Kemeruvir pills 800mg, 30pcs

Composition

One tablet contains

the Active ingredient:

Darunavir (amorphous) 800 mg

excipients:  low-substituted hyprolose, polysorbate 80, crospovidone, colloidal silicon dioxide, PROSOLV ® EASYtab SP

water-soluble film shell composition:  hypromellose E 5, iron oxide yellow dye (E 172), macrogol 6000, talc, titanium dioxide (E171).

Pharmacological action

The pharmacokinetic properties of darunavir administered concomitantly with ritonavir were evaluated in healthy, adult volunteers and HIV-1 infected patients. Darunavir exposure was higher in HIV-1 infected patients than in healthy volunteers. The increased exposure of darunavir to HIV-1 infected patients compared to healthy subjects may be due to higher concentrations of alpha-1 acid glycoprotein in HIV-1

infected patients, which leads to increased binding of darunavir to alpha-1 acid glycoprotein in blood plasma, and, consequently, to increased plasma concentrations.

Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the concentration of darunavir in blood plasma.

Suction

Darunavir is rapidly absorbed after oral use. The maximum concentration of darunavir in blood plasma in the presence of a low dose of ritonavir is generally reached within 2.5-4.0 hours.

Absolute bioavailability with oral use of a single dose of darunavir 600 mg as monotherapy was approximately 37% and increased to approximately 82% in the presence of ritonavir 100 mg taken twice daily. The overall effect of pharmacokinetic enhancement of ritonavir was approximately a 14-fold increase with systemic exposure to darunavir, when a single dose of 600 mg darunavir was administered orally in combination with 100 mg ritonavir twice daily. When using the drug on an empty stomach, the relative bioavailability of darunavir in the presence of a low dose of ritonavir decreases compared to taking it with food. Therefore, the drug Kemeruvir tablets should be taken with ritonavir together with food. Distribution

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds mainly to alpha-1 acid glycoprotein. After intravenous use, the volume of distribution of darunavir as monotherapy was 88.1 ± 59.01 (mean ± standard deviation) and increased to 131 ± 49.91 (mean ± standard deviation) in the presence of ritonavir 100 mg taken twice daily.

Biotransformation

In vitro experiments with human liver microsomes show that darunavir primarily undergoes oxidative metabolism. Darunavir is largely metabolized by the hepatic CYP system and almost exclusively by the CYP3A4 isoenzyme. A clinical study of 14C-darunavir in healthy volunteers showed that most of the radioactivity in plasma after use of a single dose of darunavir with ritonavir 400/100 mg was due to the original Active ingredient. At least 3 oxidative metabolites of darunavir were identified in humans; the activity of all these metabolites against wild-type HIV was less than 1/10 of that of darunavir itself.

Deduction

After a single dose of 400 mg 14C-darunavir and 100 mg ritonavir, approximately 79.5% and 13.9% of radioactivity was detected in the stool and urine, respectively. Unchanged darunavir accounted for about 41.2% and 7.7% of radioactivity in feces and urine, respectively. The final elimination half-life of darunavir was approximately 15 hours when taken in combination with ritonavir. The clearance of darunavir after intravenous use of 150 mg was 32.8 l / h (without ritonavir) and 5.91 l / h in the presence of a low dose of ritonavir.

Special groups

Elderly patients

Population pharmacokinetic analysis in HIV-infected patients showed no significant differences in the pharmacokinetic parameters of darunavir in the age group of 18-75 years (this analysis included 12 HIV-infected patients aged 65 years and older). However, there is insufficient data for patients over the age of 65.

Gender differences

Population pharmacokinetic analysis revealed slightly higher (16.8%) darunavir concentrations in HIV-infected women than in HIV-infected men. This difference is not clinically significant.

Patients with renal insufficiency

The results of a study using 14C-darunavir in combination with ritonavir showed that about 7.7% of the received dose of darunavir was excreted unchanged in the urine. The pharmacokinetics of darunavir were not studied in patients with impaired renal function, but population pharmacokinetic analysis showed no significant changes in the pharmacokinetic parameters of darunavir in patients with moderate renal impairment (serum creatinine clearance 30-60 ml / min, n=20).

Patients with hepatic insufficiency

Darunavir is primarily metabolized and excreted by the liver. In a study with multiple use of Kemeruvir in combination with ritonavir (600/100 mg) twice daily, it was shown that total plasma concentrations of darunavir in patients with mild (Child-Pugh class A, n=8) and moderate (Child-Pugh class B, n=8) hepatic impairment were similar to those in healthy patients. However, unbound darunavir concentrations were approximately 55% higher (Child-Pugh Class A) and 100% higher (Child-Pugh Class B), respectively. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied.

Pharmacodynamics

Darunavir is an inhibitor of dimerization and catalytic activity of HIV-1 protease. The drug selectively inhibits the cleavage of HIV Gag-Pol polyproteins in virus-infected cells, preventing the formation of full-fledged viral particles.

