Isentress - instructions for use, doses, side effects, contraindications

Active substanceRaltegravirRaltegravir

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Isentress®

pills inwards

Merck Sharp and Doum B.V. Netherlands

Isentress®

pills inwards

Merck Sharp and Doum B.V. Netherlands

Dosage form: & nbspchewing tablets

Composition:

1 chewable tablet contains:

Dosage of 25 mg:

active substance raltegravir potassium 27.16 mg (equivalent to 25 mg raltegravir);

Excipients: giprolose 2,362 mg, opadine colorless YS-1-19025-A¹ 1.771 mg, Surclease® E-7-19040² 2,657 mg, sucralose 2,334 mg, sodium saccharinate 6,999 mg, sodium citrate dihydrate 1,167 mg, mannitol 153.84 mg, iron oxide dye yellow 1,167 mg, ammonium glycyrrhiziumate (Magnasweet 135³) 2,334 mg, banana natural flavoring WONF Duraromc® 501392 TD0991 4,667 mg, orange natural and artificial flavoring 501331 TR0551 6,999 mg, natural and artificial flavoring aroma 501482 TR0424⁴ 4,667 mg, crospovdone 11.67 mg, magnesium stearate 1.167 mg, sodium stearyl fumarate 2,334 mg.

Dosage of 100 mg:

active substance raltegravir potassium 108.6 mg (equivalent to 100 mg raltegravir);

Excipients: giprolose 9.448 mg, opadine colorless YS-1-19025-A¹ 7.085 mg, Surelease® E-7-19040² 1 0.63 mg, sucralose 4,667 mg, sodium saccharinate 14.00 mg, sodium citrate dihydrate 2,333 mg, mannitol 239.6 mg, iron dye red oxide 0.28 mg, iron dye oxide yellow 2.333 mg, ammonium glycyrrhiziumate (Magnasweet® 135³) 4,667 mg, banana natural flavoring WONF Duraromc® 501392 TD0991 9,334 mg, orange natural and artificial flavoring 501331 TR0551 14,00 mg, natural and artificial masking aroma 501482ТР0424⁴ 9,334 mg, crospovdone 23,34 mg, magnesium stearate 2,334 mg, sodium stearyl fumarate 4,667 mg.

¹Ramp off colorless YS-1-19025-L consists of pistolellose 2910 /6cp and macrogol;

² Surelease® E--7-19040 consists of a 25% aqueous suspension of ethyl cellulose in water purified, cellulose 20 cP. ammonium hydroxide, medium chain and oleic acid triglycerides;

³ Magnaswcct® 135 consists of an extract of licorice, sorbitol and fructose;

⁴ contains aspartame.

Description:

Dosage of 25 mg: round planocylindrical from light yellow color with impregnations of white color, with engraving of company's logo Merck and "473" on the other side.

Dosage of 100 mg: oval biconvex tablets of light orange color with impregnations of white color, with an engraved company logo Merck and "477", separated by risk, on one side and with the risk on the other side.

Pharmacotherapeutic group:Antiviral (HIV) agent

ATX: & nbsp

J.05.A.X Other antiviral drugs

J.05.A.X.08 Raltegravir

Pharmacodynamics:

Raltegravir inhibits the catalytic activity of HIV integrase, an enzyme involved in the replication of the HIV virus. Inhibition of integrase prevents the covalent introduction (integration) of the HIV genome into the genome of the host cell in the early stages of infection.Human HIV genomes not included in human DNA are not capable of inducing the production of new viral particles, so suppressing the integration process prevents the spread of viral infection in the body. The inhibitory ability of raltegravir for human phosphotransferases, including α, β, and γ DNA polymerases, is not significantly expressed.

Microbiology

At a plasma concentration of 31 ± 20 nmol / L raltegravir provided suppression of viral replication by 95% (95% inhibitory concentration, IR₉₅) in cell cultures of human T-lymphocytes infected with variant H9IIIB HIV-1 adapted to cell cultures as compared to the control virus-infected cell culture. IR95 was achieved in concentrations from 6 to 50 nmol / L in cultures of human mitogen-activated peripheral blood mononuclear cells infected with various primary clinical HIV-1 strains, including strains of 5 non-B HIV-1 subtypes, as well as strains resistant to reverse transcriptase inhibitors and HIV protease inhibitors. When analyzing a single cycle of infection raltegravir suppressed the infection caused by 23 strains of HIV, representing 5 non-B subtypes and 5 circulating recombinant forms, with IR₅₀= 5-12 nmol / l. Raltegravir also suppressed the replication of HIV-2 strains when tested on CEMh174 cells (IC₉₅ = 6 nmol / L). With simultaneous introduction into the culture of human T-lymphocytes infected with the variant H9IIIIn the HIV-1 virus, raltegravir with nucleoside reverse transcriptase inhibitors (zidovudine, zalcitabine, stavudine, abacavir, tenofovir, didanosine and lamivudine), non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine and delavirdine) by HIV protease inhibitorsindinavir, saquinavir, ritonavir, amprenavir, lopinavir, nelfinavir and atazanavir) or a fusion inhibitor (enfuvirtide) antiretroviral activity was observed from additive to synergistic.

