higher risk for carrying the gene, as in the United States approximately 8% of Caucasian patients, 2.5% of Black patients, and 1% of Asian patients are carriers. Regardless of HLA-B*5701 status, immediately discontinue treatment in patients developing or with suspected signs or symptoms of abacavir hypersensitivity, including those presenting with 2 or more of the following: fever, rash, gastrointestinal (e.g., nausea, vomiting, diarrhea, abdominal pain), constitutional (generalized malaise, fatigue, achiness), or respiratory (dyspnea, cough, pharyngitis). Other potential signs or symptoms of hypersensitivity include: lethargy, headache, myolysis, edema, localized infiltrates on chest x-ray, arthralgia, paresthesia, lymphadenopathy, conjunctivitis, oral ulceration, elevated liver function tests, creatine phosphokinase, creatinine, and lymphopenia. Permanently discontinue abacavir if the clinical presentation of an acute illness cannot be clearly differentiated from a hypersensitivity reaction. NEVER reinitiate an abacavir containing product in a patient who experiences a hypersensitivity reaction as more severe symptoms will recur within hours of administration and may include life-threatening hypotension and death. Severe or fatal hypersensitivity reactions may also occur within hours after abacavir reintroduction in patients who have no identified history of hypersensitivity, but who discontinued abacavir for reasons unrelated to symptoms of hypersensitivity (e.g., interruption in drug supply or discontinuation while treating other medical conditions). In some cases, symptoms consistent with hypersensitivity may have been present before abacavir was discontinued, but may have been attributed to other medical conditions (e.g., acute onset respiratory diseases, gastroenteritis, or reactions to other medications). In a minority of cases, hypersensitivity reactions occurred days to weeks after abacavir reintroduction. If abacavir has been discontinued for reasons other than symptoms of hypersensitivity and if reinitiation is being considered, re-evaluate the reason for discontinuation and ensure that the patient did not have any suspected symptoms of hypersensitivity. If hypersensitivity symptoms are suspected upon review or if hypersensitivity cannot be ruled out, do not reinitiate abacavir. If symptoms consistent with hypersensitivity are not identified and the patient is HLA-B*5701-negative, undertake reintroduction with caution. If HLA-B*5701 status is unknown, screening should occur prior to restarting therapy. Dolutegravir has also been associated with hypersensitivity reactions in up to 1% of drug recipients. Dolutegravir-associated hypersensitivity reactions are characterized by rash, constitutional findings, and organ dysfunction (e.g., liver injury). Healthcare providers are advised to closely monitor the clinical status of patients, including liver function tests, during treatment. Immediately discontinue treatment and initiate appropriate therapy in any patient who develops signs of hypersensitivity reactions, such as serious rash or rash accompanied by fever, fatigue, general malaise, muscle or joint aches, blisters or peeling of skin, oral lesions, conjunctivitis, hepatitis, facial edema, angioedema, difficulty breathing, or eosinophilia. Failure to promptly discontinue therapy may result in a life-threatening reaction. Do not re-administer dolutegravir to patients who have experienced a previous hypersensitivity reaction to the drug. Report all hypersensitivity reactions to the FDA MedWatch program (800-FDA-1088).
Abacavir; dolutegravir; lamivudine is contraindicated for used in patients with moderate to severe hepatic disease (Child-Pugh B and C), and should be used with caution in persons with known risk factors for liver disease (e.g., alcoholism). In patients with mild hepatic impairment (Child-Pugh A), a reduction of abacavir dose is required; however, because this is a fixed dose combination product, the abacavir dose cannot be adjusted and, therefore, use of the drug should be avoided in patients with any hepatic impairment. Cases of hepatotoxicity, including elevated hepatic enzymes, hepatitis, and acute liver failure, have been reported in patients (including pediatric patients) receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury requiring liver transplant has also been reported with abacavir; dolutegravir; lamivudine. Monitor patients for hepatotoxicity during treatment with abacavir; dolutegravir; lamivudine. Additionally, hepatotoxicity or lactic acidosis, including fatal cases, has been associated with nucleoside analog therapy, including abacavir and lamivudine. Obesity and prolonged nucleoside exposure may be risk factors, and most of these cases have occurred in females. It is unknown if pregnant patients are at increased risk for this syndrome; however, because being pregnant itself can mimic some early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant patients receiving nucleoside analogs should have liver function tests and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. Discontinue treatment 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 increases in transaminases.
Cautious administration is recommended for patients with hepatitis. Patients with hepatitis B virus coinfection may be at increased risk for worsening or development of elevated hepatic enzymes following treatment with abacavir; dolutegravir; lamivudine. Patients who present with HIV infection should be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If abacavir; dolutegravir; lamivudine is used to treat HIV, an additional therapy should be considered for appropriate treatment of HBV; otherwise, consider an alternative regimen. If tenofovir cannot be used, entecavir should be given in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most patients with coinfection should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. It should also be noted that following discontinuation of lamivudine in patients with HBV and HIV coinfection, some patients experienced clinical or laboratory evidence of hepatitis B exacerbation, which has been fatal in some cases. This reaction may be more severe in patients with decompensated hepatic disease. Thus, patients with HBV and HIV coinfection should have transaminase concentrations monitored every 6 weeks for the first 3 months after stopping abacavir; dolutegravir; lamivudine, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct patients with hepatitis and HIV coinfection to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
Cautious administration is recommended for patients with hepatitis and HIV coinfection. In general, the safety profiles of patients with and without hepatitis C coinfection were similar; however, as compared with data from patients without hepatitis, a higher percentage of patients with hepatitis C experienced elevated AST and ALT. HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experience with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
Avoid use of abacavir, dolutegravir, lamivudine in adults with renal failure (CrCl less than 30 mL/minute) and in pediatric patients with a similar degree of renal impairment based on age-appropriate renal function assessment. Dolutegravir plasma concentrations are decreased in patients with renal failure, as compared to healthy controls; therefore, use of the drug in this patient population may result in loss of therapeutic effect and development of resistance. Conversely, lamivudine exposures may be increased in patients with renal impairment (CrCl between 30 and 49 mL/minute). Monitor these patients for lamivudine-related hematologic toxicities. If new or worsening neutropenia or anemia develops, substitute the use of abacavir; dolutegravir; lamivudine with the individual drug components to allow for a lamivudine renal dose adjustment.
