Dolutegravir 50 mg, lamivudine 300 mg and tenofovir 300 mg

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOLUTEGRAVIR 50 mg, LAMIVUDINE 300 mg and TENOFOVIR 300 mg (DOLUTEGRAVIR 50 mg, LAMIVUDINE 300 mg and TENOFOVIR 300 mg)

Composition:

Active substance: dolutegravir, lamivudine, tenofovir disoproxil fumarate;

One tablet contains 50 mg of dolutegravir as dolutegravir sodium, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil;

Excipients: mannitol, microcrystalline cellulose, povidone, iron oxide red (E 172), sodium starch glycolate, sodium stearyl fumarate, croscarmellose sodium, hypromellose, magnesium stearate, colloidal anhydrous silicon dioxide;

Tablet coating: Opadry II Pink 85F94172 (titanium dioxide (E 171), polyethylene glycol 3350, talc, iron oxide red (E 172), and iron oxide black (E 172), partially hydrolyzed polyvinyl alcohol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex, film-coated tablets of pink color, with the imprint “N33” on one side and smooth on the other.

Pharmacotherapeutic group. Direct-acting antiviral agents for systemic use. Antiviral agents for the treatment of HIV infection in combination. ATC code J05AR.

Pharmacological Properties.

Pharmacodynamics.

Dolutegravir.

Mechanism of action.

Dolutegravir inhibits HIV integrase by binding to the active site of the integrase enzyme and blocking the integration step of retroviral deoxyribonucleic acid (DNA), which is essential for the replication cycle of human immunodeficiency virus (HIV).

Lamivudine + tenofovir

Lamivudine, the negative enantiomer of 2’-deoxy-3’-thiacytidine, is a nucleoside analogue. Tenofovir disoproxil fumarate is converted in vivo to tenofovir, a nucleotide analogue of adenosine monophosphate.

Lamivudine and tenofovir are phosphorylated by cellular enzymes to form lamivudine triphosphate and tenofovir diphosphate, respectively.

Lamivudine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase (RT), leading to chain termination of DNA. Both agents are active against HIV-1 and HIV-2, as well as against hepatitis B virus.

Resistance. HIV-1 strains with reduced susceptibility to tenofovir and the K65R mutation in reverse transcriptase have been selected in vitro. This mutation may also occur in vivo following ineffective treatment regimens containing tenofovir.

In clinical trials in previously treated patients, the antiviral activity of tenofovir against HIV-1 strains resistant to nucleoside inhibitors was evaluated. Results indicated that patients whose HIV had developed 3 or more thymidine-analogue associated mutations (TAMs), including either the M41L or L210W mutation in reverse transcriptase, showed reduced response to tenofovir treatment.

In many cases, when lamivudine-containing regimens fail (although less frequently when the regimen includes a ritonavir-boosted protease inhibitor), the M184V mutation may emerge early during treatment. The M184V mutation causes a high level of resistance to lamivudine (reduced susceptibility by more than 300-fold). However, viral replication with the M184V mutation is less efficient than with wild-type virus. In vitro data suggest that continuing lamivudine as part of antiretroviral therapy despite the emergence of M184V may provide residual antiretroviral activity (likely due to impaired viral fitness). The clinical significance of these data is not established. Therefore, maintenance therapy with lamivudine in the presence of the M184V mutation may be considered only if there is a high risk of failure of the primary nucleoside reverse transcriptase inhibitor regimen.

Cross-resistance caused by the M184V mutation is limited to nucleoside/nucleotide reverse transcriptase inhibitors. M184V confers complete cross-resistance to emtricitabine. Antiretroviral activity against lamivudine-resistant HIV-1 is preserved for zidovudine and stavudine. Abacavir retains antiretroviral activity against lamivudine-resistant HIV-1 harboring only the M184V mutation. The M184V mutation results in up to a 4-fold reduction in susceptibility to didanosine; the clinical significance of this is unknown.

Clinical results. When tenofovir and lamivudine were used together with efavirenz in previously untreated HIV-1 patients, the proportion of patients with HIV-RNA < 50 copies/mL was 76.3% and 67.8% at weeks 48 and 144, respectively.

Pharmacokinetics.

Dolutegravir

The pharmacokinetics of dolutegravir are similar in healthy and HIV-infected individuals. The pharmacokinetic variability of dolutegravir is low to moderate. In Phase I studies in healthy volunteers, the coefficient of variation (CV%) for area under the concentration-time curve (AUC) and maximum concentration (Cmax) ranged from ~20 to 40%, while Cτ ranged from 30 to 65% across all studies. Pharmacokinetic variability of dolutegravir was higher in HIV-infected patients compared to healthy volunteers. Intra-patient variability (CVw%) is lower than inter-patient variability.

Absorption

Dolutegravir is rapidly absorbed after oral administration, with a median Tmax of 2–3 hours after tablet intake.

Food intake increases the extent and slows the rate of dolutegravir absorption. Dolutegravir bioavailability depends on the composition of food: low-, medium-, and high-fat meals increased AUC(0–∞) by 33%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, and prolonged Tmax to 3, 4, and 5 hours, respectively, compared to fasting conditions (Tmax of 2 hours). This increase in pharmacokinetic parameters may be clinically significant in patients with existing resistance to integrase inhibitor class drugs. Therefore, the drug is recommended to be taken with food in HIV-infected patients with resistance to integrase inhibitors (see section "Dosage and administration").

The absolute bioavailability of dolutegravir has not been determined.

Distribution

Dolutegravir has a high binding capacity (> 99%) to plasma proteins, as determined from in vitro data. The apparent volume of distribution is 17–20 L in HIV-infected patients based on population pharmacokinetic analysis. The blood-to-plasma ratios of radioactivity associated with the drug range from 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma increases with low serum albumin levels (< 35 g/L), which may be observed in patients with moderate hepatic impairment.

Dolutegravir is detectable in cerebrospinal fluid (CSF). In 13 treatment-naïve patients currently on a stable regimen of dolutegravir in combination with abacavir/lamivudine, the mean CSF concentration of dolutegravir was 18 ng/mL (at the level of unbound drug concentration in plasma and above IC50).

