Elpida^® Combi (Tablets) Instructions for Use

Marketing Authorization Holder

Elpida, LLC (Russia)

Manufactured By

Chemical Diversity Research Institute LLC (Russia)

Or

Pharmstandard-Lexredstva OJSC (Russia)

ATC Code

J05AR (Combined antiviral drugs for the treatment of HIV infection)

Active Substances

Emtricitabine (Rec.INN registered by WHO)

Tenofovir (Rec.INN registered by WHO)

Elsulfavirine (Prop.INN proposed by WHO)

Dosage Form

Elpida® Combi

Film-coated tablets, 300 mg+20 mg+200 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets blue in color, oval, biconvex; the tablet core on the cross-section is white or almost white.

Excipients: lactose monohydrate, microcrystalline cellulose 102, croscarmellose sodium, pregelatinized starch, povidone K30, magnesium stearate.

Film coating composition Vivacoat^® PC-8T-181 blue [lactose monohydrate, hypromellose, titanium dioxide, triacetin, indigo carmine dye (E132)].

30 pcs. – polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

A combined antiviral drug with fixed doses of tenofovir disoproxil fumarate and emtricitabine. It has specific activity against the human immunodeficiency virus (HIV-1 and HIV-2) and the hepatitis B virus.

Tenofovir is a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate, which is a nucleotide reverse transcriptase inhibitor. Emtricitabine is a nucleoside analogue of cytidine.

Tenofovir and Emtricitabine are phosphorylated by intracellular enzymes to form tenofovir diphosphate and emtricitabine triphosphate, respectively. Both tenofovir and Emtricitabine can be fully phosphorylated when simultaneously present in cells. Tenofovir diphosphate and emtricitabine triphosphate compete with natural substrates deoxyadenosine 5′-triphosphate and deoxycytidine 5′-triphosphate, respectively, inhibiting HIV-1 reverse transcriptase, resulting in termination of DNA chain synthesis. Both tenofovir diphosphate and emtricitabine triphosphate are weak inhibitors of mammalian DNA polymerases, and no signs of mitochondrial toxicity were observed in vitro and in vivo.

When using a combination drug containing a fixed dose of Tenofovir disoproxil fumarate and Emtricitabine, a synergy of antiviral activity was noted in vitro. In studies of the combined use of the drug with HIV protease inhibitors and with nucleoside and non-nucleoside HIV-1 reverse transcriptase inhibitors, additive or synergistic effects were observed.

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was evaluated in lymphoblastoid cell lines, primary monocytes/macrophages, and peripheral blood lymphocytes. The EC₅₀ was 0.04-8.5 µmol. In cell culture, tenofovir exhibited antiviral activity against HIV-1 subtypes A, B, C, D, E, F, G (EC₅₀ ranged from 0.5-2.2 µmol), as well as an inhibitory effect on some HIV-2 strains (EC50 ranged from 1.6-4.9 µmol).

The antiviral activity of emtricitabine against laboratory and donor strains of HIV-1 was evaluated in colonies of lymphoblastoid cells (MAGI-CCR5 cell line) and peripheral blood mononuclear cells. The EC₅₀ ranged from 0.0013 to 0.64 µmol (0.0003-0.158 mg/ml).

Emtricitabine exhibited antiviral activity in cell culture against HIV-1 subtypes A, B, C, D, E, F, and G (EC₅₀ was 0.007-0.075 µmol) and showed selective inhibitory activity against some HIV-2 strains (EC₅₀ was 0.007-1.5 µmol).

In in vitro studies and in some patients infected with HIV-1, resistance to tenofovir and emtricitabine was observed, the occurrence of which was due to K65R and M184V/I amino acid substitutions in HIV reverse transcriptase, respectively.

No other mechanisms for the development of resistance to tenofovir or emtricitabine have been identified.

Elsulfavirine is rapidly metabolized in the liver to form an active metabolite, which is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). The active metabolite inhibits HIV-1 reverse transcriptase and does not inhibit HIV-2 reverse transcriptase and human DNA polymerase (α, β, γ, δ). Elsulfavirine has a broad spectrum of antiviral activity against various strains and clinical isolates of HIV infection, including those resistant to other NNRTIs. Elsulfavirine specifically inhibits the DNA polymerase activity of HIV-RT in vitro, including with mutations V106A, G190A, L100I/K103N and K103N/Y181C.