Resistance to the drug

HIV-1 integrase mutations that promote the emergence of raltegravir-resistant strains of the virus (developed in vitro or in patients taking raltegravir), mainly involve the replacement of amino acids Y143 (substitution for C, H or R), or Q148 (replacement for H, K, or R), or N155 (replacement for H) plus one or more additional mutations (for example, L74I / M, E92Q, E138A / K, G140A / S or VI511).

Recombinant viruses with one primary mutation (Q148H, K or R or N15511) were characterized by reduced replication and reduced sensitivity to raltegravir in vitro.Secondary mutations of the virus further reduced the sensitivity to raltegravir, sometimes compensating for the reduced ability of the virus to replicate. Influence on electrophotological activity of the heart or on the parameters of the electrocardiogram.

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

Pharmacokinetics:

In adult patients

Suction

Raltegravir is rapidly absorbed after taking the drug on an empty stomach, Cmax in the blood plasma is determined after about 3 hours. The area under the concentration-time curve (AUC) and the C12h value of raltegravir increase in proportion to the dose in the dose range of 100 to 1600 mg. Values of C12h raltegravir increase in proportion to the dose in the dose range from 100 mg to 800 mg and increase to a slightly lesser extent - in the dose range from 100 mg to 1600 mg. When the regimen is taken 2 times a day, the equilibrium state is reached quickly, approximately 2 days after the start of treatment.The values of AUC and Cmax indicate the absence or minimal cumulation of the drug, the value of C12h in favor of a slight cumulation of the drug. In the monotherapy regimen of 400 mg twice a day, the value of the geometric mean for AUC_0-12hwas 14.3 μmol / l x h, the value of C 12h - 142 nmol / l.

The absolute bioavailability of raltegravir is not established. Raltegravir can be taken regardless of the mode of food intake.

Distribution

Approximately 83% of raltegravir binds to plasma proteins in a concentration range of 2 to 10 μmol / L.

Raltegravir easily crossed the placental barrier in experimental studies in rats, but did not penetrate significantly through the blood-brain barrier.

In two clinical studies involving patients infected with HIV-1 who were taking raltegravir in a dose of 400 mg 2 times a day, 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, 3% (range 1 to 61%) of the corresponding concentration in the blood plasma.Medians of the values obtained were approximately 3-6 times lower than the concentration of the free fraction of raltegravir in blood plasma.

Metabolism and excretion

Studies using selective inhibitors to the isoform of the enzyme uridine-diphosphate-glucuronyltransferase (UDF-GT), obtained by expression of complementary DNA, have shown that UDF-GT1D1 is the main enzyme involved in the formation of raltegravir-glucuronide. These data showed that the main way of metabolism of raltegravir in humans is represented by the process of glucuronation mediated by UDF-GT1A1. The duration of the final phase of the half-life of raltegravir is about 9 hours, most of the AUC corresponds to the shorter a-phase of the apparent half-life of raltegravir (approximately 1 hour). After oral administration of radiolabeled raltegravir, approximately 51% of the dose was taken through the intestine and 32% through the kidneys. 13 feces was found only raltegravir, which, probably, was formed by the hydrolysis of raltegravir-glucuronide, which was released with bile. In urine were determined raltegravir and raltegravir-glucuronide in an amount of 9% and 23% of the dose, respectively. In plasma, the main circulating radioactive component was raltegravir (about 70% of the total radioactivity), while raltegravir-glucuronide accounted for only 30%.

Pharmacokinetics in selected patient groups

Floor

Sex does not have a clinically significant effect on the pharmacokinetic parameters of raltegravir. Correction of the dose of the drug depending on the patient's sex is not required. Elderly patients

In studies on patients aged 18 years and older, there was no significant dependence of the pharmacokinetic parameters of raltegravir on the age of patients, so dose adjustment is not required depending on age.

Teens and children

According to the results of a comparative study in healthy adult volunteers, chewing tablets have a higher oral bioavailability than 400 mg tablet coated tablets. In this study, the use of chewing tablets with food containing a high fat content resulted in an AUC increase of 6% on average, a decrease of Cmax by 62%, and an increase in C12h by 188% compared with fasting.Taking chewable tablets with high-fat foods did not have a clinically significant effect on the pharmacokinetics of raltegravir, so chewing tablets can be used regardless of food intake.

Doses for adolescents and children over 2 years 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 (R), film-coated tablets, 400 mg twice a day.

The pharmacokinetics of raltegravir in the dosage form of the chewing tablets in children under 2 years of age have not been studied.