Dolutegravir is detectable in the genital tract of both men and women. AUC in cervical-vaginal secretions, cervical tissue, and vaginal tissue was 6–10% of the corresponding plasma value at steady state. AUC in semen and rectal tissue was 7% and 17% of the corresponding plasma value at steady state, respectively.

Biotransformation

Dolutegravir is primarily metabolized via glucuronidation by the UGT1A1 enzyme, with minor involvement of CYP3A. Dolutegravir circulates predominantly in blood plasma; renal excretion of unchanged active substance is low (< 1% of dose). 53% of the total orally administered dose is excreted unchanged in feces. It is unknown whether this is fully or partially related to unabsorbed drug or biliary excretion of the glucuronide conjugate, which may subsequently be hydrolyzed to release the parent compound in the intestinal lumen. 32% of the total orally administered dose is excreted in urine as dolutegravir glucuronide (18.9% of total dose), an N-dealkylated metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzyl carbon (3% of total dose).

Elimination

The elimination half-life of dolutegravir is approximately 14 hours. The apparent total plasma clearance (CL/F) is approximately 1 L/hour in HIV-infected patients, as determined by population pharmacokinetic analysis.

Tenofovir disoproxil fumarate

Tenofovir disoproxil fumarate is a water-soluble prodrug ester that is rapidly converted in vivo to tenofovir and formaldehyde.

Tenofovir is intracellularly converted to tenofovir monophosphate and then to the active component, tenofovir diphosphate.

Absorption

After oral administration to HIV-infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. Following a single dose of lamivudine/tenofovir disoproxil fumarate 300 mg/300 mg in healthy volunteers, the mean Cmax (±SD) for tenofovir was 312 (±68) ng/mL, and AUC was 2754 (±586) ng·h/mL. The mean (±SD) Tmax of tenofovir was 2.06 (±0.61) hours.

After oral administration of tenofovir disoproxil fumarate to fasting patients, the oral bioavailability was approximately 25%. Administration with a high-fat meal increased oral bioavailability, increasing AUC of tenofovir by approximately 40% and Cmax by approximately 14%. However, administration with a light meal had no significant effect on tenofovir pharmacokinetics.

Distribution

After intravenous administration, the steady-state volume of distribution of tenofovir was approximately 800 mL/kg. In vitro, binding of tenofovir to plasma or serum proteins was less than 0.7% and 7.2%, respectively, over a concentration range of 0.01 to 25 µg/mL.

Elimination

Tenofovir is primarily eliminated by the kidneys via both glomerular filtration and active tubular secretion. After intravenous administration, approximately 70–80% of the dose is excreted unchanged in urine. Total clearance was observed at approximately 230 mL/h/kg (about 300 mL/min). Renal clearance was observed at approximately glomerular filtration rate levels of 160 mL/h/kg (about 210 mL/min), indicating that tubular secretion is a significant component of tenofovir elimination. After oral administration, the terminal elimination half-life of tenofovir is 12 to 18 hours.

One study demonstrated that tenofovir is eliminated via active tubular secretion, transported through proximal tubular cells by human organic anion transporters (hOAT) 1 and 3, and excreted in urine via multidrug resistant protein 4 (MRP4).

In vitro studies showed that neither tenofovir nor tenofovir disoproxil fumarate are substrates of the CYP450 enzyme system.

Age and sex

Limited data on tenofovir in women suggest that sex has no significant effect on tenofovir pharmacokinetics. Pharmacokinetic studies in children and adolescents (under 18 years) and elderly patients (over 65 years) have not been conducted.

Renal impairment

Tenofovir pharmacokinetic parameters were evaluated after a single 245 mg dose of tenofovir disoproxil in 40 HIV- and HBV-uninfected patients with varying degrees of renal impairment, classified according to baseline creatinine clearance (CrCl) (normal renal function if CrCl > 80 mL/min; mild impairment at CrCl 50–79 mL/min; moderate at CrCl 30–49 mL/min; severe at CrCl 10–29 mL/min). Compared to patients with normal renal function, mean exposure (%CV) of tenofovir increased from 2,185 (12%) ng·h/mL in individuals with CrCl > 80 mL/min to 3,064 (30%) ng·h/mL, 6,009 (42%) ng·h/mL, and 15,985 (45%) ng·h/mL in patients with mild, moderate, and severe renal impairment, respectively. A longer dosing interval is expected to result in higher peak plasma concentrations and lower Cmin levels in patients with renal impairment compared to those with normal renal function. The clinical significance of this is unknown.

In patients with end-stage renal disease (CrCl < 10 mL/min) requiring hemodialysis, tenofovir concentrations significantly increased between dialysis sessions over 48 hours, reaching a mean Cmax of 1,032 ng/mL and a mean AUC0–48h of 42,857 ng·h/mL.

It is recommended that the dosing interval of tenofovir disoproxil fumarate 245 mg be adjusted in patients with creatinine clearance < 50 mL/min and in patients with end-stage renal disease requiring dialysis (see section "Dosage and administration").

The pharmacokinetics of tenofovir in patients not on hemodialysis with CrCl < 10 mL/min and in patients with end-stage renal disease on peritoneal or other forms of dialysis have not been studied.

Hepatic impairment. A single 245 mg dose of tenofovir disoproxil was administered to HIV- and hepatitis B-uninfected patients with varying degrees of hepatic impairment classified according to the Child–Pugh–Turcotte classification. Tenofovir pharmacokinetic parameters were not significantly altered in patients with hepatic impairment, indicating no need for dose adjustment. Mean (%CV) values of Cmax and AUC0–∞ for tenofovir were 223 (34.8%) ng/mL and 2,050 (50.8%) ng·h/mL in individuals without hepatic impairment, 289 (46.0%) ng/mL and 2,310 (43.5%) ng·h/mL in those with moderate hepatic impairment, and 305 (24.8%) ng/mL and 2,740 (44.0%) ng·h/mL in those with severe hepatic impairment.

Intracellular pharmacokinetics. In non-replicating human peripheral blood mononuclear cells, the elimination half-life of tenofovir diphosphate is approximately 50 hours, whereas in phytohemagglutinin-stimulated PBMCs it is approximately 10 hours.