Pharmacokinetics

One tablet of the drug is bioequivalent to one capsule of emtricitabine (200 mg) plus one tablet of tenofovir disoproxil fumarate (300 mg). After a single dose of the combination drug on an empty stomach and with food, the C_max of tenofovir disoproxil fumarate and emtricitabine in serum was observed in the range from 0.5 to 3 h and from 0.5 to 4.1 h, respectively. As a result of taking the combination drug tablets with food, its bioavailability increased, with the AUC and C_max of tenofovir increasing by approximately 35% and 15%, respectively, while the content of emtricitabine did not change.

Tenofovir

After oral administration in HIV-infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. The C_max of tenofovir in serum is reached within 1 h after administration on an empty stomach and within 2 h after administration with food. The bioavailability of tenofovir and tenofovir disoproxil fumarate after oral administration on an empty stomach is approximately 25%.

The binding of tenofovir disoproxil fumarate to human plasma proteins in vitro is less than 0.7% and is independent of concentration in the range of 0.01-25 µg/ml. In vitro studies have shown that neither tenofovir disoproxil fumarate nor tenofovir inhibits human cytochrome P450 enzymes. Moreover, at concentrations significantly above therapeutic levels (more than 300 times), tenofovir does not affect metabolic processes involving other cytochrome P450 isoenzymes (cytochrome P3A4, P2D6, P2C9, P2E1, etc.). Tenofovir disoproxil fumarate does not affect cytochrome P450 isoenzymes except for P1A1/2, where small but statistically significant changes (6%) were observed. The elimination of tenofovir occurs mainly through the kidneys via glomerular filtration and active tubular secretion.

After a single oral dose of the drug, the T_1/2 of tenofovir is approximately 17 h.

Studies show that the pharmacokinetics of tenofovir is independent of the dose of tenofovir disoproxil fumarate (with a dosing regimen from 75 to 600 mg), as well as in cases of multiple doses of the drug at different dosing regimens.

Emtricitabine

After oral administration, emtricitabine is rapidly and extensively absorbed; C_max in plasma is reached 1-2 h after administration. After multiple oral doses of emtricitabine in 20 HIV-infected patients, the C_max of emtricitabine in plasma at steady state (mean±standard deviation) was 1.8±0.7 µg/ml, and the AUC over a 24-hour dosing interval was 10±3.1 h×µg/ml. The mean minimum plasma concentrations of the drug 24 hours after administration at steady state are at or above the mean IC₉₀ concentration required to suppress replication of 90% of viruses in vitro.

The mean absolute bioavailability of emtricitabine in 200 mg capsules when taken on an empty stomach is 93%. The blood levels of emtricitabine do not change when emtricitabine is taken concomitantly with food.

In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of concentration in the range of 0.02 to 200 µg/ml. Data from in vitro studies indicate that Emtricitabine does not have an inhibitory effect on human cytochrome P450 isoenzymes. Emtricitabine is excreted mainly by the kidneys (approximately 86%) and through the intestines (approximately 14%). 13% of the administered dose of emtricitabine was found in the urine as three presumed metabolites. The systemic clearance of emtricitabine averages 307 ml/min.

The metabolites of emtricitabine include 3′-sulfoxide diastereomers (approximately 9% of the dose) and their glucuronic acid conjugate in the form of 2-O-glucuronide (approximately 4% of the dose). After a single oral dose, the T_1/2 of emtricitabine is approximately 10 h. With subsequent course dosing, the value of the intracellular T_1/2 of emtricitabine-5-triphosphate (the active part of emtricitabine) in peripheral blood mononuclear cells is 39 h.

Emtricitabine is excreted by glomerular filtration and active tubular secretion.

With multiple doses of the drug containing emtricitabine in doses from 25 to 200 mg, its pharmacokinetic parameters are proportionally dependent on the dose.