Patients from different racial-ethnic groups

Racial-ethnicity did not have a clinically significant effect on the pharmacokinetic parameters of raltegravir. Correction of the dose is not required.

Patients with different body mass index (BMI)

BMI had no clinically significant effect on the pharmacokinetic parameters of raltegravir in adult patients. Correction of the dose of the drug depending on the patient's BMI is not required.

Patients with hepatic insufficiency

Raltegravir is excreted primarily by glucuronation in the liver.The pharmacokinetics of the drug was studied in adult patients with moderate-level hepatic insufficiency, as well as in combined pharmacokinetic analysis. Clinically significant deviations of pharmacokinetic parameters in adult patients with hepatic insufficiency of the severity level in comparison with healthy volunteers have not been revealed. Such a braze dose adjustment for liver failure of mild to moderate severity is not required. The effect of severe hepatic insufficiency on the pharmacokinetic parameters of raltegravir has not been studied.

Patients with renal insufficiency

On the renal clearance there is an insignificant share in the excretion of raltegravir from the body. Pharmacokinetics of the drug was studied in adult patients with severe renal failure, as well as in complex pharmacokinetic analysis. Clinically significant deviations in pharmacokinetic parameters in patients with severe renal failure compared with healthy volunteers have been identified. Thus, dose adjustment in patients with severe renal failure is not required.Since the effectiveness of dialysis of raltegravir is unknown, it is recommended to take the drug on the eve of a dialysis session.

Patients with polymorphism UDF-GT1A1

Evidence or any evidence indicating that the presence of polymorphism in the enzyme UDF-GT1A1 may have a clinically significant effect on the pharmacokinetic parameters of raltegravir have not been obtained. According to a comparative study involving 30 adult healthy volunteers with genetically determined decreased activity of UDF-GG1A1 and 27 adult healthy volunteers with unchanged genotype UDF-GT1A1, the ratio of the geometric mean of AUC to raltegravir was 1.41 (90% confidence interval was 0.96, 2.09 ).

Indications:

Treatment of HIV-1 infection in combination with other antiretroviral drugs in children aged 2-11 years old, both previously received and not receiving antiretroviral therapy

Contraindications:

- Hypersensitivity to any of the components of the drug.

- Children under 2 years old and body weight less than 7 kg.

- Pregnancy.

- Lactation period.

- Sucrose deficiency / isomaltosis, fructose intolerance, glucose-galactose malabsorption.

- Phenylketonuria.

Carefully:

- Myopathy and rhabdomyolysis (including in the anamnesis), the presence of conditions and factors predisposing to their development.

- Hepatic insufficiency of a serious degree.

- Simultaneous application with strong inductors UDF-GT1A1 (rifampicin).

- Simultaneous use of Isentress ® with antacids containing aluminum or magnesium.

- Depression, including suicidal ideation and behavior, was 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.

Pregnancy and lactation:

Controlled studies of the drug Isentress ® in pregnant women have not been carried out, therefore it is not recommended to use Isentress ® during pregnancy.

There is no data on the intake of raltegravir in human breast milk. However, the secretion of raltegravir in milk in rats has been found. When the drug was administered at a daily dose of 600 mg / kg, the concentration of raltegravir in milk exceeded the plasma concentration by about 3 times.The drug Isentress® should not be given during breastfeeding. In addition, breastfeeding is not recommended for HIV-infected mothers to avoid postnatal transmission of HIV to children.

Dosing and Administration:

Inside. Tablets chewing the drug Isentress® appoint regardless of the meal.

Treatment with Isentress® should be performed by a doctor who has sufficient experience in HIV therapy.

Since raltegravir dosage forms are not bioequivalent, the chewing tablets should not be replaced with 400 mg tablet coated with film.

The maximum daily dose of chewable tablets is 300 mg twice a day.

Treatment with Isentress ® is carried out in combination with other antiretroviral drugs.

Recommended doses of Isentress in the form of chewable tablets for the treatment of HIV infection in children aged 2-11 years are calculated by body weight so that the maximum daily dose of raltegravir does not exceed 300 mg twice a day (see Table 1).

Table 1. Recommended doses * of Isentress® in the form of a tablet chewing tablets for children aged 2-11years.

Body weight, kg	Dose	Number of chewable tablets
from 7 to <10	50 mg twice a day	0.5 x 100 mg † 2 times per day
from 10 to <14	75 mg twice daily	3 x 25 mg twice daily
from 14 to <20	100 mg twice daily	1 x 100 mg twice daily
from 20 to <28	150 mg twice daily	1.5 x 100 mg † 2 times per day
from 28 to <40	200 mg twice daily	2 x 100 mg twice daily
ns less than 40	300 mg twice a day	3 x 100 mg twice daily

* - Dose recommendations for body weight are based on approximately 6 mg / kg / dose 2 times a day.
† - chewable tablets of 100 mg can be divided into two halves.

