Truvada - instructions for use, dose, side effects, contraindications

Fallen II blue Y-30-1070I 40 mg: aluminum lacquer based on indigo carmine 2L52 mg. hypromellose 11,200 mg, lactose monohydrate 16,000 mg, titanium dioxide 7.448 mg, triacetin 3,200 mg.

Description:

Tablets of capsular form, covered with a film shell of light blue color, on one side are engraved "GILEAD", on the other side - "701".

On the break the tablets are white.

Pharmacotherapeutic group:An antiviral (HIV) agent.

ATX: & nbsp

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

Pharmacodynamics:

Mechanism of action

Truvada® is a combination drug with a fixed dose of emtricitabine and tenofovir dizoproxil fumarag.

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

Emtricitabine and tnchnofovir are phosphorylated by the action of intracellular enzymes with the formation of emitricitabine triphosphate and tenofovir diphosphate, respectively. In studies in vitro it was shown that u emtricitabine, and tnchnofovir, 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 nsnucleoside inhibitors of HIV reverse transcriptase, an additive or syergic effect was observed. Resistance

In studies in vitro and some HIV-1-infected patients showed resistance to emtricitabine due to the development of a mutation M184V/I. or tenofovir, in conjunction with a mutation K65R. There are no other possible mechanisms for developing resistance to emtricitabine or tenofovir. Viral isolates resistant to emtricitabine with mutations M184V/I, were also resistant to lamivudine, however, remained susceptible to didanosypus, stavudipu. tenofovir and zidovudine. Mutation K65R can also be observed with the use of abacavir or didanosine and, in turn, can also lead to a decrease in the effect of application of these tools in combination with lamivudipom, emtricitaoipom and tenofovir. The use of tenofovir disoproxil fumarate should be avoided in patients with HIV-1 strains having a mutation K.65R.

In HIV-1 infected patients when detecting expression of three or more mutations induced thymidine analogues including substitution M41L or 1.210W in the OT gene, a decrease in the sensitivity to tenofovir of dizoproxil fumarate was noted. Resistance in vivo (in patients who have not previously received antiretroviral therapy)

In an open, randomized clinical trial involving patients who had not previously received antiretroviral treatment, genotyping was performed on HIV-1 isolates obtained from the plasma of all patients with confirmed HIV RNA concentrations of more than 400 copies / ml at 48, 96 or 144- 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 a group, Where received emtricitabine / tenofovir disoproxil fumarate / efavirenz, and 10 of 29 (34.5%) isolates analyzed the patients group, Where received lamivudine / zinovudine / efavirenz (value p <0.05, comparison according to the exact Fisher test among all patients in the group where they will receive emtricitabine + tenofovir disoproxil fumarag, 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 Truvada^® in children under the age of 18 years have not been studied.

Pharmacokinetics:

Suction

Bioequivalence of a tablet of the drug Truvada ^® , coated with a film sheath, and a combination of one 200 mg solid emtricitabine capsule and one film-coated tablet containing 300 mg of tenofovir, a dysoproxyl fumarag, when used concomitantly, was confirmed in the evaluation of a single fasting exercise in healthy volunteers. After taking the drug Truvada Inside healthy volunteers emtricitabine and tenofovir disoproxil fumarate are rapidly absorbed, and tenofovir disoproxil fumarate is converted into tenofovir. The maximum concentrations of emgricitabine and tenofovir are observed in the serum in the range of 0.5 to 3 hours after administration on an empty stomach. Taking Truvada® with food resulted in a delay in reaching maximal concentrations of tenofovir by approximately three quarters of an hour and an increase in the values AUC and C_max Tenofovir by approximately 35% and 15%, respectively, when taken with food with a high or low fat content compared with fasting. To optimize the absorption of tenofovir, it is recommended that you take Truvada® with food.

