Dokvir - instructions for use, doses, side effects, contraindications

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Dosage form: & nbspfilm-coated tablets

Composition:

Active substances:

Tenofovir disoproxil fumarate - 300.0 mg;

Emtricitabine - 200.0 mg

Excipients:

Core: lactose monohydrate - 72.0 mg; cellulose microcrystalline - 245.0 mg; carboxymethyl starch sodium (primogel) - 35.0 mg; croscarmellose sodium - 60.0 mg; hydroxypropyl methylcellulose E 15 (hypromellose E 15) 9.0 mg; magnesium stearate - 9.0 mg.

Film water-soluble shell: hydroxypropylmethylcellulose E 5 (hypromellose E 5) - 14.0 mg; Macrogol 6000 (polyethylene glycol 6000) 1.8 mg; titanium dioxide 4.0 mg; polysorbate 80 - 0.2 mg.

Description:

Oval biconvex tablets, covered with a film coat of white color; the core is white or almost white in cross section.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

Tenofovir Dizoproxil + Emtricitabine

Pharmacodynamics:

Dokvir is a combination drug with a fixed dose of emtricitabine and tenofovir dizoproxil fumarate.

Mechanism of action

Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil fumarate in vivo turns into tenofovir, nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate.

Emtricitabine and tenofovir phosphorylated by the action of intracellular enzymes with the formation of emtricitabine triphosphate and tenofovir diphosphate, respectively. how emtricitabine. and tenofovir, have specific activity against human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.

Emtricitabine and tenofovir phosphorylated by intracellular enzymes with the formation of emtricitabine triphosphate and tenofovir diphosphate, respectively. In studies in vitro it was shown that u emtricitabine, and tenofovir when they are simultaneously present in the cells, can be completely phosphorylated. Emfitabine triphosphate and tenofovir diphosphate inhibit HIV-1 reverse transcriptase by a competitive mechanism, resulting in the termination of viral DNA chain synthesis. Emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerase. In vitro and in vivo data on their toxicity in relation to mitochondria are not available.

Antiviral activity

In studies in vitro synergism of the antiviral activity of the combination of emtricitabine and tenofovir was noted. In studies of combined use of the drug with HIV protease inhibitors, as well as with nucleoside and non-nucleoside HIV reverse transcriptase inhibitors, an additive or synergistic effect was noted.

Resistance

In studies in vitro and some HIV-1-infected patients showed resistance to emtricitabine due to the development of a mutation M184V/1, or tenofovir, due to a mutation K65R. There are no other possible mechanisms for developing resistance to emtricitabine or tenofovir. Viral isolates resistant to emtricitabine with mutations M184V/1, were also resistant to lamivudine, however, remained susceptible to didanosine, stavudine. tenofovir and zidovudine. Mutation K65R can also be observed with the use of abacavir or didanosine and, in turn, lead to a decrease in the effect of these drugs in combination with lamivudine, emtricitabine and tenofovir. It should avoid the use of tenofovir disoproxide fumarate in patients with HIV-1 strains having a mutation K65R.

In HIV-1 infected patients, when an expression of sin is detected and more mutations induced by thymidine analogs, including replacement M41L or L210W in the OT gene, a decrease in the sensitivity to tenofovir of dizoproxil fumarate was noted.

Children

The safety and efficacy of a combination drug with a fixed dose of emtricitabine and tenofovir disoproxil fumarate in children under the age of 18 years has not been studied.

Pharmacokinetics:

Dokvir is a combination of fixed doses of emtricitabine and tenofovir dizoproxil fumarate.

Suction

The bioequivalence of one film-coated tablet, the combined preparation and the combination of a single 200 mg fixed emtricitabine capsule and one film-coated tablet containing 300 mg of tenofovir-dysoproxyl fumarate, when used concomitantly, was confirmed in the evaluation of a single fasting exercise in healthy volunteers. After taking the combined preparation inside by healthy volunteers emtricitabine and tenofovir disoproxil fumarate are rapidly absorbed, and tenofovir disoproxil fumarate is converted into tenofovir. The maximum concentrations of emtricitabine and tenofovir are observed in the serum in the range of 0.5 to 3 hours after administration on an empty stomach. Admission of the combined preparation with food with a high or low fat content resulted in a delay in reaching the maximum tenofovir concentrations by approximately three quarters of an hour and an increase in the values AUC and C_m_Oh tenofovir by approximately 35% and 15%, respectively, compared with fasting.To optimize the absorption of tenofovir, it is recommended to take Dokvir along with the food.

Distribution

After intravenous administration, the volume of emtricitabine and tenofovir distribution was about 1.4 l / kg and 800 ml / kg, respectively. After ingestion of emtricitabine or tenofovir disoproxil fumarate emtricitabine and tenofovir freely distributed in the body. In vitro the binding of emtricitabine to human blood plasma proteins was <4% and did not depend on concentrations ranging from 0.02 to 200 μg / ml. In vitro the binding of tenofovir to plasma or serum proteins was, respectively, less than 0.7 and 7.2% with a tenofovir concentration in the range of 0.01 to 25 μg / ml.

Metabolism

Data on the metabolism of emtricitabine are limited. It is known that emtricitabine is oxidized in the thiol part to form 3'-sulfoxide diastereomers (about 9% of the dose) and conjugates with glucuronic acid in the form of 2'-O-glucuronide (about 4% of the dose). In studies in vitro It is established that neither tenofovir disoproxil fumarate nor tenofovir, are not substrates of enzymes of the cytochrome system. In turn, neither emtricitabine, nor tenofovir, do not inhibit the metabolism of drugs occurring with the participation of basic isoenzymes CYP. Emtricitabine did not inhibit uridine 5'-diphosphoglucuronyl transferase (UDF), an enzyme responsible for the relationship with glucuronic acid.

