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

Clinical and pharmacological group: & nbsp

Means for the treatment of HIV infection

Included in the formulation

Evpplera

pills inwards

Gilead Science International Co., Ltd. United Kingdom

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

J.05.A.R.08 Emtricitabine + Tenofovir Dizoproxil + Rilpivirin

Pharmacodynamics:

Combined drug with a fixed dose of rilpivirin, tenofovir, emtricitabine.

Mechanism of action

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

Rilpivirin is a diaryl pyrimidine non-nucleoside inhibitor of HIV-1 reverse transcriptase. The activity of rilpivirin is mediated by the non-competitive inhibition of HIV-1 reverse transcriptase.

Emtricitabine and tenofovir phosphorylated by cellular enzymes with the formation of emtricitabine triphosphate and tenofovir diphosphate, respectively. Research in vitro showed that both emtricitabine, and tenofovir, can be completely phosphorylated while being in the cell.Emtricitabine triphosphate and tenofovir diphosphate inhibit HIV-1 reverse transcriptase by a competitive mechanism, leading to termination of viral DNA chain synthesis.

Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerase. In vitro and in vivo data on their toxicity in relation to mitochondria are not available. Rilpivirine does not inhibit cellular α and β human DNA polymerase and mitochondrial γ DNA polymerase.

The combination of emtricitabine, rilpivirin and tenofovir shows a synergistic antiviral activity in the cell culture.

Pharmacokinetics:

Absorption

After oral administration of the drug along with food, emtricitabine quickly and intensively absorbed into the digestive tract with the achievement of maximum concentrationin plasma for 2.5 hours. Maximum concentrationTenofovir in plasma is observed for 2 h, and the maximum concentrationrilpivirin in plasma is usually achieved within 4-5 hours. After oral administration of tenofovir, dizoproxil fumarate by HIV-infected patients, it is rapidly absorbed and converted into tenofovir. The absolute bioavailability of emtricitabine at a dose of 200 mg in the form of solid capsules was 93%.The use of hard gelatin capsules of emtricitabine at a dose of 200 mg along with fat-rich food did not affect AUC emtricitabine. The oral bioavailability of tenofovir when administered on an empty stomach of tenofovir, dizoproxil fumarate, was approximately 25%. Simultaneous reception of tenofovir with disoproxil fumarate with fat-rich food increased oral bioavailability (an increase in the AUC of tenofovir by about 40% and maximum concentrationabout 14%). There is no data on the absolute bioavailability of rilpivirin. Exposure rilpivirina was about 40% lower when taking the drug on an empty stomach than when taking with meals the usual caloric intake (533 kcal) or with food high in fat (928 kcal). When taking rilpivirin hydrochloride with a protein-enriched drink only, the exposure to rilpivirin was 50% lower than when taken with food. Taking rilpivirin hydrochloride on an empty stomach or only with a protein-enriched drink reduces the concentration of rilpivirin in the plasma, which can potentially reduce the therapeutic effect of the drug. For an optimal level of absorption, the drug should be taken with food.

Distribution

After intravenous administration, the volume of distribution of the individual components of emtricitabia and tenofovir was approximately 1400 ml / kg and 800 ml / kg, respectively. After oral administration, emtricitabine and tenofovir widely distributed in the body. In vitro the binding of emtricitabia to human plasma proteins was <4% and was independent of the concentration in the range of 0.02 to 200 μg / ml.

In vitro the binding of rilpivirin to plasma proteins is approximately 99.7%, mainly due to binding to albumins. In vitro the binding of tenofovir to plasma and serum proteins was less than 0.7% and 7.2%, respectively, in the range of tenofovir concentrations from 0.01 to 25 μg / ml.

Metabolism

Emtricitabine undergoes partial metabolism in the body. Biotransformation of emtricitabia involves the oxidation of the thiol group to form 3'-sulfoxide diasteromers (approximately 9% of the dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of the dose). In vitro Experiments show that rilpivirin hydrochloride is mainly subjected to oxidative metabolism, mediated by the cytochrome P450 isofermetic enzyme system (CYP3A). In vitro studies have demonstrated that neither tenofovir disoproxil fumarate nor tenofovir They are not substrates of CYP450 isoenzymes. Neither emtricitabine, nor tenofovir do not inhibit in vitro drug metabolism, mediated by any of the major isoenzymes of CYP450 involved in biotransformation. Besides, emtricitabine does not inhibit uridine-5-diphosphoglucuronyl transferase (enzyme responsible for glucuronization).