Distribution

After intravenous administration, the volume of distribution of emgricitabine and tenofovir was about 1.4 l / kg and 800 ml / kg, respectively. After ingestion of emtricitabine or tenofovir dizoproksil fumaraga 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 mostly excreted in the night, 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 a sin of 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.

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 Truvada preparation ^®. 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 from the magnitude of creatinine clearance (CC) (kidney function is not impaired if KK> 80 ml / min, mild violation - if the SC is 50-79 ml / min, a mild disorder with a QC of 30-49 ml / min and a severe violation with QC 10-29 ml / min.).

Average values (% CV) exposure to emtricitabine increased from 12 mkt * h / ml (25%) in patients with no renal dysfunction and up to 20 mcg / hr (6%), 25 mcg / hr (23%) and 34 mcg / ml (6%) in patients with mild, moderate and severe renal impairment, respectively.

Mean 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 15,985 uh / 45%) in patients with mild, moderate and severe impairment of renal function, respectively.

It is suggested that an increase in the interval between taking Truvada * in patients with impaired renal function of an average degree will cause an increase in peak plasma concentrations and a decrease in levels C_mi_n, 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. 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 Truvada ^®. Truvada ^® 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 Truvada ^® in patients with impaired liver function has not been studied. However, the need to adjust the dose of Truvada ^® for patients with impaired liver function is unlikely.

The pharmacokinetics of emtricitabine in patients not infected with HBV, with different degrees of impaired hepatic function, was 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 dysonroxyl fumarate was taken by patients not infected with HIV, from violation of the function liver different degrees, defined 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_max and AUCo-∞ of tenofovir were 223 (34.8%) ng / ml and 2050 (50.8%) ng * h / ml, respectively, in individuals without function violation liver, 289 (46.0%) ng / ml and 2310 (43.5%) ng * h / ml in persons with violation of the function liver 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 an integrated of therapy with others

antiretroviral drugs.

Contraindications:

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

- Children under 18 years of age (effectiveness and safety not stated).

- Renal failure of severe degree (CK <30 ml / min) or CRF. when it is necessary to conduct hemodialysis (safety is not established in this population of patients).

- Lactation period.

- Simultaneous reception with other drugs containing emgricitabine, 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 drugs" 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 concurrently taking other medications: those with nephrotoxic action (amioglycosides, amphogericin 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 genofovir and didanosine is not recommended (see "Interactions with other drugs" and "Special instructions" cracks);

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 the use of emtricitabip or tenofovir. Animal studies did not indicate the toxic effects of emtricitabip and tnofovir on reproductive function. Thus, if necessary, the possibility of using Truvada ^® during pregnancy.

Breastfeeding period

Studies have shown that emtricitabine and tenofovir are excreted in breast milk. Data on the effects of emtricitabip and tenofovir on rotated / dsts are inadequate. Therefore, we should use the drug Truvada during the feeding of the pile.

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 Truvada ^® on fertility in humans. Studies in animals do not indicate a harmful effect of emtricitabine or tenofovir for fertility.

Dosing and Administration:

Inside, with food. The tablet should be swallowed wholly, washing down with water, can not be chewed or broken.

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

Adults

The recommended dose of Truvada® is 1 tablet per day inside. To optimize the absorption of tenofovir, it is recommended that you take Truvada® with food. Even mild food improves the absorption of tenofovir from the combined tablet.

If the patient experiences difficulty swallowing, the tablet of the Truvada® preparation can be taken immediately after dissolving it in about 100 ml of water, orange or grape juice.

If you need to adjust the dose or stop taking one of the components of the drug Truvada®, the patient should be transferred to receive certain drugs emtricitabine or tenofovir.

If reception of the dose was missed and it took less than 12 hours on a normal time of dosing, the patient should be taken as soon as preparation 1 ruvada with pischei and return to normal ingestion. If, in the case of a missed dose, more than 12 hours have elapsed from the usual time of taking the drug, then the patient should take the missed dose, then return to the usual regimen.