Lamivudine

Lamivudine is rapidly absorbed after oral administration.

The bioavailability of lamivudine is 80–85%.

After a single dose of lamivudine/tenofovir disoproxil fumarate 300 mg/300 mg in healthy volunteers, the mean (±SD) Cmax of lamivudine was 2.24 µg/mL (±0.69), and the corresponding AUC was 10.54 µg·h/mL (±2.94). The mean (±SD) Tmax of lamivudine was 2.15 hours (±0.87). Concomitant administration of lamivudine with food prolongs Tmax and reduces Cmax by 47%. However, the total amount of lamivudine absorbed (as indicated by AUC) remains unchanged.

Distribution

Studies show that after intravenous administration, the mean volume of distribution of lamivudine is 1.3 L/kg. Lamivudine exhibits linear pharmacokinetics within the therapeutic dose range and shows limited binding to major plasma proteins (< 36% to serum albumin in vitro).

Metabolism

Lamivudine undergoes minimal metabolism. It is primarily excreted unchanged by the kidneys. The potential for metabolic interaction with lamivudine is low because only a small fraction (5–10%) is metabolized by the liver and due to its low plasma protein binding.

Elimination

The elimination half-life of lamivudine is 5 to 7 hours. The intracellular half-life of lamivudine triphosphate is approximately 22 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, predominantly renal clearance (> 70%), including tubular secretion via the organic cation transport system.

Special patient groups

Renal impairment.

Studies have shown that renal impairment affects lamivudine elimination. Dose reduction is recommended for patients with creatinine clearance ≤ 50 mL/min.

Clinical characteristics.

Indications.

Treatment of adults infected with human immunodeficiency virus (HIV).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Concomitant use with dofetilide.

Interaction with other medicinal products and other forms of interactions.

Dolutegravir.

Effect of other drugs on dolutegravir pharmacokinetics.

If resistance to integrase inhibitor class drugs is present, factors that reduce dolutegravir concentrations must be avoided.

Dolutegravir is primarily eliminated via metabolism mediated by the UGT1A1 enzyme. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP (breast cancer resistance protein); therefore, medicinal products that induce these enzymes may reduce plasma concentrations of dolutegravir and diminish its therapeutic effect. Concomitant administration of dolutegravir with other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentrations. Absorption of dolutegravir is reduced by certain antacids (see Table 1).

Effect of dolutegravir on the pharmacokinetics of other drugs

In vivo, dolutegravir does not affect midazolam—a CYP3A4 probe. Based on in vivo and in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters such as CYP3A4, CYP2C9, or P-gp.

In vitro, dolutegravir inhibits the renal organic cation transporter 2 (OCT2) and also inhibits the multidrug transporter MATE-1. In vivo, a 10–14% reduction in creatinine clearance has been observed in patients (the secretory component depends on OCT2 and MATE-1 transporters). In vivo, dolutegravir may increase plasma concentrations of drugs whose elimination depends on OCT2 or MATE-1.

In vitro, dolutegravir inhibits renal uptake transporters—organic anion transporters (OAT1 and OAT3). Given the minimal effect of tenofovir substrate on OAT pharmacokinetics in vivo, inhibition of OAT1 by dolutegravir in vivo is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of drugs whose elimination depends on OAT3.

Established and potential interactions with specific antiretroviral and other medicinal products are listed in Table 1, where increases are indicated by the symbol ↑, decreases by ↓, and no change by ↔. AUC denotes area under the concentration-time curve, Cmax the maximum observed concentration, and Cτ the concentration at the end of the dosing interval.