Elsulfavirine

After oral administration, elsulfavirine is rapidly absorbed into the systemic circulation. The C_max of the active metabolite after a single dose of elsulfavirine 20 mg averages 98 ng/ml and is achieved within 3.5 h. With multiple doses of elsulfavirine 20 mg/day, the C_max of its active metabolite in blood plasma is 164 ng/ml and is achieved in 7-8 days. The active metabolite of elsulfavirine is deposited in blood cells, where its content is significantly higher than in plasma. The C_max value of the active metabolite of elsulfavirine in blood cells is 1041 ng/ml and is reached after 6 days of taking elsulfavirine at a dose of 20 mg/day.

The metabolic stability of elsulfavirine in liver microsomes and hepatocytes of rats, dogs, monkeys, and humans was assessed as quite low; in fraction S9, elsulfavirine was rapidly converted into the active metabolite.

The metabolic stability of the active metabolite of elsulfavirine in liver microsomes and hepatocytes of rats, dogs, monkeys, and humans was assessed as quite high, indicating its low level of metabolism. Its main metabolites in hepatocytes were hydroxylation products followed by glucuronidation, as well as acid and aminosulfonamide.

Elsulfavirine is an inducer of the expression of CYP2B6 and CYP3A4 isoenzyme mRNA, and also strongly induces CYP3A4 activity. The degree of induction of CYP3A4 enzyme and mRNA expression by the active metabolite significantly exceeds the inducing effect of efavirenz and rifampicin. The maximum inducing effect of the active metabolite of elsulfavirine on CYP3A4 at a concentration of 0.1 µmol was comparable to efavirenz and rifampicin at a concentration of 10 µmol.

Elsulfavirine is excreted mainly in the bile as glucuronide metabolites. The T_1/2 of the active metabolite of elsulfavirine from blood plasma is 7-9 days.

Indications

Treatment of HIV-1 infection in adults who have not previously received antiretroviral therapy.

ICD codes

Dosage Regimen

Take one tablet orally once daily with a meal to enhance bioavailability.

Swallow the tablet whole; do not crush or chew.

Adhere strictly to the prescribed dosing schedule to maintain effective drug concentrations and prevent viral resistance.

If a dose is missed and remembered within 12 hours, take the missed dose immediately and then resume the normal schedule.

If more than 12 hours have passed, skip the missed dose and take the next dose at the regular time; do not double the dose.

This regimen is intended for adult patients with HIV-1 infection who are antiretroviral-naïve.

Antiretroviral therapy is typically a lifelong treatment; the specific duration is determined by the physician based on clinical response and tolerability.

Regular monitoring of viral load, CD4 count, renal function, and serum phosphorus is essential during therapy.

Adverse Reactions

Tenofovir

Metabolism disorders very common – hypophosphatemia; uncommon – hypokalemia; rare – lactic acidosis.

Nervous system disorders very common – dizziness; common – headache.

Digestive system disorders very common – diarrhea, vomiting, nausea; common – abdominal pain, bloating, flatulence, increased activity of hepatic transaminases; uncommon – pancreatitis; rare – fatty liver, hepatitis.

Urinary system disorders uncommon – increased creatinine concentration, proteinuria; rare – renal function disorders, including acute, renal failure, acute renal tubular necrosis, proximal renal tubulopathy (including Fanconi syndrome), nephritis, including acute interstitial nephritis, nephrogenic diabetes insipidus.

Skin and subcutaneous tissue disorders common – rash.

Musculoskeletal system disorders uncommon – rhabdomyolysis, muscle weakness; rare – osteomalacia (manifested by bone pain, occasionally leading to fractures), myopathy.

Allergic reactions rare – angioedema.

Other very common – asthenia.

Emtricitabine

Hematopoietic system disorders common – neutropenia; uncommon – anemia.

Metabolism disorders common – hyperglycemia, hypertriglyceridemia.

Nervous system disorders very common – headache; common – dizziness, insomnia, sleep disorders.

Digestive system disorders very common – diarrhea, nausea; common – increased amylase activity, including pancreatic amylase, increased serum lipase activity, vomiting, abdominal pain, dyspepsia, increased AST and/or ALT activity, hyperbilirubinemia.