Excretion

Emtricitabine is mainly excreted by the kidneys, the accepted dose is found in urine (almost 86%) and feces (about 14%). 13% of the accepted dose of emtricitabine is found in the urine as three metabolites. The total elimination rate of emtricitabine is 307 ml / min. After oral administration, the half-life of emtricitabine is about 10 hours.

Tenofovir is mainly excreted by the kidneys, both by filtration and by the active tubular transport system. Approximately 70-80% of the administered dose is excreted unchanged in urine after intravenous administration. The observed clearance of tenofovir was, on average, about 307 ml / min. The renal clearance was approximately 210 ml / min, which exceeds the glomerular filtration rate. This indicates that active tubular secretion is an important part of the tenofovir withdrawal process. After oral administration, the half-life of tenofovir is approximately 12-18 hours.

Pharmacokinetics the special patient groups

Elderly patients

The pharmacokinetics of emtricitabine or tenofovir in elderly patients (aged 65 years and older) have not been studied.

Floor

The pharmacokinetics of emtricitabine and tenofovir in males and females are similar.

Race

There were no clinically significant differences in the pharmacokinetics of emtricitabine in people of different ethnic origins. The characteristics of the pharmacokinetics of tenofovir in representatives of different ethnic groups have not been studied.

Children

In general, the pharmacokinetic parameters of emtricitabine in newborns, children (aged 4 months to 18 years) are similar to those observed in adults. The pharmacokinetics of tenofovir in children (under 18 years of age) has not been studied.

Violation of the function of the nights

There are few data on the pharmacokinetics of emtricitabine and tenofovir in patients with impaired renal function after simultaneous use as separate drugs or as part of a combination drug. Pharmacokinetic parameters were determined by single administration of 200 mg of emtricitabine or 300 mg of tenofovir disoproxil fumarate patients with impaired renal function varying degrees of severity, in the absence of HIV infection.The severity of renal function was determined by creatinine clearance value (CC) (kidney function is compromised if QA> 80 ml / min, slight breach - if QA is 50-79 ml / min, medium violation with CC 30-49 ml / min and severe impairment - with QC 10-29 ml / min).

Average values (% CV) Exposure of FTC increased from 12 ug * hr / ml (25%) patients in the absence of renal dysfunction and up to 20 mcg * hr / ppm (6%). 25 ug * hr / ml (23%) and 34 ug * hr / ml (6%) in patients with mild, moderate and severe renal impairment, respectively.

Mean values (%CV) Tenofovir Exposure increased from 2185 ng * h / ml (12%) in patients with normal renal function up to 3064 ng * h / ml (30%), 6009 ng * h / ml (42%) and 15985 ng * hr / ml ( 45%) in patients with mild, moderate and severe impairment of renal function, respectively.

It is assumed that an increase in the interval between doses of a combined preparation in patients with impaired renal function of an average degree will cause an increase in peak plasma concentrations and a decrease in levels Cmin, if compared with patients with normal renal function. The clinical manifestations of this are unknown.

In patients with terminal renal failure,between hemodialysis procedures, the concentration of emtricitabine in the blood gradually increases over a period of more than 72 hours to 53 μg * h / ml (19%), and the concentration of tenofovir. in the period of more than 48 hours, it rises to 42857 ng * h / ml (29%).

Patients with QC 30-49 ml / min are recommended to correct the interval between doses of the drug Dokvir. The use of a combination drug is contraindicated in patients with QC <30 ml / min or those who are on hemodialysis (see section "Method of administration and dose").

A small clinical study was conducted to assess the safety, antiviral activity, and pharmacokinetics of tenofovir disoproxil fumarate in combination with emtricitabine in HIV-infected patients with impaired renal function. In a subgroup of patients with a baseline creatinine clearance of 50-60 ml / min, taking the drug 1 time per day resulted in a 2-4 one-time increase in tenofovir exposure and impaired renal function.

Impaired liver function

The pharmacokinetics of the combined preparation in patients with impaired liver function has not been studied. However, the need for dose adjustment for patients with impaired liver function is unlikely.

The pharmacokinetics of emtricitabine in patients not infected with hepatitis B virus (HBV) with different degrees of liver function abnormalities have not been investigated. In general, the pharmacokinetics of emtricitabine in patients infected with HBV was similar to pharmacokinetics in healthy and HIV-infected patients.

A single dose of 300 mg of tenofovir, dizoproxil fumarate, was taken by patients not infected with HIV, with a violation of liver function of various degrees, as determined by the Child-Pugh classification. In patients with impaired hepatic function, no significant changes in the pharmacokinetics of tenofovir were noted, suggesting that there is no need for dose adjustment. Average (% CV) the C_mOhand AUC₀- ∞ Tenofovir was 223 (34.8%) ng / ml and 2050 (50.8%) ng * h / ml, respectively, in persons without impaired liver function, 289 (46.0%) ng / ml and 2310 (43, 5%) ng * h / ml in people with a moderate liver function disorder, and 305 (24.8%) ng / ml and 2740 (44.0%) ng * h / ml in those with severe liver dysfunction.

Indications:

Treatment of HIV-1 infection in adults in combination with other antiretroviral drugs.