Table 1

Drug classes	Interaction, mean geometric change (%)	Recommendations for co-administration
Antiretroviral agents against HIV-1
Non-nucleoside reverse transcriptase inhibitors
Etravirine (without boosted protease inhibitors)	Dolutegravir ↓ AUC ↓ 71% Cmax ↓ 52% Cτ ↓ 88% Etravirine ↔ (induction of UGT1A1 and CYP3A enzymes)	Etravirine without boosted protease inhibitors reduces dolutegravir plasma concentrations. The recommended dose of dolutegravir is 50 mg twice daily when administered with etravirine without boosted protease inhibitors. Dolutegravir should not be used with etravirine without concomitant administration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir in patients with resistance to integrase inhibitors.
Lopinavir/ ritonavir + etravirine	Dolutegravir ↔ AUC ↑ 11% Cmax ↑ 7% Cτ ↑ 28% LPV ↔ RTV ↔	No dose adjustment required.
Darunavir/ ritonavir + etravirine	Dolutegravir ↓ AUC ↓ 25% Cmax ↓ 12% Cτ ↓ 36% DRV ↔ RTV ↔	No dose adjustment required.
Efavirenz	Dolutegravir ↓ AUC ↓ 57% Cmax ↓ 39% Cτ ↓ 75% Efavirenz ↔ (historical controls) (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz. If resistance to integrase inhibitors exists, alternative combinations not including efavirenz should be considered.
Nevaripine	Dolutegravir ↓ (not studied, similar reduction expected as with efavirenz due to induction)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine. If resistance to integrase inhibitors exists, alternative combinations not including nevirapine should be considered.
Rilpivirine	Dolutegravir ↔ AUC ↑ 12% Cmax ↑ 13% Cτ ↑ 22% Rilpivirine ↔	No dose adjustment required.
Nucleoside reverse transcriptase inhibitors
Tenofovir	Dolutegravir ↔ AUC ↑ 1% Cmax ↓ 3% Cτ ↓ 8% Tenofovir ↔	No dose adjustment required.
Protease inhibitors
Atazanavir	Dolutegravir ↑ AUC ↑ 91% Cmax ↑ 50% Cτ ↑ 180% Atazanavir ↔ (historical controls) (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment required. The drug should not be used at doses exceeding 50 mg twice daily when co-administered with atazanavir due to insufficient data.
Atazanavir/ ritonavir	Dolutegravir ↑ AUC ↑ 62% Cmax ↑ 34% Cτ ↑ 121% Atazanavir ↔ Ritonavir ↔ (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment required. The drug should not be used at doses exceeding 50 mg twice daily when co-administered with atazanavir due to insufficient data.
Tipranavir/ ritonavir (TPV+RTV)	Dolutegravir ↓ AUC ↓ 59% Cmax ↓ 47% Cτ ↓ 76% (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with tipranavir/ritonavir in the absence of resistance to integrase inhibitors. This combination should be avoided if resistance to integrase inhibitors exists.
Fosamprenavir/ ritonavir (FPV+RTV)	Dolutegravir ↓ AUC ↓ 35% Cmax ↓ 24% Cτ ↓ 49% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment required in the absence of resistance to integrase inhibitors. If resistance to integrase inhibitors exists, alternative combinations not including fosamprenavir/ritonavir should be considered.
Nelfinavir	Dolutegravir ↔ (not studied)	No dose adjustment required.
Darunavir/ ritonavir	Dolutegravir ↓ AUC ↓ 22% Cmax ↓ 11% C24 ↓ 38% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment required.
Lopinavir/ ritonavir	Dolutegravir ↔ AUC ↓ 4% Cmax ↔ 0% C24 ↓ 6%	No dose adjustment required.
Other antiviral agents
Telaprevir	Dolutegravir ↑ AUC ↑ 25% Cmax ↑ 19% Cτ ↑ 37% Telaprevir ↔ (historical controls) (inhibition of CYP3A enzyme)	No dose adjustment required.
Boceprevir	Dolutegravir ↔ AUC ↑ 7% Cmax ↑ 5% Cτ ↑ 8% Boceprevir ↔ (historical controls)	No dose adjustment required.
Daclatasvir	Dolutegravir ↔ AUC ↑ 33% Cmax ↑ 29% Cτ ↑ 45% Daclatasvir ↔	Daclatasvir does not significantly alter dolutegravir plasma concentrations. Dolutegravir does not alter daclatasvir plasma concentrations. No dose adjustment required.
Other drugs
Antiarrhythmic agents
Dofetilide	Dofetilide ↑ (not studied, potential increase due to OCT2 transporter inhibition)	Concomitant use of dolutegravir and dofetilide is contraindicated due to potentially life-threatening toxicity from high dofetilide concentrations.
Anticonvulsants
Carbamazepine	Dolutegravir ↓ AUC ↓ 49% Cmax ↓ 33% Cτ ↓ 73%	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with carbamazepine. For patients with integrase inhibitor resistance, alternative agents to carbamazepine should be prescribed if possible.
Oxcarbazepine Phenytoin Phenobarbital	Dolutegravir ↓ (not studied, reduction expected due to induction of UGT1A1 and CYP3A enzymes; exposure reduction similar to that with carbamazepine expected)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with these metabolic inducers. For patients with integrase inhibitor resistance, combinations alternative to these metabolic inducers should be prescribed if possible.
Azole antifungal agents
Ketoconazole Fluconazole Itraconazole Posaconazole Voriconazole	Dolutegravir ↔ (not studied)	No dose adjustment required. Based on data from other CYP3A4 inhibitors, significant increases are not expected.
Herbal products
St. John’s wort	Dolutegravir ↓ (not studied, reduction expected due to induction of UGT1A1 and CYP3A enzymes; exposure reduction similar to that with carbamazepine expected)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with St. John’s wort. For patients with integrase inhibitor resistance, combinations not including St. John’s wort should be prescribed if possible.
Antacids and dietary supplements
Antacids containing magnesium/aluminum	Dolutegravir ↓ AUC ↓ 74% Cmax ↓ 72% (chelation with polyvalent ions)	Antacids containing magnesium/aluminum should be taken separately from dolutegravir (at least 2 hours after or 6 hours before dolutegravir administration).
Calcium-containing supplements	Dolutegravir ↓ AUC ↓ 39% Cmax ↓ 37% C24 ↓ 39% (chelation with polyvalent ions)	Calcium, iron, or multivitamin supplements should be taken separately from dolutegravir (at least 2 hours after or 6 hours before dolutegravir administration).
Iron-containing supplements	Dolutegravir ↓ AUC ↓ 54% Cmax ↓ 57% C24 ↓ 56% (chelation with polyvalent ions)
Multivitamins	Dolutegravir ↓ AUC ↓ 33% Cmax ↓ 35% C24 ↓ 32% (chelation with polyvalent ions)
Corticosteroids
Prednisone	Dolutegravir ↔ AUC ↑ 11% Cmax ↑ 6% Cτ ↑ 17%	No dose adjustment required.
Antidiabetic agents
Metformin	Metformin ↑ When co-administered with dolutegravir 50 mg once daily Metformin parameters: AUC ↑ 79% Cmax ↑ 66% When co-administered with dolutegravir 50 mg twice daily Metformin parameters: AUC ↑ 145% Cmax ↑ 111%	Dose adjustment of metformin should be considered at initiation and upon discontinuation of concomitant dolutegravir to maintain glycemic control. For patients with moderate renal impairment, metformin dose adjustment should be considered when co-administered with dolutegravir, as increased metformin concentrations increase the risk of lactic acidosis in these patients.
Antituberculosis agents
Rifampicin	Dolutegravir ↓ AUC ↓ 54% Cmax ↓ 43% Cτ ↓72% (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin in the absence of resistance to integrase inhibitors. This combination should be avoided if resistance to integrase inhibitors exists (see section "Special precautions").
Rifabutin	Dolutegravir ↔ AUC ↓ 5% Cmax ↑ 16% Cτ ↓ 30% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment required.
Oral contraceptives
Ethinylestradiol (EE) and Norelgestromin (NGMN)	Dolutegravir ↔ EE ↔ AUC ↑ 3% Cmax ↓ 1% NGMN ↔ AUC ↓ 2% Cmax ↓ 11%	Dolutegravir has no pharmacodynamic effect on luteinizing hormone (LH), follicle-stimulating hormone (FSH), or progesterone. No dose adjustment of oral contraceptives is required when co-administered with dolutegravir.
Analgesics
Methadone	Dolutegravir ↔ Methadone ↔ AUC ↓ 2% Cmax ↔ 0% Cτ ↓ 1%	No dose adjustment required for either drug.