If within 1 hour after taking Truvada® the patient has vomiting, another tablet should be taken. If vomiting in the patient occurred more than 1 hour after taking Truvada®, 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, if there are no signs of renal insufficiency, 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 Truvada ^® in patients with impaired renal function of moderate to severe severity (QC < 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 impaired renal function should use the drug 1ruvada only if the potential benefit of treatment is considered to exceed the potential risk. Patients with impaired renal function may need careful monitoring of the function of the nights. 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 50-80ml / min). Limited data, obtained as a result of clinical studies,testify in favor of maintaining the dosage regimen of Truvada® once a day for patients with minor disturbances in function of the nights.

Violations of the function of the kidneys of medium degree (KK 30-49 ml / min). Receiving 1 tablet of the drug Truvada ^® every 48 hours is recommended for the results of modeling the pharmacokinetic data of a single dose of emtricitabine and tenofovir in volunteers with no 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. Preparation of Truvada ^® 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 Truvada ^® 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, it is unlikely that a dose adjustment for Truvada ^® in patients with impaired liver function.

Careful observation of patients with concomitant HBV infection should be considered if they stop taking Truvada®, as there is a risk of exacerbation of hepatitis after the drug is discontinued.

Children

The effectiveness and safety of the drug Truvada® 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 that kidney function be monitored in patients receiving Truvada® (see "Specific guidance").

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").

Abolition of the drug Truvada® 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 trials and in routine clinical practice, considered as at least possibly associated with the components of Truvada®, are given below (Table 1) for organ system classes and frequencies.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 the administration of Truvada and related to individual components of the drug, based on clinical research and post-analysis 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		Gynophosphatemia¹
Often	Hyperglycemia, Hypertriglyceridemia
Infrequently		Gynokalemia¹
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, gosnoga	Diarrhea, vomiting, nausea

Often	The overall increase in amylase activity,including those associated with changes in the pancreas, increased lens 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 liver ², hepatitis
Disturbances from the skin and subcutaneous tissues:
Often		Skin rash
Often	Vesiculobulose, pustular, maculopapular rash, skin rash, skin itch, urticaria, skin discoloration (increased pigmentation) ³
Infrequently	Angioedema ⁴
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 some 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 gubulonathy, including Fanconi syndrome, nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus

Common disorders and disorders together:
Often		Asthenia
Often	Pain, asthenia

¹ This 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.

² A 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 (hyperpigmentacin sites) are very common.

⁴A side effect was established during follow-up, but was not recorded in randomized, controlled clinical trials involving adults or in 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 statistical calculation, based on the total number of patients receiving emtricitabn in randomized controlled clinical trials (n = 1563) or tenofovir in randomized controlled clinical trials and in an expanded access pro- gram (n = 7319).

Description of individual adverse reactions Impaired renal function

Since the drug Trunada ® 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

The simultaneous use of tenofovir and didanosine is not recommended, as this leads to an increase in the systemic effect of 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 legaloutcome.

Lipids, Pipodystrophy and metabolic disorders

Reported communications honey combined antiretroviral therapy and metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlagathemia. Reported communications honey combined antiretroviral therapy and redistribution of adipose tissue in the body of HIV-infected patients (lipodystrophy), including loss of subcutaneous adipose tissue on the limbs and face, increased volume of intraperitoneal and visceral fat, mammary hypertrophy, 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 data on the time of onset of such phenomena vary greatly,and these cases may have occurred several months after the start of treatment.

Osteonecrosis

Cases of osseonecrosis have been reported, in particular in patients with well-known risk factors, late stage of 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 nucleoside analogues should be discontinued if symptomatic hyperlactatemia and mastabolic / lactic acidosis, progressive hepagomegaly 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 Truvada is contraindicated.

Other special patient groups Older patients

The study of the use of the drug Truvada ® in patients over the age of 65 years old ns was conducted. Patients of advanced age are more likely to have a decreased renal function,therefore, during treatment with Truvada, 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 Truvada ®, it is recommended that the permanent monitoring of renal function (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

In HIV-infected patients with concomitant HBV infection, clinical and laboratory signs of hepatitis augmentation after discontinuation of treatment were noted.