Conflicting data have been published regarding the potential for increased risk of myocardial infarction (MI) in persons receiving treatment with abacavir-containing regimens. As a precaution, the manufacturer recommends considering the underlying risk of cardiac disease and taking action to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking) when prescribing antiretroviral therapies, including abacavir; dolutegravir; lamivudine. HIV guidelines recommend consideration be given to avoiding use of abacavir-containing regimens in patients with known high cardiovascular risk. Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of MI. Patients in these studies who started abacavir for the first time had worse initial cardiovascular risk profiles than observed with the other nucleoside reverse transcriptase inhibitor (NRTI) agents; therefore, it can not be ruled out that some of these results could be the result of channeling bias. The authors of these studies speculate that the underlying mechanism for increased risk of CVD may be due to an increased propensity for subclinical atherosclerosis to manifest itself clinically as a consequence of the pro-inflammatory potential of abacavir; however, a biological mechanism to explain the potential increase in risk has not been definitely established. In contrast to these two observational trials, a sponsor-conducted, pooled analysis of clinical trials showed no excess risk of MI in abacavir-treated subjects as compared with control subjects. Further, a meta-analysis of 26 randomized clinical trials conducted by the FDA failed to reveal an association between treatment with abacavir-containing regimens and development of MI (OR = 1.02; 95% CI 0.56 to 1.84).
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to abacavir; dolutegravir; lamivudine therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), Mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis jirovecii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. Resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contain multiple mutations conferring antimicrobial resistance to other NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir/lamivudine and other NRTIs, and between dolutegravir and other integrase strand transfer inhibitors should be considered when choosing new therapeutic regimens in previously treated patients.
Administer abacavir; dolutegravir; lamivudine cautiously to patients with peripheral neuropathy, as patients with peripheral neuropathy can experience exacerbations during lamivudine therapy. In one case report involving a 57-year-old male with mild neuropathy, treatment with lamivudine was associated with a fatal peripheral neuropathy exacerbation. The patient had received lamivudine 300 mg daily for treatment of hepatitis. After 3 months of treatment, the patient presented with dysphonia and progressive muscle weakness. Later, the patient developed tetraparesis followed by acute respiratory failure requiring mechanical ventilation. The patient then went into sudden cardiac arrest. Treatment with lamivudine was stopped, and the neuropathy and respiratory capacity improved; however, the patient ultimately died.
Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. Guidelines recommend the use of abacavir; dolutegravir; lamivudine as a preferred treatment option for HLA-B*5701 negative pregnant patients, irrespective of the trimester, and for non-pregnant patients who are trying to conceive. Data from the Antiretroviral Pregnancy Registry (APR), which includes 1,455 first trimester exposures to abacavir, 874 first trimester exposures to dolutegravir, and 5,613 first trimester exposures to lamivudine, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. The prevalence of defects for abacavir, dolutegravir, and lamivudine when exposure occurred in the first trimester is 3.2% (95% CI: 2.4 to 4.3), 3.3% (95% CI: 2.2 to 4.7), and 3.1% (95% CI: 2.6 to 3.6), respectively. Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in-utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant patients receiving nucleoside analogs should have liver function tests and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than or equal to 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years and have CD4 counts less than 300 cells/mm3, patients with inconsistent adherence, or patients with detectable viral loads. For patients on HAART less than 2 years but have CD4 counts greater than or equal to 300 cells/mm3, monitor CD4 counts every 6 months. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of planned delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second-trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for the development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to abacavir; dolutegravir; lamivudine; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.
HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission. Advise patients who receive a diagnosis of HIV infection while breast-feeding (acute HIV) to immediately discontinue breast-feeding and switch to replacement feeding in order to reduce the risk of postnatal HIV transmission to the infant. Replacement feeding is also recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). Although there is no information regarding the effects of abacavir, dolutegravir, or lamivudine on breast-fed infants or milk production, all 3 drug components are present in human milk. Available data show dolutegravir is found in breast milk at concentrations about 3% of those observed in maternal plasma. In 1 study conducted in Botswana, the mean breast milk-to-plasma ratio of abacavir was 0.85 in the 15 women tested. Further, an analysis of 9 breast-feeding infants found detectable plasma drug concentrations in 1 infant. In the Swiss Mother and Child HIV Cohort nested study, abacavir was measurable in 4 breast-fed infants; the relative infant dose was 0.34%. Lamivudine was found to be secreted in human breast milk during a study involving 20 breast-feeding women with HIV who were administered either 300 mg of lamivudine twice daily as a single agent (n = 10) or lamivudine 150 mg twice daily in combination with zidovudine (n = 10). The mean breast milk concentrations of lamivudine in the respective groups were similar at 1.22 mg/L (range less than 0.5 to 6.09 mg/L) and 0.9 mg/L (range less than 0.5 to 8.2 mg/L). Other antiretroviral mediations whose passage into human breast milk have been evaluated include nevirapine, zidovudine, and nelfinavir.
Patients with a history of depression or other psychiatric illness may be at increased risk for psychiatric adverse events. Depression was reported in 1% of adult patients treated with abacavir; dolutegravir; lamivudine in clinical trials. Suicidal ideation, attempt, behavior, or completion was reported in less than 2% of patients. These events were observed primarily in patients with a pre-existing history of depression or other psychiatric illness.
Starting an integrase inhibitor-containing regimen (such as abacavir; dolutegravir; lamivudine) in treatment-naive patients has been associated with weight gain. Predictors and mechanisms for the increase in weight are still unclear; however, the weight gain appears to disproportionately affect females, Hispanic patients, and Black patients (particularly Black women). It is unknown whether the increase in weight is associated with significant cardio-metabolic risks or if it is reversible upon treatment discontinuation.
HIV guidelines recommend screening for HLA-B*5701 before initiating an abacavir-containing regimen to reduce the risk of hypersensitivity reaction. HLA-B*5701-positive patients should not be prescribed abacavir.
NOTE: HIV guidelines recommend consideration be given to avoiding the use of abacavir-containing regimens in patients at high risk for cardiovascular adverse events. Although a definitive correlation has not been established, recent (within 6 months) or current use of abacavir has been associated with an increased risk of myocardial infarction.
Initiation of therapy for HIV treatment:
-For adults, initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Prior to initiating treatment, obtain baseline plasma HIV RNA (viral load) and CD4 count; results do not need to be available before starting therapy.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy in all antiretroviral treatment-naive patients and prior to changing therapy for treatment failure.
--Standard genotypic drug-resistance testing in treatment-naive people should focus on testing for mutations in reverse transcriptase (RT) and protease (PR) genes.
-Testing for mutations in the integrase gene should also be performed if integrase strand transfer inhibitor (INSTI) resistance is a concern (e.g., people who acquire HIV after pre-exposure prophylaxis with long-acting cabotegravir).