Children.

Interaction studies have been conducted only in adults.

Lamivudine and tenofovir

Interaction studies have been conducted only in adults.

Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the likelihood of CYP450-mediated interactions between tenofovir and other medicinal products is low.

Lamivudine-mediated interactions

Concomitant administration of trimethoprim/sulfamethoxazole increases lamivudine concentration by 40%. Dose adjustment is not required. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. Concomitant use of lamivudine with higher doses of co-trimoxazole used for the treatment of Pneumocystis pneumonia and toxoplasmosis is not recommended.

Tenofovir-mediated interactions

Didanosine. Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended.

Medicinal products eliminated by the kidneys. Since tenofovir is primarily eliminated via the kidneys, concomitant use of tenofovir disoproxil fumarate with medicinal products that impair renal function or compete for active tubular secretion through hOAT1, hOAT3, or MRP4 transport proteins (e.g., cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.

Concomitant use of tenofovir disoproxil fumarate with nephrotoxic medicinal products (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2) should be avoided.

Because tacrolimus may affect renal function, careful monitoring of patients is recommended when it is co-administered with tenofovir disoproxil fumarate.

Other interactions. Interactions between the combination of tenofovir disoproxil fumarate and lamivudine at a dose of 300 mg/300 mg and HIV protease inhibitors, as well as antiviral agents other than protease inhibitors, are presented in Table 2 (where increases are indicated by the symbol ↑, decreases by ↓, and no change by ↔).

Table 2

Drug classes	Interaction, geometric mean change (%)	Recommendations for co-administration
Antibacterial agents
Antiretroviral agents
Protease inhibitors
Atazanavir (400 mg once daily)	Atazanavir: AUC ↓ 25% Cmax ↓ 21% Cmin ↓ 40% Tenofovir: AUC ↑ 24% Cmax ↑ 14% Cmin ↑ 22%	When atazanavir is co-administered with tenofovir disoproxil fumarate/lamivudine tablets 300 mg/300 mg, atazanavir should be administered at a dose of 300 mg once daily with ritonavir 100 mg twice daily.
Atazanavir/ Ritonavir (300 mg/100 mg once daily)	Atazanavir: AUC ↓ 25% Cmax ↓ 28% Cmin ↓ 26% Tenofovir: AUC ↑ 37% Cmax ↑ 34% Cmin ↑ 29%	No dose adjustment is required. Enhanced tenofovir effects may potentiate tenofovir-related adverse reactions, including renal disorders. Renal function should be closely monitored.
Lopinavir/ritonavir (400 mg/100 mg twice daily)	No significant effect on the pharmacokinetic parameters of lopinavir/ritonavir was observed. Tenofovir: AUC ↑ 32% Cmax ↔ Cmin ↑ 51%	No dose adjustment is required. Enhanced tenofovir effects may potentiate tenofovir-related adverse reactions, including renal disorders. Renal function should be closely monitored.
Darunavir/ritonavir (300 mg/100 mg twice daily)	No significant effect on the pharmacokinetic parameters of darunavir/ritonavir was observed. Tenofovir: AUC ↑ 22% Cmin ↑ 37%	No dose adjustment is required. Enhanced tenofovir effects may potentiate tenofovir-related adverse reactions, including renal disorders. Renal function should be closely monitored.
Nucleoside reverse transcriptase inhibitors
Didanosine (400 mg once daily)	Didanosine AUC ↑ 40–60%	When co-administered, the risk of adverse reactions associated with didanosine (such as pancreatitis, lactic acidosis) may increase, and CD4 cell counts may significantly decrease. In addition, use of didanosine 250 mg co-administered with tenofovir in several different combinations has been associated with a high rate of virological failure. Co-administration of tenofovir disoproxil fumarate/lamivudine 300 mg/300 mg with didanosine is not recommended.
Adefovir dipivoxil	AUC ↔ Cmax ↔	Tenofovir disoproxil fumarate/lamivudine 300 mg/300 mg should not be co-administered with adefovir dipivoxil.
Entecavir	AUC ↔ Cmax ↔	No clinically significant pharmacokinetic interaction was observed when tenofovir disoproxil fumarate/lamivudine 300 mg/300 mg was co-administered with entecavir.

Studies conducted with other medicinal products. No clinically significant pharmacokinetic interactions were observed when lamivudine/tenofovir disoproxil fumarate 300 mg/300 mg was administered with indinavir, efavirenz, nelfinavir, saquinavir (ritonavir-boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimine/ethinylestradiol.

Effect of food. The medicine should be taken with food, as food increases the bioavailability of tenofovir.

Special precautions for use.

Dolutegravir

Although effective viral suppression with antiretroviral agents has been proven to substantially reduce the risk of sexual transmission of HIV, residual transmission risk cannot be excluded. Preventive measures to prevent virus transmission should be taken in accordance with national recommendations.

Drug resistance to integrase inhibitors of particular concern.

When making a decision to use a medicinal product containing dolutegravir in the presence of resistance to integrase inhibitor class drugs, it should be considered that the activity of dolutegravir is significantly reduced in patients infected with virus strains harboring secondary mutations Q148+≥2 among G140A/C/S, E138A/K/T, L74I. It is unclear whether dolutegravir provides additional efficacy in the presence of such resistance to integrase inhibitors.

Hypersensitivity reactions.

Hypersensitivity reactions characterized by rash, constitutional symptoms, and sometimes organ dysfunction, including severe hepatic reactions, have been reported with dolutegravir. Dolutegravir and other suspected agents associated with hypersensitivity reactions should be discontinued immediately if signs or symptoms of hypersensitivity occur (including severe rash or rash accompanied by elevated liver enzymes, fever, malaise, fatigue, muscle or joint pain, blistering, oral mucosal lesions, conjunctivitis, facial edema, eosinophilia, angioedema, etc.). Clinical status should be monitored, including assessment of liver aminotransferases and bilirubin levels. Delay in discontinuing dolutegravir or other suspected agents after onset of hypersensitivity reactions may lead to life-threatening allergic reactions.