Darunavir is resistant to mutations that cause resistance to protease inhibitors. Darunavir does not inhibit any of the 13 human cellular proteases studied.

Indications

Inflammatory and degenerative joint diseases accompanied by pain syndrome: rheumatoid arthritis; osteoarthritis;ankylosing spondylitis (Ankylosing spondylitis).

Contraindications

-hypersensitivity to darunavir or to any components of the drug.

– Severe hepatic insufficiency (Child-Pugh class C).

– concomitant use with any of the following medications is contraindicated due to the expected decrease in the concentration of darunavir and ritonavir in blood plasma and the potential loss of therapeutic effect (see the section “Drug interactions”).

– simultaneous use of lopinavir / ritonavir with the drug Kemeruvir (their combined use leads to a significant decrease in the concentration of darunavir, which, in turn, can lead to a clinically significant decrease in the therapeutic effect of darunavir.

– concomitant use of herbal preparations containingSt. John’s wort (Hypericum perforatum) with the drug Kemeruvir (due to the risk of a decrease in plasma concentrations and a decrease in the clinical effectiveness of darunavir).

– concomitant use of the drug Kemeruvir with ritonavir in low doses with a number of other drugs (see the section “Drug interactions”).

Darunavir, enhanced with ritonavir, inhibits the elimination of active active substances that are highly dependent on CYP3A for clearance, which leads to increased exposure to concomitant medications. Therefore, concomitant use with such drugs, for which an increase in blood plasma concentrations is due to serious and/or life-threatening adverse events, is considered contraindicated (for darunavir, enhanced with ritonavir). These active ingredients include:

– alfuzosin (alpha-1-adrenergic blocker)

– amiodarone, bepridil, dronedarone, quinidine, ranolazine, systemic lidocaine (antiarrhythmic / antianginal drugs)

– astemizole, terfenadine (antihistamines)

– colchicine when used in patients with renal and/or hepatic insufficiency (an anti-gouty drug) (see section 4.5)

– ergot derivatives (e. g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)

– cisapride (drugs for gastrointestinal motility)

– pimozide, quetiapine, sertindol (neuroleptics)

– triazolam, midazolam for oral use (sedatives/hypnotics) (with caution when parenteral use of midazolam)

– sildenafil – when used for the treatment of pulmonary arterial hypertension, avanafil (PDE-5 inhibitors)

– simvastatin and lovastatin (HMG-CoA reductase inhibitors)

– ticagrelor (antiplatelet drugs).

Side effects

The following classification of adverse reactions was used depending on the frequency of occurrence: very common (>1/10), often (>>1/100,1/1000,1/10,000, >>

Very often:  Diarrhea.

Often:

– nausea, vomiting, abdominal pain, increased amylase activity, dyspepsia, bloating, flatulence

-increased alanine aminotransferase

activity-headache, peripheral neuropathy, dizziness, insomnia. – rash (macular, maculopapular, papular, erythematous and pruritic), pruritus. Diabetes mellitus, lipodystrophy (including lipohypertrophy, lipodystrophy, lipoatrophy), hypertriglyceridemia, hypercholesterolemia, hyperlipidemia

-asthenia, fatigue

Infrequently:

– thrombocytopenia, neutropenia, anemia, leukopenia

– tachycardia, increased blood pressure, congestion, angina, prolonged QT interval, heart attack

– shortness of breath, cough, epistaxis, sore throat,

hepatitis, including cytolytic, stenosis of the hepatic artery, hepatomegaly, hepatic steatKemeruvir should always be taken orally with a low dose of ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medications. Before starting treatment with Kemeruvir, you should read the instructions for medical use of the drug ritonavir.

Adults and children over 12 years of age with a body weight of 40 kg or more who have not previously received antiretroviral therapy:

The recommended dosage is 800 mg once daily in combination with 100 mg of ritonavir once daily with meals.

Adults and children over 12 years of age with a body weight of 40 kg or morewho have previously received antiretroviral therapy:

The following dosage regimen is recommended:

In respect of patients previously held antiretroviral therapy with no strains of HIV-1 mutations (DRV-RAM)* associated with resistance to darunavir, with a plasma concentration of HIV RNA-1 less than 100,000 copies/ml and CD4 count+ ≥ 100 x 106/l, can be applied dosage of 800 mg once a day together with 100 mg ritonavir once a day during meals.

– For all other patients who have previously received antiretroviral therapy, or if HIV-1 genotyping is not available, the recommended dosage is 600 mg twice daily together with 100 mg of ritonavir twice daily with meals.

* DRV-RAM: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V.

