Dovato (dolutegravir sodium/lamivudine)

Fixed-combination tablets of dolutegravir/lamivudine contain dolutegravir sodium and lamivudine; dosages are expressed in terms of dolutegravir and lamivudine, respectively.

Each fixed-combination tablet of dolutegravir/lamivudine contains 50 mg of dolutegravir and 300 mg of lamivudine.

The fixed combination dolutegravir/lamivudine is administered orally once daily with or without food.

Store dolutegravir/lamivudine tablets below 30degreesC.

No dosing information is available for this tab.

Concomitant use of dolutegravir/lamivudine and certain other drugs may result in known or potentially clinically important drug interactions, some of which may lead to loss of therapeutic effect of dolutegravir/lamivudine and possible development of resistance or result in greater exposures of the concomitant drug.

Consider the potential for drug interactions prior to and during dolutegravir/lamivudine therapy; review concomitant drugs during dolutegravir/lamivudine therapy and monitor the patient for adverse effects.

The following drug interactions are based on studies using the individual components of the fixed combination of dolutegravir and lamivudine (dolutegravir/lamivudine) or are predicted to occur with the fixed combination. When dolutegravir/lamivudine is used, consider interactions associated with both drugs in the fixed combination.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Anti-Retrovirals/Atidarsagene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Atidarsagene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of atidarsagene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the medication) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of atidarsagene autotemcel therapy.(1)

Anti-Retrovirals/Elivaldogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Elivaldogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of elivaldogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of elivaldogene autotemcel therapy.(1)

Anti-Retrovirals/Etuvetidigene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Etuvetidigene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating HIV-based lentiviral vector. Antiretrovirals may interfere with the manufacturing of the apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of etuvetidigene autotemcel.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should not take antiretrovirals for at least one month prior to mobilization and until at least 7 days after etuvetidigene autotemcel infusion.(1) If a patient requires antiretroviral agents for HIV post-exposure prophylaxis, etuvetidigene autotemcel treatment should be delayed until HIV testing is negative at 6 months post-exposure.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of etuvetidigene autotemcel therapy.(1)

Anti-Retrovirals/Lovotibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lovotibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of lovotibeglogene autotemcel.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed.(1) There are some long-acting antiretroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of lovotibeglogene autotemcel therapy.(1)

Anti-Retrovirals; Hydroxyurea/Betibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Betibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells. Hydroxyurea may interfere with hematopoietic stem cell (HSC) mobilization of CD34+ cells.(1)

CLINICAL EFFECTS: Use of hydroxyurea before mobilization may result in unsuccessful stem cell mobilization. Use of antiretrovirals before mobilization and apheresis may interfere with the production of betibeglogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals and hydroxyurea for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications and hydroxyurea may interfere with the manufacturing of betibeglogene autotemcel therapy.(1)

Dolutegravir/Dofetilide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dolutegravir may inhibit the elimination of dofetilide by the renal organic cation transporter (OCT2).(1)

CLINICAL EFFECTS: Concurrent use of dolutegravir may result in elevated levels of dofetilide.(1) Dofetilide has been shown to prolong the QTc interval in a dose-dependent fashion. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes(TdP).(2)

PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: Concurrent use of dofetilide and dolutegravir is contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting dolutegravir.(1,2) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Dolutegravir has been shown to inhibit OCT2 in vitro and in vivo and is expected to inhibit the excretion of dofetilide.(1)

Emtricitabine; Lamivudine/Islatravir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Emtricitabine and lamivudine may inhibit the intracellular phosphorylation of islatravir by deoxycytidine kinase (dCK).(1)

CLINICAL EFFECTS: Concurrent administration of emtricitabine or lamivudine with islatravir may result in decreased clinical efficacy of islatravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of the doravirine-islatravir fixed-dose combination states that co-administration with emtricitabine or lamivudine is contraindicated.(1)

DISCUSSION: Islatravir undergoes a series of phosphorylations to its active metabolites.(1) In a clinical study in healthy participants, co-administration of multiple daily doses of 300 mg lamivudine and a single dose of 2 mg islatravir (8 times the recommended dosage) decreased intracellular ISL-TP (islatravir active metabolite) area under the curve (AUC) level by 87% and maximum concentration (Cmax) by 76% relative to islatravir alone. A similar effect is anticipated when islatravir is co-administered with emtricitabine.(1,2) Compounds phosphorylated by dCK and linked to this monograph include: emtricitabine and lamivudine.