Patients should explain the need to follow the dosing schedule, since the dose of Isentress® should be adjusted as the child grows.

Side effects:

The safety profile of Isentress® is based on the results of general safety data obtained from clinical trials involving patients who had previously received antiretroviral therapy (ARVT) and patients who had not previously received ARVT.

In a combined analysis of the results of clinical trials of antiretroviral therapy in adult patients who had previously received ARVT, the frequency of discontinuation of therapy due to adverse reactions was 3.9%who took Isentress ® and optimized complementary therapy (ODT), and 4.6% in the placebo and ODT group. The frequency of withdrawal of therapy due to adverse reactions in adult patients who had not previously received ARV was 5.0% in the group of patients taking Isentress ® concurrently with emtricitabine and tenofovir, and 10.0% in the group of patients taking concomitantly efavirenz, emtricitabine and tenofovir.

The following are data on adverse events observed in clinical trials with varying degrees of likelihood associated with Isentress® or a combination of it with another ARVT. Adverse events are listed according to system-organ classes and frequency classification: "frequent" (≥1 / 100 and <1/10), "infrequent" (≥1 / 1000 and <1/100).

Infectious and parasitic diseases

Infrequent: genital herpes, folliculitis, gastroenteritis, herpes simplex, herpetic infection, herpes zoster, influenza, lymph node abscess, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Infrequent: papillomatosis of the skin.

On the part of the blood and lymphatic system

Infrequent: anemia, iron deficiency anemia, tenderness of lymph nodes, lymphadenopathy, neutropenia, thrombocytopenia¹.

From the immune system

Infrequent: immune reconstitution syndrome, hypersensitivity to the drug, hypersensitivity reactions.

From the side of metabolism and nutrition

Frequent: decreased appetite.

Infrequent: cachexia, diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperphagia, increased appetite, polydipsia, impaired fat metabolism.

Disorders of the psyche

Frequent: unusual dreams, insomnia, nightmares, impaired behavior², depression.

Infrequent: mental disorders, suicidal attempts, feelings of anxiety, confusion, depressed mood, major depressive disorder, mid-sleeplessness, mood changes, panic attacks, sleep disorders, suicidal ideation¹, suicidal behavior¹ (especially in patients with psychiatric illness in the history).

From the nervous system

Frequent: dizziness, headache, psychomotor hyperreactivity.

Infrequent: amnesia, carpal tunnel syndrome, cognitive disorders, attention disorders, postural dizziness, dysgeusia, hypersomnia, hypoesthesia, lethargy, memory disorder, migraine, peripheral neuropathy, paresthesia, drowsiness, tension headache, tremor, decreased sleep quality.

From the side of the organ of vision

Infrequent: decreased visual acuity.

From the side of the hearing organ and labyrinthine disorders

Frequent: Vertigo.

Infrequent: noise in ears.

From the heart

Infrequent: heart palpitations, sinus bradycardia, ventricular extrasystole.

From the side of the vessels

Infrequent: "tides" of blood to the skin of the face with a feeling of heat, hypertension.

On the part of the respiratory system, the organs of the thorax and the mediastinum

Infrequent: dysphonia, nosebleeds, nasal congestion.

From the gastrointestinal tract

Frequent: a feeling of raspiraniya in the abdomen, abdominal pain, diarrhea, flatulence, nausea, vomiting, indigestion.

Infrequent: gastritis, a feeling of discomfort in the abdomen, pain in the upper abdomen, soreness in the abdomen, discomfort in the anus, constipation, dry mouth,a feeling of discomfort in the epigastric region, erosive duodenitis, belching, gastroesophageal reflux, gingivitis, glossitis, painful swallowing, acute pancreatitis, peptic ulcer, rectal bleeding.

From the liver and biliary tract

Infrequent: hepatitis, steatosis of the liver, alcoholic hepatitis, hepatic insufficiency¹.

From the skin and subcutaneous tissues

Frequent: skin rash.

Infrequent: acne, alopecia, acne, dry skin, erythema, lipoatrophy of the face, hyperhidrosis, lipoatrophy, acquired lipodystrophy, lipohydrophy, night sweats, prurigo, itching (local and generalized), macular rash, maculopapular rash, itching rash, hives, xeroderma, others skin lesions, Stevens-Johnson syndrome¹, a drug rash with eosinophilia and systemic symptoms¹.

From the musculoskeletal and connective tissue

Infrequent: arthralgia, arthritis, back pain, side pain, musculoskeletal pain, myalgia, neck pain, osteopenia, pain in the extremities, osteoporosis, polyarthritis, tendonitis, myopathy, rhabdomyolysis¹.

From the side of the kidneys and urinary tract

Infrequent: renal failure, nephritis, nephrolithiasis, nocturia, kidney cyst, renal dysfunction, tubulointerstitial nephritis.

From the genitals and breast

Infrequent: erectile dysfunction, gynecomastia, the symptoms of menopause.

