Docvir (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J05AR03 (Tenofovir disoproxil and Emtricitabine)

Active Substances

Emtricitabine (Rec.INN registered by WHO)

Tenofovir (Rec.INN registered by WHO)

Dosage Form

Docvir

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

Dosage Form, Packaging, and Composition

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

Excipients: lactose monohydrate – 72 mg, microcrystalline cellulose 101 – 245 mg, sodium carboxymethyl starch (primogel) – 35 mg, croscarmellose sodium – 60 mg, hydroxypropylmethylcellulose E15 (hypromellose E15) – 9 mg, magnesium stearate – 9 mg.

Composition of the film water-soluble coating: hydroxypropylmethylcellulose E5 (hypromellose E5) – 14 mg, macrogol 6000 (polyethylene glycol 6000) – 1.8 mg, titanium dioxide – 4 mg, polysorbate 80 – 0.2 mg.

10 pcs. – blister packs (3) – cardboard packs.
30 pcs. – polymer jars with first-opening control (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; combinations of antiviral agents for the treatment of HIV infections

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 combined 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 a suppressive 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 on 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 suppressive effect on 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 were identified.

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 combined drug on an empty stomach and with food, the C_max of tenofovir disoproxil fumarate and emtricitabine in serum were 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 combined 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 disoproxil fumarate

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 1 h after administration on an empty stomach and 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 proven that neither Tenofovir disoproxil fumarate nor tenofovir inhibit 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 administration of the drug at different dosing regimens.

Emtricitabine

After oral administration, rapid and significant absorption of emtricitabine is noted; 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) is 1.8±0.7 µg/ml, and the AUC at a 24-hour dosing interval is 10±3.1 h×µg/ml. The mean minimum plasma concentrations of the drug 24 hours after administration at steady state are equal to or exceed the mean IC₉₀ value – the concentration required to suppress the replication of 90% of viruses in vitro.

The mean absolute bioavailability value of emtricitabine in 200 mg capsules when taken on an empty stomach is 93%. The blood content of emtricitabine does not change when emtricitabine is taken simultaneously with food.

In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of concentration in the range from 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 mainly excreted by the kidneys (approximately 86%) and through the intestines (approximately 14%). 13% of the administered dose of emtricitabine was found in the urine in the form of 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 administration of the drug containing emtricitabine in doses from 25 to 200 mg, its pharmacokinetic parameters are proportionally dependent on the dose.

Preclinical safety data

Tenofovir disoproxil fumarate did not show significant carcinogenic activity in long-term studies in rats with oral administration. In mice, a low incidence of duodenal tumors was noted, which were considered probably related to the high concentrations of tenofovir disoproxil fumarate in the gastrointestinal tract when the drug was administered at a sufficiently high dose of 600 mg/kg. The mechanism of tumor formation in mice and the potential significance of this effect for humans are not fully understood. The in vitro mouse lymphoma cell test of tenofovir disoproxil fumarate showed a mutagenic effect, but when studying the mutagenic effect in vitro in a bacterial test (Ames test), negative results were obtained. In the in vivo mouse micronucleus test with the administration of tenofovir disoproxil fumarate to males at doses up to 2000 mg/kg, the result was also negative.

Emtricitabine did not show mutagenic or clastogenic effects in standard genetic toxicity tests. In long-term carcinogenicity studies of emtricitabine administered to rats and mice, no carcinogenic effect of the drug was identified.

Indications

Treatment of HIV-1 and HIV-2 infection in adults (as part of combined antiretroviral therapy).

ICD codes

Dosage Regimen

The drug is taken orally, with meals or on an empty stomach, 1 tablet of the drug once a day.

Antiretroviral therapy is usually indicated for life. The duration of therapy with the drug is determined individually by the attending physician.

Elderly patients should have their dosage regimen carefully selected, taking into account the higher frequency of impaired liver, kidney or heart function, as well as concomitant diseases or the use of other medications.

There is no need to adjust the dose for patients with CrCl 50-80 ml/min. In such patients, constant monitoring of CrCl and serum phosphate levels is necessary. In patients with CrCl 30-49 ml/min, the interval between doses of the drug should be adjusted according to the recommendations given in the table. When treating such patients, it is necessary to monitor the clinical response to treatment and renal function. The drug should not be prescribed to patients with CrCl less than 30 ml/min or with end-stage renal failurerequiring dialysis.

Table. Dose adjustment in patients with altered CrCl

¹ Ideal body weight was used in the calculations.