Immune reconstitution syndrome

In HIV-infected patients with advanced immunodeficiency, initiation of combination antiretroviral therapy (cART) may result in an inflammatory response to asymptomatic or residual opportunistic pathogens, leading to severe clinical manifestations or worsening of symptoms. These reactions are typically observed within the first few weeks or months after starting cART. Appropriate examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated, and treatment initiated if necessary. Autoimmune disorders (such as Graves' disease) have also been reported during immune reconstitution. However, the reported time to onset is highly variable, and these events may occur many months after initiation of therapy.

In some patients co-infected with hepatitis B and/or C virus, increased biochemical markers of liver function have been observed at the beginning of dolutegravir treatment. Monitoring of liver function tests is recommended in patients co-infected with hepatitis B and/or C virus. Particular caution is required when initiating or maintaining effective hepatitis B therapy in patients starting dolutegravir-based therapy who are co-infected with hepatitis B virus (see section "Adverse reactions").

Opportunistic infections.

Patients should be informed that dolutegravir or any other antiretroviral agent does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical supervision by physicians experienced in managing HIV-associated diseases.

Drug interactions.

In patients with resistance to integrase inhibitor class drugs, factors that reduce the effect of dolutegravir should be avoided. These include concomitant use of medicinal products that reduce dolutegravir concentrations (such as antacids containing magnesium/aluminum, iron or calcium supplements, multivitamins, stimulants, etravirine (without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, and certain antiepileptic drugs) (see section "Interaction with other medicinal products and other forms of interaction").

Dolutegravir increases metformin concentrations. Dose adjustment of metformin may be required at the initiation and upon discontinuation of concomitant dolutegravir and metformin therapy to maintain glycemic control. Since metformin is eliminated by the kidneys, renal function should be monitored during concomitant use with dolutegravir. The combination of these agents may increase the risk of lactic acidosis in patients with moderate renal impairment (stage 3a, creatinine clearance [CrCl] 45–59 mL/min), so particular attention is recommended. The physician should consider reducing the metformin dose.

Osteonecrosis.

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, bisphosphonates, alcohol consumption, severe immunosuppression, increased body mass index), cases have been reported in patients with advanced HIV infection and/or long-term cART exposure. Patients should be advised to consult a physician if they experience joint pain, stiffness, or difficulty moving.

Lamivudine and tenofovir.

General recommendations. Elderly patients are more likely to have impaired renal function; therefore, caution is required when treating these patients with tenofovir disoproxil fumarate.

All HIV-infected patients should be offered HIV antibody testing before initiating tenofovir disoproxil fumarate therapy.

Patients should be informed that current antiretroviral therapy, including treatment with this medicinal product, does not prevent HIV transmission to others via sexual contact or blood exposure. Therefore, appropriate preventive measures should continue to be used.

Concomitant administration of other medicinal products.

This medicinal product should not be used with other medicinal products containing lamivudine, tenofovir disoproxil fumarate, adefovir dipivoxil, lamivudine, or emtricitabine.

Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended. Concurrent use increases the risk of didanosine-related adverse events. Rare, sometimes fatal cases of pancreatitis and lactic acidosis have been reported. Concomitant administration of tenofovir disoproxil fumarate and didanosine 400 mg daily was associated with a significant decrease in CD4 cell count, possibly due to intracellular interaction increasing phosphorylated (i.e., active) didanosine. Reduced dosing of 250 mg didanosine administered during tenofovir disoproxil fumarate therapy was associated with a high rate of virological failure in several studied HIV-1 treatment regimens.

Triple nucleoside/nucleotide therapy. Reports have indicated a high rate of early virological failure and emergence of resistance in HIV patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, or with lamivudine and didanosine administered once daily.

Renal function.

Tenofovir is primarily eliminated by the kidneys via a combination of glomerular filtration and tubular secretion. Thus, clearance is reduced in patients with impaired renal function. The renal safety of tenofovir has been studied only in patients with mild renal impairment (creatinine clearance < 80 mL/min). Dolutegravir 50 mg, Lamivudine 300 mg and Tenofovir Disoproxil Fumarate 300 mg should be used in patients with hepatic impairment only if the benefit outweighs the potential risk.

In patients with moderate or severe renal impairment, lamivudine elimination half-life is prolonged due to reduced renal clearance. Dose reduction is recommended in patients with creatinine clearance < 50 mL/min.

Dolutegravir 50 mg, Lamivudine 300 mg and Tenofovir Disoproxil Fumarate 300 mg is not recommended in patients with creatinine clearance < 50 mL/min, as dose reduction of the active ingredient in the fixed-dose combination product is not feasible.

Renal failure, renal impairment, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir disoproxil fumarate in clinical practice.

Calculation of creatinine clearance is recommended in all patients before initiating tenofovir disoproxil fumarate therapy, and renal function should be monitored during treatment as clinically indicated. Regular monitoring of estimated creatinine clearance and serum phosphate levels is recommended in patients at risk of renal impairment.

If serum phosphate level is < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases to < 50 mL/min in any patient receiving tenofovir disoproxil fumarate, renal function should be reassessed within 1 week, including measurement of blood glucose, serum potassium, and urine glucose (see section "Adverse reactions"). Consideration should also be given to discontinuing tenofovir disoproxil fumarate in patients whose creatinine clearance decreases to < 50 mL/min or whose serum phosphate level decreases to < 1.0 mg/dL (0.32 mmol/L).

Concomitant use of the medicinal product with nephrotoxic agents (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2) should be avoided. If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.

Bone effects

In a controlled clinical trial, decreased bone mineral density in the spine was observed in both treatment groups, but changes in bone turnover markers from baseline were significantly greater in the group receiving tenofovir disoproxil fumarate (in combination with lamivudine and efavirenz) compared to the stavudine group at week 144. Decreased bone mineral density in the hip was significant in this group up to week 96. However, no increased risk of fracture or clinically significant bone abnormalities was observed over 144 weeks.

Bone abnormalities (rarely leading to fracture) may be associated with proximal renal tubulopathy. If bone abnormalities are suspected, appropriate medical consultation should be obtained.

Osteonecrosis.