General disorders and disorders at the site of administration

Frequent: asthenia, weakness, fever.

Infrequent: discomfort in the chest, chills, swelling of the face, increased fat tissue, anxiety, malaise, submandibular growth, peripheral edema, pain.

Laboratory and instrumental data

Frequent: an increase in plasma activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), lipase and amylase of the pancreas, an increase in the concentration of triglycerides and the number of atypical lymphocytes.

Infrequent: decrease in the absolute number of plasma neutrophils; increased activity in plasma of alkaline phosphatase, amylase, creatine phosphokinase, decrease in albumin concentration; increasing the concentration of bilirubin, cholesterol, creatinine, glucose (including fasting defined), urea nitrogen, cholesterol, high density lipoprotein,low-density lipoprotein cholesterol; increase the importance of the international normalized relationship; decrease in the number of platelets and leukocytes in the blood; the presence of glucose in the urine, the presence of erythrocytes in the urine; an increase in the circumference of the waist; increase or decrease in body weight.

Trauma, intoxication and complications of manipulation

Infrequent: unintentional overdose.

^1.Undesirable phenomena without the presence of a cause-and-effect relationship with the use of Isentress®, which were observed during the post-registration period of observation and were not observed during clinical trials.

^2.In one child of the child age, adverse drug reactions associated with taking the drug were observed: psychomotor hyperreactivity of the 3rd degree and behavioral disorder; also this patient had insomnia.

In clinical trials, patients who had previously received and previously did not receive ARVs had malignant tumors when using the combination of Isentress ® with other antiretroviral drugs. The characteristics and frequency of malignant neoplasms corresponded to those for patients with severe immunodeficiency.The risk of developing malignant neoplasms in clinical trials was the same both in the groups of patients taking Isentress® and in the groups of patients taking the comparator drugs.

In patients taking Isentress ®, an increase in activity of creatine phosphokinase 2-4 was observed. There have been cases of myopathy and rhabdomyolysis. Patients with myopathy or rhabdomyolysis in the history, and also having other risk factors (including concomitant therapy), the drug should be administered with caution.

Osteonecrosis has been reported, especially in patients with recognized risk factors, late HIV disease, or long-term exposure to combined ARV. The frequency of its development is unknown.

In clinical trials in patients previously treated with ARVT, skin rashes, regardless of etiology, were more common with Isentress® concomitantly with darunavir than with the use of these drugs alone. However, the incidence of skin rash associated with taking medications was comparable in all three treatment groups.Skin rash was mild and moderate severity and did not affect the continuation of ARVT. In patients who had not previously taken ARVT with Isentress® in combination with emtricitabine and tenofovir, the development of rash was less common than with efavirenz in combination with emtricitabine and tenofovir.

Patients with co-infection with hepatitis B and / or hepatitis C

In general, the safety profile of Isentress® in patients who had previously received or who did not receive ARVT co-infected with chronic (but not acute) active hepatitis B and / or hepatitis C was similar to the safety profile in patients without co-infection with hepatitis B and / or hepatitis C, although the incidence of abnormal ALT and ACT activity was sometimes higher in groups with co-infection with hepatitis B and / or hepatitis C.

Children

According to the results of clinical studies on the use of raltegravir in the recommended doses in combination with other antiretroviral drugs in HIV-1 infected children and adolescents 2 to 18 years, it was found that the frequency, type and severity of adverse reactions associated with taking the drug were comparable to those in adult patients.

In one patient, the following adverse drug reactions were observed: psychomotor hyperactivity of grade 3, behavioral disorders and insomnia. Another patient experienced a serious adverse reaction of the 2nd degree - an allergic rash.

Another patient had an increase in ACT 4 degree activity and grade 3 ALT, which was regarded as serious.

Overdose:

Specific symptoms of an overdose of Isentress ® have not been revealed. Raltegravir was well tolerated by healthy volunteers in a mode of 1600 mg x once a day and 800 mg x 2 times a day, without any manifestations of toxicity.

Single dose of 1800 mg per day in studies IIPhase III did not have toxic effects. Based on the available data, it can be concluded that raltegravir is well tolerated in doses up to 800 mg twice a day, as well as when taken with drugs that increase its exposure by 50-70% (for example, tenofovir and atazanavir). Raltegravir has a wide therapeutic range, so the potential for toxic effects from overdose is limited.

In case of an overdose, follow the standard recommendations, such as removing the non-sucking drug from the gastrointestinal tract, monitoring for indicators of vital activity, including ECG, the appointment of symptomatic therapy. Data on the effectiveness of dialysis in case of an overdose of Isentress ® is not available.

Interaction:

In studies in vitro it was shown that raltegravir It is not a substrate of cytochrome P450 isoenzymes and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A. Besides, in vitro raltegravir does not induce CYP3A4 and is not an inhibitor of P-glycoprotein-mediated transport. Based on these data, it can be concluded that Isentress® does not affect the pharmacokinetic parameters of drugs that are substrates of these enzymes or P-glycoprotein.

