Isentress, 400 mg 60 pcs

Antiviral (HIV) medicine

ATX code: J05AX08

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

Raltegravir inhibits the catalytic activity of HIV integrase-an enzyme involved in HIV virus replication. Inhibition of pitegrase prevents covalent insertion (integration) of the HIV genome into the host cell genome in the early stages of infection.

The HIV genomes not incorporated into human DNA are incapable of inducing production of new viral particles, so suppression of the integration process prevents the spread of viral infection in the body.

The inhibitory ability of raltegravir against human phosphotransferases, including DNA polymerases α, β and γ, is insignificant.

Microbiology

At a plasma concentration of 31 ± 20 nmol/L, raltegravir provides 95% suppression of viral replication (95% inhibitory concentration, IC95) in human T cell cultures infected with an H9IIIB HIV-1 cell culture-adapted variant, compared to control virus-infected cell culture.

IK95 was achieved at concentrations ranging from 6 to 50 nmol/L in cultures of human mitogen-activated peripheral blood mononuclear cells. infected with various primary clinical strains of HIV-1, including strains of 5 non-B HIV-1 subtypes as well as strains resistant to HIV reverse transcriptase inhibitors and protease inhibitors.

In a single infection cycle assay, raltegravir suppressed infection caused by 23 strains of HIV representing non-B subtypes and 5 circulating recombinant forms, with IK50 at concentrations ranging from up to 12 nmol/L. Raltegravir also suppressed HIV-2 strain replication when tested on CEMx174 cells (IK95 = 6 nmol/L).

When raltegravir and nucleoside reverse transcriptase inhibitors (zidovudine, zalcitabine, stavudine, abacavir, tenofovir. didanosine and lamnvudine) were simultaneously introduced into cultures of human T cells infected with variant H9IIIB of HIV-1 virus.

. Non-nucleoside reverse transcriptase inhibitors (efavirenz, jevirapine and delavirdine), HIV protease inhibitors (indinavir, saquinavir, ritonavir, amnrenavir, loninavir, nelfinavir and atazanavir) or fusion inhibitor (enfuvirtide) showed additive to synergistic antiretroviral activity.

Drug resistance

. HIV-1 nntegrase mutations that contribute to raltegravir-resistant strains of the virus (developed either in vitro or in patients taking raltegravir) Mainly include substitutions at positions 155 (N155 substitution for H), 148 (Q148 substitution for H, K or R) or 143 (Y143 substitution for C, H or R), combined with one or more additional mutations (e.g., L74M, E92Q, T97A, E138L/K, G140A/S. V151I, G163R, S230R).

The recombinant viruses with a single primary mutation (Q148H, K or R or N15511) were characterized by reduced replication ability and reduced sensitivity to raltegravir in vitro.

Secondary mutations of the virus further reduced sensitivity to raltegravir. sometimes compensating for the reduced replication ability of the virus. Mutations associated with the development of resistance to raltegravir can also lead to resistance to another integrase chain transfer inhibitor elvitegravir.

The substitution at position 143 reduces the sensitivity to raltegravir to a greater extent than the sensitivity to elvitegravir, while mutations in E92Q- greater resistance to elvitegravir than to raltegravir. Viruses with a mutation at position 148 in combination with one or more additional mutations causing resistance to raltegravir can also show clinically significant resistance to dolutegravir.

Impact on cardiac electrophysiologic activity or electrocardiogram scores

. In a placebo-controlled clinical study involving healthy volunteers, a single dose of 1,600 mg of raltegravir had no effect on QTc interval duration, even though the maximum plasma concentration (Cmax) of raltegravir was 4 times greater than that of a single dose of 400 mg raltegravir.

Pharmacokinetics

In adult patients

Intake

Raltegravir is rapidly absorbed after the drug is taken on an empty stomach; Cmax in plasma is determined after approximately 3 hours. The area under the curve “concentration-time” (AUC) and the value of Cmax of raltegravir increase in proportion to dose in the dose range from 100 mg to 1600 mg.

The Cmax values of raltegravir increase in proportion to dose in the dose range from 100 mg to 800 mg and increase to a somewhat lesser extent in the dose range from 100 mg to 1600 mg. With the twice-daily regimen, equilibrium is reached rapidly, within approximately 2 days of initiating treatment.