Skin and subcutaneous tissue disorders common – vesiculobullous, pustular rash, maculopapular rash, pruritus, skin discoloration.

Allergic reactions common – urticaria; uncommon – angioedema.

Other very common – increased creatine kinase activity; common – pain, asthenia.

The adverse reactions listed below may occur with the use of combined antiretroviral therapy.

Metabolic disorders hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperlactatemia, lipodystrophy, including loss of peripheral and facial subcutaneous fat, increase in intra-abdominal and visceral fat, breast hypertrophy, dorsocervical obesity (“buffalo hump”).

Osteonecrosis. Cases of osteonecrosis have been reported, especially in patients with risk factors or on long-term combined antiviral therapy. Frequency unknown.

Immune reconstitution syndrome. Inflammatory reactions in response to asymptomatic or residual opportunistic infections, such as cytomegalovirus retinitis, generalized and/or focal mycobacterial infection and pneumonia, autoimmune disorders (e.g., Graves’ disease), may occur several months after initiation of treatment.

Elsulfavirine

Infectious and parasitic diseases common – herpes simplex; uncommon – genital herpes, oral herpes, fungal infection.

Blood and lymphatic system disorders common – leukopenia, neutropenia.

Endocrine system disorders uncommon – autoimmune thyroiditis.

Psychiatric disorders common – sleep disorder, depressive states (low mood), anxiety, apathy, irritability; uncommon – aggression, mood changes, attention disturbance, obsessive thoughts, nightmares.

Nervous system disorders very common – headache; common – dizziness, unusual dreams, drowsiness; uncommon – decreased concentration, memory impairment, insomnia, poor sleep quality, taste disturbance, paresthesia.

Ear and labyrinth disorders uncommon – hyperacusis, tinnitus.

Respiratory system disorders uncommon – cough, dyspnea, oropharyngeal pain, rhinorrhea, smell disorder.

Digestive system disorders common – nausea, diarrhea, dry mouth, vomiting; uncommon – abdominal discomfort, abdominal pain, belching, glossalgia, colitis.

Skin and subcutaneous tissue disorders common – rash, pruritus; uncommon – hair loss, furunculosis.

Musculoskeletal system disorders uncommon – arthralgia.

Renal and urinary disorders common – mild proteinuria, polyuria; uncommon – urolithiasis, leukocyturia.

Reproductive system and breast disorders uncommon – delayed menstruation, polymenorrhea, sexual dysfunction.

General disorders and administration site conditions common – asthenia, weakness, decreased appetite, increased body temperature; uncommon – chest pain.

Laboratory and instrumental data very common – increased GGT; common – increased ALT activity, increased CPK, increased blood glucose levels; uncommon – increased AST, increased blood pressure, weight loss.

Contraindications

Hypersensitivity to the components of the combination; severe hepatic impairment (Child-Pugh class C), moderate and severe renal impairment (CrCl <60 ml/min); concomitant use with other drugs containing Emtricitabine, tenofovir or other cytidine analogues such as lamivudine; concomitant use with other drugs containing elsulfavirine; concomitant use with adefovir, atorvastatin, omeprazole, clarithromycin, rifabutin, the combination of levonorgestrel + ethinyl estradiol; children and adolescents under 18 years of age; pregnancy and breastfeeding period.

With caution

Concomitant use with other drugs that have nephrotoxic effects (aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, interleukin-2, cidofovir) should be avoided; concomitant use with other drugs containing didanosine is not recommended; patients with diabetes mellitus; elderly patients over 65 years of age; history of hepatic impairment, including chronic hepatitis; mild and moderate hepatic impairment (Child-Pugh class A and B); patients with osteoporosis, at high risk of fractures; severe anemia and pancytopenia; when used concomitantly with NSAIDs, HIV protease inhibitors, boosted with ritonavir or cobicistat; when used concomitantly with antiviral drugs for the treatment of viral hepatitis B (HBV) or C (HCV); when used concomitantly with drugs whose metabolism involves cytochrome isoenzymes CYP2B6 and CYP3A4/

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

Use is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

Use with caution: history of hepatic impairment, including chronic hepatitis; mild to moderate hepatic impairment (Child-Pugh class A and B).