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-It is not necessary to delay treatment until resistance test results are available; however, subsequent modifications to the treatment regimen should be made, if needed, once the test results are available.
-Pediatric guidelines are also available.
Place in therapy for HIV infection:
-Abacavir; dolutegravir; lamivudine is a recommended initial regimen for most adults and adolescents (including pregnant women, irrespective of trimester, and women who are trying to conceive) with HIV-1, HIV-2, or HIV-1/HIV-2 coinfection, except for individuals:
--who are HLA-B*5701 positive
-who have a history of using long-acting cabotegravir as pre-exposure prophylaxis and need to start treatment before results of INSTI genotypic resistance testing are available
-with hepatitis B virus (HBV) coinfection
-Pediatric guidelines are also available.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of human immunodeficiency virus (HIV) infection:
Oral dosage (Triumeq only):
NOTE: Do not interchange tablets (Triumeq) and tablets for oral suspension (Triumeq PD) on a milligram-per-milligram basis due to differing pharmacokinetic profiles.
Adults: One tablet (600 mg abacavir; 50 mg dolutegravir; 300 mg lamivudine) PO once daily. During coadministration with efavirenz, fosamprenavir plus ritonavir, tipranavir plus ritonavir, carbamazepine, or rifampin, the dolutegravir dose needs to be increased to 50 mg twice daily; therefore, give an ADDITIONAL 50 mg per day of dolutegravir (separated by 12 hours from abacavir; dolutegravir; lamivudine). Avoid use in patients with clinically suspected integrase strand transfer inhibitor (INSTI) resistance or resistance associated integrase substitutions.
Children and Adolescents weighing 25 kg or more: One tablet (600 mg abacavir; 50 mg dolutegravir; 300 mg lamivudine) PO once daily. During coadministration with efavirenz, fosamprenavir plus ritonavir, tipranavir plus ritonavir, carbamazepine, or rifampin, the dolutegravir dose needs to be increased to 50 mg twice daily; therefore, give an ADDITIONAL 50 mg per day of dolutegravir (separated by 12 hours from abacavir; dolutegravir; lamivudine). Avoid use in patients with clinically suspected integrase strand transfer inhibitor (INSTI) resistance or resistance associated integrase substitutions.
Oral dosage (Triumeq PD only):
NOTE: Do not interchange tablets (Triumeq) and tablets for oral suspension (Triumeq PD) on a milligram-per-milligram basis due to differing pharmacokinetic profiles.
Children weighing 20 to 24 kg: Six tablets (360 mg abacavir; 30 mg dolutegravir; 180 mg lamivudine) PO once daily. During coadministration with efavirenz, fosamprenavir plus ritonavir, tipranavir plus ritonavir, carbamazepine, or rifampin, the dolutegravir dose needs to be increased to 30 mg twice daily; therefore, give an ADDITIONAL 30 mg per day of dolutegravir (separated by 12 hours from abacavir; dolutegravir; lamivudine). Avoid use in patients with clinically suspected integrase strand transfer inhibitor (INSTI) resistance or resistance associated integrase substitutions.
Children weighing 14 to 19 kg: Five tablets (300 mg abacavir; 25 mg dolutegravir; 150 mg lamivudine) PO once daily. During coadministration with efavirenz, fosamprenavir plus ritonavir, tipranavir plus ritonavir, carbamazepine, or rifampin, the dolutegravir dose needs to be increased to 25 mg twice daily; therefore, give an ADDITIONAL 25 mg per day of dolutegravir (separated by 12 hours from abacavir; dolutegravir; lamivudine). Avoid use in patients with clinically suspected integrase strand transfer inhibitor (INSTI) resistance or resistance associated integrase substitutions.
Children weighing 10 to 13 kg: Four tablets (240 mg abacavir; 20 mg dolutegravir; 120 mg lamivudine) PO once daily. During coadministration with efavirenz, fosamprenavir plus ritonavir, tipranavir plus ritonavir, carbamazepine, or rifampin, the dolutegravir dose needs to be increased to 20 mg twice daily; therefore, give an ADDITIONAL 20 mg per day of dolutegravir (separated by 12 hours from abacavir; dolutegravir; lamivudine). Avoid use in patients with clinically suspected integrase strand transfer inhibitor (INSTI) resistance or resistance associated integrase substitutions.
Children weighing 6 to 9 kg: Three tablets (180 mg abacavir; 15 mg dolutegravir; 90 mg lamivudine) PO once daily. During coadministration with efavirenz, fosamprenavir plus ritonavir, tipranavir plus ritonavir, carbamazepine, or rifampin, the dolutegravir dose needs to be increased to 15 mg twice daily; therefore, give an ADDITIONAL 15 mg per day of dolutegravir (separated by 12 hours from abacavir; dolutegravir; lamivudine). Avoid use in patients with clinically suspected integrase strand transfer inhibitor (INSTI) resistance or resistance associated integrase substitutions.
Infants 3 to 11 months weighing 10 to 13 kg: Four tablets (240 mg abacavir; 20 mg dolutegravir; 120 mg lamivudine) PO once daily. During coadministration with efavirenz, fosamprenavir plus ritonavir, tipranavir plus ritonavir, carbamazepine, or rifampin, the dolutegravir dose needs to be increased to 20 mg twice daily; therefore, give an ADDITIONAL 20 mg per day of dolutegravir (separated by 12 hours from abacavir; dolutegravir; lamivudine). Avoid use in patients with clinically suspected integrase strand transfer inhibitor (INSTI) resistance or resistance associated integrase substitutions.
Infants 3 to 11 months weighing 6 to 9 kg: Three tablets (180 mg abacavir; 15 mg dolutegravir; 90 mg lamivudine) PO once daily. During coadministration with efavirenz, fosamprenavir plus ritonavir, tipranavir plus ritonavir, carbamazepine, or rifampin, the dolutegravir dose needs to be increased to 15 mg twice daily; therefore, give an ADDITIONAL 15 mg per day of dolutegravir (separated by 12 hours from abacavir; dolutegravir; lamivudine). Avoid use in patients with clinically suspected integrase strand transfer inhibitor (INSTI) resistance or resistance associated integrase substitutions.
