Virophil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIROPIl (VIROPIL)

Composition:

Active substances: dolutegravir, lamivudine, tenofovir disoproxil fumarate;

One film-coated tablet contains dolutegravir sodium equivalent to dolutegravir 50 mg, lamivudine 300 mg, tenofovir disoproxil fumarate 300 mg;

Excipients: mannite (E 421), microcrystalline cellulose*, sodium starch glycolate, povidone, sodium stearyl fumarate, croscarmellose sodium, lactose monohydrate, pregelatinized starch, magnesium stearate, Opadry II White 85F18422 coating**;

* microcrystalline cellulose Avicel PH 101 and Avicel PH 102 are used.

** composition of Opadry II White 85F18422 coating: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped film-coated tablets, white to almost white in color, with "HP553" debossed 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

Mechanism of action and pharmacodynamic effects. Lamivudine, the negative enantiomer of 2’-deoxy-3’-thiacytidine, is a nucleoside analogue. Tenofovir disoproxil fumarate is converted in vivo into 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), resulting in chain termination of DNA. Both compounds 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. Resistance may also occur in vivo following an ineffective treatment regimen containing tenofovir.

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

In many cases where lamivudine-containing regimens fail (less frequently when the regimen includes a ritonavir-boosted protease inhibitor), the M184V mutation may emerge early during treatment. The M184V mutation confers high-level resistance to lamivudine (reduced susceptibility by more than 300-fold). Viral replication with the M184V mutation is lower than that of 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 nucleoside reverse transcriptase inhibitor-based regimens.

Cross-resistance due to 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 retained for zidovudine and stavudine. Abacavir retains antiretroviral activity against lamivudine-resistant HIV-1 with 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 antiretroviral-naïve patients with HIV-1, 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 individuals and HIV-infected individuals. The pharmacokinetic variability of dolutegravir is low to moderate. In Phase I studies involving healthy volunteers, the coefficient of variation (CV%) for area under the concentration-time curve (AUC) and maximum concentration (Cmax) ranged from ~20% to 40%, and 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. The bioavailability of dolutegravir depends on the composition of food: low-, medium-, and high-fat meals increased AUC(0–∞) of dolutegravir 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 inhibitors. Therefore, the drug is recommended to be taken with food in HIV-infected patients with resistance to integrase inhibitors (see section "Directions for use and dosage").

The absolute bioavailability of dolutegravir has not been determined.

Distribution.

Dolutegravir has a high binding capacity (> 99%) to plasma proteins, as established from in vitro data. The apparent volume of distribution is 17–20 L in HIV-infected patients based on population pharmacokinetic analysis. The total blood-to-plasma ratio of radioactivity associated with the drug ranges from 0.441 to 0.535, indicating minimal binding of radioactivity to 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 concentration of dolutegravir in CSF averaged 18 ng/mL (at the level of unbound drug concentration in plasma and above IC50).

Dolutegravir is detectable in the genital tracts of 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 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 due to unabsorbed drug or biliary excretion of the glucuronide conjugate, which may subsequently be hydrolyzed to 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), N-dealkylation 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 ester prodrug 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 tenofovir Cmax (±SD) was 312 (±68) ng/mL, and AUC was 2754 ng·h/mL (±586). The mean (±SD) Tmax of tenofovir was 2.06 (±0.61) hours.

After oral administration of tenofovir disoproxil fumarate under fasting conditions, the oral bioavailability was approximately 25%. Administration of tenofovir disoproxil fumarate 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 transport, with approximately 70–80% of the dose excreted unchanged in urine after intravenous administration. Total clearance was observed at approximately 230 mL/h/kg (about 300 mL/min). Renal clearance was observed at approximately 160 mL/h/kg (about 210 mL/min), which is close to the glomerular filtration rate, indicating that tubular secretion is an important component of tenofovir elimination. After oral administration, the terminal elimination half-life of tenofovir is 12 to 18 hours.

