Tenofovir + Emtricitabine - instructions for use, dose, side effects, contraindications

Active substances:
emtricitabine	200 mg
tenofovir disoproxil fumarate	300 mg
Excipients:
The core of the tablet:
pregelatinized starch	50.0 mg
lactose monohydrate	80.0 mg
microcrystalline cellulose	295.0 mg
croscarmellose sodium	60.0 mg
magnesium stearate	15.0 mg
Sheath:
Opaprai II blue 32K10849	25.0 mg
- lactose monohydrate	10.0 mg
- hypromellose	7.0 mg
- titanium dioxide	4.74 mg
- triacetin	2.00 mg
- Aluminum lacquer based on indigo carmine dye (11-14%)	1.26 mg

Description:

Capsule-shaped tablets covered with a film coating of blue color.

On one side is engraved "H", on the other "124".

On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:antiviral [HIV] agent

ATX: & nbsp

J.05.A.R.03 Tenofovir Dizoproxil + Emtricitabine

Pharmacodynamics:

Mechanism of action

Tenofovir + Emtricitabine is a combination drug with a fixed dose of emtricitabine and tenofovir dizoproxil fumarate.

Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil fumarate is converted in vivo at tenofovir, nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate. how emtricitabine, and tenofovir show specific activity against human immunodeficiency virus (HIV-1 and HIV-2), and hepatitis B virus (HBV).

Emtricitabine and tenofovir phosphorylated by the action of 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. Emtricitabine triphosphate and tenofovir diphosphate inhibit HIV-1 reverse transcriptase by a competitive mechanism, leading to termination of viral DNA chain synthesis. Emtricitabine triphosphate, as well as tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases, signs of their toxicity to mitochondria in vitro and in vivo was not observed.

Antiviral activity in vitro

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

Resistance

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

In HIV-1 infected patients when detecting expression of three or more mutations induced thymidine analogues including substitution M41L or L210W in the OT gene, a decrease in the sensitivity to tenofovir of the disoproxil fumarate was noted.

Resistance in vivo (in patients who have not previously received antiretroviral therapy)

In an open, randomized clinical trial involving patients not previously treated with antiretroviral therapy, genotyping was carried out on isolates of HIV-1 obtained from the plasma of patients with confirmed HIV RNA level more than 400 copies / ml at the 48th, 96th or 144th week, or at the time of early discontinuation of the study drug.

As of the 144th week:

- in accordance with the analysis, the mutation M184V/I developed in 2 of 19 (10.5%) isolates obtained from patients in the group, where prepared emtricitabine / tenofovir disoproxil fumarate / efavirenz, and 10 of 29 (34.5%) isolates analyzed in a group of patients where the received lamivudine / zidovudine / efavirenz (p value <0.05, comparison by exact Fisher test among all patients in the group receiving emtricitabine+ tenofovir disoproxil fumarate, with all patients in the group receiving lamivudine / zidovudine);

- none of the analyzed viruses contained a mutation K65R;

- genotypic resistance to efavirenz, mainly mutation of the virus K103N, developed in a virus obtained from 13 of 19 (68%) patients in the group receiving emitricitabine / tenofovir disoproxil fumarate / efavirenz, compared with 21 of 29 (72%) patients in the comparison group.

Children

Safety and efficacy of the drug Tenofovir + Emtricitabine children under the age of 18 do not have studied.

Pharmacokinetics:

Suction

Bioequivalence of one tablet of the drug Tenofovir + Emtricitabinecoated with a film sheath and a combination of one 200 mg solid emtricitabine capsule and one film-coated tablet containing 300 mg of tenofovir disoproxil fumarate, when used concomitantly, was confirmed in the evaluation of a single fasting exercise in healthy volunteers. After taking the drug Tenofovir + Emtricitabine inside 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. Reception of the drug Tenofovir + Emtricitabine with food resulted in a delay in reaching the maximum concentrations of tenofovir by approximately three quarters of an hour and an increase in the values AUC and C_mOh tenofovir by approximately 35% and 15%, respectively, when taking food with a high or low fat content compared with fasting. To optimize the absorption of tenofovir, it is recommended to take the drug Tenofovir + Emtricitabine together with 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 diastereoisomers (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 elimination half-life of emtricitabine is 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.