Recommendations for skipping a dose

If you miss the next dose of 800/100 mg of the combination Kemeruvir / ritonavir once a day for 12 hours from the usual time of taking the drug, patients should be advised to take the prescribed dose of Kemeruvir and ritonavir as soon as possible with meals. If more than 12 hours have passed since the usual time of taking the missed dose, the missed dose should not be taken, the patient should resume taking the drug according to the standard scheme. This guideline is based on the elimination half-life of darunavir, which is 15 hours in the presence of ritonavir, and the recommended intake interval of about 24 hours.

If you miss the next dose of 600/100 mg of the combination Kemeruvir/ ritonavir within 6 hours of the usual time of taking the drug, patients should be advised to take the prescribed dose of Kemeruvir and ritonavir as soon as possible with a meal. If more than 6 hours have passed since the usual time of taking the missed dose, the missed dose should not be taken, the patient should resume taking the drug according to the standard scheme. This guideline is based on the elimination half-life of darunavir of 15 hours in the presence of ritonavir, and the recommended intake interval of about 12 hours.

Special patient groups

Elderly patients

There are insufficient data for this group of patients, therefore, the drug Kemeruvir should be prescribed with caution in this category of patients.

Liver failure

Darunavir is metabolized by the liver. Dose adjustment is not recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic insufficiency, however, Kemeruvir should be administered with caution in these patients. There are no available pharmacokinetic data for patients with severe hepatic insufficiency. Severe hepatic insufficiency can lead to increased exposure to darunavir and a worsening of its safety profile. Therefore, Kemeruvir should not be used in patients with severe hepatic insufficiency (Child-Pugh class C).

Kidney failure

No dose adjustment is required in patients with renal insufficiency.

Children

Kemeruvir is indicated for children aged from 12 years with a body weight of at least 40 kg.

Method of application

Patients should be instructed that Kemeruvir is taken with a low dose of ritonavir within 30 minutes of the end of a meal. The type of food does not affect the concentration of darunavir.

Overdose

Treatment: No specific antidote is known. In case of overdose, general maintenance therapy should be carried out with monitoring of the main physiological parameters. To remove the non-absorbed drug, gastric lavage or a cleansing enema is indicated. You can use activated carbon. Darunavir is highly bound to plasma proteins, so it is not removed in significant amounts by dialysis.

Special instructions

Patients should be informed that current antiretroviral drugs do not cure HIV infection or prevent HIV transmission. Patients should be made aware of the need to take appropriate precautions.

This dosage form with the indicated available dosage is not used in children under 12 years of age and weighing less than 40 kg. Information on the treatment of patients aged 65 years and older with the darunavir/ritonavir combination is very limited. Caution should be exercised when treating patients in this age group with darunavir, as they are more likely to have liver dysfunction, suffer from concomitant diseases, or receive concomitant therapy.

Absolute bioavailability after a single 600 mg dose of darunavir is approximately 37% and increases to approximately 82% after taking darunavir in combination with 100 mg of ritonavir twice daily. There was a 14-fold increase in the concentration of darunavir in plasma after taking a single dose of 600 mg in combination with ritonavir (100 mg 2 times a day). Therefore, darunavir should only be taken in combination with a low dose of ritonavir (100 mg) as a pharmacokinetic enhancer. Increasing the indicated dose of ritonavir does not significantly increase the concentration of darunavir in plasma, so it is not recommended to increase the dose of ritonavir.

Severe skin reactions

In 0.4% of patients taking darunavir, severe skin reactions were recorded, which may be accompanied by fever and / or an increase in the level of hepatic transaminases. Stevens-Johnson syndrome and DRESS-syndrome (drug rash with eosinophilia and systemic manifestations) were rarely reported (

Toxic epidermal necrolysis and acute generalized exentematous pustulosis were very rare in the post-marketing period (

Rash (of all types) was observed in 10.3% of patients receiving darunavir. The rash was generally mild to moderate and was often observed during the first four weeks of treatment and decreased with continued therapy. In 0.5% of cases, the rash was the reason for the withdrawal of the darunavir/ritonavir combination.

Rash was more frequently observed in patients taking raltegravir and the darunavir/ritonavir combination simultaneously compared to patients receiving raltegravir and the darunavir/ritonavir combination separately. Rash associated with drug use occurred with the same frequency in all three groups. The rash was mild to moderate in severity and did not limit therapy. The rash was not a reason for discontinuation of therapy.

Darunavir contains a sulfonamide group. Darunavir should be used with caution in patients allergic to sulfonamides. In clinical trials of the darunavir/ritonavir combination, the degree and frequency of rash occurrence were similar in both patients with and without a history of sulfonamide allergy.

Patients with liver diseases

Caution should be exercised when using the drug in patients with mild to moderate hepatic impairment. Data on the use of the drug in severe hepatic impairment are not available.