Lamivudine/Zalcitabine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of each other.(1-6)

CLINICAL EFFECTS: Concurrent administration of lamivudine and zalcitabine may result in decreased clinical efficacy of one or both agents.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and zalcitabine is not recommended.(1-3)

DISCUSSION: Both lamivudine(1-3) and zalcitabine(7) undergo a series of phosphorylations to their active metabolites. In an in vitro study, the presence of lamivudine significantly decreased the phosphorylation of zalcitabine, resulting in a 50% decrease in zalcitabine triphosphate levels.(4) In an in vitro study in peripheral blood mononuclear cells (PBMCs) and U937 cells, zalcitabine significantly inhibited the phosphorylation of lamivudine. No lamivudine triphosphate was found in the PBMCs and the amount of lamivudine triphosphate was decreased 33% when compared to control values in the U937 cell line.(5) In another in vitro study, lamivudine decreased total zalcitabine phosphates by 57%. There was no effect on lamivudine phosphorylation.(6)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Anti-Retrovirals/Marnetegragene Autotemcel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Marnetegragene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of transduced cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of marnetegragene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the antiretrovirals) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of marnetegragene autotemcel.(1)

Cimetidine; Dolutegravir/Dalfampridine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cimetidine and dolutegravir inhibit the organic cation transporter 2 (OCT2). Dalfampridine is eliminated mainly via the kidneys with active renal secretion by OCT2.(1-3)

CLINICAL EFFECTS: The concurrent administration of dalfampridine with an inhibitor of OCT2 may result in elevated levels of dalfampridine and signs of toxicity. Elevated levels of dalfampridine may increase the risk of seizures.(1,2)

PREDISPOSING FACTORS: Renal impairment.

PATIENT MANAGEMENT: The US manufacturer of dalfampridine states that the potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures. If concurrent use is warranted, carefully monitor patients for adverse effects. Permanently discontinue dalfampridine in patients who have a seizure while on treatment.(1) The UK and Canadian manufacturers of dalfampridine states that concurrent use of dalfampridine and OCT2 inhibitors is contraindicated.(4,5)

DISCUSSION: In a single dose clinical study in 23 healthy volunteers, the combined use of cimetidine (400 mg every 6 hours) increased the area-under-curve (AUC) of cimetidine approximately 25% due to a reduction in the clearance of dalfampridine.(1)

Deoxycytidine Kinase Substrates/Cladribine Oral

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine and zalcitabine may inhibit the intracellular phosphorylation of cladribine by deoxycytidine kinase (dCK).

CLINICAL EFFECTS: Concurrent administration of clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine, or zalcitabine with cladribine may result in decreased clinical efficacy of cladribine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and cladribine is not recommended.(1) The manufacturer of cladribine states that concurrent use of compounds that require activation by intracellular phosphorylation should be avoided.(2)

DISCUSSION: Cladribine undergoes a series of phosphorylations to its active metabolites. In a case report, a patient on lamivudine who received cladribine concurrently did not experience a decrease in his lymphocyte count. After discontinuation of lamivudine and readministration of cladribine, his lymphocytes dropped as expected.(3) It is expected that other compounds phosphorylated by dCK would also decrease cladribine's efficacy.(4) Compounds phosphorylated by dCK include: clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine and zalcitabine.

Dolutegravir/Etravirine; Efavirenz; Nevirapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Etravirine, efavirenz, and nevirapine may induce the metabolism of dolutegravir via CYP3A4.(1,2) Efavirenz and etravirine may also induce dolutegravir metabolism via UGT enzymes.