Impaired renal function

There are few data on the pharmacokinetics of emtricitabine and tenofovir in patients with impaired renal function after simultaneous administration of individual drugs or as part of the drug Tenofovir + Emtricitabine. Pharmacokinetic parameters were determined with a single admission of 200 mg emtricitabine or 300 mg tenofovir dizoproxil fumarate to patients with renal dysfunction of varying severity, with no HIV infection.

The degree of severity of renal dysfunction was determined by the amount of creatinine clearance (KK) (renal function is not impaired if KK> 80 ml / min, mild violation - if KK is 50-70 ml / min, mild violation at QC 30-49 ml / min and severe violation - with QC 10-29 ml / min).

Average values (% CV) exposure to emtricitabine increased from 12 μg * h / ml (23%) and 34 μg * h / ml (6%) in patients with mild, moderate and severe renal impairment, respectively.

Average values (% CV) exposure to tenofovir increased from 2185 ng * h / ml (12%) in patients with normal renal function to 3064 ng * h / ml (30%), 6009 ng * h / ml (42%) and 15985 ng * h / ml (45%) in patients with lung,moderate degree and severe impairment of renal function, respectively.

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

In patients with terminal renal insufficiency, 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 increases to 42,857 ng / h / ml (29%).

Patients with QC 30-49 ml / min are recommended to correct the interval between doses of the drug Tenofovir + Emtricitabine. Tenofovir + Emtricitabine not suitable for 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

Pharmacokinetics of the drug Tenofovir + Emtricitabine in patients with impaired liver function has not been studied. However, the need for dose adjustment Tenofovir + Emtricitabine for patients with impaired liver function is unlikely.

The pharmacokinetics of emtricitabine in patients not infected with HBV, with different degrees of liver function abnormalities, has 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. Medium (% CV) meanings FROM_max and AUC_0-∞ 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 complex therapy 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 (CC <30 ml / min) or CRF, when hemodialysis is required (safety not established in this population of patients);

- lactation period;

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

- simultaneous admission with adefovir (see sections "Interaction with other medicines" and "Special instructions");

- in patients with lactase deficiency, lactose intolerance, glucose galactose malabsorption.

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 taking other medications simultaneously:

possessing nephrotoxic action (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");

- co-administration 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.Animal studies did not indicate the toxic effects of emtricitabine and tenofovir on reproductive function. Thus, if necessary, the possibility of using the drug Tenofovir + Emtricitabine during pregnancy.

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 the drug Tenofovir + Emtricitabine during lactation.

In general, women who are HIV-positive are not recommended to breast-feed in order to avoid HIV transmission to the child.

Fertility

There is no evidence of the effect of the drug Tenofovir + Emtricitabine 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 appoint a doctor who has experience in the treatment of HIV infection.

Adults

The recommended dose of the drug Tenofovir + Emtricitabine - 1 tablet a day inside. To optimize the absorption of tenofovir, it is recommended to take the drug Tenofovir + Emtricitabine together 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 Tenofovir + Emtricitabine, the patient should be transferred to receive certain preparations of emtricitabine or tenofovir.

If the dose was missed and less than 12 hours have elapsed from the usual dose-taking time, the patient should take the drug as soon as possible Tenofovir + Emtricitabine together with food and return to the usual mode of taking the drug. 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 Tenofovir + Emtricitabine the patient has vomiting, you should take another pill. If the patient's vomiting occurred more than 1 hour after taking the drug Tenofovir + Emtricitabine, 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.

Impaired renal function

Emtricitabine and tenofovir are excreted from the body with urine, so patients with impaired renal function have a longer period of excretion of emtricitabine and tenofovir. Data on the safety and efficacy of the drug Tenofovir + Emtricitabine in patients with impaired renal function of medium and severe degree (CK <50 ml / min) are limited. Evaluation of safety indicators for mild renal dysfunction (CK 50-80 ml / min) in the long term was not performed. For this reason, patients with impaired renal function should use the drug Tenofovir + Emtricitabine 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 drug Tenofovir + Emtricitabine once a day for patients with minor renal dysfunction.

Violation of the function of the kidneys of medium degree (KK 30-49 ml / min). Taking 1 tablet of the drug Tenofovir + Emtricitabine every 48 hours is recommended by 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. A drug Tenofovir + Emtricitabine contraindicated in patients with impaired renal function of severe degree (CK <30 ml / min) and patients who require hemodialysis, since the required dose reduction can not be achieved with a combination tablet.

Impaired liver function

Pharmacokinetics of the drug Tenofovir + Emtricitabine and emtricitabine has 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 adjustment. Given the minimal hepatic metabolism and what emtricitabine is excreted in the urine, unlikely. That a dose adjustment for the drug will be required Tenofovir + Emtricitabine in patients with impaired liver function.