A study demonstrated that tenofovir is eliminated via active tubular secretion, passing through proximal tubular cells via human organic anion transporters (hOAT) 1 and 3, and is excreted into 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 (up to 18 years) and elderly patients (over 65 years) have not been conducted.

Renal impairment.

Tenofovir pharmacokinetic parameters were assessed 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 (CrCl > 80 mL/min), mild impairment (CrCl 50–79 mL/min), moderate impairment (CrCl 30–49 mL/min), and severe impairment (CrCl 10–29 mL/min). Compared to patients with normal renal function, mean tenofovir exposure (%CV) increased from 2,185 (12%) ng·h/mL in those 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. Dose interval extension 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 increased significantly 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 "Directions for use and dosage").

The pharmacokinetics of tenofovir in patients not on hemodialysis with creatinine clearance < 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, respectively, 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 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 delays Tmax and reduces Cmax by 47%. However, the total amount of lamivudine absorbed (as indicated by AUC) remains unchanged.

Distribution.

Studies showed 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 due to minimal hepatic metabolism (5–10%) and 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, with 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 substances or to any of the excipients.

Concomitant use with dofetilide.

Interaction with other medicinal products and other forms of interaction.

Dolutegravir.

Effect of other medicinal products on dolutegravir pharmacokinetics.

If resistance to integrase inhibitor class drugs exists, 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 dolutegravir plasma concentrations and thereby diminish its therapeutic effect. Concomitant administration of dolutegravir with other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentrations.

The absorption of dolutegravir is reduced by certain antacids (see Table 1).

Effect of dolutegravir on the pharmacokinetics of other medicinal products.

In vivo, dolutegravir does not affect midazolam—a CYP3A4 probe. Based on in vivo and in vitro data, no effect of dolutegravir on the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters such as CYP3A4, CYP2C9, or P-gp is expected.

In vitro, dolutegravir inhibits the renal organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion transporter 1 (MATE-1). In vivo, patients showed a 10–14% reduction in creatinine clearance (the secretory component being transporter-dependent via OCT2 and MATE-1). In vivo, dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OCT2 or MATE-1 (such as dofetilide, metformin).

In vitro, dolutegravir inhibits renal uptake transporters for substrates, namely organic anion transporters OAT1 and OAT3. Given the limited effect of tenofovir substrate on OAT pharmacokinetics in vivo, inhibition of OAT1 in vivo is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OAT3.

Established and potential interactions with specific antiretroviral and other medicinal products are listed in Table 1 below, where increase is denoted by ↑, decrease by ↓, no change by ↔, area under the concentration-time curve by AUC, maximum observed concentration by Cmax, and trough concentration at the end of the dosing interval by Cτ.