CLINICAL EFFECTS: Concurrent use of etravirine, efavirenz, or nevirapine and dolutegravir may result in decreased levels of and clinical effectiveness of dolutegravir.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of dolutegravir states that dolutegravir should not be used with etravirine without atazanavir/ritonavir (ATVr), darunavir/ritonavir (DRVr), or lopinavir/ritonavir (LPVr).(1) The Canadian(3) and UK(4) manufacturers of dolutegravir state that INSTI-naive patients may use etravirine concurrently with dolutegravir at an increased dose of 50 mg twice daily. In pediatric patients, the weight-based once daily dose should be given twice daily. No dose adjustment for dolutegravir is needed when used with etravirine along with concurrent ATVr, DRVr, or LPVr.(1,3-5) When used with efavirenz in patients without INSTI resistance, the dosage of dolutegravir should be 50 mg twice daily.(1,2) When using the combination abacavir-dolutegravir-lamivudine product, an additional 50 mg dolutegravir table should be taken 12 hours apart from the combination product.(2) Alternative combinations that do not induce metabolic inducers should be considered when possible for patients with certain INSTI-associated resistance or clinically suspected INSTI resistance. In pediatric patients, increase the weight-based dose to twice daily. Refer to the current labeling for the specific dosing recommendation.(1) Although the US(1) and Canadian(3) manufacturers of dolutegravir recommend avoiding concurrent use of nevirapine, the US Department of Health and Human Services HIV guidelines recommend standard doses of dolutegravir when administered concurrently with nevirapine.(5) The UK manufacturer of dolutegravir recommends increasing the dose of dolutegravir to 50 mg twice daily when used concurrently with nevirapine.(4)

DISCUSSION: In a study in 12 subjects, the administration of efavirenz with dolutegravir (50 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 39%, 57%, and 75%, respectively.(1) In a study in 16 subjects, the administration of etravirine with dolutegravir (50 mg daily) decreased the Cmax, AUC, and Cmin of dolutegravir by 52%, 71%, and 88%, respectively.(1) In a study in 9 subjects, the administration of etravirine and darunavir/ritonavir (200 mg and 600/100 mg BID) with dolutegravir (50 mg daily) decreased the Cmax, AUC, and Cmin of dolutegravir by 12%, 25%, and 37%, respectively.(1) In a study in 8 subjects, the administration of efavirenz and lopinavir/ritonavir (200 mg and 400/100 mg BID) with dolutegravir (50 mg daily) increased the Cmax, AUC, and Cmin of dolutegravir by 7%, 11%, and 28%, respectively.(1)

Dolutegravir/Selected Ugt1a & Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dolutegravir is metabolized by UGT1A1 and to a smaller extent by CYP3A4. Inducers of UGT1A1 and CYP3A4 may induce the metabolism of dolutegravir.(1-6)

CLINICAL EFFECTS: Concurrent use of UGT1A1 and CYP3A4 inducers may result in decreased levels of and clinical effectiveness of dolutegravir.(1-6)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: When used with carbamazepine, fosamprenavir/ritonavir, rifampin, or tipranavir/ritonavir, the dosage of dolutegravir should be 50 mg twice daily. When using the combination abacavir-dolutegravir-lamivudine or dolutegravir-lamivudine product, an additional 50 mg dolutegravir table should be taken 12 hours apart from the combination product. In pediatric patients, increase the weight-based dose to twice daily. Refer to the current labeling for the specific dosing recommendation. Alternative combinations that do not induce metabolic inducers should be considered when possible for INSTI-experience patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.(1,4-6) Recommendations for other UGT1A1 and CYP3A4 inducers differ by region. The US manufacturer of dolutegravir states that concurrent use should be avoided due to insufficient data to make dosing recommendations for concomitant use.(1,4) The Canadian and UK manufacturers of dolutegravir state that the dosage of dolutegravir should be 50 mg twice daily when used concurrently with other UGT1A1 and CYP3A4 inducers. When using the combination abacavir-dolutegravir-lamivudine product, an additional 50 mg dolutegravir table should be taken 12 hours apart from the combination product. In pediatric patients, increase the weight-based dose to twice daily. Refer to the current labeling for the specific dosing recommendation. Alternative combinations that do not induce metabolic inducers should be considered when possible for patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.(5,6)