Use in Renal Impairment

Use is contraindicated in renal failure with CrCl <30 ml/min, as well as in patients requiring hemodialysis.

Use with caution in renal failure with CrCl >30 ml/min and <50 ml/min.

Pediatric Use

Use is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients over 65 years of age.

Special Precautions

To avoid complications, use under the supervision of a physician experienced in the management of HIV-infected patients.

Patients should be warned not to self-administer other drugs concurrently.

Irregular use may lead to the development of viral resistance and reduced treatment effectiveness.

Therapy does not reduce the risk of transmitting HIV to others through sexual contact or blood transfusion and therefore does not eliminate the need to observe appropriate precautions.

The use of nucleotide and nucleoside analogues in combination with other antiretroviral drugs in HIV-infected individuals has been reported to cause lactic acidosis and severe hepatomegaly with steatosis, including fatal cases.

Clinical and laboratory signs of lactic acidosis are usually detected several months after starting treatment, but this complication may also develop in a shorter period.

It occurs more frequently in patients with liver disease and in obese patients, especially women.

Due to the high risk of lactic acidosis, caution should be exercised when prescribing the drug to patients (especially overweight women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis (including certain medications and ethanol).

Patients with co-infection with hepatitis C virus receiving therapy with interferon alfa and ribavirin may represent a special risk group.

Administration of nucleoside or nucleotide analogues should be discontinued in patients with symptoms of hyperlactatemia, metabolic lactate acidosis, progressive hepatomegaly, or rapid increase in aminotransferase activity.

If the patient develops clinical (nausea, vomiting, abdominal pain, general malaise, loss of appetite, weight loss, respiratory distress, neurological symptoms – impaired motor functions, muscle weakness) or laboratory signs of lactic acidosis (serum lactate level above 5 mmol/L), or overt hepatotoxicity (which may include liver enlargement and steatosis even in the absence of a marked increase in transaminase activity), treatment with the drug should be discontinued.

The risk of hepatotoxic effects of antiretroviral drugs is higher in patients co-infected with HIV and hepatitis virus than in those with HIV infection alone.

Therefore, patients with chronic hepatitis B or C who are concurrently taking antiretroviral drugs are at increased risk of adverse effects on the liver, potentially with fatal outcomes.

Such patients require careful clinical and laboratory monitoring.

All HIV-infected patients are recommended to be tested for chronic hepatitis B or C before initiating antiretroviral therapy.

The efficacy and safety of the drug in the treatment of chronic hepatitis B have not been established.

Emtricitabine, tenofovir, and their combination have demonstrated activity against hepatitis B virus in pharmacodynamic studies.

Limited experience suggests that Emtricitabine and tenofovir are active against hepatitis B virus when used as part of combination antiretroviral therapy for HIV infection.

In patients co-infected with HIV and hepatitis B virus, severe exacerbations of hepatitis may occur after discontinuation of therapy with the drug.

In HIV and hepatitis B virus co-infected patients who discontinue the drug, liver function should be monitored clinically and by laboratory methods for at least 6 months.

In some cases, resumption of chronic hepatitis B therapy may be required.

In patients with severe liver disease (cirrhosis), discontinuation of treatment is not recommended, as post-treatment flare-ups of hepatitis can lead to hepatic decompensation.

Caution should be exercised when prescribing nucleotide and nucleoside analogues to patients with concomitant hepatitis C receiving therapy with interferon alfa and ribavirin, due to the high risk of lactic acidosis.

Such patients should be carefully monitored, with laboratory parameters controlled.

Cases of renal failure, acute renal failure, increased creatinine concentration, hypophosphatemia, and proximal renal tubulopathy (including Fanconi syndrome) have been reported in clinical practice with the use of tenofovir.

All patients are recommended to determine CrCl before starting treatment and during therapy with the drug as clinically indicated.

In patients at risk of developing renal impairment, including those with previously identified renal impairment, including during therapy with adefovir, CrCl and serum phosphorus levels should be continuously monitored.

The potential benefit of taking the drug should be weighed against the potential risk of renal toxicity.

Avoid concurrent or recent use of nephrotoxic drugs.