Hepatotoxicity

When using the darunavir/ritonavir combination, hepatitis caused by the use of medications may develop (for example, acute hepatitis, cytolytic hepatitis). Hepatitis was observed in 0.5% of patients receiving darunavir/ritonavir combination therapy. Patients with impaired liver function, including those with chronic active hepatitis B or C, have an increased risk of developing severe liver side effects.

Appropriate laboratory parameters should be monitored before prescribing the darunavir / ritonavir combination and during treatment. Monitoring for increased AST and ALT activity should be considered in patients with chronic hepatitis, cirrhosis of the liver, or in patients who have experienced increased transaminase activity before starting therapy and, especially, during the first few months of darunavir/ritonavir combination therapy. Discontinuation or discontinuation of darunavir/ritonavir therapy should be considered if symptoms of hepatic impairment or progression are detected (including clinically significant increase in liver enzyme activity and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, pain on palpation of the liver, hepatomegaly).

Patients with kidney disease

The kidneys play a minor role in the clearance of darunavir, so in patients with kidney disease, the total clearance of darunavir practically does not decrease. Darunavir and ritonavir have a high degree of binding to plasma proteins, so hemodialysis or peritoneal dialysis do not play a significant role in the elimination of these drugs from the body.

Patients with hemophilia

Increased bleeding, including spontaneous cutaneous hematomas and hemarthrosis, has been reported in patients with type A and B hemophilia treated with protease inhibitors. Some of these patients received clotting factor VIII. In more than half of the cases described, treatment with protease inhibitors was continued without interruption or resumed after being suspended for some time.A causal relationship has been suggested between treatment with protease inhibitors and increased bleeding in patients with hemophilia, but the mechanism of this relationship has not been established. Patients with hemophilia receiving a combination of darunavir / ritonavir should be informed about the possibility of increased bleeding.

Diabetes mellitus/hyperglycemia

New cases of diabetes mellitus, hyperglycemia, or worsening of pre-existing diabetes mellitus have been reported in patients receiving antiretroviral therapy, including protease inhibitors. In some of these patients, hyperglycemia was severe and in some cases accompanied by ketoacidosis. Many patients had concomitant diseases, some of which required treatment with drugs that promote the development of diabetes or hyperglycemia.

Fat redistribution and metabolic disorders

Combined antiretroviral therapy can cause fat redistribution (lipodystrophy) in HIV-infected patients. An increased risk of developing lipodystrophy is associated with factors such as old age, as well as with long-term therapy with antiretroviral drugs and associated metabolic disorders. In clinical studies of HIV-infected patients receiving antiretroviral drugs, it is necessary to pay attention to the physical signs of fat redistribution. It is recommended to determine the content of lipids and fasting blood glucose. Lipid metabolism disorders should be treated with appropriate medications.

Osteonecrosis

Despite the multifactorial etiology (use of corticosteroids, alcohol, severe immunosuppression, elevated body mass index), cases of osteonecrosis have been reported, especially in patients with late-stage HIV disease and/or in patients receiving long-term combination antiretroviral therapy. Patients should be informed about the need for immediate medical attention in case of joint pain or movement difficulties.

Immune recovery syndrome

HIV-infected patients with severe immunodeficiency may develop an inflammatory response to asymptomatic or residual opportunistic infections at the beginning of combined antiretroviral therapy, which causes serious clinical complications or worsening of symptoms. These reactions usually occur in the first weeks or months of combined antiretroviral therapy. Cytomegalovirus retinitis, generalized and/or local mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci may occur. It is necessary to determine the severity of any symptoms of inflammation and conduct appropriate therapy. Autoimmune diseases (such as Graves ‘ disease) They were also noted when the inflammatory syndrome of restoring the immune system occurs. However, the time of primary manifestations varied, and the disease could occur many months after the onset.

Use during pregnancy and lactation

Full-fledged studies of darunavir in pregnant women have not been conducted. Animal studies have not shown that darunavir has toxic activity or negative effects on reproductive function and fertility. The darunavir / ritonavir combination should only be given to pregnant women when the expected benefit to the expectant mother outweighs the potential risk to the fetus. It is not known whether darunavir is able to enter human breast milk. Given the potential for transmission of HIV through breast milk, as well as the risk of serious side effects in children associated with exposure to darunavir, HIV-infected women receiving darunavir should refrain from breastfeeding. Experimental animal studies did not reveal the toxic activity of darunavir or its negative effect on reproductive function and fertility. Darunavir has been shown to be excreted in breast milk in lactating rats. Category of action on the fetus according to the FDA-B.

Features of the drug’s effect on the ability to drive a vehicle or potentially dangerous mechanisms

Studies on the effect of using the darunavir/ritonavir combination on the ability to drive a car and moving mechanisms have not been conducted. However, when considering the patient’s ability to drive a car and move machinery, the patient’s clinical condition should be taken into account, as well as the nature of the side effects of darunavir.

Active ingredient

Darunavir

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Indications

HIV infection