Maximum Dosage Limits:
-Adults
1 Triumeq tablet per day PO (abacavir 600 mg/day PO; dolutegravir 50 mg/day PO; lamivudine 300 mg/day PO).
-Geriatric
1 Triumeq tablet per day PO (abacavir 600 mg/day PO; dolutegravir 50 mg/day PO; lamivudine 300 mg/day PO).
-Adolescents
1 Triumeq tablet per day PO (abacavir 600 mg/day PO; dolutegravir 50 mg/day PO; lamivudine 300 mg/day PO).
-Children
weighing 25 kg or more: 1 Triumeq tablet per day PO (abacavir 600 mg/day PO; dolutegravir 50 mg/day PO; lamivudine 300 mg/day PO).
weighing 20 to 24 kg: 6 Triumeq PD tablets per day PO (abacavir 360 mg/day PO; dolutegravir 30 mg/day PO; lamivudine 180 mg/day PO).
weighing 14 to 19 kg: 5 Triumeq PD tablets per day PO (abacavir 300 mg/day PO; dolutegravir 25 mg/day PO; lamivudine 150 mg/day PO).
weighing 10 to 13 kg: 4 Triumeq PD tablets per day PO (abacavir 240 mg/day PO; dolutegravir 20 mg/day PO; lamivudine 120 mg/day PO).
weighing 6 to 9 kg: 3 Triumeq PD tablets per day PO (abacavir 180 mg/day PO; dolutegravir 15 mg/day PO; lamivudine 90 mg/day PO).
-Infants
3 to 11 months weighing 10 to 13 kg: 4 Triumeq PD tablets per day PO (abacavir 240 mg/day PO; dolutegravir 20 mg/day PO; lamivudine 120 mg/day PO).
3 to 11 months weighing 6 to 9 kg: 3 Triumeq PD tablets per day PO (abacavir 180 mg/day PO; dolutegravir 15 mg/day PO; lamivudine 90 mg/day PO).
1 to 2 months or weighing less than 6 kg: Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Because abacavir may require a dose adjustment in the presence of hepatic impairment, the fixed-dose combination of abacavir; dolutegravir; lamivudine is not recommended for patients with impaired hepatic function.
Patients with Renal Impairment Dosing
CrCl 50 mL/minute or more: No dosage adjustment is needed.
CrCl 30 to 49 mL/minute: No dosage adjustment is needed, but monitor for lamivudine-related hematologic toxicities. If new or worsening neutropenia or anemia develops, discontinue use of the fixed-dose combination product and administer the individual components to allow for a lamivudine dose adjustment.
CrCl less than 30 mL/minute and pediatric patients with a similar degree of renal impairment based on age-appropriate renal function assessment: Use not recommended.
*non-FDA-approved indication
Abrocitinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with abrocitinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and abrocitinib is a P-gp inhibitor.
Acalabrutinib: (Moderate) Coadministration of acalabrutinib and dolutegravir may increase dolutegravir exposure and increase the risk of dolutegravir toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Dolutegravir is a BCRP transporter substrate in vitro.
Adagrasib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with adagrasib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir 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).
Alogliptin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Aluminum Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain magnesium and calcium which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing gastrointestinal medications such as magnesium hydroxide. The chemical structure of these GI drugs that contain polyvalent cations, such as magnesium hydroxide, can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing gastrointestinal medications such as magnesium hydroxide. The chemical structure of these GI drugs that contain polyvalent cations, such as magnesium hydroxide, can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain magnesium which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
Amiloride: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Amiodarone: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with amiodarone. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and amiodarone is a P-gp inhibitor.
Apalutamide: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with apalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Apalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
Aprepitant, Fosaprepitant: (Moderate) Use caution if dolutegravir and aprepitant, fosaprepitant are used concurrently and monitor for an increase in dolutegravir-related adverse effects for several days after administration of a multi-day aprepitant regimen. Dolutegravir is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and may increase plasma concentrations of dolutegravir. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
Armodafinil: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with armodafinil; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Armodafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Asciminib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with asciminib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and asciminib is a BCRP inhibitor.
Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and uridine glucuronyltransferase (UGT). Atazanavir is an inhibitor of CYP3A4 and UGT1A1.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and uridine glucuronyltransferase (UGT). Atazanavir is an inhibitor of CYP3A4 and UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Berotralstat: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with berotralstat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Bexarotene: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with bexarotene; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Bexarotene is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Bosentan: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with bosentan; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Bosentan is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Brigatinib: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with brigatinib is necessary. Dolutegravir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
Cabozantinib: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with abacavir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and abacavir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (Minor) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with cabozantinib is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
Calcium Acetate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium Carbonate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium Carbonate; Simethicone: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium Chloride: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium Gluconate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium; Vitamin D: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Canagliflozin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Cannabidiol: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with cannabidiol. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and cannabidiol is a P-gp inhibitor.
Capivasertib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with capivasertib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of UGT1A1; capivasertib is an UGT1A1 inhibitor.
Capmatinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with capmatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
Carbamazepine: (Major) When possible, avoid concurrent use of dolutegravir with carbamazepine in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with carbamazepine. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and carbamazepine is an inducer of CYP3A4.
Carvedilol: (Moderate) Increased concentrations of dolutegravir may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and dolutegravir is a P-gp substrate in vitro.
Cenobamate: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with ceritinib is necessary. Dolutegravir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
Chromium: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Clobazam: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with clobazam; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Clobazam is a weak inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Conivaptan: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with conivaptan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
Daclatasvir: (Moderate) Systemic exposure of dolutegravir, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of dolutegravir; monitor patients for potential adverse effects.
Dalfampridine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
Danicopan: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with danicopan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Dapagliflozin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Daridorexant: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with daridorexant. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and daridorexant is a P-gp inhibitor.
Darolutamide: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with darolutamide is necessary. Dolutegravir is a BCRP substrate and darolutamide is a BCRP inhibitor.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Dofetilide: (Contraindicated) Concurrent use of dolutegravir with dofetilide is contraindicated due of the potential for serious and life-threatening adverse events, such as QT prolongation and torsade de pointes (TdP). Dolutegravir inhibits the renal organic cation transporter OCT2, dofetilide is eliminated via this transporter. If coadministered, the plasma concentration of dofetilide may increase. (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
Donepezil; Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
Duvelisib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with duvelisib. Coadministration may increase the exposure of dolutegravir. Dolutegravir is a CYP3A substrate; duvelisib is a moderate CYP3A inhibitor.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Efavirenz: (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Elacestrant: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with elacestrant. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of BCRP and P-gp and elacestrant is a BCRP and P-gp inhibitor.