Contraindications:

- Hypersensitivity to active ingredients or any other component of the drug;

- Children under 18 years of age (effectiveness and safety not established);

- Renal failure of severe degree (CK <30 ml / min) or CRF, when hemodialysis is required (safety not established in this patient population);

- Lactation period;

- Simultaneous reception with other drugs containing emtricitabine, tenofovir, or other cytidine analogs, such as lamivudine (see the sections "Interaction with other drugs" and "Special instructions");

- Simultaneous admission with adefovir (see the sections "Interaction with other drugs" and "Special instructions");

- In patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption, since the preparation contains lactose.

Carefully:

- in patients with diabetes mellitus;

- in elderly patients (over the age of 65);

- in patients with impaired renal function (see section "Special instructions");

- in patients who simultaneously take other drugs that have a nephrotoxic effect (aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, interleukin-2, cidofovir); tacrolimus; non-steroidal anti-inflammatory drugs; HIV protease inhibitors, potentiated with ritonavir or a cobicystate (see "Interactions with other drugs" and "Special instructions");

- in patients with a history of liver disease, including hepatitis (see section "Special instructions");

- joint taking of tenofovir and didanosine is not recommended (see the sections "Interaction with other drugs" and "Special instructions").

Pregnancy and lactation:

Pregnancy

Data from a sample of the average volume in pregnant women (300 to 1000 pregnancies) indicate a lack of developmental or toxic effects on the fetus / newborn that would be associated with taking emtricitabine or tenofovir. Studies on animals did not indicate the toxic effects of emtricitabine and tenofovir on reproductive function. Thus, if necessary, the possibility of using Dokvir during pregnancy can be considered.

Breastfeeding period

Studies have shown that emtricitabine and tenofovir are excreted in breast milk.Data on the effects of emtricitabine and tenofovir on neonates / infants are inadequate. Therefore do not use Dokvir during lactation. In general, women who are infected with HIV are not recommended to breast-feed to prevent the transmission of HIV to the child.

Fertility

There is no evidence of the effect of the combination drug on fertility in humans. Studies in animals do not indicate a harmful effect of emtricitabine or tenofovir on fertility.

Dosing and Administration:

Inside, with food. The tablet should be swallowed whole, washed down with water. Tablets can not be chewed or broken.

Treatment should begin with a doctor who has experience in the treatment of HIV infection.

Adults

The recommended dose of Dokvir is 1 tablet per day inside. To optimize the absorption of tenofovir, it is recommended to take the drug with food. Even mild food improves the absorption of tenofovir from the combined tablet.

If it is necessary to adjust the dose or stop taking one of the components of the drug Dokvir, the patient should be transferred to receive certain preparations of emtricitabine or tenofovir.

If the dose was missed and passed less than 12 hours from the usual dose, the patient should take the drug as soon as possible with food and return to the usual regimen. If, in case of missed dose, more than 12 hours have elapsed from the usual time of taking the drug, the patient should not take the missed dose, but it is necessary to return to the usual mode of taking the drug.

If within 1 hour after taking the drug the patient has vomiting, you should take another pill. If vomiting in the patient occurred more than 1 hour after taking the drug, then another tablet should not be taken.

Special patient groups

Elderly patients

There are no data on which to base recommendations for dosing for patients over the age of 65 years. However, in the absence of signs of renal failure, correction of the recommended daily dose for adults is not required.

Violation kidney function

Emtricitabine and tenofovir are excreted from the body with urine, therefore, patients with impaired renal function have a longer period of excretion emtricitabine and tenofovir. Data on the safety and efficacy of using a combination drug in patients with impaired renal function of medium and severe degree (CC <50 ml / min) are limited. Evaluation of safety indicators for mild renal dysfunction (KK 50-80 ml / min) was not conducted in the long term. For this reason, patients with dysfunctions should use Dokvir only if the potential benefit of treatment is considered to be greater than the potential risk. Patients with impaired renal function may need careful monitoring of kidney function. Correction of the dosing interval is recommended for patients with QC from 30 to 49 ml / min. This dose adjustment has not been confirmed by clinical studies, so the clinical response to treatment in these patients should be carefully monitored.

Violation of the function of the kidneys of mild degree (KK 50-80 ml / min). Limited data obtained as a result of clinical studies, support the preservation of the dosing regimen of the combined preparation once a day for patients with minor renal dysfunction.

Violations of the function of the kidneys of medium degree (KK 30-49 ml / min).The intake of 1 tablet of the combined preparation every 48 hours is recommended based on the results of modeling the pharmacokinetic data of a single dose of emtricitabine and tenofovir in volunteers without HIV infection with varying degrees of renal impairment.

Violation of the function of the kidneys of severe degree (CK <30 ml / min) and patients on hemodialysis. Dokvir is contraindicated in patients with severe renal dysfunction (CK <30 ml / min) and patients who require hemodialysis, because the required dose reduction can not be achieved with a fixed combination.

Impaired liver function

The pharmacokinetics of the drug and emtricitabine have not been studied in patients with impaired hepatic function. The pharmacokinetics of tenofovir has been studied in patients with impaired hepatic function, there is no need for dose correction. Given the minimal hepatic metabolism and what emtricitabine is excreted in the urine, it is unlikely that a dose adjustment of the combined drug in patients with impaired liver function will be required.

It is necessary to closely monitor patients with concomitant HBV infection.if they stopped taking the drug, since after the drug is discontinued there is a risk of exacerbation of hepatitis.

Children

The effectiveness and safety of the use of a combination drug in children under 18 years of age is not established.