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, bisphosphonates, alcohol consumption, severe immunosuppression, increased body mass index), cases have been reported in patients with advanced HIV infection and/or long-term cART exposure. Patients should be advised to consult a physician if they experience joint pain, stiffness, or difficulty moving.

HIV patients with concomitant hepatitis B or C virus infection.

Patients with chronic hepatitis B or C receiving antiretroviral therapy are at increased risk of serious and potentially fatal hepatic adverse reactions. Physicians should follow current guidelines for HIV treatment to appropriately manage HIV infection in patients co-infected with hepatitis B virus. When using concomitant antiviral agents for treatment of hepatitis B and C, refer to the respective product information for those agents.

Lamivudine and tenofovir are active against hepatitis B virus when used as part of combination antiretroviral therapy for HIV control. The combination of tenofovir disoproxil fumarate 300 mg and lamivudine 300 mg has not been studied for treatment of hepatitis B virus.

The combination of lamivudine and tenofovir disoproxil fumarate 300 mg/300 mg is not indicated for treatment of chronic hepatitis B virus infection.

Severe hepatitis exacerbation may occur after discontinuation of lamivudine and tenofovir disoproxil fumarate 300 mg/300 mg combination therapy in patients co-infected with hepatitis B virus and HIV. Liver function should be monitored monthly by clinical and laboratory parameters for at least 6 months after discontinuation of lamivudine and tenofovir disoproxil fumarate 300 mg/300 mg. Reinitiation of hepatitis B treatment may be warranted if necessary. Discontinuation of therapy is not recommended in patients with advanced liver disease or cirrhosis, as post-treatment hepatitis flare may lead to hepatic decompensation.

Liver disease.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, are at increased risk of liver function deterioration during combination antiretroviral therapy and should be monitored closely. Consideration should be given to interrupting or discontinuing therapy if signs of worsening liver function occur in such patients.

Lactic acidosis.

Lactic acidosis is a rare but serious, potentially life-threatening complication associated with nucleoside reverse transcriptase inhibitors (NRTIs). Other drugs in this class are known to cause lactic acidosis. Preclinical and clinical data suggest that the risk of lactic acidosis associated with the nucleoside analog class is very low for tenofovir disoproxil fumarate. However, this risk cannot be excluded because tenofovir is structurally similar to nucleoside analogs. Lactic acidosis may occur several months after starting NRTI therapy. Hyperlactatemia may be asymptomatic or may progress to a critical condition or present with nonspecific symptoms such as dyspnea, fatigue, nausea, vomiting, diarrhea, and abdominal pain. Women and patients with obesity are at higher risk for nucleoside reverse transcriptase inhibitor-associated acidosis.

Patients at increased risk of lactic acidosis should be closely monitored. Patients exhibiting symptoms of lactic acidosis typically have lactate levels > 5 mmol/L; treatment with the medicinal product should be discontinued in such patients. Lactate levels > 10 mmol/L generally require emergency medical intervention.

Lipodystrophy.

In HIV-infected patients, combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy). This adverse reaction is characteristic of some other antiretroviral agents, but the effect of tenofovir on lipodystrophy has not been established. A shift from a thymidine analog (e.g., stavudine) to tenofovir was associated with increased peripheral fat accumulation in patients with lipoatrophy. Higher risk of lipodystrophy has been observed, for example, in elderly patients or those with longer duration of antiretroviral therapy and associated metabolic disturbances. Clinical evaluation should include assessment of physical signs of fat redistribution. Monitoring of serum lipid and blood glucose levels and appropriate management of lipid disorders should be considered.

Mitochondrial dysfunction. Nucleotide and nucleoside analogs have been shown in vitro and in vivo to cause mitochondrial dysfunction of varying severity. Mitochondrial dysfunction has been reported in HIV-negative infants exposed to nucleoside analogs in utero or postnatally. Hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipidemia) have been primarily reported. It is currently unknown whether neurological disorders are transient or permanent. Delayed neurological disorders (hypertonia, seizures, abnormal behavior) have been reported. Any child, even if HIV-negative, exposed in utero to nucleoside or nucleotide analogs should be under clinical and laboratory surveillance. A complete evaluation for mitochondrial dysfunction should be performed if appropriate symptoms occur. Recommendations for antiretroviral therapy in pregnant women to prevent vertical HIV transmission should also be followed.

Pancreatitis.

The medicinal product should be discontinued immediately if clinical symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Immune reconstitution syndrome. In HIV-infected patients with advanced immunodeficiency, initiation of antiretroviral therapy may trigger an inflammatory response to asymptomatic or residual opportunistic infections, potentially causing severe clinical conditions or symptom exacerbation. Such reactions typically occur within the first weeks or months of antiretroviral therapy. Examples include cytomegalovirus retinitis, mycobacterial infections, or Pneumocystis jirovecii (P. carinii) pneumonia.

This medicinal product contains sodium. Caution is advised when administering to patients on a sodium-controlled diet.

This medicinal product contains mannitol, which may have a mild laxative effect.

Use during pregnancy or breastfeeding.

Dolutegravir.

Pregnancy.

Data on the use of dolutegravir in pregnant women are limited. The effect of dolutegravir on human pregnancy is unknown. In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta (see section "Preclinical safety data"). Due to the potential risk of neural tube defects, dolutegravir should not be used during the first trimester of pregnancy. Dolutegravir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding.

It is unknown whether dolutegravir is excreted in human breast milk. Available toxicological data from animal studies show excretion of dolutegravir in milk. HIV-infected women should not breastfeed under any circumstances to avoid HIV transmission.

Lamivudine and tenofovir

Pregnancy

Animal studies did not show direct or indirect harmful effects of tenofovir on pregnancy, fetal development, delivery, or postnatal development.

Clinical data on the effect of tenofovir on pregnancy are limited. A sufficient number of pregnant women in the first trimester have been studied to detect at least a doubling of the risk of overall congenital malformations. No increase in congenital defects has been observed.

No increase in congenital defects has been observed with lamivudine use either. However, the risk to the fetus cannot be fully excluded.