Elagolix: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with elagolix; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Elagolix is a weak to moderate inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with elagolix; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Elagolix is a weak to moderate inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Empagliflozin; Linagliptin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Empagliflozin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Emtricitabine: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Enasidenib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Encorafenib: (Moderate) Monitor for increased toxicity or decreased efficacy of dolutegravir if coadministered with encorafenib. Concurrent use may increase or decrease the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and BCRP substrate and encorafenib is a strong CYP3A inducer and BCRP inhibitor. The net effect on dolutegravir exposure is unknown.
Enzalutamide: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with enzalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Enzalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
Erdafitinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with erdafitinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and erdafitinib is a P-gp inhibitor.
Ertugliflozin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking abacavir. Abacavir is metabolized via alcohol dehydrogenase. Alcohol decreases the elimination of abacavir causing an increase in overall exposure to abacavir. In a study involving HIV-infected men, coadministration of alcohol and abacavir resulted in a 41% increase in abacavir AUC and a 26% increase in abacavir half-life. In males, abacavir had no effect on the pharmacokinetic properties of alcohol; this interaction has not been studied in females. Abacavir has no effect on the pharmacokinetic properties of alcohol. (Major) Because abacavir is metabolized via alcohol dehydrogenase, alcohol decreases the elimination of abacavir causing an increase in overall exposure to abacavir. In a study involving HIV-infected men, coadministration of alcohol and abacavir resulted in a 41% increase in abacavir AUC and a 26% increase in abacavir half-life. In males, abacavir had no effect on the pharmacokinetic properties of alcohol; this interaction has not been studied in females. Abacavir has no effect on the pharmacokinetic properties of alcohol.
Etravirine: (Major) Coadministration of dolutegravir with etravirine should be avoided, unless also administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. When administered with etravirine (a CYP3A4 inducer), the plasma concentration of dolutegravir (a CYP3A4 substrate) is significantly reduced; however, this effect is diminished by the presence of one of the above mentioned protease inhibitors.
Fedratinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with fedratinib. Coadministration may increase the exposure of dolutegravir. Dolutegravir is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
Ferric Maltol: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Fosamprenavir: (Major) Avoid concurrent use of dolutegravir and fosamprenavir boosted with ritonavir in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For INSTI-naive adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with fosamprenavir/ritonavir. Use of these drugs together results in decreased dolutegravir plasma concentrations.
Fosphenytoin: (Major) Avoid concurrent use of dolutegravir with phenytoin or fosphenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Fostamatinib: (Moderate) Monitor for dolutegravir toxicities that may require dolutegravir dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4, BCRP, or P-gp substrate may increase the concentration of the CYP3A4, BCRP, or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a CYP3A4 and BCRP inhibitor; dolutegravir is a substrate for CYP3A4, BCRP, and P-gp. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%.
Fostemsavir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with fostemsavir. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and fostemsavir is a BCRP inhibitor.
Futibatinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with futibatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP and P-gp substrate and futibatinib is a P-gp and BCRP inhibitor.
Gilteritinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with gilteritinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
Glipizide; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Glyburide; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with dolutegravir, a CYP3A substrate, as dolutegravir toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Interferon Alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Alfa-n3: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Gamma-1b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferons: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Iron Salts: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Iron: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with dolutegravir may result in increased serum concentrations of dolutegravir. Dolutegravir is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) When possible, avoid concurrent use of dolutegravir with rifampin in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with rifampin. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and rifampin is an inducer of CYP3A4.
Isoniazid, INH; Rifampin: (Major) When possible, avoid concurrent use of dolutegravir with rifampin in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with rifampin. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and rifampin is an inducer of CYP3A4.
Itraconazole: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministered with itraconazole. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is an in vitro substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); itraconazole inhibits both P-gp and BCRP.
Lasmiditan: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lasmiditan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and lasmiditan is a P-gp inhibitor.
Lenacapavir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lenacapavir. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A, P-gp, and BCRP substrate and lenacapavir is a moderate CYP3A, P-gp, and BCRP inhibitor.
Leniolisib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with leniolisib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and leniolisib is a BCRP inhibitor.
Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of dolutegravir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dolutegravir is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Linagliptin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Lonafarnib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lonafarnib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor.
Lopinavir; Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Lorlatinib: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with lorlatinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). Lorlatinib is a moderate CYP3A4 inducer and a P-gp inducer.
Lumacaftor; Ivacaftor: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with lumacaftor; ivacaftor; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is partially metabolized by CYP3A and, in vitro, is a substrate for the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp.
Lumacaftor; Ivacaftor: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with lumacaftor; ivacaftor; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is partially metabolized by CYP3A and, in vitro, is a substrate for the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp.
Magnesium Citrate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing laxatives such as magnesium citrate. The chemical structure contains polyvalent cations which can bind dolutegravir in the GI tract. Taking magnesium citrate simultaneously may result in reduced bioavailability of dolutegravir.
Magnesium Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing gastrointestinal medications such as magnesium hydroxide. The chemical structure of these GI drugs that contain polyvalent cations, such as magnesium hydroxide, can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
Magnesium Salts: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain magnesium and calcium which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain magnesium which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
Maribavir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with maribavir. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and maribavir is a P-gp and BCRP inhibitor.
Mavacamten: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with mavacamten. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A substrate and mavacamten is a moderate CYP3A inducer.
Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
Meropenem: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with meropenem. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and meropenem is a P-gp inhibitor.
Meropenem; Vaborbactam: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with meropenem. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and meropenem is a P-gp inhibitor.
Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Repaglinide: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Saxagliptin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Sitagliptin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Methadone: (Moderate) In a study of 11 adult HIV-infected subjects receiving methadone maintenance therapy (40 to 90 mg/day) and abacavir 600 mg twice daily (twice the current recommended dose), methadone clearance increased by 22% (6% to 42%). While this interaction will not require dosage adjustment in the majority of patients, a small number of patients may require increased doses of methadone. In addition, a significant decrease in abacavir Cmax (34%) and increase in Tmax (67%) were noted, but no changes in overall abacavir clearance or half-life were reported. The clinical significance regarding abacavir therapy is not known.
Midostaurin: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with midostaurin. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and midostaurin is a BCRP inhibitor.
Mitapivat: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with mitapivat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and mitapivat is a P-gp inhibitor.
Mitotane: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with mitotane; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Mitotane is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
Modafinil: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with modafinil; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Modafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Momelotinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with momelotinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and momelotinib is a BCRP inhibitor.
Neratinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with neratinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
Nevirapine: (Major) Avoid concurrent use of nevirapine and dolutegravir. Concomitant use may decrease plasma concentrations of dolutegravir and there are insufficient data to make dosing recommendations. Dolutegravir is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Nirmatrelvir; Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Nirogacestat: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with nirogacestat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Oritavancin: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with oritavancin; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer.