Excretion

Emtricitabine is mainly excreted by the kidneys (about 86%) and through the intestine (about 14%). 13% of the dose of emtricitabia was found in the urine as three metabolites. The systemic clearance of emtricitabia was, on average, 307 ml / min. Half-lifeafter oral administration of emtricitabia is approximately 10 hours.

Final half-liferilpivirin is approximately 45 hours. After applying a single oral dose ¹⁴C-rilpivirin, radioactive doses were detected in feces and urine on average at 85% and 6.1%, respectively. In the stool unchanged rilpivirine averaged 25% of the dose. In the urine, only minor concentrations of rilpivirin (<1% of the dose) were detected.

Tenofovir is mainly excreted by the kidneys, both as a result of filtration,and with the help of the active tubular transport system (human organic ion transport 1 [hOAT1]). Approximately 70-80% of the dose taken is excreted unchanged in urine after intravenous administration. The apparent clearance of tenofovir averaged about 307 ml / min. Kidney clearance should be approximately 210 ml / min, which exceeds the rate of glomerular filtration. This indicates that active tubular secretion is an important part of the tenofovir withdrawal process. After oral administration, the half-life of tenofovir is on average 12 to 18 hours.

Indications:

Treatment of HIV-1 infection as first-line therapy in adult patients with HIV-1 RNA levels of not more than 100,000 copies / ml.

ICD-10

I.B20-B24.B24 Disease caused by human immunodeficiency virus [HIV], unspecified

Contraindications:

Hypersensitivity to rilpivirin, tenofovir, emtricitabine and / or other components of the drug.
Children under 18 years.
Violation of the function of the kidneys of moderate and severe severity (creatinine clearance <50 ml / min).
Violation of the liver function of severe severity (class C by Child-Pugh).
Breastfeeding period.
Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Carefully:

Violation of the liver function of an average degree (class B on the Child-Pugh scale).
Age over 65 years.
Impaired renal function (creatinine clearance 50-80 ml / min).
Simultaneous use with drugs that can cause a polymorphic ventricular tachycardia such as "pirouette"; blockers of H2-histamine receptors; antacids (for example, magnesium or aluminum hydroxide, calcium carbonate); inhibitors of isoenzymes P450; substrates of P-glycoprotein (digoxin, megformin, dabigatran).

Pregnancy and lactation:

The drug should not be used during pregnancy, except when the potential benefit of treatment for the mother exceeds the possible risk to the fetus.

It was shown that emtricitabine and tenofovir are excreted in breast milk in women. There are no data on the excretion of rilpivirin with breast milk in women. There is insufficient data on the effect of the drug components on newborns / children. Therefore, the drug should not be used by women during breastfeeding.

To exclude the transmission of HIV to a newborn, it is recommended that HIV-infected women completely abandon breastfeeding.

Dosing and Administration:

Inside.

The drug is used only orally, one tablet once a day with a niche. The tablet should be swallowed whole, washed down with water. Tablets can not be chewed or broken, as this can affect the absorption of the drug. If you want to cancel or change the dose of one of the components of the drug, you should use other available on the market individual dosage forms of emtricitabine, rilpivirina hydrochloride and tenofovir dizoproxil fumarate (see instructions for use of these drugs).

If the delay in taking the drug is less than 12 hours, the missed dose should be taken as soon as possible with food and resume the usual dosage regimen. If the delay in taking the drug is more than 12 hours, the missed dose should not be taken; the next tablet is taken at the usual time.

If a patient has vomiting within 4 hours after taking the drug, another tablet should be taken along with the food.If the patient has vomiting more than 4 hours after taking the drug, there is no need to take another tablet of the drug until the time of the next planned dose of the drug.

In case of withdrawal of the drug in patients with HIV infection and with concomitant hepatitis B, the condition of patients should be carefully monitored for signs of exacerbation of hepatitis.

Side effects:

The most frequently reported adverse events probably associated with the reception rilpivirine hydrochloride, emtricitabine, tenofovir disoproxil fumarate, were nausea (9%), dizziness (8%), abnormal dreams (7%), headache (6%), diarrhea (5% ) and insomnia (5%). The safety profile of emtricitabine and tenofovir disoproxil fumarate in these studies corresponded to previous experience of the use of these drugs, when each of them was used with other antiretroviral agents.