Careful monitoring of patients with concomitant HBV infection is necessary if they stop taking the drug Tenofovir + Emtricitabine, since after drug withdrawal there is a risk of exacerbation of hepatitis.

Children

Efficacy and safety of the drug Tenofovir + Emtricitabine in children under 18 years of age is not established.

Side effects:

Safety Profile Summary

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.The safety profile of emtricitabine and tenofovir in this study matched the previous experience with the use of these drugs when each was used with other 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 the drug Tenofovir + Emtricitabine (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").

Data on adverse reactions in the form of summary tables

Adverse reactions observed in clinical trials and routine clinical practice, considered as at least possibly related to the drug components Tenofovir + Emtricitabine, are given below (Table 1) for classes of organ systems and frequency. Within each frequency group, adverse reactions are given in order of severity. Frequency adverse reactions are defined as: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely (from ≥ 1 / 10,000 to <1/1000).

Table 1. Adverse reactions associated with taking the drug Tenofovir + Emtricitabine and relating to individual components of the drug, based on clinical research and post-registration analysis.

Frequency	Emtricitabine	Tenofovir
Violations of 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
Impaired 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 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 insipidus
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.

⁴ A secondary reaction was established during post-registration observation, but was not recorded in randomized,controlled clinical trials involving adults or clinical studies 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 the drug Tenofovir + Emtricitabine 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 with HIV infection.Concomitant therapy with nephrotoxic drugs) are at increased risk of incomplete recovery of kidney function, despite the elimination of tenofovir (see section "Special instructions").

Interactions 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.

The relationship between combination antiretroviral therapy and the redistribution of adipose tissue in the body of HIV-infected patients (lipodystrophy), including the loss of subcutaneous fat on the limbs and face, an increase in the volume of intraperitoneal and visceral fat,hypertrophy of the mammary glands and fat accumulation in the dorso-cervical region ("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 andmetabolic / lactic acidosis, progressive hepatomegaly, or a rapid increase in the level of aminotransferase (see section "Specific guidance").

Children

Data on safety for children under 18 years is not enough. In this population, the use of the drug Tenofovir + Emtricitabine is contraindicated.

Other special patient groups

Elderly patients

Study of the use of the drug Tenofovir + Emtricitabine in patients over the age of 65 years was not conducted. Older patients are more likely to have decreased renal function, therefore, during treatment with the drug Tenofovir + Emtricitabine, patients from this population should be especially careful.

Patients with impaired renal function

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

Co-infection with 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, increased activity ACT and ALT in this group of patients were 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 under the supervision of a physician to identify signs of toxicity. If necessary, conduct standard maintenance therapy. Hemodialysis displays up to 30% of the dose of emtricitabine and approximately 10% of the dose of tenofovir dizoproxil fumarate. It is not known whether emtricitabine or tenofovir by peritoneal dialysis.

Interaction:

Since the preparation Tenofovir + Emtricitabine is contained emtricitabine and tenofovir, all cases of drug interaction detected with these active substances may also occur when the drug is used Tenofovir + Emtricitabine.

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 a low probability CYP 450-mediated interactions between emtricitabine and tenofovir with other medications.

Simultaneous use is not recommended

A drug Tenofovir + Emtricitabine should not be administered simultaneously with other cytidine analogues, such as lamivudine.

Tenofovir + Emtricitabine - a combined medicinal product, so it should not be used concurrently with other drugs containing any of the components: emtricitabine or tenofovir.

A drug Tenofovir + Emtricitabine Do not use concomitantly with adefovir.

Didanosine

Simultaneous use of the drug Tenofovir + Emtricitabine and didanosine is not recommended (see section "Special instructions").

Medicines that are excreted by the kidneys

Because the emtricitabine and tenofovir are excreted mainly by the kidneys, the joint use of the drug Tenofovir + Emtricitabine with drugs that reduce renal function or compete for active tubular secretion (eg, with cidofovir),may increase serum concentrations of emtricitabine, tenofovir, and / or co-administered medications.

It is necessary to avoid the use of the drug Tenofovir + Emtricitabine with simultaneous or recent use of nephrotoxic drugs (for example, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2) (see section "Special instructions").