Orlistat: (Moderate) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Osimertinib: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is a BCRP and P-glycoprotein (P-gp) substrate and osimertinib is a BCRP and P-gp inhibitor.
Oteseconazole: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with oteseconazole. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Oxcarbazepine: (Major) Avoid concurrent use of dolutegravir with oxcarbazepine, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Oxcarbazepine is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Pacritinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pacritinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP and P-gp substrate; pacritinib is a BCRP and P-gp inhibitor.
Peginterferon Alfa-2a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon Alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon beta-1a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Pexidartinib: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with pexidartinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer.
Phenobarbital: (Major) Avoid concurrent use of dolutegravir with phenobarbital, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenobarbital is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concurrent use of dolutegravir with phenobarbital, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenobarbital is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Phentermine; Topiramate: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
Phenytoin: (Major) Avoid concurrent use of dolutegravir with phenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Pioglitazone; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Pirtobrutinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pirtobrutinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and pirtobrutinib is a P-gp and BCRP inhibitor.
Polysaccharide-Iron Complex: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Pretomanid: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pretomanid. Concurrent use may increase the exposure of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and pretomanid is a P-gp and BCRP inhibitor.
Primidone: (Major) Avoid concurrent use of dolutegravir with primidone, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Primidone is metabolized to phenobarbital, which is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Procainamide: (Moderate) Cationic drugs that are eliminated by renal tubular secretion such as procainamide may compete with lamivudine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of the response to lamivudine and/or procainamide is recommended to individualize dosage. In selected individuals, procainamide serum concentration monitoring may be appropriate.
Pyridoxine, Vitamin B6: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Regorafenib: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with regorafenib is necessary. Dolutegravir is a BCRP substrate and regorafenib is a BCRP inhibitor.
Repotrectinib: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with repotrectinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer.
Ribavirin: (Moderate) Use abacavir with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Ribociclib: (Moderate) Use caution if coadministration of ribociclib with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Rifampin: (Major) When possible, avoid concurrent use of dolutegravir with rifampin in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with rifampin. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and rifampin is an inducer of CYP3A4.
Rifapentine: (Major) Do not administer rifapentine and dolutegravir together in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance who are receiving twice daily doses of dolutegravir. Additionally, avoid use of once daily rifapentine in any patient receiving dolutegravir. However, once weekly doses of rifapentine may be administered with caution to treatment-naive or treatment-experienced, but INSTI-naive patients receiving once daily dolutegravir. Monitor for virologic efficacy if these drugs are administered concurrently. In a drug interaction study, administration of rifapentine (900 mg once weekly) decreased the AUC and trough concentration of dolutegravir by 26% and 47%, respectively. Dolutegravir is a CYP3A and UGT1A substrate and rifapentine is a strong CYP3A and UGT1A inducer.
Riociguat: (Moderate) Monitor for an increase in riociguat-related adverse effects like hypotension if concomitant use with abacavir is necessary. Consider a riociguat dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Concomitant use of riociguat and abacavir may increase riociguat exposure although the magnitude of increase is unknown. Riociguat is a CYP1A1 substrate; abacavir may inhibit CYP1A1.
Ritlecitinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with ritlecitinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Ropeginterferon alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Selpercatinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with selpercatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and selpercatinib is a P-gp inhibitor.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with taurursodiol. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and taurursodiol is a P-gp and BCRP inhibitor.
Sorafenib: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with sorafenib is necessary. Dolutegravir is a P-glycoprotein (P-gp) and UGT1A1 substrate. Sorafenib inhibits both P-gp and UGT1A1 in vitro, and may increase the concentrations of concomitantly administered drugs that are P-gp or UGT1A1 substrates.
Sorbitol: (Major) Avoid coadministration of lamivudine oral solution and sorbitol if possible due to sorbitol dose-dependent reduction in lamivudine exposure. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol. Consider more frequent monitoring of viral load when treating with lamivudine oral solution. In a drug interaction study in 16 healthy adult patients, coadministration of a single 300 mg dose of lamivudine oral solution with sorbitol 3.2 g, 10.2 g, or 13.4 g resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC24 and 28%, 52%, and 55% in the Cmax of lamivudine.
Sotorasib: (Moderate) Monitor for decreased efficacy or increased toxicity of dolutegravir if coadministered with sotorasib. Concurrent use may alter the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4, BCRP, and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and a BCRP and P-gp inhibitor.
Sparsentan: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with sparsentan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and sparsentan is a P-gp and BCRP inhibitor.
St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of dolutegravir with St. John's Wort, Hypericum perforatum as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. St. John's Wort is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Sucralfate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking sucralfate. The chemical structure of sucralfate contains aluminum, which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis and dolutegravir as coadministration may increase the plasma concentrations of dolutegravir increasing the risk of adverse effects. Dolutegravir is a substrate of the breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
Tedizolid: (Moderate) If possible, stop use of dolutegravir temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for dolutegravir-associated adverse events. Dolutegravir plasma concentrations may be increased when dolutegravir is administered concurrently with oral tedizolid. Dolutegravir is a in vitro substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
Temsirolimus: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with temsirolimus is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of dolutegravir.
Tepotinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with tepotinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and tepotinib is a P-gp inhibitor.
Tipranavir: (Major) When possible, avoid concurrent use of dolutegravir and tipranavir boosted with ritonavir in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with tipranavir/ritonavir. Use of these drugs together results in decreased dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT), P-glycoprotein (P-gp), and CYP3A4 (minor). Tipranavir is an inducer of P-gp and inhibitor of CYP3A4; while ritonavir is an inducer of UGT, an inhibitor of P-gp, and a mixed inducer/inhibitor of CYP3A4. (Moderate) Concurrent administration of tipranavir and ritonavir with abacavir results in decreased abacavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for abacavir dosage adjustments are available.
Topiramate: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
Trospium: (Moderate) Trospium is eliminated by active tubular secretion and has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion including lamivudine. In theory, coadministration of trospium with lamivudine may increase the serum concentrations of trospium or lamivudine due to competition for the drug elimination pathway.
Tucatinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Vitamin D: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Voclosporin: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with voclosporin. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and voclosporin is a P-gp inhibitor.
Voriconazole: (Moderate) Use caution if coadministration of voriconazole with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Voxelotor: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with voxelotor. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Abacavir; dolutegravir; lamivudine is active against infections caused by human immunodeficiency virus type 1 (HIV-1). Both abacavir and lamivudine are nucleoside analogs that work by inhibiting HIV reverse transcriptase, while dolutegravir works by inhibiting the catalytic activity of HIV integrase.