The AUC and Cmax values indicate in favor of no or minimal cumulation of the drug, the C12h value in favor of minor cumulation of the drug. In monotherapy regimen of 400 mg twice daily, the geometric mean for AUC0-12h was 14.3 μmol/L x h, the C12h value was 14 nmol/L.

The absolute bioavailability of raltegravir has not been established. Raltegravir can be taken regardless of the food regimen.

Distribution

About 83% of raltegravir is bound to plasma proteins in the concentration range of 2 to 10 µmol/L. Raltegravir easily crossed the placental barrier in experimental studies in rats, but did not penetrate the blood-brain barrier to any appreciable degree.

In two clinical studies involving patients infected with HIV-1 who took raltegravir at a dose of 400 mg twice daily, raltegravir was rapidly detected in the cerebrospinal fluid. In the first study, the mean concentration of raltegravir in the cerebrospinal fluid was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration.

In the second study, the mean concentration of raltegravir in the cerebrospinal fluid was 3% (range 1 to 61%) of the corresponding plasma concentration. The median values obtained were approximately 3-6 times lower than the concentrations of the free raltegravir fraction in plasma.

Metabolism and excretion

Studies using selective inhibitors of the uridine diphosphate-glucuronyltransferase (UDF-GT) enzyme isoform obtained by complementary DNA expression. showed that the UDF-GT1A1 isoform is the major enzyme involved in the formation of raltegravir-glucuronide. These data showed that the main pathway of raltegravir metabolism in humans is represented by the UDF-GT1A1-mediated glucuronidation process.

The duration of the terminal phase of the elimination half-life of raltegravir is approximately 9 hours, most of the AUC corresponds to the shorter a-phase apparent elimination half-life of raltegravir (is approximately 1 hour).

After oral administration of radioactively labeled raltegravir, approximately 51% of the administered dose was excreted through the intestine and 32% through the kidneys. Only raltegravir was detected in the feces, which was probably formed by hydrolysis of raltegravir-glucuronide excreted with the bile.

In the urine, raltegravir and raltegravir-glucuronide were detected at 9% and 23% of the dose taken, respectively. In plasma, the main circulating radioactive component was raltegravir (approximately 70% of total radioactivity), whereas raltegravir-glucuronide accounted for only 30%.

Pharmacokinesis in selected patient groups

Pass

Pass has no clinically significant effect on the pharmacokinetic parameters of raltegravir. There is no need to adjust the dose of the drug depending on the gender of the patient. Elderly patients

In studies in patients 18 years of age and older no significant effect of raltegravir pharmacokinetic parameters on patients’ age was found; therefore no dose adjustment of the drug according to age is required.

Adolescents and Children

Doses for adolescents and children over 6 years of age for the treatment of HIV-1 infection are recommended on the basis that the pharmacokinetic parameters of raltegravir are comparable to those of adult patients. The pharmacokinetics of raltegravir in children younger than 2 years have not been studied.

Patients of different racial and ethnic groups

Racial ethnicity had no clinically significant effect on the pharmacokinetic parameters of raltegravir. No dose adjustment is required.

Patients with different body mass index (BMI)

BMI had no clinically significant effect on the pharmacoknetic parameters of raltegravir in adult patients. There is no need to adjust the drug dose depending on the patient’s BMI.

Patients with hepatic impairment

Naltegravir is eliminated primarily by glucuronidation and hepatic excretion.

The pharmacokinetics of the drug have been studied in adult patients with moderate hepatic impairment and in a combined pharmacokinetic analysis. No clinically significant deviations of pharmacokinetic parameters were found in adult patients with moderate hepatic impairment compared to healthy volunteers.

Hence, correction of the drug dose in mild to moderate hepatic insufficiency is not required. The effect of severe hepatic impairment on the pharmacokinetic parameters of raltegravir has not been studied.

Patients with renal impairment

Relative clearance accounts for a small fraction of the elimination of raltegravir from the body. The pharmacokinetics of the drug have been studied in adult patients with severe renal impairment and in a complex pharmacokinetic analysis.

There were no clinically significant deviations of pharmacokinetic parameters in patients with severe renal failure compared to healthy volunteers. Thus, there is no need to adjust the drug dose in patients with severe renal failure.

Because the dialysis efficacy of raltegravir is unknown, it is not recommended to take the drug on the eve of a dialysis session.