Table 1

Medicinal product interactions

Drug Classes	Interaction, mean geometric change (%)	Recommendations for co-administration
Antiviral drugs 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 used 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 inhibitor class drugs.
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 inhibitor class drugs is present, alternative combinations not including efavirenz should be considered.
Nevaripine	Dolutegravir ↓ (not studied, expected similar reduction in effect as seen with efavirenz due to induction)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine. If resistance to integrase inhibitor class drugs is present, 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 inhibitor class drugs. If resistance to integrase inhibitor class drugs is present, this combination should be avoided.
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 inhibitor class drugs. If resistance to integrase inhibitor class drugs is present, 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 drugs
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 drugs
Dofetilide	Dofetilide ↑ (not studied, potential increase due to inhibition of OCT2 transporter)	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. In patients with integrase inhibitor resistance, alternative agents to carbamazepine should be considered if possible.
Oxcarbazepine Phenytoin Phenobarbital	Dolutegravir ↓ (not studied, expected decrease due to induction of UGT1A1 and CYP3A enzymes, expected reduction in exposure similar to that with carbamazepine)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with these metabolic inducers. In patients with integrase inhibitor resistance, alternative combinations not including these inducers should be considered if possible.
Antifungal azoles
Ketoconazole Fluconazole Itraconazole Posaconazole Voriconazole	Dolutegravir ↔ (not studied)	No dose adjustment required. Based on data from other CYP3A4 inhibitors, a significant increase is not expected.
Herbal products
St. John's wort	Dolutegravir ↓ (not studied, expected decrease due to induction of UGT1A1 and CYP3A enzymes, expected reduction in exposure similar to that with carbamazepine)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with St. John's wort. In patients with integrase inhibitor resistance, combinations not including St. John's wort should be considered 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 drugs
Metformin	Metformin ↑ With concomitant administration of dolutegravir 50 mg once daily Metformin parameters: AUC ↑ 79% Cmax ↑ 66% With concomitant administration of dolutegravir 50 mg twice daily Metformin parameters: AUC ↑ 145% Cmax ↑ 111%	Dose adjustment of metformin should be considered at the initiation and discontinuation of concomitant dolutegravir to maintain glycemic control. In 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 drugs
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 inhibitor class drugs. If resistance to integrase inhibitor class drugs is present, this combination should be avoided (see section "Special warnings and precautions for use").
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 by the kidneys, concomitant use of tenofovir disoproxil fumarate with medicinal products that impair renal function or compete for active tubular secretion via hOAT 1, hOAT 3, or MRP 4 transporters (e.g., cidofovir) may increase serum concentrations of tenofovir and/or the co-administered drugs.

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 the patient 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 denoted by the symbol ↑, decreases by ↓, and no change by ↔).

Table 2

Drug classes	Interaction, mean geometric change (%)	Recommendations for concomitant use
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 300 mg/300 mg tablets, 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%	Concomitant use may increase the risk of adverse reactions associated with didanosine (such as pancreatitis, lactic acidosis), and CD4 cell counts may significantly decrease. In addition, use of didanosine 250 mg with tenofovir in several different combinations has been associated with a high rate of virological failure. Concomitant use 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 norgestimone/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 by antiretroviral agents has been shown to substantially reduce the risk of sexual transmission of HIV, residual risk cannot be excluded. Preventive measures to avoid virus transmission should be taken in accordance with national guidelines.

Resistance to integrase inhibitor class drugs of particular concern.

When considering the use of dolutegravir in the presence of resistance to integrase inhibitor class drugs, it is important to note that the antiviral activity of dolutegravir is significantly reduced in patients infected with virus strains harboring the secondary mutations Q148+ ≥ 2 of G140A/C/S, E138A/K/T, L74I. It is unclear whether dolutegravir provides additional efficacy in such cases of 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 lesions, conjunctivitis, facial swelling, eosinophilia, or angioedema, but not limited to these). Clinical status, including liver aminotransferases and bilirubin levels, should be monitored. 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 severe immunodeficiency at the start of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, leading to severe clinical manifestations or worsening of symptoms. These reactions are typically observed within the first few weeks or months of initiating cART. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and appropriate treatment initiated if necessary. Autoimmune disorders (such as Graves' disease) have also been reported in the context of immune reconstitution. However, the time to onset of such disorders is more variable, and these events may occur several months after initiation of treatment.

In some patients co-infected with hepatitis B and/or C viruses, increases in biochemical liver function parameters have been observed at the beginning of dolutegravir therapy. Monitoring of liver function tests is recommended in patients co-infected with hepatitis B and/or C viruses. Particular caution is advised when initiating or maintaining effective hepatitis B therapy if dolutegravir-based treatment is started in patients co-infected with hepatitis B virus.

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. 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 reducing 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-containing dietary supplements, multivitamins, stimulants, etravirine [without boosted protease inhibitors], tipranavir/ritonavir, rifampicin, St. John's wort, and certain antiepileptic drugs).