Given the minimal hepatic metabolism and predominant renal excretion of emtricitabine, the need for dose adjustment of the drug in hepatic impairment seems unlikely.

Adverse Reactions

Since the drug contains Emtricitabine and tenofovir disoproxil fumarate, its use may cause adverse reactions, similar in nature and severity to those that occur when taking these antiretroviral drugs.

Adverse effects were classified by frequency according to WHO recommendations as follows: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%).

Tenofovir disoproxil fumarate

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

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

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

Renal and urinary 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 and connective tissue disorders uncommon – rhabdomyolysis, muscle weakness; rare – osteomalacia (manifested by bone pain, occasionally leading to fractures), myopathy.

Immune system disorders rare – angioedema.

General disorders and administration site conditions very common – asthenia.

Emtricitabine

Blood and lymphatic system disorders common – neutropenia; uncommon – anemia.

Metabolism and nutrition disorders common – hyperglycemia, hypertriglyceridemia.

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

Gastrointestinal 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.

Immune system disorders common – urticaria; uncommon – angioedema.

General disorders and administration site conditions very common – increased creatine kinase activity; common – pain, asthenia.

The adverse reactions presented 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 may occur in response to asymptomatic or residual opportunistic infections, such as cytomegalovirus retinitis, generalized and/or focal infection caused by mycobacteria and pneumonia, autoimmune disorders (e.g., Graves’ disease), which may occur several months after starting treatment.

Contraindications

Renal failure with CrCl <30 ml/min, as well as patients requiring hemodialysis; lactation period; age under 18 years; simultaneous use with didanosine, adefovir and other drugs containing tenofovir or Emtricitabine; hypersensitivity to tenofovir, emtricitabine and/or any other component of the drug.

With caution renal failure with CrCl >30 ml/min and <50 ml/min; elderly age over 65 years.

Use in Pregnancy and Lactation

The drug should be used during pregnancy only if the intended treatment benefit for the mother outweighs the potential risk to the fetus.

HIV-infected women are not recommended to breastfeed to prevent the risk of postnatal HIV transmission.

Use in Hepatic Impairment

The need for dose adjustment of the drug in hepatic impairment is unlikely.

Use in Renal Impairment

The use of the drug is contraindicated in renal failure with CrCl <30 ml/min, as well as in patients requiring hemodialysis.

The drug should be prescribed with caution in renal failure with CrCl >30 ml/min and <50 ml/min.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years.

Geriatric Use

The drug should be prescribed with caution to elderly patients over 65 years of age.

Special Precautions

The drug should not be prescribed simultaneously with drugs that contain tenofovir, Emtricitabine, or with drugs that contain lamivudine (due to its similarity to emtricitabine) or adefovir (due to its similarity to tenofovir).

The use of the drug as a component of a three-component nucleoside treatment regimen is not recommended.

To avoid complications, the drug should be used under the supervision of a physician experienced in the management of HIV-infected patients.

Patients should be warned that they should not simultaneously use other drugs on their own.

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

Therapy with the drug does not reduce the risk of transmitting HIV to other people through sexual contact or blood transfusion and therefore does not cancel the need to observe appropriate precautions.

When using nucleotide and nucleoside analogues in HIV-infected individuals in combination with other antiretroviral drugs, the development of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, has been reported. Clinical and laboratory signs of lactic acidosis are usually detected several months after the start of treatment, but the development of this complication in a shorter time is possible. It develops more often in patients with liver diseases and in obese patients, especially women. Due to the high risk of developing 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). A special risk group may be patients with co-infection with hepatitis C virus receiving therapy with interferon alfa and ribavirin. The use 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 a patient develops clinical signs (nausea, vomiting, abdominal pain, general malaise, loss of appetite, weight loss, breathing difficulties, neurological symptoms – impaired motor functions, muscle weakness) or laboratory signs of lactic acidosis (lactic acid concentration in blood serum 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 in patients co-infected with HIV and hepatitis virus is higher than in those with HIV infection alone. Therefore, patients with chronic hepatitis B or C who are concurrently receiving antiretroviral therapy are at an increased risk of adverse liver effects with a potentially fatal outcome. 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 for the treatment of chronic hepatitis B have not been established. Emtricitabine, tenofovir, and their combination have demonstrated activity against the hepatitis B virus in pharmacodynamic studies. Limited experience suggests that Emtricitabine and tenofovir possess activity against the 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 acute exacerbations of hepatitis may occur after discontinuation of therapy with the drug. In HIV and hepatitis B co-infected patients who discontinue the drug, liver function should be monitored clinically and laboratory for at least 6 months. In some cases, resumption of chronic hepatitis B therapy may be required. Discontinuation of therapy is not recommended in patients with severe liver disease (cirrhosis), 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 closely 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 with the use of tenofovir in clinical practice. It is recommended to determine creatinine clearance in all patients 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 dysfunction, including during therapy with adefovir, creatinine clearance and serum phosphorus levels should be regularly monitored. The potential benefit of taking the drug should be weighed against the potential risk of renal toxicity.