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

Other interactions

Interactions between the components of the drug Tenofovir + Emtricitabine and protease inhibitors, as well as nucleoside reverse transcriptase inhibitors are presented below in Table 2 (the increase is indicated by "↑", the decrease is - "↓", no change - "↔", 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.

Table 2. Interaction between individual components of the preparation Tenofovir + Emtricitabine and other medicinal products

Medicinal preparation according to therapeutic directions	Effect on drug levels Average percent change in AUC, С_m_Oh, C_min with a 90% confidence interval, if available (mechanism)	Recommendation for simultaneous use with the drug Tenofovir + Emtricitabine (200 mg emtricitabine, 300 mg of tenofovir, dizoproxil fumarate)
ANTI-INFECTIOUS
Antiretroviral drugs
Protease Inhibitors
Atazanavir / Ritonavir / Tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./ 300 mg q.d.)	Atazanavir AUC: ↓ 25% (1 42 -1 3) FROMmOh: ↓ 28% (1 50 -1 5) Cmin: ↑ 26% (↓ 46 -↑ 10) Tenofovir AUC:↑37% FROMmah: ↑ 34% Cmin: ↑ 29%	Correction of the dose is not required. Increased exposure to tenofovir may increase
Atazanavir / Ritonavir / Emtricitabine	The interaction was not studied
Darunavir / Ritonavir / Tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./ 300 mg q.d.)	Darunavir AUC: ↔ Cmin: ↔ Tenofovir AUC: ↑ 22% Cmin: ↑37%
Darunavir / Ritonavir / Emtricitabine	The interaction was not studied
Lopinavir / Ritonavir / Tenofovir disoproxil fumarate (400 mg b.i.d./100 mg b.i.d./ ZO mg q.d.)	Lopinavir / Ritonavir AUC: ↔ FROMmah: ↔ Cmin: ↔ Tenofovir AUC: ↑ 32% (↑ 25 -↑38) FROMmah: ↔ Cmin: ↑ 51% (↑37-↑66)
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. There have been reports of unfortunate, sometimes lethal, cases of pancreatitis and lactic acidosis. Simultaneous administration 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 in connection with the intercellular interaction, which increases 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.
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 people: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. 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.

Tenofovir + Emtricitabine

Joint use of the drug Tenofovir + Emtricitabine and tacrolimus did not cause clinically significant pharmacokinetic interaction.

Special instructions:

Simultaneous use with other medicinal products

A drug Tenofovir + Emtricitabine should not be administered in conjunction with other medications containing emtricitabine, tenofovir or other cytidine analogs, for example lamivudine. A drug Tenofovir + Emtricitabine Do not take concomitantly with adefovir.

The simultaneous use of tenofovir and didanosine

The combined use of tenofovir and didanosine is not recommended,since the systemic effect of didanosine increases by 40-60%, which may increase the risk of adverse reactions associated with didanosine. There have been reports of rare cases of pancreatitis and lactic acidosis, sometimes with a fatal outcome. Simultaneous 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, possibly due to intercellular interaction, which increases the phosphorylated (i.e., 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 the drug Tenofovir + Emtricitabine with a third nucleoside analog.

Opportunistic infections

Patients receiving the drug Tenofovir + Emtricitabine 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 cautioned that the ability of antiretroviral drugs, including the drug Tenofovir + Emtricitabine, to prevent the risk of HIV transmission to others through sexual contact or through blood, is not 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 all patients before starting treatment with the drug Tenofovir + Emtricitabine, as well as assess kidney function (creatinine clearance and phosphate concentration in plasma) after 2-4 weeks of treatment, after 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 kidney failure, adefovir should be monitored more often by kidney function.

Patients with impaired renal function (CC <80 ml / min), including those who need hemodialysis

Safety data for the preparation Tenofovir + Emtricitabine on the impact 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. Moreover, in a small clinical study in a subgroup of patients with CK of 50-60 ml / min, who received tenofovir in combination with emtricitabine every 24 hours, there was a 2-4 times higher exposure of tenofovir and impaired renal function. Therefore, when taking the drug Tenofovir + Emtricitabine Patients with CC <60 mL / min need a thorough assessment of the benefit-risk ratio, as well as careful monitoring of kidney function. In addition, in patients taking the drug Tenofovir + Emtricitabine with a long interval between doses, the clinical response to treatment should be monitored continuously. Application of the drug Tenofovir + Emtricitabine is contraindicated in patients with impaired renal function of severe degree (CK <30 ml / min) and those who need hemodialysis, because the corresponding dose reduction is not possible with the combination of a combination tablet.

