Исентресс®

General characteristics. Structure:

Active ingredient: 27,16 mg or 108,6 mg of a raltegravir of potassium that 25 mg or 100 mg of a raltegravir are equivalent.

Excipients: a hypro rod, опадрай colourless YS-1-19025-A1, Surelease® E-7-190402, a sukraloz, sodium saccharinate, citrate sodium a dihydrate, Mannitolum, dye ferrous oxide red, dye ferrous oxide yellow, ammonium glycyrrhizinate (Magnasweet® 1353), fragrance banana natural WONF Duraromc® 501392 TD0991, fragrance orange natrualny and artificial 501331 TP0551, fragrance the stearate masking natrulny and artificial 501482 TP04244, кросповидон, magnesium, the sodium stearylfumarating.

1 - опадрай colourless YS-1-19025-A consists of a gipromelloza 2910/6cP a macrogoal;
2 - Surelease E-7-19040 consists of 25% of water suspension of ethyl cellulose in the water purified of ethyl cellulose 20 of Wednesday, ammonium of hydroxide, triglycerides srednetsepochny and oleic acid;
3 - Magnasweet 135 consists of extract of a glycyrrhiza, sorbitol and fructose;
4 - contains aspartame.

Pharmacological properties:

Pharmacodynamics. Raltegravir inhibits catalytic activity of HIV of an integraza - the enzyme participating in replication of the HIV virus. The inhibition of an integraza prevents covalent introduction (integration) of a genome of HIV to a genome of a cell of the owner at early stages of development of an infection. The genomes of HIV which are not included in DNA of the person are not capable to induce products of new virus particles therefore suppression of process of integration prevents spread of a viral infection in an organism. The inhibiting ability of a raltegravir concerning phosphotransferases of the person, including DNA polymerases and, P and at, is expressed slightly.

Microbiology. At plasma concentration 31 ± the 20th nmol/l ралтегравир provided suppression of replication of a virus for 95% (95% the inhibiting concentration, IK95) in cellular cultures of the human T lymphocytes infected with the H9IIIB VICh-1 option adapted to cultures of cells in comparison with control a virus - the infected culture of cells. IK95 was reached in concentration from 6 to 50 nmol/l in cultures human a mitogen - the activated mononuklear of peripheral blood infected with various primary clinical strains of VICh-1 including strains 5 ne-V the VICh-1 subtypes, and also strains, resistant to inhibitors of the return transcriptase and inhibitors of HIV protease.

In the analysis of one cycle of an infection ралтегравир suppressed the infection caused by 23 strains of HIV representing 5 ne-V subtypes and 5 circulating recombinant forms with IK50 - 5-12 nmol/l. Raltegravir also suppressed replication of strains of VICh-2 when testing on Semkh174 line cells (IK95 = the 6th nmol/l).

At simultaneous introduction to culture of human T lymphocytes. the infected H9IIIB option of the VICh-1 virus, a raltegravir with nukleozidny inhibitors of the return transcriptase (a zidovudine, зальцитабин, ставудин, абакавир, тенофовир, диданозин and ламивудин), nenukleozidny inhibitors of the return transcriptase (эфавиренз, not Virapinum and делавирдин), HIV protease inhibitors (индинавир, саквинавир, ритонавир, ампренавир, лопинавир, нелфинавир and атазанавир) or fusion inhibitor (энфувиртид) observed anti-retrovirus activity from the additive to synergistic.

Resistance to drug. The mutations of an iitegraza of VICh-1 promoting emergence of virus strains, resistant to a raltegravir (in vitro or at the patients accepting ралтегравир developed), generally include replacement of Y143 amino acids (replacement on With, N or R), or Q148 (replacement by N, To or R), or N155 (replacement by N) plus of one more or more additional mutations (for example, L74I/M, E92Q, E138A/K, G140A/S or V151I).

Recombinant viruses with one primary mutation (Q148H, K or R or N155II) differed in reduced ability to replication and the reduced sensitivity to in vitro raltegravir. Secondary mutations of a virus reduced sensitivity to a raltegravir even more, sometimes compensating reduced ability of a virus to replication.