Concomitant or recent use of the drug with nephrotoxic drugs should be avoided.

A clinical study observed a decrease in bone mineral density in the lumbar spine and hip bones during treatment with the fixed-dose combination product containing tenofovir disoproxil fumarate and emtricitabine. Most cases of decreased bone mineral density were observed within the first 24-48 weeks and persisted through 144 weeks of the study. Bone status should be monitored in HIV-infected patients with a history of pathological bone fractures and risk of osteopenia. If a bone abnormality is suspected, appropriate examination should be performed.

Fat accumulation/redistribution has been observed in patients receiving antiretroviral therapy, including central obesity, dorsocervical fat deposition (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance.” The mechanism and long-term consequences of these events 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 whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Such reactions are usually observed within the first few weeks or months of initiating antiretroviral therapy. Patients should be closely monitored by physicians experienced in treating patients with HIV-associated diseases. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome) may also occur in the setting of immune reconstitution. The time to onset is variable and can occur many months after initiation of therapy and may present with atypical course.

Clinical studies in HIV-infected patients have shown that regimens containing three nucleoside reverse transcriptase inhibitors are generally less effective than triple therapeutic regimens containing two nucleoside reverse transcriptase inhibitors in combination with either a non-nucleoside reverse transcriptase inhibitor or an HIV-1 protease inhibitor. A reduced virologic response has been reported with triple nucleoside therapy (tenofovir in combination with abacavir and lamivudine, as well as in combination with lamivudine and didanosine), along with the development of resistance early in the use of these combinations when the drugs were taken once daily. Therefore, triple nucleoside reverse transcriptase inhibitor regimens should be used with caution. Patients taking a triple regimen consisting only of nucleoside reverse transcriptase inhibitors should be carefully evaluated and consideration given to modifying therapy.

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases have been reported, particularly in patients with advanced HIV disease and/or long-term exposure to antiretroviral therapy. Patients should be advised to seek medical consultation if they experience symptoms such as joint stiffness, aches and pains, or difficulty in movement.

Nucleotide and nucleoside analogues have been shown to cause mitochondrial damage in vitro and in vivo. Data exist on the development of mitochondrial dysfunction in HIV-negative children exposed in utero and/or postnatally to nucleoside analogues. The main manifestations of mitochondrial dysfunction, which were often transient, were hematological disorders (anemia, neutropenia), hyperlactatemia, and increased lipase activity. Some delayed neurological disorders have been reported (hypertonia, convulsions, behavioral disorders). It is currently unknown whether these neurological disorders are transient or permanent. Children exposed in utero to nucleos(t)ide analogues, including HIV-negative children, who present with serious clinical symptoms, particularly neurological symptoms, should be offered clinical and laboratory follow-up to assess potential mitochondrial dysfunction.

Hepatotoxic reactions occur at various 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 Use Machines

No studies on the effects of the drug on the ability to drive or operate machinery have been performed. Patients should be informed about possible dizziness during treatment with the drug. If dizziness occurs, they should refrain from such activities.

Drug Interactions

Concomitant administration of tenofovir with didanosine increases the systemic exposure of didanosine by 40-60%, thereby increasing the risk of didanosine adverse 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 (likely due to increased intracellular phosphorylation of didanosine). Concomitant use of the tenofovir+Emtricitabine combination and didanosine is not recommended.

The drug should not be used concomitantly with adefovir, as in vitro studies have shown nearly identical antiviral activity of tenofovir and adefovir.

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

Atazanavir may increase the concentration of tenofovir. The mechanism of this interaction has not been established. 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.

Concomitant use with lopinavir/ritonavir or with darunavir/ritonavir increases the AUC of tenofovir by 32% and 22%, respectively, which may potentially lead to tenofovir adverse effects, including renal impairment. Careful monitoring of renal function is necessary.

Tenofovir is eliminated from the body primarily 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 eliminated by the kidneys. Concomitant or recent use of the tenofovir+Emtricitabine combination with nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, foscarnet, pentamidine, vancomycin, cidofovir, ganciclovir, or interleukin-2) should be avoided.

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.

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.