Side effects:

Since Dokvir contains emtricitabine and tenofovir disoproxil fumarate, then it can lead to the occurrence of adverse reactions, in nature and severity similar to those that occur when taking these antiretroviral drugs. There have been reports of rare cases of renal failure and proximal tubulopathy (including Fanconi syndrome) in patients who received tenofovir, which sometimes led to disturbances in the metabolism of bone tissue (occasionally contributing to the development of fractures). It is recommended to monitor kidney function in patients receiving a combination drug (see section "Special instructions").

The use of tenofovir and emtricitabine may be accompanied by the development of lactic acidosis, severe hepatomegaly with fatty liver infiltration and lipodystrophy (see section "Special instructions").

The simultaneous use of tenofovir and didanosine is not recommended,as this may lead to an increased risk of adverse reactions (see section "Interaction with other drugs"). Rarely reported pancreatitis and lactic acidosis, sometimes with a fatal outcome (see section "Special instructions").

Cancellation of the drug Dokvir in HIV-infected patients with concomitant hepatitis B may be accompanied by severe exacerbation of hepatitis (see section "Special instructions").

Data on adverse reactions in the form of summary tables

Adverse reactions observed in clinical studies and in routine clinical practice, considered as at least possibly associated with the components of the combined preparation, are given below (Table 1) for organ system classes and frequency. Among the adverse reactions possibly associated with emtricitabine and / or tenofovir, nausea (12%) and diarrhea (7%) were most commonly reported in an open, randomized clinical trial.

Within each frequency group, adverse reactions are given in order of severity. Adverse reactions in frequency are defined as: very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1000 to <1/100) and rarely (> 1 / 10,000 to <1/1000). Table 1

Adverse reactions associated with taking the combined preparation and relating to individual components, based on clinical research and post-registration analysis

Frequency		Emtricitabine	Tenofovir
Violations from the blood and lymphatic system:
Often		Neutropenia
Infrequently		Anemia³
Immune system disorders:
Often		Allergic reaction
Disorders from the metabolism and nutrition:
Often			Hypophosphatemia¹
Often		Hyperglycemia, hypertriglyceridemia
Infrequently			Hypokalemia¹
Rarely			Lactic acidosis²
Disorders of the psyche:
Often		Unusual dreams, insomnia
Disturbances from the nervous system:
Often		Headache	Dizziness
Often		Dizziness	Headache
Disorders from the gastrointestinal tract:
Often		Diarrhea, nausea	Diarrhea, vomiting, nausea
Often		A general increase in amylase activity, including those associated with changes in the pancreas, increased lipase activity, vomiting, abdominal pain, indigestion	Abdominal pain, swelling, flatulence
Infrequently			Pancreatitis²
Disorders from the liver and bile ducts:
Often		Increased activity of ACT and / or ALT, hyperbilirubinemia	Increased activity of "liver" transaminases
Rarely			Fatty degeneration of the liver², hepatitis
Disturbances from the skin and subcutaneous tissues:
Often			Skin rash
Often		Vesiculobuluse, pustular, maculopapular rash, skin rash, itching, urticaria, skin discoloration (increased pigmentation)³
Infrequently		Angioedema⁴
Rarely			Angioedema
Disturbances from the musculoskeletal and connective tissue:
Often		Increased activity of creatine kinase
Infrequently			Rhabdomyolysis¹, muscle weakness¹
Rarely			Osteomalacia (manifested by pains in the bones and fractures of bones in individual cases)^1,4, myopathy¹
Disorders from the kidneys and urinary tract:
Infrequently			Increase in creatinine, proteinuria
Rarely			Renal failure (acute and chronic), acute tubular necrosis, proximal tubulopathy including Fanconi syndrome, nephritis (including acute interstitial nephritis)⁴, nephrogenic diabetes mellitus
General disorders and disorders at the site of administration:
Often			Asthenia
Often	Pain, asthenia

¹This side effect may appear as a consequence of proximal tubulopathy. In the absence of this condition, it is considered that the occurrence of this side reaction is not a causal relationship with the use of tenofovir.

²A detailed description of the individual adverse reactions is given below.

³With the use of emtricitabine in children, anemia has been observed frequently, and skin color changes (areas of hyperpigmentation) are very common.

⁴A side effect was established during post-registration follow-up, but was not recorded in randomized, controlled clinical trials involving adults or clinical trials using emtricitabine with HIV-infected children, or in randomized controlled clinical trials, or in an expanded tenofovir access program. The frequency was determined by the method of statistical calculation, based on the total number of patients who received emtricitabine in randomized controlled clinical trials (n = 1563) or tenofovir in randomized controlled clinical trials and in an extended access program (n = 7319).

Description of individual adverse reactions

Impaired renal function

Since taking Dokvir can lead to impaired renal function, it is recommended to monitor their function (see section "Special instructions"). Proximal tubulopathy, as a rule, disappeared or there was an improvement after the withdrawal of tenofovir. However, in some patients, the elimination of tenofovir resulted in incomplete recovery of the lowered QC level. Patients at risk of developing renal failure (eg, patients with a baseline risk of kidney failure, concomitant HIV infection, concomitant therapy with nephrotoxic drugs) are at increased risk of incomplete renal function recovery despite the withdrawal of tenofovir (see section "Specific guidance").

Interaction with didanosine

Simultaneous use of tenofovir and didanosine is not recommended, as this leads to an increase in systemic exposure to didanosine by 40-60%, which may increase the risk of side effects associated with didanosine (see section "Interaction with other drugs"). Rarely reported cases of pancreatitis and lactic acidosis, sometimes with a fatal outcome.