Studies have shown in vitro and in vivo, raltegravir is excreted mainly through the metabolism (glucuronation) of the UDF-GT1A1-mediated pathway. Although research in vitro showed that raltegravir is not an inhibitor of UDF-GT1A1 and 2B7, in one clinical study some signs of inhibition of UDF-GT1A1 in vivo on the basis of the observed effect on bilirubin glucuronium. Nevertheless, it is unlikely that this effect leads to clinically significant inter-drug interactions.

In the pharmacokinetics of raltegravir, significant inter- and intra-individual variability was observed. The information given below on interactions with drugs is based on geometric mean values; the effect of an individual patient can not be accurately predicted.

The effect of raltegravir on the pharmacokinetics of other drugs In studies on the study of drug interactions raltegravir did not have a clinically significant effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, midazolam and boceprevir.

In some studies, while use of the drug with Isentress® darunovirom there was a slight decrease in darunovira plasma concentrations. The mechanism of this phenomenon is unknown. However, the effect of raltegravir on the concentration of darunavir in blood plasma is not considered clinically significant.

The effect of other drugs on the pharmacokinetics of raltegravir Caution should be exercised when using Isentress® with strong UDF-GT1A1 inducers (eg, rifampicin) while taking into account that raltegravir is metabolized mainly by UDF-GT1A1. Rifampicin reduces the concentration of raltegravir in blood plasma. The effect on the efficacy of raltegravir is unknown. However, if simultaneous use with rifampicin is not possible, you can double the dose of Isentress ® in adults. Data on concurrent use of Isentress ® and rifampicin in patients younger than 18 years are absent. The influence of other strong inducers of isozymes metabolizing drugs such as phenytoin and phenobarbital, the system UDF-GT1A1 is unknown. Less powerful inducers (for example, efavirenz, nevirapine, etravirine, rifabutin, glucocorticosteroids, St. John's wort, pioglitazone) can be used concomitantly with the drug Isentress® at the recommended dose. The simultaneous use of Isentress® with strong inhibitors of UDF-GT1A1 (eg, atazanavir) can increase the concentration of raltegravir in blood plasma. Less potent inhibitors of UDF-HT1A1 (for example, indinavir and saquinavir) can also increase the concentration of raltegravir in blood plasma, but to a lesser extent than atazanavir. Besides, tenofovir may increase the concentration of raltegravir in blood plasma, but the mechanism of this effect is unknown. The safety profile observed in patients receiving atazanavir and / or tenofovir, is generally identical to the profile of patients who did not take these drugs, so dose adjustment is not required. Simultaneous use of Isentress® with antacids containing bivalent metal ions can reduce the absorption of raltegravir by chelation, which leads to a decrease in the concentration of raltegravir in the blood plasma. Since taking antacids containing aluminum or magnesium 2 hours after taking Isentress® leads to a significant reduction in the concentration of raltegravir in the blood plasma, simultaneous use of Isentress® and antacids containing aluminum or magnesium is not recommended. Simultaneous use of Isentress® with antacids containing calcium carbonate reduces the concentration of raltegravir in plasma, but this interaction is not considered clinically significant. As a result, with simultaneous use of Isentress ® with antacids containing calcium carbonate, dose adjustment is not required.

Simultaneous use of Isentress ® with other drugs that increase the pH of gastric juice (for example, omeprazole or famotidine), can increase the absorption rate of raltegravir and, accordingly, the concentration of raltegravir in blood plasma. In a clinical study, the safety profile in a subset of patients taking proton pump inhibitors or H blockers₂-gistaminovyh receptors, was comparable with the safety profile in a subgroup of patients who did not take these drugs. Correction of the dose of Isentress® is not required when used simultaneously with proton pump inhibitors or H blockers₂-gistaminovyh receptors.

Table 1. Data on the pharmacokinetic interaction of drugs in adult patients.