Bone status should be monitored in HIV-infected patients with a history of pathological bone fractures and risk of osteopenia.

If a bone system abnormality is suspected, appropriate examination should be performed.

Accumulation/redistribution of adipose tissue has been observed in patients receiving antiretroviral therapy, including central obesity, dorsocervical fat deposition (“buffalo hump”), peripheral fat loss, facial fat loss, breast enlargement, and “cushingoid appearance”.

The mechanism of development and long-term effects of these changes are unknown.

A causal relationship has not been established.

Immune reconstitution syndrome has been reported in HIV-infected patients receiving combination antiretroviral therapy.

During the initial phase of combination antiretroviral treatment, patients with severe immunodeficiency may experience exacerbation of asymptomatic or residual opportunistic infections (infections caused by Mycobacterium avium, cytomegalovirus infection, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may require further examination and treatment.

Such reactions are generally observed within the first few weeks or months of antiretroviral therapy, and patients should be under careful clinical supervision by specialists experienced in treating patients with HIV-associated diseases.

Autoimmune diseases (Graves’ disease, polymyositis, Guillain-Barré syndrome) may also occur in the context of immune reconstitution syndrome.

The timing of initial manifestations varies, and the disease may occur many months after starting therapy and have an atypical course.

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, increased BMI), such cases have been reported, especially in patients with advanced HIV infection and/or those receiving long-term antiretroviral therapy.

Patients should consult their physician if symptoms such as lethargy, joint stiffness, pain, or difficulty moving occur.

Nucleotide and nucleoside analogues have been shown to cause mitochondrial damage in vitro and in vivo.

There are data on the development of mitochondrial dysfunction in HIV-negative children exposed to nucleoside analogues in utero and/or postnatally.

The main manifestations of mitochondrial dysfunction, often transient, were anemia, neutropenia, hyperlactatemia, and increased lipase activity.

Some delayed neurological disorders (hypertension, convulsions, behavioral disorders) have been reported.

It is currently unknown whether these neurological disorders are transient or permanent.

Children exposed to nucleos(t)ide analogues in utero, including HIV-negative children with described or similar symptoms, should be clinically and laboratory monitored for mitochondrial dysfunction.

Hepatotoxic reactions occur at different times during combination antiretroviral therapy.

The risk of hepatotoxicity with combination antiretroviral therapy is higher in patients with pre-existing liver function impairment.

Patients with liver disease receiving the tenofovir+Emtricitabine combination as part of combination antiretroviral therapy should be closely monitored; if signs of worsening liver function appear, the possibility of interrupting or discontinuing therapy should be considered.

Effect on Ability to Drive and Operate Machinery

Patients should be informed about possible dizziness during treatment with the drug.

If dizziness occurs, refrain from engaging in these activities.

Drug Interactions

When tenofovir is taken concomitantly with didanosine, the systemic exposure of didanosine increases by 40-60%, thereby increasing the risk of didanosine side effects (such as pancreatitis, lactic acidosis, including fatal cases).

Concomitant administration of tenofovir and didanosine at a dose of 400 mg/day led to a decrease in CD4 lymphocyte count (probably due to increased intracellular phosphorylation of didanosine).

Concomitant use of the tenofovir+Emtricitabine combination and didanosine is not recommended.

Should not be used concomitantly with adefovir, as in vitro studies have shown almost identical antiviral activity of tenofovir and adefovir.

No significant drug interaction was identified when tenofovir was co-administered with entecavir.

Atazanavir may increase tenofovir concentrations.

The mechanism of this interaction has not been established.

The condition of patients receiving atazanavir together with the tenofovir+Emtricitabine combination should be carefully monitored.

When co-administered with the tenofovir+Emtricitabine combination, it is recommended to take atazanavir at a dose of 300 mg together with ritonavir at a dose of 100 mg.

The drug should not be taken concomitantly with atazanavir without ritonavir.

When used concomitantly with lopinavir/ritonavir or with darunavir/ritonavir, the AUC of tenofovir increases by 32% and 22%, respectively, which may potentially lead to tenofovir side effects, including renal impairment.

Careful monitoring of renal function is necessary.

Tenofovir is eliminated from the body mainly by the kidneys.