Lipids, lipodystrophy and metabolic disorders

It is marked link between the combination antiretroviral therapy and metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia. It noted the link between combination antiretroviral therapy, and the redistribution of fat tissue in the body of HIV-infected patients (lipodystrophy), including the loss of subcutaneous fat in the limbs and face, increased intraperitoneal and visceral fat hypertrophy of the mammary glands and fat accumulation in dorsotservikalnoy area ( "buffalo hump ").

Immunodeficiency Syndrome

In HIV-infected patients with severe forms of immunodeficiency, the onset of combined antiretroviral therapy may result in an inflammatory response to asymptomatic or residual opportunistic infections. Also reported were autoimmune disorders (such as Graves' disease); However, the time of onset of such events varies greatly, and these cases may have occurred several months after the start of treatment.

Osteonecrosis

Osteonecrosis has been reported, in particular in patients with known risk factors, late stage HIV infection, or long-term use of combined antiretroviral therapy. The frequency of occurrence of this phenomenon is unknown (see section "Special instructions").

Lactic acidosis and severe hepatomegaly with fatty dystrophy

When using nucleoside analogues, lactoacidosis was reported, which is usually accompanied by fatty liver dystrophy. Treatment with analogues of nucleosides should be discontinued in the presence of symptomatic hyperlactatemia and metabolic lactic acidosis, progressive hepatomegaly or a rapid increase in the level of aminotransferase (see section "Special instructions").

Children

Data on safety for children under 18 years is not enough. In this population, taking a combination drug is contraindicated.

Other special patient groups

Elderly patients

The study of the use of a combination drug in patients over the age of 65 years was not conducted. Patients of advanced age are more likely to have a decreased renal function,therefore, during treatment with Dokvir, patients from this population should be especially careful.

Patients with impaired renal function

Because the tenofovir can cause kidney damage, patients with renal dysfunction who take the combined drug, continuous monitoring of renal function is recommended (see sections "Special instructions" and "Method of administration and dose").

Co-infections of HIV / HBV or HIV / HCV

The safety profile of emtricitabine and tenofovir in patients with coinfection with HIV / HBV or HIV / HCV was similar to the safety profile observed in patients infected with HIV alone. Nevertheless, as expected, the increase in ACT and ALT activity in this group of patients was more common than in the general population of HIV-infected patients.

Exacerbations of hepatitis after discontinuation of treatment

HIV-infected patients with concomitant HBV infection had clinical and laboratory signs of worsening of hepatitis after discontinuation of treatment.

Overdose:

In case of an overdose, the patient should be observed regarding the manifestations of toxicity and, if necessary,apply standard maintenance treatment.

Up to 30% of the dose of emtricitabine and approximately 10% of the dose of tenofovir can be withdrawn by hemodialysis. It is not known whether emtricitabine or tenofovir by peritoneal dialysis.

Interaction:

Since the Dokvir preparation contains emtricitabine and tenofovir, all cases of drug interaction found with these active substances may also occur with the use of the combined preparation. Studies of drug interactions were conducted only in adults.

Admission of emtricitabine along with tenofovir did not affect the pharmacokinetics of emtricitabine and tenofovir in a steady state, unlike the administration of each drug alone. Research in vitro, as well as clinical studies of pharmacokinetic interactions have confirmed the low probability of CD450-mediated interactions between emtricitabine and tenofovir with other drugs.

Simultaneous use is not recommended

Dokvir should not be given concomitantly with other cytidine analogues, such as lamivudine.

Dokvir is a combination drug with a fixed dose of emtricitabine and tenofovir, so it should not be used concomitantly with other drugs containing any of the components: emtricitabine or tenofovir.

The drug should not be used concomitantly with adefovir.

Didanosine

The simultaneous use of Dokvir and didanosine is not recommended (see section "Special instructions").

Medicines that are excreted by the kidneys

Because the emtricitabine and tenofovir are mainly excreted by the kidneys, the combined use of the drug Dokvir with drugs that reduce renal function or compete for active tubular secretion (for example, with cidofovir) can increase serum concentrations of emtricitabine, tenofovir and / or co-administered medications.

Doctrine should be avoided with simultaneous or recent use of nephrotoxic drugs (for example, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2) (see section "Specific guidance").

Given that tacrolimus can affect the function of the kidneys, careful monitoring is recommended when it is used simultaneously with the drug Dokvir.

Other interactions

Interactions between the components of the drug Dokvir and protease inhibitors, as well as nucleoside reverse transcriptase inhibitors are presented below in Table 2 (the increase is indicated by "↑", the decrease is "↓", the absence of changes is "↔", twice a day - "b.i.d." and once a day - "q.d."). If there is a 90% confidence interval (CI), it is indicated in parentheses.