Influence on electrophysiologic activity of heart or on electrocardiogram indicators. In placebo - controlled clinical trial with participation of healthy volunteers the single dose of 1600 mg of a raltegravir did not exert impact on QTc interval duration in spite of the fact that the maximum concentration (Cmax) of a raltegravir in a blood plasma was 4 times more, than at a single dose of a raltegravir in a dose of 400 mg.

Pharmacokinetics. At adult patients. Absorption. Raltegravir is quickly soaked up after administration of drug on an empty stomach, Cmax in a blood plasma is defined approximately in 3 hours. The area under a curve "concentration - time" (AUC) and Cmax value of a raltegravir increase in proportion to a dose in the range of doses from 100 to 1600 mg. S12ch values of a raltegravir increase in proportion to a dose in range of doses from 100 mg to 800 mg and increase in a little smaller degree - in the range of doses from 100 mg to 1600 mg.

At the mode of administration of drug 2 times a day the equilibrium state is reached quickly, approximately within 2 days after an initiation of treatment. AUC and Cmax values testify in favor of absence or the minimum cumulation of drug, S12ch value - in favor of insignificant cumulation of drug. In the monotherapy mode on 400 mg of 2 times/days value of an average geometrical for AUC0-12ch made 14.3 µmol/l x h, S12ch value - the 142nd nmol/l.

Absolute bioavailability of a raltegravir is not established. Raltegravir it is possible to accept regardless of the meal mode.

Distribution. About 83% of a raltegravir contact proteins of plasma in the range of concentration from 2 to 10 µmol/l. Raltegravir easily broke a placental barrier in pilot studies on rats, but did not get through a blood-brain barrier in noticeable degree.

In two clinical trials decided on participation of the patients infected with VICh-1 which accepted ралтегравир in a dose 400 mg 2 times a day ралтегравир quickly in cerebrospinal fluid. In the first research average concentration of a raltegravir in cerebrospinal fluid made 5,8% (in the range from 1 to 53.5%) from the corresponding concentration in a blood plasma, and in the second research - 3% (in the range from 1 to 61%) from the corresponding concentration in a blood plasma. Medians of the received values were about 3-6 times lower, than concentration of free fraction of a raltegravir in a blood plasma.

Metabolism and removal. Researches with use of the selection inhibitors to the enzyme isoform uridinediphosphate-glyukuroniltransferazy (UDF-GT) received by an expression of complementary DNA showed that UDF-GT1L1 is the main enzyme participating in formation of a raltegravir-glucuronide. These data showed that the main way of metabolism of a raltegravir at the person is presented by process of the glyukuronirovaniye mediated by UDF-GT1L1 Duration of the final phase T1/2 of a raltegravir makes about 9 hours, the most part of AUC corresponds to shorter and - a phase of the seeming elimination half-life of a raltegravir (makes about 1 hour). After intake it is radioactive a marked raltegravir about 51% of the accepted dose it was removed through intestines and 32% — through kidneys. In Calais it was found only ралтегравир which was probably formed by hydrolysis of the raltegravir-glucuronide allocated with bile. In urine were defined ралтегравир and a raltegravir-glucuronide in number of 9% and 23% of the accepted dose respectively. In a blood plasma the main circulating radioactive component was ралтегравир (about 70% of the general radioactivity) while only 30% were the share of a raltegravir-glucuronide.

Pharmacokinetics at separate groups of patients. Floor. A floor does not exert clinically significant impact on pharmacokinetic parameters of a raltegravir. Dose adjustment of drug depending on a sex of the patient is not required.

Elderly patients. In researches on patients of 18 years is also more senior significant dependence of pharmacokinetic parameters of a raltegravir on age of patients therefore dose adjustment of drug depending on age is not required was not revealed

Teenagers and children. By results of a comparative research at healthy adult volunteers chewable tablets have higher peroral bioavailability in comparison with tablets, film coated, on 400 mg. In this research use of chewable tablets with the food containing the high content of fats led to increase in AUC on average for 6%, to decrease in Cmax by 62% and increase S12ch by 188% in comparison with administration of drug on an empty stomach. Reception of chewable tablets with food with the high content of fats did not exert clinically significant impact on pharmacokinetics of a raltegravir therefore chewable tablets can be applied irrespective of meal.

Doses for teenagers and children are more senior than 2 years for treatment of VICh-1 of an infection are recommended that pharmacokinetic parameters of a raltegravir are comparable to those at the adult patients accepting Isentress, tablets, film coated on 400 mg 2 times a day.

The pharmacokinetics of a raltegravir in a dosage form chewable tablets at children is younger than 2 years was not studied.

Patients from different racial ethnic groups. The racial ethnic origin did not exert clinically significant impact on pharmacokinetic parameters of a raltegravir. Dose adjustment is not required.

Patients with various body weight index (BWI). IMT did not exert clinically significant impact on pharmacokinetic parameters of a raltegravir at adult patients. Dose adjustment of drug depending on IMT of the patient is not required.

Patients with a liver failure. Raltegravir is brought preferential by a glyukuronirovaniye in a liver. The pharmacokinetics of drug was studied at adult patients with a liver failure of moderate severity, and also in the combined pharmacokinetic analysis. Clinically significant deviations of pharmacokinetic parameters at adult patients with a liver failure of moderate severity in comparison with healthy volunteers are not revealed. Thus, dose adjustment of drug at a liver failure easy and moderate severity is not required. Influence of a liver failure of heavy degree on pharmacokinetic parameters of a raltegravir was not studied.

Patients with a renal failure. The insignificant share in removal of a raltegravir from an organism is the share of renal clearance. The pharmacokinetics of drug was studied at adult patients with heavy degree of a renal failure, and also in the complex pharmacokinetic analysis. Clinically significant deviations of pharmacokinetic parameters at patients with heavy degree of a renal failure in comparison with healthy volunteers are not revealed. Thus, drug dose adjustment is not required to patients with heavy degree of a renal failure. As efficiency of dialysis of a raltegravir is unknown, it is not recommended to accept drug on the eve of dialysis session.

Patients with polymorphism of UDF-GT1A1. The proofs or any data, testimonial that existence of polymorphism at UDF-GT1A1 enzyme can exert clinically significant impact on pharmacokinetic parameters of a raltegravir were not received. According to a comparative research with participation of 30 adults of healthy volunteers with the genetic determined reduced activity of UDF-GT1A1 and 27 adults of healthy volunteers with not changed UDF-GT1A1 genotype the relation of average geometrical AUC of a raltegravir made 1.41 (90% the confidence interval made 0.96; 2.09).

Indications to use:

— treatment of VICh-1 of an infection in a combination with other anti-retrovirus drugs at children at the age of 2-11 years as which were earlier receiving, not receiving anti-retrovirus therapy.

Route of administration and doses:

Inside. Chewable tablets of drug of Isentress are appointed regardless of meal. The doctor having sufficient experience of therapy of HIV infection has to carry out by drug of Isentress treatment.

As dosage forms of a raltegravir are not bioequivalent, chewable tablets should not be replaced with tablets, film coated, on 400 mg.

The maximum daily dose of chewable tablets makes 300 mg 2 times a day. Treatment by drug of Isentress is carried out to combinations with other anti-retrovirus drugs.

The recommended doses of drug of Isentress in a dosage form of a tablet chewing for treatment of VICh-1 of an infection at children at the age of 2-11 years are calculated on body weight so that the maximum daily dose of a raltegravir did not exceed 300 mg 2 times a day (see Table 1).

Table 1. The recommended doses * drug of Isentress in a dosage form chewable tablets for children at the age of 2-11 years.

 

* - recommendations of doses about body weight are based approximately on reception of 6 mg/kg / a dose 2 times in days.

¹ chewable tablets on 100 mg - can be divided into two half.

Patients should explain need of observance of the schedule of dosing as the dose of drug of Isentress should be adjusted in process of growth of the child.

Features of use:

Use at pregnancy and feeding by a breast. