Isentress, 400 mg, 60 pcs.

Raltegravir inhibits catalytic activity of HIV integrase, an enzyme involved in HIV virus replication.

Inhibition of integrase prevents covalent insertion (integration) of HIV genome into host cell genome at early stages of infection development. HIV genomes that are not incorporated into the human DNA are unable to induce the production of new viral particles, so inhibiting the process of integration 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 expressed insignificantly.

Microbiology

At a plasma concentration of 31±20 nmol/L, raltegravir provided 95% suppression of viral replication (95% inhibitory concentration, IC95) in human T lymphocyte cell cultures infected with the H9IIIB HIV-1 cell culture adapted variant compared to the 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 analysis, raltegravir suppressed infection caused by 23 strains of HIV representing 5 non-B subtypes and 5 circulating recombinant forms, with an IC50 of 5-12 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 lamivudine) were simultaneously introduced into a culture of human T lymphocytes infected with variant H9IIIB of HIV-1 virus, non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine and delavirdine), HIV protease inhibitors (indinavir, saquinavir, ritonavir, amprenavir, lopinavir, nelfinavir and atazanavir) or fusion inhibitor (enfuvirtide) had additive to synergistic antiretroviral activity.

Drug resistance

HIV-1 integrase mutations that contribute to raltegravir-resistant virus strains (developed in vitro or in patients taking raltegravir) primarily 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, E138A/K, G140A/S, V151I, G163R, S230R).

Recombinant viruses with a single primary mutation (Q148H, K or R or N155H) 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 ability of the virus to replicate.

Mutations associated with the development of resistance to raltegravir can also lead to resistance to another integrase chain transfer inhibitor elvitegravir.

When substituted at position 143, sensitivity to raltegravir is reduced more than sensitivity to elvitegravir, whereas mutations in E92Q cause greater resistance to elvitegravir than to raltegravir.

Viruses with a mutation at position 148 in combination with one or more additional mutations that cause resistance to raltegravir may also exhibit clinically significant resistance to dolutegravir.

Effect on cardiac electrophysiologic activity or ECG parameters

In a placebo-controlled clinical study involving healthy volunteers, a single dose of 1600 mg of raltegravir had no effect on QTc interval duration despite the fact that the Cmax of raltegravir in plasma was 4 times greater than that of a single dose of 400 mg of raltegravir.

Pharmacokinetics

In adult patients

Absorption

Raltegravir is rapidly absorbed after ingestion on an empty stomach, Cmax in plasma is determined approximately 3 hours later. Values of AUC and Cmax of raltegravir increase in proportion to the dose in the dose range from 100 to 1600 mg.

The C12h 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.

When the drug is taken twice daily, equilibrium is reached rapidly, approximately within 2 days of starting treatment.

AUC and Cmax values testify in favor of absence or minimal drug cumulation, C12h value – in favor of insignificant drug cumulation. In monotherapy at 400 mg twice daily, the geometric mean for AUC0-12h was 14.3 μmol/L x h, the C12h value was 142 nmol/L.

The absolute bioavailability of raltegravir has not been established. Raltegravir can be taken regardless of dietary intake.

Distribution

Approximately 83% of raltegravir is bound to plasma proteins at concentrations ranging from 2 to 10 µmol/L. Raltegravir readily crossed the placental barrier in experimental studies in rats, but did not penetrate the blood-brain barrier appreciably.

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, and in the second study it was 3% (range 1 to 61%) of the corresponding plasma concentration.

The median values obtained were approximately 3 to 6 times lower than the plasma free fraction concentrations of raltegravir.

Metabolism and excretion

Studies using selective inhibitors to the uridine diphosphate-glucuronyltransferase (UDF-GT) enzyme isoform obtained by complementary DNA expression showed that UDF-GT1A1 is the major enzyme involved in raltegravir-glucuronide formation.

These data showed that the major pathway of raltegravir metabolism in humans is represented by the UDF-GT1A1-mediated glucuronidation process. The T1/2 of raltegravir in the terminal phase is about 9 h, most of the AUC corresponds to the shorter α-phase apparent T1/2 of raltegravir (is about 1 h).