Dolutegravir increases metformin concentrations. Dose adjustment of metformin may be required at the initiation and upon discontinuation of concomitant therapy with dolutegravir and metformin to maintain glycemic control. Since metformin is excreted 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 special 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, and high body mass index), cases have been reported in patients with advanced HIV disease and/or prolonged 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 tested for HIV antibodies 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 has been associated with a significant decrease in CD4 cell count, possibly due to intracellular interaction increasing phosphorylated (i.e., active) didanosine. A reduced dose of 250 mg didanosine administered during tenofovir disoproxil fumarate therapy has been associated with a high rate of virological failure in several HIV-1 treatment regimens.

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

Renal function. Tenofovir is primarily eliminated by the kidneys via a combination of glomerular filtration and tubular secretion. Therefore, 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). Virupil should be used in patients with hepatic impairment only if the benefit outweighs the potential risk.

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

Virupil is not recommended in patients with creatinine clearance < 50 mL/min, as dose reduction of the active ingredients in this fixed-dose combination product is not feasible.

Cases of renal failure, renal impairment, increased 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 levels fall below 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 one 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 levels fall below 1.0 mg/dL (0.32 mmol/L).

Concomitant use of 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.

Tenofovir disoproxil fumarate may also cause a decrease in bone mineral density (BMD). In a 144-week controlled clinical trial in antiretroviral-naïve adult HIV-infected patients comparing tenofovir disoproxil fumarate versus stavudine, both in combination with lamivudine and efavirenz, small decreases in BMD of the hip and spine were observed in both treatment groups. Over 144 weeks, decreases in spine BMD and changes in bone biomarkers were significantly greater in the tenofovir disoproxil fumarate group. Decreased hip BMD was significant in this group up to week 96. However, no increased fracture risk or clinically significant bone abnormalities were observed over 144 weeks.

In other studies (prospective and crossover), the most pronounced BMD reductions occurred in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Overall, due to bone abnormalities associated with tenofovir disoproxil and limited long-term data on the impact of tenofovir disoproxil fumarate on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis or at high risk of fractures. Appropriate consultations should be obtained if bone abnormalities are suspected.

Osteonecrosis. Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, and high body mass index), cases have occurred predominantly in patients with advanced disease and/or prolonged use of combination antiretroviral therapy. Patients should be advised to seek medical attention if they experience joint pain, stiffness, or movement difficulties.

Patients co-infected with hepatitis B and C viruses.

In patients with chronic hepatitis B or C receiving antiretroviral therapy, there is an increased risk of serious and potentially fatal hepatic adverse reactions. Physicians should follow current guidelines for managing HIV infection in patients co-infected with hepatitis B virus. When used concomitantly with other antiviral agents for hepatitis B and C treatment, refer to the respective product information for these 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 the treatment of hepatitis B.

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

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

Liver disorders.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased risk of liver function deterioration during combination antiretroviral therapy and should be closely monitored. If signs of worsening liver function occur, interruption or discontinuation of therapy should be considered.

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 entirely excluded, as tenofovir is structurally similar to nucleoside analogs. Lactic acidosis may occur several months after starting NRTI therapy. Hyperlactatemia may be asymptomatic or progress to a critical condition, or present with nonspecific symptoms such as dyspnea, fatigue, nausea, vomiting, diarrhea, and abdominal pain. Women and obese patients are at higher risk for NRTI-associated acidosis.

Patients at increased risk of lactic acidosis should be closely monitored. Patients with symptoms suggestive of lactic acidosis typically have lactate levels > 5 mmol/L; treatment with the medicinal product should be discontinued in such cases. 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 contribution of tenofovir to lipodystrophy has not been established. In patients with lipoatrophy, a switch from a thymidine analog (e.g., stavudine) to tenofovir has been associated with increased fat accumulation in the limbs. Higher risk of lipodystrophy has been observed, for example, in elderly patients or 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 glucose levels is necessary, and appropriate management of lipid disorders should be implemented.