Interaction between individual components of the combined preparation and other medications

table 2

Medicinal preparation according to therapeutic directions	Influence on the level Medium percent change AUC, Cmax, Cmin with 90% confidence interval, if available (mechanism)	Recommendation relatively simultaneous with the drug Dokvir (200 mg emtricitabine, 300 mg of tenofovir disoproxyl fumarate)
Anti-infectious
*Antiretroviral drugs*
Protease Inhibitors
Atazanavir / Ritonovir / Tenofovir dizoproxyl fumarate (300 mg q.d / 100 mg q.d / 300 mg q.d)	Atazanavir AUC: ↓ 25% (↓ 42- ↓ 3) Cmax: ↓ 28% (↓ 50- ↑ 5) Cmin: ↓ 26% (↓ 46- ↑ 10) Tenofovir AUC: ↑37% Cmax: ↑24% Cmin: ↑29%	Correction of the dose is not required. The increased exposure to tenofovir may increase the associated adverse effects with tenofovir, including renal pathology. Kidney function should be carefully monitored.
Atazanavir / Ritonavir / Emtricitabine	Interaction is not was studied
Darunavir / Ritonovir / Tenofovir dizoproxyl fumarate (300 mg q.d/ 100 mg q.d / 300 mg q.d)	Darunavir AUC: ↔ Cmin: ↔ Tenofovir AUC: ↑ 22% Cmin: ↑ 37%	Correction of the dose is not required. Increased exposure to tenofovir may increase the adverse reactions associated with tenofovir, including renal pathology. Kidney function should be carefully monitored.
Darunavir / Ritonavir / Emtricitabine	The interaction was not studied
Lopinavir / Ritonovir / Tenofovir disoproxil fumarate (400 mg b.i.d / 100 mg b.i.d / 300 mg q.d)	Lopinavir / Ritonavir AUC: ↔ Сmах: ↔ Cmin: ↔ Tenofovir: AUC: ↑32% (↑25-↑38) FROMmOh: ↔ Cmin: ↑ 51 (↑ 37- ↑ 66)	Correction of the dose is not required. Increased exposure to tenofovir may increase Related to tenofovir, adverse events, including renal pathology. Required carefully control kidney function.
Lopinavir / Ritonavir / Emtricitabine	The interaction was not studied
Nucleoside reverse transcriptase inhibitors
Didanosine / Tenofovir	The simultaneous use of tenofovir and didanosine leads to a 40-60% increase in the systemic exposure of didanosine, which may increase the risk of didanosine-related adverse events. Reported infrequent, sometimes lethal, cases of pancreatitis and lactic acidosis. The simultaneous administration of tenofovir and didanosine and a dose of 400 mg per day was associated with a significant decrease in the number of cells Cd4, possibly in connection with the intercellular interaction, that enhances phosphorylated (i.e., active) didanosine. The reduction in didanosine dosage to 250 mg, which is administered with tenofovir, was associated with reports of a high incidence of virologically unsuccessful treatment with several of the combinations studied for the treatment of HIV-1 infection.	The simultaneous use of Dokvir and didanosine is not recommended
Didanosine / Emtricitabine	The interaction was not studied

Studies conducted with other drugs

Emtricitabine

In vitro Emtricitabine does not inhibit metabolism, mediated by the action of any of the following isoenzymes CYP450 human: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 4. Emtricitabine does not inhibit the activity of the enzyme responsible for glucuronidation. There is no clinically significant pharmacokinetic relationship in the co-administration of emtricitabine with indinavir, zidovudine, stavudine, or famciclovir.

Tenofovir

The co-administration of lamivudine, indinavir, efavirenz, nelfinavir or saquinavir (ritonavir-boosted), methadone, ribavirin, rifampicin, or hormonal contraceptive norgestimate / ethinylestradiol with tenofovir did not cause clinically significant pharmacokinetic interaction.

The combination of tenofovir / emtricitabine

The combined use of the combined drug and tacrolimus did not cause clinically significant pharmacokinetic interaction.

Special instructions:

Simultaneous use with other medicinal products

The drug Dokvir should not be administered in conjunction with other medications containing emtricitabine, tenofovir or other cytidine analogs, for example lamivudine. The drug should not be taken concomitantly with adefovir.

The simultaneous use of tenofovir and didanosine

The combined use of tenofovir and didanosine is not recommended, since systemic exposure to didanosine is increased by 40-60%, which may increase the risk of side effects associated with didanosine. There have been reports of rare cases of pancreatitis and lactic acidosis, sometimes with a fatal outcome. Simultaneous the use of tenofovir and didanosine at a dose of 400 mg per day was associated with a significant decrease in the number of cells Cd4, probably due to intercellular interaction, which increases the phosphorylated (ie, active) didanosine. The use of didanosine at a reduced dosage of 250 mg, together with tenofovir therapy, was associated with reports of a high incidence of virologic failure in several combinations studied for the treatment of HIV-1 infection.

A regimen comprising three nucleoside analogs

There have been reports of a high incidence of virologically unsuccessful treatment and the emergence of resistance at an early stage in patients with HIV infection, if tenofovir was combined with lamivudine and abacavir, as well as with lamivudine and didanosine according to the regimen of administration once a day. Lamivudine and emtricitabine have close structural similarity, as well as similar pharmacokinetics and pharmacodynamics. Thus, the same problems can be observed when using a combination of tenofovir / emtricitabine with a third nucleoside analogue.

Opportunistic infections

Patients receiving Dokvir or any other antiretroviral drug may have clinical manifestations of opportunistic infections or complications of HIV infection, and should therefore be observed regularly with a doctor experienced in the treatment of HIV-associated diseases.

Transmission of HIV

Patients should be warned that the ability of antiretroviral drugs, including Dokvir, to prevent the transmission of HIV to others through sexual contact or through blood, has not been proven. Therefore, appropriate measures should be taken to prevent transmission of the virus.

Impaired renal function

Emtricitabine and tenofovir are deduced, mainly, through the kidneys by glomerular filtration and active tubular secretion. When used in clinical practice, tenofovir reported renal failure, impaired renal function, increased creatinine concentration, hypophosphatemia and proximal tubulopathy (including Fanconi syndrome).

