TIVICAY

Integrase Strand Transfer Inhibitor (INSTI)s

Oral Administration

Do not interchange tablets and tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles.
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.[55594]

Oral Solid Formulations

Regular tablets
For patients who have difficulty swallowing tablets whole, tablets may be either split into halves followed by immediate ingestion of both halves of the tablet or crushed and added to a small amount of semisolid food or liquid, all of which should be consumed immediately.[42452]
 
Oral tablets for suspension (2 administration methods)
Do not chew, cut, or crush.[55594]
 
Intact tablets
Swallow whole.
If more than 1 tablet is required, swallow 1 tablet at a time to reduce the risk of choking.[55594]
 
Dispersed in water
1 to 3 tablets: Fully disperse in 5 mL of drinking water in the supplied cup.
4 to 6 tablets: Fully disperse in 10 mL of drinking water in the supplied cup.
Swirl the suspension so that no lumps remain.
After full dispersion, administer within 30 minutes of mixing.[55594]

Severe

suicidal ideation / Delayed / 0-2.0
hepatic failure / Delayed / Incidence not known
hyperkalemia / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known

Moderate

elevated hepatic enzymes / Delayed / 1.0-18.0
hyperglycemia / Delayed / 6.0-14.0
neutropenia / Delayed / 2.0-4.0
hyperbilirubinemia / Delayed / 0-3.0
hepatitis / Delayed / 0-2.0
depression / Delayed / 0-1.0
anemia / Delayed / Incidence not known

Mild

insomnia / Early / 0-7.0
pruritus / Rapid / 0-2.0
headache / Early / 0-2.0
diarrhea / Early / 0-2.0
vomiting / Early / 0-2.0
nausea / Early / 0-2.0
flatulence / Early / 0-2.0
abdominal pain / Early / 0-2.0
fatigue / Early / 0-2.0
maculopapular rash / Early / 0-1.0
rash / Early / 0-1.0
dizziness / Early / 0-1.0
weight gain / Delayed / Incidence not known
arthralgia / Delayed / Incidence not known
myalgia / Early / Incidence not known
anxiety / Delayed / Incidence not known

TIVICAY, Tivicay PD

Rx

HIV integrase strand transfer inhibitor (INSTI)
Used as part of a combination regimen to treat HIV infection in INSTI-naive adults and pediatric patients 4 weeks and older weighing at least 3 kg; also approved for INSTI-experienced adults with certain resistance profiles; also can be given with rilpivirine to be a complete regimen for adults who are virologically suppressed and on a stable antiretroviral regimen for at least 6 months
Increased dose needed when given with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, rifampin, or carbamazepine

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents. Oral dosage (tablets)

NOTE: Do not interchange tablets and tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles.[55594]
NOTE: Tablets for oral suspension are preferred in pediatric patients weighing less than 20 kg.[55594]

Adults who are treatment-naive or treatment-experienced but integrase strand transfer inhibitor (INSTI)-naive

50 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adults who are INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance

50 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Dolutegravir has less resistance overlap with raltegravir than does elvitagravir and may retain activity against strains containing the Y143 and N155 pathway mutations. The efficacy of dolutegravir 50 mg PO twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.

Adults who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components

50 mg PO once daily plus rilpivirine. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children and Adolescents weighing 40 kg or more who are INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance†

50 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Dolutegravir has less resistance overlap with raltegravir than does elvitagravir and may retain activity against strains containing the Y143 and N155 pathway mutations. The efficacy of dolutegravir 50 mg PO twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.

Children and Adolescents weighing 20 kg or more who are treatment-naive or treatment-experienced but INSTI-naive

50 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children weighing 14 to 19 kg who are treatment-naive or treatment-experienced but INSTI-naive

40 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[55594]

Oral dosage (tablets for oral suspension)

NOTE: Do not interchange tablets and tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles.
NOTE: Tablets for oral suspension are preferred in pediatric patients weighing less than 20 kg.

Children and Adolescents weighing 20 kg or more who are treatment-naive or treatment-experienced but INSTI-naive

30 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[55594]

Children weighing 14 to 19 kg who are treatment-naive or treatment-experienced but INSTI-naive

25 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[55594]

Infants and Children 4 weeks and older weighing 10 to 13 kg who are treatment-naive or treatment-experienced but INSTI-naive

20 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[55594]

Infants 4 weeks and older weighing 6 to 9 kg who are treatment-naive or treatment-experienced but INSTI-naive

15 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[55594]

Infants 4 weeks and older weighing 3 to 5 kg who are treatment-naive or treatment-experienced but INSTI-naive

5 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[55594]

For human immunodeficiency virus (HIV) prophylaxis†. For human immunodeficiency virus (HIV) prophylaxis† after occupational exposure. Oral dosage (tablets) Adults

50 mg PO once daily in combination with tenofovir and either emtricitabine or lamivudine for 28 days are preferred HIV post-exposure prophylaxis (PEP) regimens. A 3-drug regimen is recommended; however, the use of a 2-drug regimen would be preferred to discontinuing prophylaxis completely if tolerability is a concern. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis.  Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).