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 bile.

Raltegravir and raltegravir-glucuronide were detected in the urine at 9% and 23% of the administered dose, respectively.

In plasma, raltegravir was the major circulating radioactive component (approximately 70% of total radioactivity), whereas raltegravir-glucuronide accounted for only 30%.

Pharmacokinetics in selected patient groups

Gender

Gender has no clinically significant effect on the pharmacokinetic parameters of raltegravir. There is no need to adjust the drug dose depending on the patient’s sex.

elderly patients

In studies involving patients aged 18 years and older no significant dependence of raltegravir pharmacokinetic parameters on patient age was found, so no adjustment of the drug dose depending on age is required.

Adolescents and children

According to the results of a comparative study in healthy adult volunteers, chewable tablets have higher oral bioavailability compared to film-coated tablets of 400 mg.

In this study, use of chewable tablets with a high-fat diet resulted in an average 6% increase in AUC, a 62% decrease in Cmax, and an 188% increase in C12 h compared with fasting drug intake.

Chewable tablets with a high-fat diet had no clinically significant effect on the pharmacokinetics of raltegravir, so chewable tablets can be used regardless of food intake.

Doses for adolescents and children over 2 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 taking Isentress®, film-coated tablets, 400 mg twice daily.

Pharmacokinetics of raltegravir in dosage form of chewable tablets in children younger than 2 years old has not been studied.

Patients from different racial-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 pharmacokinetic 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

Raltegravir is excreted primarily by glucuronidation in the liver.
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 in adult patients with mild to moderate hepatic insufficiency compared to healthy volunteers were revealed.
Thus, 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

Renal clearance accounts for a minor portion of raltegravir excretion. The pharmacokinetics of the drug have been studied in adult patients with severe renal impairment and in a complex pharmacokinetic analysis.

No clinically significant deviations of pharmacokinetic parameters in patients with severe renal failure compared to healthy volunteers were found. Thus, correction of the drug dose in patients with severe renal failure is not required.

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

Patients with UDF-GT1A1 polymorphism

There is no evidence or any data indicating that the presence of the UDF-GT1A1 enzyme polymorphism may have a clinically significant effect on the pharmacokinetic 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

Active ingredient:

Associates:

hyprolose,

Opadray colorless YS-1-19025-A1,

Surelease® E-7-190402,

succralose,

sodium saccharinate,

sodium citrate dihydrate,

mannitol,

iron oxide yellow dye,

ammonium glycyrrhizinate (Magnasweet® 1353),

Banana flavoring natural WONF Durarome® 501392 TD0991,

Orange flavoring natural and artificial 501331 TP0551,

/p>

masking flavoring natural and artificial 501482 TP04244,

crospovidone,

magnesium stearate,

How to take, the dosage

Isentress is taken orally.

The recommended dose is 400 mg twice a day.

The maximum dose is 1600 mg/day.

The treatment is given in combination with other antiretroviral drugs.

Interaction

Concomitant use with uridine diphosphate glucuronosyltransferase 1A1 (UDF-GT1A1) inducers, such as rifampicin, decreases plasma concentrations of raltegravir. The effect of other enzyme inducers – such as phenytoin, phenobarbital, involved in the metabolism of raltegravir, on UDF-GT1A1, is unknown.

Concomitant use of raltegravir with UDF-GT1A1 inhibitors (including atazanavir) shows a moderate increase in plasma concentrations of raltegravir.

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.

Patients should continue to observe appropriate safety precautions during treatment with Isentress®.

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 the care of a physician.

Raltegravir has a relatively low genetic barrier to the development of resistance, so raltegravir should be prescribed in combination with two other active antiretroviral agents, 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 directions for use before starting therapy with Isentress® 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.

Immune reconstitution syndrome

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

This may contribute to a worsening of the clinical condition and exacerbation of existing symptoms. Usually such a 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.

In the development of immune reconstitution syndrome, autoimmune disorders such as Graves’ disease have been described. The development of these disorders may be seen many months after starting treatment.