It is recommended to evaluate the creatinine clearance in those patients before starting treatment with a combination drug, and also to assess kidney function (creatinine clearance and plasma phosphate concentration) after 2-4 weeks of treatment, 3 months of treatment and every 3-6 months after. In patients with a risk of developing renal dysfunction, including patients with a history of renal dysfunction while adefovir is being used, kidney function should be monitored more often.

Patients with disturbed function of night (CC <80 ml / min), including those who need hemodialysis

Data on the safety of the combined drug in relation to the effects on kidney function are limited. For patients with a creatinine clearance of 30-49 ml / min, it is recommended that the interval between doses be corrected. Limited data from clinical studies suggest that a large interval between doses is not optimal and may lead to an increase in toxicity and the probability of an inadequate response.

When taking Dokvir, patients with CC <60 ml / min need a thorough evaluation of the benefit / risk ratio, as well as careful monitoring of kidney function.In addition, patients taking the drug with a long interval between doses should constantly monitor the clinical response to treatment. The use of a combination drug is contraindicated in patients with impaired renal function of a serious degree (QC <30 ml / min) and those who need hemodialysis, as an adequate dose reduction is not possible with a combination pill. If the patient receiving the drug has a serum phosphate concentration of <1.5 mg / dL (0.48 mmol / L), or the CC is reduced to <50 mL / min, renal function should be re-evaluated within one weeks, including the determination of the concentration of glucose and potassium in the blood, as well as the concentration of glucose in the urine. Consideration should be given to the need to interrupt treatment with Dokvir in patients with a confirmed decrease in CK <50 ml / min or a decrease in serum phosphate concentrations <1.0 mg / dl (0.32 mmol / L).

Do not use the drug Dokvir with the simultaneous or recent appointment of a nephrotoxic drug. If this can not be avoided, the renal function should be monitored weekly.

Cases of acute renal failure were reported after initiating therapy with a high dose or several non-steroidal anti-inflammatory drugs (NSAIDs) in patients who received tenofovir and having risk factors for renal dysfunction. Renal function should be monitored appropriately by the combined use of Dokvir and NSAIDs.

A high risk of kidney damage has been reported in patients receiving tenofovir in combination with a protease inhibitor, ritonavir-enhanced or a cobicystate. Such patients need careful monitoring of kidney function (see section "Interaction with other drugs"). In patients with risk factors for renal dysfunction, co-administration of tenofovir with an enhanced protease inhibitor should be carefully analyzed.

Patients with mutations of HIV-1 resistance

Dokvir should not be given to patients with HIV-1 infection who have a mutation in the codon K65R.

Effects on bone tissue

In a controlled 144-week clinical trial comparing tenofovir with stavudine in combination with lamivudine and efavirenz in HIV-infected adult patients who had not previously received antiretroviral treatment,in both groups there were slight decreases in bone mineral density (BMD) in the region of the femur and spine. Decrease in the BMD of the spine and changes from baseline biomarkers of bone tissue metabolism were significantly more pronounced in the tenofovir group at week 144. The decrease in the BMD of the femur was significantly more pronounced in this group up to 96 weeks. However, after 144 weeks of increased risk of fractures or signs of clinically significant pathologies of bone tissue was not observed. Pathological changes in bone tissue (occasionally leading to fractures) may be due to damage to the proximal tubules of the kidneys. If you suspect or detect pathological changes in bone tissue, consult a specialist.

Patients with simultaneous infection with HIV, hepatitis B viruses or hepatitis C

Patients with chronic viral hepatitis B or C receiving combination antiretroviral therapy are at high risk for severe and potentially fatal liver complications. Doctors need to follow recommendations for treatment of HIV infection and choose the optimal treatment for patients infected with HIV and hepatitis B virus.The efficacy and safety of the combined drug for chronic hepatitis B have not been studied. AT pharmacodynamic studies have established the efficacy of emtricitabine and tenofovir in their use in both monotherapy and combination therapy in patients with concomitant HIV infection and hepatitis B virus. A few data indicate that emtricitabine and tenofovir demonstrate activity against hepatitis B virus. The abolition of the combined drug in patients with concomitant HIV infection and hepatitis B virus can cause severe exacerbation of hepatitis. Patients infected with HIV and hepatitis B virus should be closely monitored, both clinically and laboratory, for at least several months after discontinuation therapy with a combined drug. In a number of cases, hepatitis B therapy may need to be resumed. In patients with severe liver disease or cirrhosis, it is not recommended to cancel treatment, since the aggravation of hepatitis that occurs after cancellation of treatment can lead to decompensation of liver function.

Diseases of the liver

Data on the safety and efficacy of taking a combination drug for patients in whom serious liver function disorders are a major disease have not been studied. Data on the pharmacokinetics of the combination of tenofovir / emtricitabine and emtricitabine in patients with hepatic impairment are limited. The study of the pharmacokinetics of tenofovir in patients with hepatic insufficiency showed that dose adjustments in these patients are not required. Emtricitabine is not subjected to significant metabolism by liver enzymes and has a renal excretion pathway, so considering the minimal hepatic metabolism and renal elimination pathway of emtricitabine, it can be assumed that patients with hepatic insufficiency do not need a dose adjustment.

In patients with a previously diagnosed liver disease, including chronic active hepatitis, combined antiretroviral therapy may exhibit more frequent liver dysfunction. These patients should be closely monitored in accordance with standard practice. With signs of progression of liver disease for such patients, consideration should be given to the possibility of interrupting or discontinuing treatment.