Patients with UDF-GT1AI polymorphism

There is no evidence or any data suggesting that the presence of a polymorphism in the UDF-GT1A1 enzyme may have a clinically significant effect on the pharmacoknetic parameters of raltegravir.

In a comparative study involving 30 adult healthy volunteers with genetically determined reduced UDF-GT1A1 activity and 27 adult healthy volunteers with unchanged UDF-GT1A1 genotype, the ratio of the geometric mean AUC of raltegravir was 1.41 (90% confidence interval was 0.96; 2.09).

Indications

Active ingredient

Composition

1 film-coated tablet contains:

The active ingredient: raltegravir potassium 434.4 mg (equivalent to 400 mg of raltegravir);

Auxiliary substances: microcrystalline cellulose 169.4 mg. lactose monohydrate 26.06 mg, calcium hydrophosphate 69.50 mg, hypromellose 2208 43.44 mg, poloxamer 407* 104.3 mg, sodium stsarylfumarate 8.688 mg, magnesium stearate 13.03 mg;

film coating: Opadray II pink dye (85F94224) 26.06 mg;

film coating composition: polyvinyl alcohol 44.75%, macrogol 22.0%, talc 21.415%, titanium dioxide 11.32%, iron oxide red dye 0.495%. iron oxide dye black 0.02%.

* contains 0.01% butylgndroxytoluene as an antioxidant.

How to take, the dosage

Ingestion. Tablets of the drug Isentress should not be chewed, crumbled or broken. The drug is used regardless of meals.

The treatment with Isentress should be done by a physician with sufficient experience in HIV therapy. Treatment with Isentress is carried out in combination with other antiretroviral drugs.

The recommended doses of Isentress for treatment of HIV-1 infection:

– for adults: 400 mg x 2 times daily;

– for children with a body weight of at least 25 kg: 400 mg x 2 times daily.

If pediatric patients have difficulty swallowing film-coated tablets, consider taking Isentress Chewable Tablets (see Instructions for Use for Isentress, Chewable Tablets).

Elderly patients

Dose adjustment in elderly patients is not necessary.

Patients with impaired renal function

Dose adjustment in patients with impaired renal function is not required.

Patients with impaired liver function

Dose adjustment is not required in patients with mild to moderate hepatic impairment.

Special Instructions

Patients should be informed that current antiretroviral drugs do not cure HIV infection or prevent transmission of HIV to others through blood or sexual contact. During treatment with Isentress, patients should continue to observe appropriate safety precautions.

Patients should also be informed that they may still develop infections or other conditions common among HIV-infected patients (opportunistic infections). During therapy with Isentress, it is very important to remain under medical supervision. Raltegravir has a relatively low genetic barrier to the development of resistance.

Therefore, raltegravir should be administered in combination with two other active antiretrovirals, if possible, to increase treatment efficacy and reduce the risk of developing resistance to the drug. It is important to explain to patients the need to read the instructions for use before starting therapy with Isentrsss and to reread them each time they get another prescription from their doctor.

Patients should be informed to tell their doctor if any unusual symptoms occur, or if any known symptom persists or worsens.

The immune reconstitution syndrome

. In the initial stages of combination ART, HIV-infected patients with severe immunodeficiency may develop what is known as immune reconstitution syndrome, which is an inflammatory response to asymptomatic ongoing or residual opportunistic infections (cytomegalovirus retinitis, Pneumocystis jiroveci pneumonia, disseminated or focal mycobacterial infections, etc.).).

This may contribute to a worsening of the clinical condition and exacerbation of existing symptoms. Usually this reaction can be observed in the first weeks or months after the start of combination therapy.

Any inflammatory symptoms should be evaluated and treatment prescribed if necessary. Autoimmune disorders such as Based’s disease have been described in the development of immune reconstitution syndrome. However, the development of such disorders may be seen many months after the start of treatment.

Osteonecrosis

. Although the etiology of this complication is considered to be multifactorial (including corticosteroid therapy, alcohol use, severe immunodeficiency, high body mass index), cases of osteonecrosis have been described, particularly in the late stages of HIV infection and/or with long-term use of combination ART.

Patients who have symptoms such as joint pain, stiffness, or limited mobility should see a specialist right away.

Serious skin reactions and hypersensitivity reactions have been reported in patients who have had severe (potentially life-threatening) and fatal adverse skin reactions when taking Isentress in combination therapy with other drugs associated with these adverse reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Hypersensitivity reactions have also been reported, which have manifested as a generalized rash, and sometimes organ dysfunction, including liver failure.