DISCUSSION: In a study in 12 subjects, the administration of fosamprenavir/ritonavir (700/100 mg BID) with dolutegravir (50 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 24%, 35%, and 49%, respectively.(1) In a study in 11 subjects, the administration of rifampin (600 mg daily) with dolutegravir (50 mg BID) decreased the Cmax, AUC, and Cmin of dolutegravir by 43%, 54%, and 32%, respectively, when compared to the administration of dolutegravir (50 mg BID) alone.(1) In a study in 11 subjects, the administration of rifampin (600 mg daily) with dolutegravir (50 mg BID) increased the Cmax, AUC, and Cmin of dolutegravir by 18%, 33%, and 22%, respectively, when compared to the administration of dolutegravir (50 mg daily) alone.(1) In a study in 14 subjects, the administration of tipranavir/ritonavir (500/200 mg BID) with dolutegravir (50 mg daily) decreased the Cmax, AUC, and Cmin of dolutegravir by 46%, 59%, and 76%, respectively.(1) In a study in 16 subjects, the administration of carbamazepine (300 mg twice daily) with dolutegravir (50 mg daily) decreased the Cmax, AUC, and Cmin of dolutegravir by 33%, 49%, and 73%, respectively. (1) UGT1A1 and CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosamprenavir/ritonavir, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mitotane, oxcarbazepine, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and tipranavir/ritonavir.(1,7)

Lamivudine/Sorbitol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sorbitol increases the osmotic pressure in the intestine, resulting in accelerated small intestinal transit time and decreased absorption and bioavailability of lamivudine.

CLINICAL EFFECTS: Concurrent administration of sorbitol and lamivudine may result in decreased clinical efficacy of lamivudine.(1) Reduction in lamivudine exposure is sorbitol dose-dependent.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and sorbitol should be avoided.(1) Consider more frequent monitoring of HBV viral load when chronic coadministration cannot be avoided.

DISCUSSION: In an open label, randomized sequence, 4-period, crossover trial in 16 healthy adults, coadministration of a single dose of lamivudine (300 mg) with sorbitol (3.2 grams) resulted in a dose-dependent decrease of lamivudine's area-under-the-curve (AUC(0-24), AUC infinity) and maximum concentration (Cmax) of 20%, 28%, and 28%. A single dose of lamivudine with sorbitol (10.2 grams) resulted in a decrease of lamivudine's AUC and Cmax of 39%, 52%, and 52%. A single dose of lamivudine with sorbitol (13.4 grams) resulted in a decrease of lamivudine's AUC and Cmax of 36%, 55%, and 55%.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Dolutegravir/Metformin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Dolutegravir may inhibit the renal organic cation transporter, OCT2, responsible for the elimination of metformin.(1)

CLINICAL EFFECTS: Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: With concomitant use, assess the benefit and risk of metformin in patients on dolutegravir. When starting or stopping dolutegravir, the metformin dose may require an adjustment. Monitor blood glucose when initiating concomitant use and after stopping dolutegravir.(1) Monitor patient's renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio.(1)

DISCUSSION: Dolutegravir has been shown to inhibit OCT2 in vitro and in vivo and is expected to inhibit the excretion of metformin.(1) In a study in 15 subjects, concomitant metformin (500 mg twice daily) with dolutegravir (50 mg daily) increased the concentration maximum (Cmax) and area-under-curve (AUC) of metformin by 66% and 79%, respectively. In a study in 15 subjects, concomitant metformin (500 mg twice daily) with dolutegravir (50 mg twice daily) increased the Cmax and AUC of metformin by 111% and 145%, respectively.(1)