Overdose:

In case of an overdose, the patient should be observed regarding toxicity manifestations and, if necessary, use 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 preparation Truvada ® contains emtricitabine and tenofovir, all cases of drug interaction found with these active substances may also occur with the use of the Truvada preparation. Studies of drug interactions were conducted only in adults.

Receiving emtricitabine together with tepofovirom no effect on the pharmacokinetics of tenofovir and emtricitabine in a steady state, as opposed to receiving each drug separately.

Research in vitro, as well as clinical studies have confirmed the pharmacokinetic interactions of low probability SUR450-mediated interactions between emtricitabine and tsnofovirom with other drugs.

Simultaneous use is not recommended

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

Truvada ® is a combined medicinal product,so it should not be used concurrently with other drugs containing any of the components: emtricitabine or tenofovir.

Truvada® should not be used concomitantly with adefovir.

Didaposi

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

Medicinal products, which are excreted by the kidneys

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

Truvada® should be avoided with simultaneous or recent use of nephrotoxic medicines (eg, aminoglycosides, amphotritsia B, foscarnet, ganciclovir, pengamidine, vancomycin, cidofovir and interleukip-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 preparation of Truvada®.

Other interactions (see Files)

Studies conducted with other drugsand Emtricitabine

In vitro Emtricitabine nc inhibits metabolism, mediated by the action of any of the following isoenzymes CYP450 human: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 4. Emtricitabine ns inhibits the activity of the enzyme responsible for picuronidation. There is no clinically significant pharmacokinetic relationship in the co-administration of emtricitabine with indinavir, zidovudine, stavudip, or famciclovir.

Tenofovir

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

Truvada®

Joint use of the drug Truvada ® and tacrolimus did not cause clinically significant pharmacokinetic interaction.

Special instructions:

Simultaneous use with other medicinal products

Truvada ® should not be given together with other medicinal products.

preparations containing emtricitabine, tenofovir or other cytidine analogs, for example laminudim. The drug Truvada should not be taken simultaneously with adefovir.

Simultaneous application 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 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 (i.e., active) didanoznn. 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 regime 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 lamivudiiom and abakavir, as well as lamivudipom and didanosine according to the scheme of administration once a day. Lamivudine and emtricitabia have a close structural similarity, as well as similar pharmacokinetics and pharmacodynamics. Thus, the same problems can be observed when using Truvada® as the third nucleoside analogue.

Opportunistic infections

Patients receiving Truvada® 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 Truvada's drug, 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

Emtricitabium 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 that creatinine clearance be evaluated in all patients prior to treatment with Truvada®, and nighttime function (creatinine clearance and plasma phosphate concentration) after 2-4 weeks of treatment, at 3 months of treatment and every 3-6 months after. In patients at risk of developing renal dysfunction, including patients with a history of renal dysfunction, adefovir should be monitored more often by kidney function.

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

Data on the safety of Truvada® in relation to effects on kidney function are limited. For patients with creatinine clearance of 30-49 ml / min, correction of the interval between doses is recommended. 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 tfnofovir in combination with emtricitabine every 24 hours, there was a 2-4 times higher exposure of tenofovir and impaired renal function. Therefore, when receiving Truvada patients with QC <60 ml / m and u need a thorough assessment of the relationship between benefit and risk, as well as careful monitoring of kidney function. In addition, patients receiving Truvada® with a long interval between doses should constantly monitor the clinical response to treatment. The use of the drug Truvada® is contraindicated in patients with impaired renal function of a serious degree (CK <30 ml / min) and those who need hemodialysis, since a corresponding dose reduction is not possible with a combination pill. If a patient receiving the Truvada® preparation has a serum phosphate concentration of <1.5 mg / dl (0.48 mmol / L) or a QC lowered to <50 mL / min, renal function should be re-evaluated for one week, including determining 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 discontinue treatment with Truvada * in patients with a confirmed reduction in CK <50 ml / min or a decrease in serum phosphate concentrations <1.0 mg / dl (0.32 mmol / l).