Concomitant use of the tenofovir+Emtricitabine combination with drugs that affect renal function or compete for active tubular secretion may increase the serum concentration of tenofovir and/or other co-administered drugs that are renally eliminated.

Avoid using the tenofovir+Emtricitabine combination concomitantly with or after recent treatment with nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, foscarnet, pentamidine, vancomycin, cidofovir, ganciclovir, or interleukin-2).

Given that tacrolimus affects renal function, careful monitoring of the patient’s condition is recommended when tacrolimus is co-administered with the tenofovir+Emtricitabine combination.

Antiretroviral Agents

As part of a phase 3 clinical trial, the drug is used as part of complex ART with a fixed combination of 2 NRTIs – tenofovir and Emtricitabine.

This combination was well tolerated by patients.

In a clinical drug interaction study, the use of elsulfavirin in combination with the HIV protease inhibitors darunavir and ritonavir, as well as the integrase inhibitor raltegravir, was evaluated.

Overall, the concomitant use of the drugs was well tolerated.

Administration of atazanavir after completion of elsulfavirin therapy in another clinical trial led to the development of severe gastrointestinal adverse reactions (nausea, vomiting) characteristic of atazanavir.

Elsulfavirin induces the activity of CYP2B6 and CYP3A4 isoenzymes and may reduce plasma concentrations and, consequently, decrease the activity of drugs that are substrates of these isoenzymes.

Concomitant use of these drugs should be done with caution.

Substrates of CYP2B6 and CYP3A4 isoenzymes whose activity may be reduced when co-administered with elsulfavirin

Substrates of CYP2B6 and CYP3A4

Immunosuppressants (cyclosporine, tacrolimus, sirolimus);

Chemotherapeutic agents (docetaxel, tamoxifen, paclitaxel, cyclophosphamide, doxorubicin, erlotinib, etoposide, ifosfamide, teniposide, vinblastine, vincristine, vindesine, imatinib, sorafenib, sunitinib, vemurafenib, temsirolimus, anastrozole, gefitinib);

Azole antifungals (ketoconazole, itraconazole);

Macrolides (clarithromycin, erythromycin, telithromycin; except azithromycin);

Tricyclic antidepressants (amitriptyline, clomipramine, imipramine, cyclobenzaprine);

Selective serotonin reuptake inhibitors (citalopram, norfluoxetine, sertraline);

Other antidepressants (mirtazapine, nefazodone, reboxetine, venlafaxine, trazodone);

Antipsychotics (haloperidol, aripiprazole, risperidone, ziprasidone, pimozide);

Opioid analgesics (alfentanil, buprenorphine, codeine, fentanyl, hydrocodone, methadone, levacetylmethadol, tramadol);

Benzodiazepines (alprazolam, midazolam, triazolam, diazepam);

Hypnotics (zopiclone, zaleplon, zolpidem);

Statins (atorvastatin, lovastatin, simvastatin, cerivastatin; except pravastatin and rosuvastatin);

Calcium channel blockers (diltiazem, felodipine, nifedipine, verapamil, amlodipine, lercanidipine, nitrendipine, nisoldipine, bepridil);

Antiarrhythmics (amiodarone, dronedarone, quinidine);

PDE5 inhibitors (sildenafil, tadalafil);

Sex hormone agonists and antagonists (finasteride, estradiol, progesterone, ethinyl estradiol, testosterone, toremifene, bicalutamide);

Histamine H₁-receptor antagonists (terfenadine, astemizole, chlorphenamine);

HIV protease inhibitors (indinavir, ritonavir, saquinavir, nelfinavir);

Some corticosteroids (budesonide, hydrocortisone, dexamethasone).

Other CYP2B6 substrates

Bupropion, valproic acid, methoxetamine, propofol, efavirenz.

Other CYP3A4 substrates

Aprepitant, buspirone, warfarin, dapsone, domperidone, donepezil, caffeine, clopidogrel, lidocaine, montelukast, nateglinide, nevirapine, omeprazole, ondansetron, propranolol, salmeterol, cisapride, eplerenone, ergot alkaloids (ergotamine, dihydroergotamine, ergonovine, methylergonovine).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.