Lamivudine and tenofovir disoproxil fumarate 300 mg/300 mg should be used during pregnancy only if the potential benefit to the woman outweighs the risk to the fetus/child.

Current guidelines on antiretroviral therapy during pregnancy (e.g., WHO guidelines) should be considered when prescribing the medicinal product to this patient group.

Breastfeeding

Animal studies have shown that tenofovir passes into breast milk. It is unknown whether tenofovir passes into human breast milk. Lamivudine passes into human breast milk.

Therefore, women receiving the medicinal product are advised not to breastfeed.

Prescribing decisions should follow current guidelines on HIV treatment and breastfeeding (e.g., WHO guidelines). The optimal choice may vary depending on local circumstances.

Ability to affect reaction speed when driving or operating machinery.

Studies specifically investigating the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. However, patients should be informed about possible dizziness during treatment with tenofovir disoproxil fumarate. Patients experiencing dizziness should refrain from driving or operating machinery.

Method of Administration and Dosage

For the treatment of HIV infection resistant to other medicinal products similar to dolutegravir 50 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg, the usual dose is one tablet daily.

The tablet should be taken with sufficient fluid and can be administered regardless of food intake.

Children

This medicinal product is not intended for use in children.

Overdose

Dolutegravir

Experience with dolutegravir overdose is currently limited.

Based on limited experience with single high doses (up to 250 mg of dolutegravir in healthy volunteers), no additional specific symptoms were observed beyond those listed as adverse reactions. There is no specific antidote for dolutegravir overdose. In case of overdose, the patient should receive symptomatic treatment with appropriate monitoring, if necessary. Since dolutegravir is highly protein-bound in plasma, significant elimination by hemodialysis is unlikely.

Lamivudine and Tenofovir

In case of overdose, the patient should be monitored for signs of toxicity. If necessary, standard supportive treatment should be initiated.

Tenofovir can be removed by hemodialysis; the median tenofovir clearance value is 134 mL/min. Removal of tenofovir by peritoneal dialysis has not been studied.

Lamivudine is eliminated by hemodialysis and by peritoneal dialysis in very small amounts (4-hour dialysis session). Therefore, prolonged hemodialysis may be used in overdose, although appropriate studies have not been conducted.

Adverse reactions

Adverse reactions considered possibly related to the use of dolutegravir are listed by system organ class and frequency category according to the absolute frequency of occurrence. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000).

Table 3

Body systems	Frequency	Adverse reactions
Immune system disorders	Uncommon	Hypersensitivity, immune reconstitution syndrome
Psychiatric disorders	Common	Insomnia, abnormal dreams, depression, anxiety
	Uncommon	Suicidal thoughts or suicide attempts (particularly in patients with a history of depression or psychiatric illness)
Nervous system disorders	Very common	Headache
	Common	Dizziness
Gastrointestinal disorders	Very common	Nausea, diarrhea
	Common	Vomiting, flatulence, upper abdominal pain, abdominal pain, abdominal discomfort
Hepatobiliary disorders	Uncommon	Hepatitis
	Rare	Acute liver failure
Skin and subcutaneous tissue disorders	Common	Rash, pruritus
Musculoskeletal and connective tissue disorders	Uncommon	Arthralgia, myalgia
General disorders	Common	Fatigue
Abnormal laboratory test results	Common	Elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), elevated creatine phosphokinase (CPK)

Lamivudine + Tenofovir

Adverse reactions considered possibly related to the use of lamivudine or tenofovir are listed by system organ classes and frequency of occurrence.

Frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (frequency cannot be estimated from available data).

Blood and lymphatic system disorders: uncommon – neutropenia, anemia (sometimes severe), thrombocytopenia; very rare – pure red cell aplasia.

Metabolism and nutrition disorders: very common – hypophosphatemia; rare – lactic acidosis; not known – hypokalemia.

Nervous system disorders: very common – dizziness; common – headache, insomnia; very rare – peripheral neuropathy (paresthesia).

Respiratory system disorders: common – cough, cold symptoms; very rare – dyspnea.

Gastrointestinal disorders: very common – diarrhea, nausea, vomiting; common – abdominal pain/spasms, flatulence; rare – pancreatitis, increased serum amylase.

Hepatobiliary disorders: uncommon – transient elevation of liver enzymes; rare – hepatitis; not known – hepatic steatosis.

Skin and subcutaneous tissue disorders: common – rash, alopecia; not known – rhabdomyolysis, osteomalacia (manifested as bone pain and rarely leading to fractures), muscle weakness, myopathy, osteonecrosis.

Renal and urinary disorders: rare – acute renal failure, renal failure, proximal renal tubulopathy (including Fanconi syndrome), increased serum creatinine; very rare – acute tubular necrosis; not known – nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus.

General disorders: common – fatigue, malaise, fever; very rare – asthenia; not known – immune reconstitution syndrome.

Other: increased fatigue, malaise, fever.

As a consequence of proximal renal tubulopathy, the following adverse reactions listed above may occur: rhabdomyolysis, osteomalacia (manifested as bone pain and rarely leading to fractures), hypokalemia, muscle weakness, myopathy, and hypophosphatemia. These reactions are not considered causally related to tenofovir disoproxil fumarate in the absence of proximal renal tubulopathy.

In patients with hepatitis B, clinical and laboratory signs of hepatitis flare have been observed after discontinuation of antiviral therapy. With the use of combined antiretroviral drugs, disturbances in metabolism such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia have been reported.

Combined antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV-infected patients, including loss of peripheral and subcutaneous fat, increased intra-abdominal and visceral fat, breast enlargement, and fat accumulation in the dorsocervical area ("buffalo hump").

Shelf life. 2 years.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 30°C, in the original packaging.

Packaging. 30 film-coated tablets in a plastic bottle with a cap and first-opening control. One plastic bottle in a cardboard box with the instruction for medical use.

Prescription status. Prescription only.

Manufacturer. Aurobindo Pharma Limited, Unit–VII/Aurobindo Pharma Limited–Unit VII.

Manufacturer's address and location of manufacturing site.

Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/R, 425/R, 434/R, 435/R and 458/R, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India / Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/R, 425/R, 434/R, 435/R and 458/R, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India.