Lactic acidosis

With the use of nucleoside analogues, lactic acidosis, usually accompanied by fatty liver dystrophy, has been reported. Early signs (symptomatic hyperlactatemia) include mild symptoms on the part of the digestive system (nausea, vomiting and abdominal pain), nonspecific malaise, loss of appetite, weight loss, respiratory system symptoms (frequent and / or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high lethality and may be accompanied by pancreatitis, hepatic or renal insufficiency. Usually, lactic acidosis is observed after several months of treatment.

Treatment with analogues of nucleosides should be discontinued in the presence of symptomatic hyperlactatemia and metabolic / lactic acidosis, progressive hepatomegaly or a rapid increase in the level of aminotransferases. Caution should be exercised when prescribing nucleoside analogues to anyone the patient (especially women with obesity) with hepatomegaly, hepatitis, or other known risk factors for liver disease and fatty liver disease (including certain drugs and alcohol).Interferon-alpha and ribavirin treatment of patients with concomitant hepatitis C virus infection may present a particular risk. Patients with an increased risk should be closely monitored.

Lipodystrophy

In patients with HIV infection, combined antiretroviral therapy was associated with the redistribution of adipose tissue in the body (lipodystrophy). The remote consequences of these phenomena are unknown to date. Data on the mechanism of development are incomplete. There is a hypothesis about the relationship between the development of visceral lipomatosis and the intake of protease inhibitors and the development of lipoatrophy with the use of nucleoside reverse transcriptase inhibitors. The increased risk of lipodystrophy was due to individual factors, such as the elderly age of patients, and factors associated with the drug, such as the long duration of antiretroviral therapy and the resulting metabolic disorders. Clinical examination should include an assessment of the physical signs of redistribution of adipose tissue in the body. You should pay attention to the indices of lipids of blood serum fasting and the level of glucose in the blood.Dyslipidemia should be adjusted in accordance with clinical recommendations.

Tenofovir is structurally related to nucleoside analogs, so the risk of developing lipodystrophy can not be ruled out. However, 144-week data obtained from HIV-infected patients who had not previously been treated with antiretroviral drugs indicate that the risk of lipodystrophy in the case of tenofovir was less than with stavudine when tenofovir and stavudine were used in combination with lamivudine and efavirenz.

Mitochondrial disorders

In vitro and in vivo it was shown that nucleoside and nucleotide analogues lead to damage to mitochondria of different degrees. There have been reports of the development of mitochondrial disorders in HIV-negative newborns exposed to intrauterine and / or postnatal effects of nucleoside analogues. The main undesirable phenomena reported were hematologic disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipazemia). These phenomena are often short-lived. There were reports of some neurological disorders that began later (hypertension, seizures, abnormal behavior).To date, it is not known whether neurological disorders are temporary or permanent. All children exposed to prenatal exposure to nucleoside or nucleotide analogues, even HIV-negative newborns, should be under close clinical and laboratory supervision and have a thorough examination for possible presence of mitochondrial changes in case of manifestation of the corresponding signs or symptoms. The available data do not influence the current national recommendations, according to which HIV-positive pregnant women need antiretroviral therapy to prevent vertical transmission of HIV.

Immunodeficiency Syndrome

At the onset of antiretroviral therapy, HIV-infected patients with severe immunodeficiency may develop an inflammatory response to pathogens of asymptomatic or residual opportunistic infections, and lead to severe clinical conditions or increased severity of symptoms. Usually such reactions are observed during the first weeks after the start of treatment.Examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumocystis (Pneumocystis jirovecii) pneumonia. You should monitor any symptoms of inflammation and, if necessary, prescribe treatment in a timely manner.

Also reported were autoimmune diseases (such as Graves' disease) that accompanied reactivation of immunity; However, the time of onset of such events varies greatly, and these cases may have occurred several months after the start of treatment.

In patients with co-infection with HIV / HBV, a sharp exacerbation of hepatitis caused by the immune reactivation syndrome may occur in response to the initiation of antiretroviral therapy.

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (including the use of glucocorticosteroids, alcohol use, the presence of severe immunosuppression, a higher body mass index), cases of osteonecrosis have been recorded especially frequently in patients with progressive HIV infection and / or with prolonged use of combined antiretroviral therapy. Patients should seek medical advice if they develop aches or joint pain, joint stiffness or difficulty in movement.

Elderly patients

The combined drug was not studied in patients older than 65 years. Older patients are more likely to have reduced renal function, so the drug should be administered with caution in this group of patients.

Effect on the ability to drive transp. cf. and fur:

There were no studies to study the effect of the drug on the ability to drive vehicles or other mechanisms. Patients should be informed of possible dizziness in the treatment with this medication.

When dizziness occurs, patients should refrain from driving vehicles and practicing other potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions, taking into account the profile of side effects.

Form release / dosage:

The tablets covered with a film cover, 300 mg + 200 mg.

Packaging:

Primary packaging of medicinal product.

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 30 tablets are placed in a can of polymeric polyethylene with a cover pulled with the control of the first opening.Free space is filled with cotton wool. On cans are labeled with paper label or from polymer materials, self-adhesive.

Secondary packaging of medicinal product.

3 the contour of cellular packaging together with instructions for use placed in a pile of cardboard for packaging consumer. The packets are placed in a group package.

On 1 bank together with instructions on application place in a pack from a cardboard for consumer tare.

The packets are placed in a group package.

Storage conditions:

In the original packaging of the manufacturer at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003888

Date of registration:06.10.2016

Expiration Date:06.10.2021

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp27.10.2016

Illustrated instructions

Instructions

Dokvir (Docvir)