Abacavir: Intracellularly, abacavir is converted by cellular enzymes to the active metabolite carbovir triphosphate. Carbovir triphosphate is an analog of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3'-hydroxyl group in the incorporated nucleoside analog prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is inhibited. In cell cultures, the 50% effective concentration (EC50) of abacavir for HIV-1 and HIV-2 ranged from 70 to 5,800 nM and 24 to 490 nM, respectively.
Lamivudine: Intracellularly, lamivudine is phosphorylated to produce the active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The primary mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase via viral DNA chain termination after incorporation of the nucleotide analog. In cell cultures, EC50 values for lamivudine ranged from 3 to 15,000 nM for HIV-1 and 3 to 120 nM for HIV-2 isolates.
Dolutegravir: Antiviral activity results from inhibiting HIV integrase, one of the three enzymes required for viral replication. The integration of HIV into cellular DNA is a multi-step process. The first reaction is the "3'-processing" step. During 3'-processing, HIV integrase removes two or three nucleotides from each 3' end of the viral DNA by endonucleolytic processing. This prepares the viral DNA for the next step, the "strand transfer" reaction. In the strand transfer step, integrase inserts the 3' ends of viral DNA into the cellular (target) DNA. Dolutegravir interferes with the strand transfer reaction by displacing the viral DNA from the active site; thereby preventing integration of reverse-transcribed viral DNA into the host genome and blocking the formation of the HIV provirus. In cell cultures, the mean EC50 for HIV-1 was 0.5 nM in peripheral blood mononuclear cells (PBMC) and 2.1 nM in MT-4 cells. The EC50 values against HIV-2 in PBMC ranged from 0.09 to 0.61 nM.
Antiviral drug resistance is a problem in the treatment of HIV infection. The combination of abacavir and lamivudine has demonstrated decreased susceptibility to viruses with certain viral mutations, including M184V/I, K65R, L74V, and Y115F. Decreases in dolutegravir susceptibility have been observed in HIV-1 with the following amino acid substitutions: E92Q, G118R, S153F, S153Y, G193E, and R263K. Combination therapy targets different points in the life cycle of HIV, reducing the ability of HIV to mutate to drug-resistant strains.
Cross-resistance between abacavir; lamivudine and other nucleoside reverse transcriptase inhibitors has been observed in strains of HIV-1 containing multiple reverse transcriptase mutations. Cross-resistance between abacavir; lamivudine and non-nucleoside reverse transcriptase inhibitors or HIV protease inhibitors is unlikely because of different binding sites on reverse transcriptase and different targets enzymes. Cross-resistance to dolutegravir has not been observed in reverse transcriptase inhibitor-resistant nor protease inhibitor-resistant strains; however, decrease dolutegravir susceptibility has occurred in integrase stand transfer inhibitor-resistant HIV-1 and HIV-2 strains.
Abacavir; dolutegravir; lamivudine is administered orally.
-Abacavir: Once in the systemic circulation, abacavir distributes into extravascular space. Protein binding is approximately 50% and is independent of concentration. Based on radiolabeled studies, the drug readily distributes into erythrocytes. In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase (to form the 5'-carboxylic acid) and glucuronyl transferase (to form the 5'-glucuronide). The metabolites have no antiviral activity. Elimination of abacavir was quantified in a mass balance study after administration of a 600-mg dose of 14C-abacavir: 83% of the radioactivity was recovered in urine, 1.2% as unchanged drug, 30% as the 5'-carboxylic acid metabolite, 36% as the 5'-glucuronide metabolite, and 15% as unidentified minor metabolites. Fecal elimination accounted for 16% of the dose. In single-dose studies, the observed elimination half-life was 1.54 +/- 0.63 hours.
-Lamivudine: Once in systemic circulation, lamivudine is less than 36% bound to human plasma proteins. The apparent volume of distrubution after intravenous administration of lamivudine is 1.3 +/- 0.4 L/kg, suggesting the drug distributes into extravascular spaces. This volume of distribution is independent of dose and does not correlate with body weight. Metabolism is a minor route of elimination, with the only known metabolite being the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). The majority of a lamivudine dose (approximately 70%) is excreted unchanged in the urine by active organic cationic secretion. In most single-dose studies with plasma sampling up to 48 or 72 hours after dosing, the observed mean elimination half-life ranged from 13 to 19 hours.
-Dolutegravir: The drug is highly protein bound (98.9% or more), with an estimated volume of distribution of 17.4 L. Although the clinical relevance has not been established, dolutegravir distributes into the cerebrospinal fluid (CSF) at a median concentration of 13 ng/mL (range, 3 to 18 ng/mL) 2 to 6 hours postdose. Metabolism occurs via UDP-glucuronosyltransferase (UGT)1A1 (major) and by the hepatic isoenzyme CYP3A (minor). The terminal half-life is approximately 14 hours, with more than half of the total dose (53%) excreted unchanged in the feces. Excretion in the urine accounts for 31% of the total dose; however, less than 1% of the renally eliminated drug is unchanged.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A1, CYP3A4, UGT1A1, UGT1A3, UGT1A9, P-gp, BCRP, OCT2, MATE1
Data from in vitro studies show abacavir has the potential to inhibit CYP1A1 and the limited potential to inhibit CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP isoenzymes (e.g., CYP2C9 and CYP2D6). Similarly, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of substrates of the following drug transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.
Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A4. When administered with atazanavir, an inhibitor of UGT1A1, the maximum plasma concentration (Cmax) of dolutegravir increased by 50%, and the systemic concentration (AUC) increased by 91%; however, no dolutegravir dosage adjustment was recommended. Dolutegravir is a substrate, in vitro, for the enzymes UGT1A3 and UGT1A9. It is also a substrate, in vitro, for the transporters P-gp and BCRP. It is an inhibitor of renal OCT2 and potentially MATE1. Dolutegravir is an inhibitor of the renal organic anion transporters OAT1 and OAT3 in vitro; however, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir, which is a substrate of OAT1 and OAT3. The drug does not inhibit the following: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-gp, BCRP, bile salt export pump (BSEP), OATP1B1, OATP1B3, OCT1, multidrug resistant protein (MRP)2, or MRP4. Additionally, the drug does not induce CYP1A2, CYP2B6, or CYP3A4.