Dolutegravir/Selected Oral Cations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may form chelation compounds with dolutegravir.(1)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate close to the administration time of dolutegravir may result in decreased absorption and clinical effectiveness of dolutegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with dolutegravir and cation-containing products. If it is necessary to use these agents concurrently, dolutegravir should be administered 2 hours before or 6 hours after taking these medications.(1) Alternatively, dolutegravir and supplements containing calcium or iron can be taken together with food.(1)

DISCUSSION: In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) simultaneously with dolutegravir (50 mg single dose) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 72%, 74%, and 74%, respectively.(1) In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) 2 hours after dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 18%, 26%, and 30%, respectively.(1) In a study in 16 subjects, the administration of a multiple vitamin (One-A-Day) simultaneously with dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 35%, 33%, and 32%, respectively.(1)

Oct2 Inhibitors/Cisplatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of cisplatin by OCT2 in the kidneys.(1,2)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicities from cisplatin, including nephrotoxicity, ototoxicity, neuropathy, and myelosuppression.(1,2)

PREDISPOSING FACTORS: Pre-existing renal insufficiency, advanced age, and dehydration may increase the risk of nephrotoxicity.

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of cisplatin with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor closely for toxicities of cisplatin and consider dosage reduction of cisplatin.(1,2)

DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, dolutegravir, givinostat, isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(3)

Oct2 Inhibitors/Clofarabine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of clofarabine by OCT2 in the kidneys.(1,2)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from clofarabine, including myelosuppression, serious hemorrhages, enterocolitis, nephrotoxicity, and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of clofarabine with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of the clofarabine and consider dosage reduction of clofarabine.(1)

DISCUSSION: In an animal study, cimetidine, an OCT2 inhibitor, decreased the clearance of clofarabine in rats by 61%. The clinical implications of this finding are unclear.(1,2) In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(3) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, cimetidine, dolutegravir, givinostat, isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(5)

Oct2 Inhibitors/Oxaliplatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of oxaliplatin by OCT2 in the kidneys.(1)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from oxaliplatin, including myelosuppression and potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of oxaliplatin with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of oxaliplatin and consider dosage reduction.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(3) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4) OCT2 inhibitors linked to this monograph include: arimoclomol, brepocitinib, dolutegravir, givinostat, trilaciclib, and vimseltinib.(5)

Oct2 Inhibitors/Pindolol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of pindolol by OCT2 in the kidneys.(1,2)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from pindolol.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of pindolol with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of pindolol and consider dosage reduction of pindolol.(1,2)

DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2) OCT2 inhibitors linked to this monograph include: arimoclomol, brepocitinib, cimetidine, dolutegravir, givinostat, and vimseltinib.(3)

Oct2 Inhibitors/Procainamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of procainamide by OCT2 in the kidneys.(1,2)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicities of procainamide,(1,2) including potentially life-threatening cardiac arrhythmias, like torsades de pointes (TdP).(3)

PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of procainamide with OCT2 renal transport inhibitors. If concurrent use is appropriate, check procainamide and N-acetylprocainamide (NAPA) levels, monitor for toxicities of procainamide and consider dosage reduction of procainamide.(1) Since other H-2 antagonists (e.g., ranitidine, famotidine) do not appear to interact, substituting cimetidine with one of these agents may be desirable. However, if a patient is already receiving this combination and is not experiencing adverse effects, substitution is probably not necessary. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, cimetidine, dolutegravir, givinostat, isavuconazole, trilaciclib, tucatinib, and vimseltinib.(4)

*Prior hypersensitivity to dolutegravir or lamivudine.

*Concomitant use with dofetilide because of the potential for serious and/or life-threatening adverse effects resulting from increased dofetilide plasma concentrations.