Do not replace the drug Trunada ® 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-staging anti-inflammatory drugs (NSAIDs) in patients who received tfnofovir and who have risk factors for renal dysfunction. Renal function should be properly monitored when the Truvada ® and NSAIDs are combined. A high risk of kidney damage has been reported in patients receiving tenofovir in combination with a protease inhibitor with enhanced ritoiavir or a cobicystate. These patients require careful monitoring of kidney function (see section "Interaction with other drugs").In patients with risk factors, renal dysfunction, co-administration of tenofovir with an enhanced protease inhibitor should be carefully analyzed.

Patients with mutations of HIV-1 resistance

Truvada® 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, 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 best treatment for patients infected with HIV and hepatitis B virus. The efficacy and safety of Truvada® in chronic hepatitis B have not been 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 suggest that emtricitabine and tenofovir demonstrate activity against hepatitis B virus. The abolition of Truvada® 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 of Truvada therapy. In some cases, the resumption of therapy with hepatitis B may be required. In patients with severe liver disease or cirrhosis, it is not recommended to cancel treatment, since the exacerbation 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 Truvada ® for nazis, in whom serious liver function disorders are the main disease, have not been studied. Data on the pharmacokinetics of the drug Truvada 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 tic is subjected to a substantial metabolism by liver enzymes and has a renal excretion pathway, so taking into account the minimal hepatic metabolism and renal excretion pathwayemtricitabine, it can be assumed that patients with hepatic insufficiency ns require dose adjustment.

In patients with a previously diagnosed liver disease, including chronic active hepatitis, with combinantiretroviral there may be more frequent liver dysfunction. These patients should be carefully monitored in accordance with standard practice. With signs of increased liver disease for such patients, consideration should be given to the possibility of interruption or cessation of treatment.

Lactic acidosis

With the use of nucleoside analogues, lactic acidosis, usually accompanied by fatty liver dystrophy, has been reported. Early symptoms (symptomatic giperlakgatemiya) include symptoms of mild from the digestive system (nausea, vomiting and abdominal pain), nesnetsificheskoe malaise, loss of appetite, loss of body weight, with the 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 assigning nucleoside analogs to any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and fatty liver disease (including certain medicines 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 is 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-thereby-impaired metabolism. 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, weekly data from HIV-infected patients who had not previously been treated with antiretrovirals indicate that the risk of lipodystrophy in the case of teiofovir was less than with d4T 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 neonates exposed to intrauterine and / or postnatal effects of nucleoside analogues. The main undesirable events reported were haematological disorders (anemia, peitropenia) and metabolic disorders (hyperlactatemia, hyperlinaemia). 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-positive newborns, should be under close clinical and laboratory supervision and have a thorough examination for possible mitochondrial changes if any signs or symptoms appear. The available data do not influence the current national recommendations, according to which HIV-positive pregnant women need antiretroviral therapy for preventionvertical transmission 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 beginning of ltion. Examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections, and the non-nosocomial (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 be advised to seek medical advice if they develop aches or joint pain, joint stiffness, or difficulty walking.

Elderly patients

The drug Truvada ® 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 the transpot and work with mechanisms were conducted. However, patients should be informed that dizziness has been reported during treatment with both emtricitabine, hack and tenofovir. When dizziness occurs, you should refrain from performing these activities.

Form release / dosage:

Film coated tablets shell, 300 mg + 200 mg.

30 tablets per bottle of high density polyethylene, sealed with aluminum foil, with a cover with anti-tamper protection children.

Inside the vial is placed absorber of moisture (silica gel).

Packaging:(30) - polyethylene bottles (1) - packs cardboard

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

4 years.

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

Terms of leave from pharmacies:On prescription