It reported rare cases of renal failure and proximal tubulopathy (including Faikoni syndrome) in patients treated with tenofovir disoproxil fumarate, sometimes leading to bone abnormalities (occasionally contributed to the development of fractures).It is recommended to monitor kidney function in patients receiving the drug.

The use of tenofovir, dizoproxil fumarate and emtricitabine may be accompanied by the development of lactic acidosis, severe hepatomegaly with fatty liver infiltration and lipodystrophy.

Abolition of the drug in HIV-infected patients with concomitant hepatitis B may be accompanied by severe exacerbation of hepatitis.

Overdose:

If an overdose occurs, the patient's condition should be carefully monitored for signs of toxicity. Also, if necessary, standard maintenance therapy should be conducted, including monitoring the clinical condition, monitoring the body's key indicators and ECG data (QT interval length).

There is no specific antidote. Up to 30% of the dose of emtricitabia and approximately 10% of the dose of tenofovir can be eliminated from the body by hemodialysis. There is no evidence of the possibility of excretion of emtricitabia or tenofovir from the body with peritoneal dialysis. Because the rilpivirine characterized by a high binding ability with plasma proteins, dialysis in case of an overdose is ineffective. To remove non-absorbed rilpivirin hydrochloride in the gastrointestinal tract, it can also be used Activated carbon.

Interaction:

The drug should not be used concomitantly with the following drugs: preparations containing monocomponents of the drug; non-nucleoside reverse transcriptase inhibitors; anticonvulsants - carbamazepine, oxcarbazepine, phenobarbital, phenytoin; antituberculous drugs - rifabutin, rifampicin, rifapentin; proton pump inhibitors - such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole; glucocorticosteroid preparations of systemic action-dexamethasone (when taking more than one dose of the drug); preparations based on St. John's wort (Hypericum perforatum); didanosine; analogues of cytidine (lamivudine); adefovir dipivoxyl; nephrotoxic drugs (aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin) or soon after their cancellation.

Contraindicated co-administration with didanosine, since the systemic effect of didanosine significantly increases after the joint use of tenofovir with dizoproxil fumarate, which may increase the risk of adverse reactions associated with didanosine.There have been reports of rare cases of pancreatitis and lactic acidosis, sometimes fatal.

Special instructions:

Treatment should be performed by a doctor who has experience of HIV therapy.

Patients should be warned that modern antiretroviral drugs do not cure HIV, nor can HIV infection be prevented through blood or through sexual contact. Take the necessary precautions to prevent HIV infection.

The drug was not evaluated in patients who had a history of virological inefficiency when treated with an antiretroviral agent. The drug should not be given to patients with HIV-1 infection having a mutation in the K65R codon. A list of mutations associated with rilpivirin should be followed only when the drug is administered to patients who have not previously received therapy.

As with other antiretroviral drugs, genotypic resistance should be analyzed before initiating therapy.

Influence on the cardiovascular system.

The administration of rilpivirin in super therapeutic doses (75 mg and 300 mg once a day) is accompanied by an extension of the QTc interval on the ECG.The use of a recommended dose of rilpivirin 25 mg 1 time per day is not accompanied by a clinically significant effect on the length of the QTc interval. The drug should be used with caution when combined with drugs known for its ability to cause ventricular tachycardia such as pirouette.

Effect on bone tissue.

With the help of dual-energy X-ray absorptiometry, a small but statistically significant decrease in bone mineral density and mineral content in bone tissue was revealed compared to the initial value, which was the same for the rilpivirin and control group.

There is evidence of a decrease in bone mineral density in the spine and a change in the level of biomarkers of bone tissue in comparison with the initial value in patients receiving therofovir dizoproxil fumarate. However, there was no increase in the risk of fractures or signs of clinically significant bone disorders.

Bone disorders (sometimes contributing to the development of fractures) may be associated with proximal renal tubulopathy.If you suspect a bone disorder, consult a specialist doctor for advice.

Patients with HIV and concomitant infection caused by the hepatitis B or C virus.

In patients with chronic hepatitis B or C receiving antiretroviral therapy, there is an increased risk of developing severe and potentially fatal undesirable reactions associated with impaired liver function.

To select the optimal method for treating patients with HIV infection and concomitant hepatitis B, doctors should refer to modern guidelines for HIV treatment.