Drug taking into account the therapeutic field of application	Interaction (mechanism, if known)	Recommendations for correcting the dosing regimen
Antiretroviral medications
Inhibitors of protease (IP)
atazanavir / ritonavir (raltegravir 400 mg twice a day)	raltegravir AUC ↑ 41% raltegravir C 12h ↑ 77% raltegravir Сmax ↑ 24% (inhibition of UDF-GT1A1)	Correction of the dose of Isentress® is not required.
tipranavir / ritonavir (raltegravir 400 mg twice a day)	raltegravir AUC ↓ 24% raltegravir C12h ↓ 55% raltegravir C max ↓ 18% (induction of UDF-GT1A1)	Correction of the dose of Isentress® is not required.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
efavirenz (raltegravir 400 mg once a day)	raltegravir AUC ↓ 36% raltegravir C_12h ↓21% raltegravir C max ↓ 36% (induction of UDF-GT1A1)	Correction of the dose of Isentress® is not required.
etravirine (raltegravir 400 mg twice a day)	raltegravir AUC ↓ 10% raltegravir C12h ↓ 34% raltegravir C_max ↓11% (induction of UDF-GT1A1) etravirine AUC ↑ 10% etravirine C12h ↑ 17% etravirine C max ↑ 4%	Correction of doses of Isentress® or etravirine is not required.
Nucleoside reverse transcriptase inhibitors (nit)
tenofovir (raltegravir 400 mg twice a day)	raltegravir AUC ↑ 49% raltegravir С12Ч ↑ 3% raltegravir Cmax ↑ 64% (the interaction mechanism is unknown) tenofovir AUC ↓ 10% tenofovir C24 ↓ 13% tenofovir Cmax ↓ 23%	Correction of doses of the drug Isentress® or tenofovir Dizoproxil fumarate is not required.
CCR5 chemokine receptor antagonists
Maraviroc (raltegravir 400 mg twice daily)	RALTEGRAVIR AUC ↓ 37% raltegravir C 12h ↓ 28% raltegravir C max ↓ 33% (the interaction mechanism is unknown) maraviroc AUC ↓ 14% maraviroc C 12h. ↓ 10% maraviroc Cmax ↓ 21%	Correction of doses of the drug isentress or maraviroc is not required.
Medicines against hepatitis C virus
NS3 / 4A protease inhibitors of hepatitis C virus
boceprevir (raltegravir 400 mg once a day)	raltegravir AUC ↑ 4% raltegravir C12h ↓ 25% raltegravir Cmax ↓ 11% (the interaction mechanism is unknown)	Correction of a dose of Isentress ® or bocuprevir is not required.
Antimicrobial medications
Anti-TB drugs
rifampicin (raltegravir 400 mg once a day)	raltegravir AUC ↓ 40% raltegravir C 12h. ↓ 61% raltegravir C max ↓ 38% (induction of UDF-GT1A1)	Rifampicin reduces the concentration of raltegravir in the blood plasma. If combination therapy with rifampicin can not be avoided, consider increasing the dose of Isentress® 2 times.
Sedatives
Antacids containing calcium carbonate (raltegravir 400 mg twice a day)	raltegravir AUC ↓ 55% raltegravir С12ч ↓ 32% raltegravir C max ↓ 52% (chelation by metal cations)	Correction of the dose of Isentress® is not required.
H2-histamine receptor blockers and proton pump inhibitors
omeprazole (raltegravir 400 mg twice a day)	raltegravir AUC ↑ 37% raltegravir C12h ↑ 24% raltegravir C max ↑ 51% (increase in solubility)	Correction of the dose of Isentress® is not required.
famotidine (raltegravir 400 mg twice a day)	raltegravir AUC ↑ 44% raltegravir С12ч ↑ 6% raltegravir Сmax ↑ 60% (increase in solubility)	Correction of the dose of Isentress® is not required.
Hormonal contraceptives
ethinylestradiol noregestromine (raltegravir 400 mg twice a day)	ethinylestradiol AUC ↓ 2% ethinyl estradiol C max ↑ 6% noregestromine AUC ↑ 14% noregestromine C max ↑ 29%	Correction of doses of Isentress® or hormonal contraceptives (estrogen and / or progestagen-containing) is not required.
Opioid analgesics
methadone (raltegravir 400 mg twice a day)	methadone AUC↔ methadone C max ↔	Correction of doses of Isentress ® or methadone is not required.

All drug interaction studies were conducted with the participation of adult patients.

Special instructions:

Patients should be informed that modern antiretroviral drugs do not cure HIV infection and do not prevent the transmission of HIV to other people with blood or during sexual intercourse.Patients should continue to follow appropriate safety measures 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). It is very important to stay under medical supervision during therapy with Isentress®.

Raltegravir has a relatively low genetic barrier to the development of resistance, so to improve the effectiveness of treatment and reduce the risk of developing resistance to the drug raltegravir should be given in combination with two other active antiretroviral agents, if possible.

It is important to explain to patients the need to study the instructions for use before starting therapy with Isentress® and to re-read it every time you receive the next prescription from your doctor. Patients should be informed of the need to tell the doctor about any unusual symptoms, or to maintain or worsen any known symptom.

Immunodeficiency Syndrome

At the initial stages of combined ARVT in HIV-infected patients with severe immunodeficiency, the so-called immune reconstitution syndrome may develop, that is, an inflammatory response to asymptomatically recurrent or residual opportunistic infections (cytomegalovirus retinitis, pneumocystic pneumonia caused by Pneumocystis jiroveci, disseminated or focal mycobacterial infections, etc.). This can contribute to a worsening of the clinical state and an increase in the existing symptoms. Typically, this reaction can occur in the first weeks or months after the onset of combination therapy. Any inflammatory symptoms should be evaluated and, if necessary, treated.