For human immunodeficiency virus (HIV) prophylaxis† after nonoccupational exposure, including sexual assault. Oral dosage (tablets) Adults

50 mg PO once daily with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adults. Dolutegravir in combination with zidovudine and lamivudine for 28 days is a preferred HIV PEP regimen in adults with renal dysfunction (CrCl 59 mL/minute or less). A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective. Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.

Adolescents

50 mg PO once daily with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adolescents. Dolutegravir in combination with zidovudine and lamivudine for 28 days is a preferred HIV PEP regimen in adolescents with renal dysfunction (CrCl 59 mL/minute or less). A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective. Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.

†Indicates off-label use

Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh A or B). Use is not recommended in patients with severe hepatic impairment (Child-Pugh C), as studies have not been conducted in this population.

Renal Impairment

No dosage adjustment is necessary for patients with mild to moderate renal impairment. In patients with severe renal impairment, no dosage adjustment is necessary for those who are integrase strand transfer inhibitor (INSTI)-naive, though caution is advised if administering to INSTI-experienced patients.

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.
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]).
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.
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.
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 CYP3A4 and P-gp substrate and berotralstat is a P-gp and moderate CYP3A4 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.
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 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]).
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.
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.
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]).
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: (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.
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.
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) 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: (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: (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]).
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]).
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 of dolutegravir if coadministered with encorafenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and encorafenib is a BCRP inhibitor.
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.
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]).
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.
Felbamate: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with felbamate; 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. Felbamate is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
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.
Folic Acid, Vitamin B9: (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.
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]).
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]).
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.
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]).
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.
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.
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 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.
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]).
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]).
Metformin; Rosiglitazone: (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]).
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]).
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]).
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.
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.
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.
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.
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]).
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.
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.
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.
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.
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.
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.
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.
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.
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.

TIVICAY Oral Tab: 10mg, 25mg, 50mg
Tivicay PD Oral Tab for Susp: 5mg

Adults

100 mg/day PO regular tablets.

Geriatric

100 mg/day PO regular tablets.

Adolescents

60 mg/day PO tablets for oral suspension; 100 mg/day PO regular tablets.

Children

weight 20 kg or more: 60 mg/day PO tablets for oral suspension; 100 mg/day PO regular tablets.
weight 14 to 19 kg: 50 mg/day PO tablets for oral suspension; 80 mg/day PO regular tablets.
weight less than 14 kg: 40 mg/day PO tablets for oral suspension; regular tablets are not FDA-approved.

Infants

weight 10 to 13 kg: 40 mg/day PO tablets for oral suspension; regular tablets are not FDA-approved.
weight 6 to 9 kg: 30 mg/day PO tablets for oral suspension; regular tablets are not FDA-approved.
weight 3 to 5 kg: 10 mg/day PO tablets for oral suspension; regular tablets are not FDA-approved.
weight less than 3 kg: Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Dolutegravir inhibits the catalytic activity of HIV integrase, which is an HIV encoded enzyme required for viral replication. Integrase is one of the three HIV-1 enzymes required for viral replication. Integration of HIV into cellular DNA is a multi-step process. First, the assembly of integrase in a stable complex with the viral DNA occurs. Second, the terminal dinucleotides from each end of the viral DNA are removed by endonucleolytic processing. Lastly, the viral DNA 3' ends are covalently linked to the cellular (target) DNA by strand transfer. The last 2 processes, which are catalytic, require integrase to be appropriately assembled on a specific viral DNA substrate. Inhibition of integrase by dolutegravir prevents the covalent insertion, or integration, of unintegrated linear HIV DNA into the host cell genome preventing the formation of the HIV provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection.
 
Dolutegravir has less resistance overlap with raltegravir than does elvitagravir and may retain activity against strains containing the Y143 and N155 pathway mutations. Efficacy of dolutegravir 50 mg PO twice daily is reduced in patients with an integrase strand transfer inhibitor (INSTI)-resistance Q148 substitution plus 2 or mores additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R. Cell culture studies have observed up to a 4-fold decrease in dolutegravir susceptibility in HIV-1 viruses with the following amino acid substitutions: E92Q, G118R, S153F, S153Y, G193E, and R263K. Mutant viruses containing Q148R and Q148H substitutions, in addition to other integrase substitutions, confer a 13-fold and 46-fold decrease in susceptibility, respectively. Cross-resistance to dolutegravir has not been observed in reverse transcriptase inhibitor-resistant and protease inhibitor-resistant strains; however, decrease dolutegravir susceptibility has occurred in integrase stand transfer inhibitor-resistant HIV-1 and HIV-2 strains. In HIV-1 viruses, single INSTI-resistant substitutions (T66K, I151L, and S153Y) and multiple INSTI-resistant substitutions (T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R, or K, Q148R/N155H, T97A/G140S/Q148, E138/G140/Q148) have conferred a > 2-fold decrease in dolutegravir susceptibility. For HIV-2 viruses, a 4-fold decrease in susceptibility occurred with substitutions in A153G/N155H/S163G and E92Q/T97A/N155H/S163D; a 8.5-fold decrease occurred with substitutions in E92Q/N155H; and a 17-fold decrease occurred with substitutions in G140S/Q1148R.
 