-Route-Specific Pharmacokinetics
Oral Route
Triumeq and Triumeq PD are bioequivalent for the abacavir and lamivudine components, but not for the dolutegravir component. The relative dolutegravir bioavailability of Triumeq PD is approximately 1.7-fold higher than Triumeq; therefore, the 2 dosage forms are NOT interchangeable on a mg-per-mg basis. Triumeq PD is NOT indicated for use in adults or patients weighing 25 kg or more.
-Abacavir: The drug is rapidly absorbed with a bioavailability of about 83% for the tablets. Administration of Triumeq to healthy adults with a high-fat meal (53% fat, 869 calories) decreased the Cmax by 23%. Administration of Triumeq PD to healthy adults with a high-fat meal (50% fat, 917 calories) resulted in a 55% decrease in the Cmax; the AUC was unaffected.
-Lamivudine: Absorption is rapid, with a mean absolute bioavailability of approximately 85%. Food has no significant effect on systemic exposure of Triumeq. Administration of Triumeq PD to healthy adults with a high-fat meal (50% fat, 917 calories) resulted in a 36% decrease in the Cmax; the AUC was unaffected.
-Dolutegravir: The absolute bioavailability is unknown. Peak plasma concentrations are obtained 2 to 3 hours after an oral dose, with steady-state concentrations achieved within 5 days. Administration of Triumeq to healthy adults with a high-fat meal (53% fat, 869 calories) increased the Cmax and AUC by 37% and 48%, respectively. Administration of Triumeq PD to healthy adults with a high-fat meal (50% fat, 917 calories) resulted in a 29% decrease in the Cmax; the AUC was unaffected.
-Special Populations
Hepatic Impairment
-Abacavir: Patients with mild hepatic impairment (Child-Pugh score 5 to 6) show a mean increase in abacavir half-life and AUC of 58% and 89%, respectively, after a single oral dose of 600 mg. The AUC of the metabolites are not changed by mild liver disease; however, the rates of formation and elimination of the metabolites are decreased. Abacavir pharmacokinetic parameters have not been assessed in patients with moderate or severe hepatic impairment.
-Lamivudine: Lamivudine pharmacokinetics are not altered by hepatic dysfunction.
-Dolutegravir: Moderate hepatic impairment (Child-Pugh B) does not produce a clinically relevant effect on the pharmacokinetics of dolutegravir. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh C).
Renal Impairment
-Abacavir: The pharmacokinetics of abacavir have not been determined in patients with renal impairment; however, renal excretion of unchanged abacavir is a minor route of elimination.
-Lamivudine: Total clearance of lamivudine decreases as creatinine clearance decreases; therefore, exposure (AUC), Cmax, and half-life increase with diminishing renal function. Hemodialysis increases clearance; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single dose. The hemodialysis extraction ratio is approximately 53% to 65%. Continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis have negligible effects on lamivudine clearance. After correction of dose for creatinine clearance, no additional dose modification is necessary after routine hemodialysis or peritoneal dialysis. It is not known if continuous (24-hour) hemodialysis can remove lamivudine. The effect of renal impairment on pharmacokinetic parameters in pediatric patients is not known.
-Dolutegravir: Mild to moderate renal impairment does not produce a clinically relevant effect on the pharmacokinetics of dolutegravir. However, an evaluation of the pharmacokinetic parameters in 8 patients with severe renal impairment (CrCl less than 30 mL/minute) found the AUC, Cmax, and C24 were decreased by 40%, 23%, and 43%, respectively, when compared to patients with normal renal function. Dolutegravir has not been adequately studied in patients requiring dialysis.
Pediatrics
Triumeq and Triumeq PD are bioequivalent for the abacavir and lamivudine components, but not for the dolutegravir component. The relative dolutegravir bioavailability of Triumeq PD is approximately 1.7-fold higher than Triumeq; therefore, the 2 dosage forms are NOT interchangeable on a mg-per-mg basis. Triumeq PD is NOT indicated for use in pediatric patients weighing more than 25 kg. The pharmacokinetics of Triumeq and Triumeq PD were evaluated in the IMPAACT 2019 trial. The overall exposures of abacavir, dolutegravir, and lamivudine at the recommended doses for Triumeq and Triumeq PD were within the observed exposure ranges at the recommended doses of the individual products in adults and pediatrics.
Gender Differences
No significant or clinically relevant gender differences in the pharmacokinetics of abacavir, dolutegravir, or lamivudine have been identified based on available data.
Ethnic Differences
No significant or clinically relevant ethnic differences in the pharmacokinetics of abacavir, dolutegravir, or lamivudine have been identified based on available data.
Other
UGT1A1 Polymorphism
A meta-analysis of healthy patients found individuals with UGT1A1 genotypes that result in poor dolutegravir metabolism (n = 7) had a 32% lower clearance and 46% higher drug exposure when compared to individuals with UGT1A1 genotypes that are associated with normal metabolism (n = 41).
Pregnancy
-Abacavir: A population pharmacokinetic analysis of 266 samples from 36 pregnant and 114 non-pregnant patients found the pharmacokinetic parameters of abacavir to be unchanged during pregnancy. Similarly, 1 pharmacokinetic study found abacavir exposure in 25 pregnant patients receiving 300 mg twice daily during the third trimester to be comparable to exposures observed in postpartum patients and historical controls of non-pregnant patients with HIV. Abacavir crosses the placenta via passive diffusion, with drug concentrations in neonatal plasma cord samples at birth being essentially equal to those in the maternal plasma at the time of delivery.
-Dolutegravir: In a pharmacokinetic study of 29 pregnant patients, dolutegravir plasma concentrations were lower during pregnancy than during the postpartum period. Specifically, systemic exposure (AUC) was reduced by 21% during pregnancy and trough concentrations were reduced by 34% in the third trimester; however, trough concentrations were still well above the 90% effective concentration of 0.064 mcg/mL. Another study involving 15 pregnant patients showed similar results with the AUC and Cmin being decreased by 14% and 26%, respectively, during pregnancy as compared to postpartum. Dolutegravir has also been shown to cross the placenta. In a study of 15 patients who received dolutegravir 50 mg once daily during the last trimester of pregnancy, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range, 0.51 to 2.11).
-Lamivudine: Although population pharmacokinetic modeling suggests the oral clearance of lamivudine is increased by 22% during pregnancy, limited data from 2 studies involving 36 pregnant patients (16 at 36 weeks, 20 at 38 weeks gestation) found the pharmacokinetic parameters of lamivudine to be similar to those observed in non-pregnant and postpartum adults. No change in dose is indicated. In addition, placental transfer of lamivudine results in drug concentrations that are 2 times greater than maternal serum levels.