• Acute pancreatitis
• Chronic pancreatitis
• Lactation
• Lactic acidosis

• Chronic hepatitis B
• Chronic hepatitis C
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• UGt1a1*28 polymorphism

Adverse effects reported in 2% or more of patients receiving dolutegravir/lamivudine include headache, nausea, diarrhea, insomnia, fatigue, and anxiety.

More Frequent

• Elevated serum lipase
• Paresthesia

Less Frequent

• Hyperbilirubinemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Neutropenic disorder
• Thrombocytopenic disorder

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal hepatic function tests
• Acute hepatic failure
• Anaphylaxis
• Anemia
• Angioedema
• Eosinophilia
• Graves' disease
• Guillain-barre syndrome
• Hepatitis
• Hypersensitivity drug reaction
• Lactic acidosis
• Lymphadenopathy
• Myositis
• Pancreatitis
• Polymyositis
• Pure red cell aplasia
• Rhabdomyolysis
• Sideroblastic anemia
• Skin rash
• Splenomegaly
• Steatosis of liver
• Suicidal
• Suicidal ideation

More Frequent

• Cough
• Diarrhea
• Fatigue
• Fatigue
• Fever
• Headache disorder
• Headache disorder
• Infection of ear
• Insomnia
• Malaise
• Nausea
• Peripheral neuropathy
• Sore throat

Less Frequent

• Abdominal pain with cramps
• Acute abdominal pain
• Anorexia
• Arthralgia
• Chills
• Depression
• Depression
• Diarrhea
• Dizziness
• Dizziness
• Dream disorder
• Dyspepsia
• Flatulence
• Hypercholesterolemia
• Hyperglycemia
• Hyperlipidemia
• Hypertriglyceridemia
• Insomnia
• Myalgia
• Nausea
• Pruritus of skin
• Rhinitis
• Vertigo
• Vomiting
• Vomiting

Rare or Very Rare

• Alopecia
• Arthralgia
• Conjunctivitis
• Cramps
• Facial edema
• Fever
• General weakness
• Hyperglycemia
• Hyperlipidemia
• Malaise
• Muscle weakness
• Myalgia
• Pruritus of skin
• Skin rash
• Stomatitis
• Symptoms of anxiety
• Urticaria
• Weight gain
• Wheezing

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The efficacy and safety of dolutegravir/lamivudine for the treatment of HIV-1 infection have been established in adolescents 12 years of age and older and weighing at least 25 kg. Use is supported by results from a clinical trial in treatment-naive adolescents and evidence from adequate and well-controlled trials in adults.

The efficacy and safety of dolutegravir/lamivudine have not been established in pediatric patients less than 12 years of age or weighing less than 25 kg.

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to dolutegravir/lamivudine during pregnancy. Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting https://www.apregistry.com/.

Dolutegravir crosses the placenta. In a clinical trial conducted in Uganda and South Africa in pregnant women receiving dolutegravir 50 mg once daily in the last trimester, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range, 0.51-2.11).

Human data regarding use of dolutegravir/lamivudine in pregnant women are insufficient to definitively assess a drug-associated risk for birth defects and miscarriage associated with the fixed combination; however, registry data involving the individual components of the fixed combination do not indicate an increased risk of birth defects.

Data from two, ongoing birth outcome surveillance studies in Botswana and Eswatini, which together include over 14,000 individuals evaluated during pregnancy, reveal a comparable prevalence of neural tube defects among infants born to individuals taking dolutegravir at the time of conception compared to those born to individuals taking non-dolutegravir-containing regimens at conception or infants born to HIV-negative individuals.

Dolutegravir and lamivudine are distributed into human milk. It is not known whether dolutegravir/lamivudine or its components affect human milk production or affect the breast-fed infant.

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.

The manufacturer makes no specific dosage recommendations for dolutegravir/lamivudine in geriatric patients, but recommends caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Clinical trials of dolutegravir/lamivudine did not include a sufficient number of patients >=65 years of age to determine whether they respond differently compared with younger patients.

Use dolutegravir/lamivudine with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.