When concurrently prescribing drugs for the treatment of hepatitis B or C, see also instructions for the use of these drugs.

The safety and effectiveness of the drug in the treatment of chronic hepatitis B has not been evaluated. Emtricitabine and tenofovir individually and in combination, demonstrated activity against hepatitis B virus in pharmacodynamic studies.

With the withdrawal of the drug in patients with HIV infection and concomitant hepatitis B, severe exacerbation of hepatitis can occur. Clinical and laboratory parameters of patients with HIV infection and concomitant hepatitis B, in whom the drug was withdrawn,should be carefully monitored for at least several months after discontinuation of treatment. In such cases, the resumption of treatment of hepatitis B can be justified. In patients with severe liver disease or cirrhosis, it is not recommended to discontinue therapy, since exacerbation of hepatitis after drug cancellation can lead to decompensation.

Laktatatsidoz.

With the use of nucleoside analogs, the development of lactic acidosis, usually accompanied by fatty liver infiltration, was reported. Early manifestations of this condition (symptomatic hyperlactatemia) include symptoms of poor digestion (nausea, vomiting, abdominal pain), nonspecific symptoms (malaise, loss of appetite, weight loss), respiratory symptoms (frequent and / or deep breathing) or neurological symptoms symptoms (including muscle weakness). Lactatecidosis is associated with a high mortality rate and may be accompanied by pancreatitis, deficiency in liver and kidney function. Lactatecidosis usually occurs after several months of therapy.

Treatment with analogues of nucleosides should be discontinued in case of development of symptomatic hyperlactatemia and metabolic lactic acidosis,progressive hepatomegaly or rapidly increasing aminotransferase activity.

Nucleoside analogues should be carefully administered to all patients (especially women with obesity) with hepatomegaly, hepatitis, or other known risk factors (including certain drugs and alcohol). Particular risk may be exposed to patients with concomitant viral hepatitis C who receive alpha-interferon and ribavirin.

Patients with an increased risk should be carefully monitored.

Redistribution of subcutaneous fat.

Combined antiretroviral therapy and Russian therapy can cause redistribution of subcutaneous fat (lipodystrophy) in HIV-infected patients. The exact mechanism of occurrence and the long-term consequences of this phenomenon are not known at present. It is suggested that there is a link between the development of visceral lipomatosis and the intake of protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors. The increased risk of lipodystrophy is associated with such individual factors as the elderly age, as well as factors,related to the use of medicines, for example, a longer course of antiretroviral therapy and associated metabolic disorders. Clinical examination of patients should include an assessment of the physical signs of redistribution of subcutaneous fat. Consideration should be given to the need to monitor the concentration of lipids in the fasting serum and the concentration of glucose in the blood. If there are clinical indications, lipid disorders should be treated.

Mitochondrial disorders.

Nucleosides and nucleoside analogues have demonstrated the ability to cause in vitro and in vivo mitochondrial disorders of varying degrees. The development of mitochondrial disorders in HIV-negative neonates exposed to prenatal and / or postnatal effects of nucleoside analogues has been reported. Among the main recorded adverse reactions are hematologic disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipazemia). These changes are often transitory. Some distant neurological disorders (hypertension, seizures, behavioral disorders) have been reported.At present, it is not known whether neurological disorders are transitory or permanent. All children exposed to prenatal exposure to nucleosides or nucleoside 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 relevant signs or symptoms.

Syndrome of restoration of immunity.

At the onset of antiretroviral therapy in HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic opportunistic infections in the form of an appearance or worsening of the symptoms of the disease may develop. previously occurring asymptomatically (immune reconstitution syndrome), which may require further careful monitoring and treatment. 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 pneumonia.You should evaluate any symptoms of inflammation and, if necessary, prescribe treatment in a timely manner.

Osteonecrosis.

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

Influence on driving and working with machinery.

The drug has no effect or has little effect on the ability to manage transport and work with mechanisms. Studies to study the effect of the drug on the ability to manage transport and work with mechanisms were not conducted. However, patients should be informed about the possibility of fatigue, dizziness and drowsiness during drug treatment. This should be taken into account in assessing the ability of the patient to manage transport and work with mechanisms.When these undesirable phenomena appear, one should refrain from performing these activities.

Instructions

Emtricitabine + Rilpivirin + Tenofovir (Emtricitabinum + Rilpivirinum + Tenofovirum)