The use of Isentress and other drugs suspected of causing such reactions should be stopped immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions (including severe skin rash or rash Fever, general malaise, weakness, muscle or joint pain, blistering of the skin, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, but not limited to these).

In these cases, the clinical status, including hepatic aminotransferase activity, should be monitored and appropriate therapy initiated. Failure to discontinue therapy with Isentress or other drugs associated with these adverse reactions in a timely manner after the onset of a severe rash may lead to life-threatening reactions.

Myopathy and rhabdomyolysis

The development of myopathy and rhabdomyolysis has been reported. Caution should be exercised when prescribing the drug in patients with a history of myopathy and rhabdomyolysis or with any factors predisposing to their development, particularly in concomitant therapy with drugs that may cause these adverse reactions.

Hepatic impairment

The safety and efficacy of Iseitress in patients with severe concomitant liver disease has not been established. Caution should be exercised when prescribing Isentrees in patients with severe hepatic impairment.

Patients with existing liver dysfunction, including chronic hepatitis, have an increased incidence of hepatic dysfunction on combination ART. and should be monitored according to standard practice. If such patients show signs of worsening liver disease, discontinuation or discontinuation of treatment should be considered.

Patients with chronic hepatitis B or C also receiving combination ART are at risk for severe and potentially fatal liver adverse events.

Skin rash

In patients who have previously received ARV therapy, skin rash is more common when using Isentress concomitantly with darunavprom than in patients using the drugs alone (see SIDE ACTIVITY).

Depression

Depression, including suicidal ideation and behavior, has been observed mainly in patients with a history of depression or psychiatric illness. Caution should be exercised when prescribing Isentress to patients with a history of depression or psychiatric illness.

Simultaneous use with other drugs

Powerful inducers of UDF-GT1AI

Caution should be exercised when prescribing Isentress concomitantly with other inducers of UDF-GT1A1, such as rifampicin. due to the decrease in plasma concentrations of raltegravir caused by them.

If combination therapy with rifampicin and Isentress is required, the dose of Isentress should be doubled in adult patients. There are no data to support dose adjustments when Isentress and rifampicin are used concomitantly in patients under 18 years of age (see section INTRODUCTION WITH OTHER MEDICINARY MEDICINATIONS).

Antacids

The concomitant use of Isentress with antacids containing aluminum or magnesium leads to decreased plasma concentrations of raltegravir. Concomitant use of Isentress with antacids containing aluminum or magnesium is not recommended (see section INTRODUCTION WITH OTHER MEDICINATIONS).

Impact on the ability to drive vehicles and operate machinery

There have been no studies on the effect on the ability to drive vehicles and operate machinery. Taking into account that dizziness, weakness, somnolence and blurred vision may occur during treatment with Isentress which may influence the above mentioned abilities, special caution should be exercised while driving and operating machinery.

Contraindications

The drug contains lactose. Therefore, patients with rare hereditary lactose intolerance, lactase deficiency, or impaired glucose-galactose absorption should not take Isentress.

WARNING

Myopathy and rhabdomyolysis (including a history), conditions and factors predisposing to their development.

Hepatic insufficiency is severe.

Concomitant use with strong inducers of UDF-GT1A1 (rifampicin).

Concomitant use of Isentress with antacids containing aluminum or magnesium.

Depression, including suppurative ideas and behavior, has been observed mainly in patients with a history of depression or psychiatric illness. Caution should be exercised when prescribing Isentress to patients with a history of depression or psychiatric illness.

Elderly age (because of limited information on the use of raltegravir in patients older than 65 years).

Side effects

The safety profile of Isentress is based on the results of pooled safety data from clinical trials involving patients previously treated with antiretroviral therapy (ART) and patients not previously treated with ART.

Overdose

Pregnancy use

There have been no controlled studies of Isentress in pregnant women; therefore, Isentress is contraindicated for use during pregnancy.

There are no data on the uptake of raltegravir into human breast milk. However, raltegravir was found to enter the milk in rats: when administered in a daily dose of 600 mg/kg, the concentration of raltegravir in milk exceeded the plasma concentration by approximately 3 times.

Breastfeeding is not recommended for HIV-infected mothers to avoid postnatal HIV transmission to their children. If it is necessary to use the drug during lactation, it is recommended to stop breastfeeding.