Mitochondrial dysfunction. Nucleotide and nucleoside analogs have been shown in vitro and in vivo to cause mitochondrial dysfunction of varying degrees. Cases of mitochondrial dysfunction have 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 the most commonly reported adverse effects. It is currently unknown whether neurological disorders are transient or permanent. Late-onset neurological disorders (hypertonia, seizures, abnormal behavior) have been reported. Any child, even if HIV-negative, exposed to nucleoside or nucleotide analogs in utero should be under clinical and laboratory surveillance. A thorough evaluation for mitochondrial dysfunction should be performed if relevant 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 severe immunodeficiency at the initiation of antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections may occur, leading to severe clinical manifestations or worsening of symptoms. Such reactions typically occur within the first weeks or months of antiretroviral therapy. Examples include cytomegalovirus retinitis, mycobacterial infections, or Pneumocystis jirovecii pneumonia (P. carinii pneumonia).

Excipients.

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

The medicinal product contains lactose and should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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. Due to the potential risk of neural tube defects, dolutegravir should be used during the first trimester of pregnancy only if no alternative is available. Dolutegravir may be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.

Breastfeeding.

It is unknown whether dolutegravir is excreted in human breast milk. Toxicological studies in animals have shown excretion of dolutegravir in milk. HIV-infected women should not breastfeed under any circumstances to avoid transmission of HIV to the infant.

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

No increase in congenital defects has been observed after lamivudine use either. However, a potential effect on the fetus cannot be entirely 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/infant.

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

Breastfeeding.

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

Lamivudine is excreted in human milk. Therefore, women receiving this 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.

No studies have been conducted to evaluate the effect of this medicinal product on the ability to drive or operate machinery. However, patients should be informed about the possibility of dizziness during treatment with tenofovir disoproxil fumarate. Patients experiencing dizziness should refrain from driving or operating machinery.

Method of Administration and Dosage

For HIV-infected patients resistant to other medicinal products of the integrase inhibitor class similar to dolutegravir 50 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg, the usual dose is 1 tablet per day.

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

Children

This medicinal product is not intended for use in children.

Overdose

Dolutegravir

Currently, experience with dolutegravir overdose is limited.

Based on limited data from single high doses (up to 250 mg 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, it is unlikely that it will be substantially removed by hemodialysis.

Lamivudine and Tenofovir

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

Tenofovir can be removed by hemodialysis, with a median clearance value of 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). Therefore, prolonged hemodialysis may be considered in case of overdose, although no specific studies have been conducted.

Adverse reactions.

Unwanted reactions considered possibly related to the use of dolutegravir are listed by system organ classes and absolute frequency of occurrence. The 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).

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 levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), elevated creatine phosphokinase (CPK) levels

Lamivudine + Tenofovir

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

Frequency of occurrence is defined as follows: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1000 – < 1/100), rare (≥ 1/10,000 – < 1/1000), very rare (< 1/10,000), unknown (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; unknown – 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; unknown – hepatic steatosis.

Skin and subcutaneous tissue disorders: common – rash, alopecia; unknown – rhabdomyolysis, osteomalacia (manifesting 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; unknown – nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus.

Musculoskeletal and connective tissue disorders: common – decreased bone mineral density.

General disorders: common – fatigue, malaise, fever; very rare – asthenia; unknown – 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 (manifesting 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 medicinal products, 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 hypertrophy, and fat accumulation in the dorsocervical region (buffalo hump).

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

30, 90, or 180 tablets in a plastic bottle containing a silica gel desiccant container.

30, 90, or 180 tablets in a plastic bottle containing a silica gel desiccant container; 1 plastic bottle in a cardboard package.

Prescription category.

Prescription only.

Manufacturer.

Emcure Pharmaceuticals Ltd.

Manufacturer's address and place of business.

Plot No. P-1 and P-2, ITBP Park, Phase II, MIDC, Hinjewadi, Pune - 411 057, Maharashtra, India.