If any patient receiving the drug Tenofovir + Emtricitabine, the serum phosphate concentration is <1.5 mg / dL (0.48 mmol / L), or the QC is reduced to <50 ml / min, renal function should be re-evaluated for one week, including glucose and potassium concentration in blood, as well as the concentration of glucose in the urine. Consideration should be given to the need to interrupt drug treatment Tenofovir + Emtricitabine in patients with confirmed reduction 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 Tenofovir + Emtricitabine with simultaneous or recent administration of a nephrotoxic drug. If such an application is not possible, weekly renal function should be monitored.

Cases of acute renal failure after initiating high-dose therapy 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 when the drug is administered together Tenofovir + Emtricitabine and NSAIDs.

A high risk of kidney damage has been reported in patients receiving tenofovir in combination with protease inhibitors by enhanced ritonavir or cobicystate. These patients require careful monitoring of kidney function (see section "Interaction with other drugs"). In patients with risk factors for renal dysfunction, joint use of tenofovir with an enhanced protease inhibitor should be carefully analyzed.

Patients with mutations of HIV-1 resistance

A drug Tenofovir + Emtricitabine should not be administered 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, small decreases in the BMD in the femur and spine were observed in both groups.

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 caused by damage to the proximal tubules of the kidneys. If you suspect or detect pathological changes in bone tissue, consult a specialist.

Patients with concomitant HIV infection, 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.

Efficacy and safety of the drug Tenofovir + Emtricitabine with chronic hepatitis B were not studied. In pharmacodynamic studies, the efficacy of emtricitabine and tenofovir has been established 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. Tenofovir + Emtricitabine in patients with concomitant HIV infection and hepatitis B virus can cause severe exacerbation of hepatitis. For patients infected with HIV and hepatitis B virus,careful monitoring, both clinical and laboratory, should be conducted, at least for several months after discontinuation of therapy with the drug Tenofovir + Emtricitabine. 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 the drug Tenofovir + Emtricitabine for patients in whom serious liver function disorders are the main disease, have not been studied. Data on the pharmacokinetics of the drug Tenofovir + Emtricitabine and emtricitabine in patients with hepatic insufficiency 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 excretory pathway, so given the minimal hepatic metabolism and renal excretion pathwayemtricitabine, 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 increased liver disease, such patients should consider 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 symptoms (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 (private 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 assigning nucleoside analogues to any patient (especially obese women) 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 they 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.

Available data do not affect current national recommendations, according to which HIV-positive pregnant women need antiretroviral therapy toprevention of 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. Typically, 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, data on the onset of such events vary widely, 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 be advised to seek medical advice if they develop aches or joint pain, joint stiffness, or difficulty walking.

Elderly patients

A drug Tenofovir + Emtricitabine It has not been 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:

Studies to study the effect of the drug on the ability to manage transport and work with mechanisms have not been carried out. However, patients should be informed that, during treatment with both emtricitabine and tenofovir, dizziness has been reported. When dizziness occurs, you should refrain from performing these activities.

Form release / dosage:

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

Packaging:

When manufacturing on Hetero Labe Limited

For 30 tablets in a bottle of high density polyethylene, sealed with aluminum foil, with a polyethylene or polypropylene lid, protected from accidental opening by children.

It is allowed to put a package of silica gel in the bottle.

Vial with instructions for medical use in a pack of cardboard.

In production, packaging and packaging at OOO "MAKIZ-PHARMA"

30 tablets in a bank imported from high-density polyethylene (HDPE), sealed with a lid of high-density polyethylene (HDPE) with a multilayer gasket for induction welding or in a bottle imported from high-density polyethylene (HDPE), sealed with aluminum foil, capped with polypropylene lid.

Free space in a jar / vial if necessary fill with cotton absorbent cotton absorbent cotton wool or imported.

On the jar / bottle stick a label of paper label or writing, or self-adhesive.

1 jar or bottle together with instructions for use in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003631

Date of registration:16.05.2016

Expiration Date:16.05.2021

The owner of the registration certificate:Heterose Labs LimitedHeterose Labs Limited India

Manufacturer: & nbsp

HETERO LABS, Limited India

MAKIZ-PHARMA, LLC Russia

Representation: & nbspHeterose Labs LimitedHeterose Labs LimitedIndia

Information update date: & nbsp12.07.2016

Illustrated instructions

Instructions

Tenofovir + Emtricitabine (Tenofovir + Emtricitabine)