The antiviral activity of dolutegravir is not antagonistic when administered concurrently with raltegravir, maraviroc, enfuvirtide, non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine), nucleoside reverse transcriptase inhibitors (abacavir and stavudine), protease inhibitors (amprenavir and lopinavir), adefovir, or ribavirin.

Dolutegravir is administered orally. It is at least 98.9% bound to human plasma protein, 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 18 ng/mL. 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.[55594]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, UGT1A1, UGT1A3, UGT1A9, P-gp, BCRP, OCT2, MATE1
Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A4. When administered with atazanavir, an inhibitor of UGT1A1, the dolutegravir Cmax increased by 50%, the 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-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). It is an inhibitor of the renal organic cation transporter OCT2 and potentially the multidrug and toxin extrusion transporter 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), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistant protein (MRP)2, or MRP4. Additionally, the drug does not induce CYP1A2, CYP2B6, or CYP3A4.[55594]

Oral Route

Tablets
The absolute bioavailability of dolutegravir is unknown. Peak plasma concentrations are obtained 2 to 3 hours after an oral dose, with steady-state concentrations achieved within 5 days. Administration with food increases the extent and slows the rate of absorption, although there are no restrictions regarding administration with or without food. When given with a low-, moderate-, and high-fat meal, the AUC is increased by 33%, 41%, and 66%, respectively; the Cmax is increased by 46%, 52%, and 67%, respectively; and the Tmax is prolonged from 2 hours (under fasting conditions) to 3 hours, 4 hours, and 5 hours, respectively. At doses more than 50 mg/day, dolutegravir exhibits non-linear pharmacokinetics, with increasing doses producing less than proportional increases in plasma concentrations. An evaluation of the drugs steady-state pharmacokinetics found doses of 50 mg once daily produced an AUC of 53.6 mcg x hour/mL, whereas a dose of 50 mg twice daily produced an AUC of only 75.1 mcg x hour/mL.[55594]
 
Tablets for oral suspension
Dolutegravir tablets and dolutegravir PD tablets for oral suspension are not bioequivalent. The relative bioavailability of dolutegravir PD tablets is approximately 1.6-fold higher than dolutegravir tablets; therefore, the 2 dosage forms are not interchangeable on a milligram-per-milligram basis. The tablets for oral suspension may be adminstered with or without food.[55594]

Pregnancy

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 use of dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) as a preferred treatment regimen in pregnant patients, irrespective of the trimester, and in non-pregnant patients who are trying to conceive. Exposure to dolutegravir around the time of conception may be associated with a small increased risk of infant neural tube defects (NTD). Data from an observational surveillance study identified NTD in 9 infants born to 5,860 mothers (0.15%) who were exposed to a dolutegravir-containing regimen around the time of conception (periconception exposure). The incidence of NTD in infants of mothers receiving other antiretroviral regimens at the time of conception was 0.1% (95% CI: -0.03% to 0.2%) and in infants of mothers without HIV was 0.07% (95% CI: 0.01% to 0.23%). Of the 9 dolutegravir-associated cases, 4 infants had myelomeningocele, 3 infants had encephalocele, 1 infant had anencephaly, and 1 infant had iniencephaly. In the same study, NTD was found in 3 infants out of 5,535 (0.05%) deliveries to mothers who started dolutegravir during pregnancy. Data from the Antiretroviral Pregnancy Registry (APR) regarding dolutegravir exposure and central nervious system birth defects are available. Among the reported exposures to dolutegravir, 5 central nervious system birth defects were identified (2 of 571 periconception, 1 of 125 late first trimester, 2 of 434 second/third trimester). One of these defects was an NTD in an infant with periconception exposure; no encephalocele defects were reported. Additional data from the APR, which includes over 695 first trimester exposures to dolutegravir, 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 first trimester birth defect rate for dolutegravir is 3.2% (95% CI: 2 to 4.8). 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 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, patients with CD4 count less than 300 cells/mm3, or patients with inconsistent adherence or detectable viral loads. 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 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 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 dolutegravir; 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; thus, replacement feeding is 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).[42452] Although there is no information regarding the effects of dolutegravir on breast-fed infants or milk production, available data show dolutegravir is found in breast milk at concentrations about 3% of those observed in maternal plasma. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.