With the development of the immune reconstitution syndrome, autoimmune disorders such as Based's disease have been described. Nevertheless, the development of such disorders can be observed many months after the start of treatment.

Osteonecrosis

Although the etiology of this complication is considered multifactorial (including corticosteroid therapy, alcohol use, severe immunodeficiency, high body mass index), cases of osteonecrosis have been described, especially in the late stages of HIV infection and / or long-term use of combined ARVT.Patients who have symptoms such as joint pain, stiffness, or mobility restriction need urgent advice from a specialist.

Severe skin reactions and hypersensitivity reactions

Data were obtained on severe (potentially life threatening) and fatal undesirable skin reactions in patients taking Isentress® as part of a combination therapy with other drugs associated with these unwanted reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Also reported were hypersensitivity reactions that manifested as a rash of a generalized nature, and sometimes organ dysfunction, including liver failure. The use of Isentress® and other drugs presumably capable of causing such reactions should be stopped immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions appear (including a severe skin rash or rash accompanied by fever, general malaise, weakness, muscle pain or joints, the appearance of blisters on the skin,damage to the oral cavity, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, but not limited to them). In these cases, it is necessary to monitor the clinical status, including the activity of "hepatic" aminotransferases, and initiate appropriate therapy. The untimely cessation of therapy with Isentress® or other drugs associated with these unwanted reactions, after the onset of severe rash, can lead to life-threatening reactions.

Myopathy and rhabdomyolysis

The development of myopathy and rhabdomyolysis was reported. Care should be taken when prescribing the drug to patients with myopathy and rhabdomyolysis in the history or with any factors predisposing to their development, in particular, with concomitant therapy with drugs that can cause these undesirable reactions.

Impaired liver function

The safety and efficacy of Isentress® in patients with severe concomitant liver disease have not been established. Care should be taken when prescribing Isentress patients with severe impairment of liver function.

In patients with existing liver dysfunction, including chronic hepatitis, the incidence of hepatic impairment increases with combined ARVT, and they are monitored in accordance with standard practice. If such patients show signs of worsening liver disease, the issue of interruption or termination of treatment should be considered.

Patients with chronic hepatitis B or C, also receiving combined ARVT, are at risk of developing severe and potentially fatal adverse events on the part of the liver.

Skin rash

In patients who received ARVT earlier, with Isentress simultaneously with darunavir, a skin rash is observed more often than in patients who take drugs separately (see the section on ADVERSE EFFECTS).

Depression

Depression, including suicidal ideation and behavior, was 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

Strong inductors UDF-GT1A1

Caution should be exercised when prescribing Isentress® simultaneously with strong UDF-HT1A1 inducers, such as rifampicin, due to the decrease in the plasma concentration of raltegravir caused by them. If it is necessary to carry out combination therapy with rifampicin and Isentress®, the dose of Isentress® should be doubled in adult patients. There is no data available for the possibility of adjusting the doses of drugs with concurrent use of Isentress® and rifampicin in patients younger than 18 years of age (see INTERACTION WITH OTHER DRUGS).

Antacids

Simultaneous use of Isentress ® with antacids containing aluminum or magnesium, leads to a decrease in the concentration of raltegravir in blood plasma. The simultaneous use of Isentress® with antacids containing aluminum or magnesium is not recommended (see INTERACTION WITH OTHER DRUGS).

Fructose and sorbitol

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

Phenylketonuria

The drug Isentress® in the dosage form of the tablet chewing in the fragrance of the masking contains phenylalanine as a component of aspartame. Each chewable tablet of 25 mg of Isentress contains approximately 0.05 mg of phenylalanine, and each chewable tablet of 100 mg is about 0.10 mg of phenylalanine. Phenylalanine can harm patients with phenylketonuria.

Effect on the ability to drive transp. cf. and fur:

Studies to study the impact on the ability to drive vehicles and the use of mechanisms were not carried out. Considering the possibility of developing dizziness, weakness, drowsiness and blurred vision on the background of treatment with Isentress®, care must be taken when driving and working with machinery.

Form release / dosage:

Tablets chewing 25 mg, 100 mg.

Packaging:For 60 tablets in a bottle of high-density polyethylene, sealed with a protective membrane and closed with a plastic lid with a device against opening the bottle by children, and a container of silica gel. 1 bottle with instructions for use in a cardboard box.

Storage conditions:

In a dry place at a temperature of no higher than 30 ° C in a tightly closed original package with a moisture absorbing agent.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002927

Date of registration:24.03.2015

Expiration Date:24.03.2020

The owner of the registration certificate:Merck Sharp and Doum B.V.Merck Sharp and Doum B.V. Netherlands

Manufacturer: & nbsp

PATHEON PHARMACEUTICALS, Inc. USA

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp27.06.2018

Illustrated instructions

Instructions

Isentress® (Isentress®)