Osteonecrosis

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

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

Serious skin reactions and hypersensitivity reactions

There have been reports of severe (potentially life-threatening) and fatal adverse skin reactions in patients who have taken Isentress

sup>® as part of combination therapy with other drugs associated with these adverse reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

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

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

In these cases, 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 result in 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 effectiveness of Isentress® in patients with severe concomitant liver disease has not been established. Caution should be exercised when prescribing Isentress® 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 termination of treatment should be considered.

Patients with chronic hepatitis B or C who are 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 darunavir than in patients using the drugs alone (see section “Side effects”).

Depression

Depression, including suicidal ideation and behavior, has been observed mostly 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 medicinal products

Powerful inducers of UDF-GT1A1. Caution should be exercised when prescribing Isentress® concomitantly with strong inducers of UDF-GT1A1, such as rifampicin, because of the decrease in plasma concentration of raltegravir they cause.

If combined therapy with rifampicin and Isentress® is required, the dose of Isentress® should be doubled in adult patients.

There are no data to adjust the doses of the drugs when Isentress® and rifampicin are used simultaneously in patients under 18 years of age (see section “Drug Interactions”).

Antacids. Concomitant use of Isentress® with antacids containing aluminum or magnesium leads to decreased plasma concentrations of raltegravir.

The concomitant use of Isentress® with antacids containing aluminum or magnesium is not recommended (see section “Drug Interactions”).

Fructose and sorbitol

The drug Isentress® in the dosage form of chewable tablets contains fructose and sorbitol. Patients with rare hereditary disorders in the form of fructose intolerance should not take Isentress®.

Phenylketonuria

The drug Isentress® in the dosage form of chewable tablets contains phenylalanine as an aspartame flavoring component.

Each 25 mg chewable tablet of Isentress® contains approximately 0.05 mg of phenylalanine, and each 100 mg chewable tablet contains approximately 0.10 mg of phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

Impact on driving and operating machinery

There have been no studies to study the effect on driving and operating machinery.

With regard to the possibility of dizziness, weakness, drowsiness and blurred vision while treating with Isentress®, special caution should be exercised while driving and operating machinery.

Contraindications

With caution:

Side effects

The digestive system: diarrhea, nausea, abdominal pain; rarely – vomiting, discomfort and pain in the upper abdomen, constipation, dyspepsia, flatulence, gastritis, glossitis, gastro-oesophageal reflux, hepatitis, hepatomegaly, hyperbilirubinemia, increased serum AST, ALT and ALP activity.

CNS and peripheral nervous system disorders: headache, dizziness, asthenia, weakness; rarely – irritability, peripheral neuropathy, paresthesias, polyneuropathy, sleepiness, depression, insomnia, unusual dreams, anxiety.

Hematopoietic system: rarely – anemia including macrocytic anemia, neutropenia.

Cardiovascular system: rare – myocardial infarction, palpitation, ventricular extrasystole.

Senses: rare – blurred vision.

Metabolism: rare – increase of appetite, decrease or increase in body weight, lipomatosis, fat metabolism disorders, diabetes mellitus, hyperglycemia, hyperlactatemia, hyperlipidemia, hypertriglyceridemia.

Muscular system disorders: rare – arthralgia, myalgia, pain in extremities, back pain, muscle spasms, myositis, muscle atrophy, increased CPK activity.

Urinary system disorders: rarely – toxic nephropathy, nephrotic syndrome, nycturia, pollakiuria, renal failure, tubular necrosis.

On the genital system: rarely – erectile dysfunction, gynecomastia.

Allergic reactions: hypersensitivity reactions.

Dermatological reactions: rarely – acquired lipodystrophy, hyperhidrosis, erythema, rash, including.macular and maculopapular rash, xeroderma, itching.

Other: rare – feeling of discomfort in the chest, chills, fever, phlegmon, infections caused by Herpes simplex virus, nose bleeds.

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 intake of raltegravir into human breast milk. However, raltegravir was found to enter milk in lactating rats: when administered at 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.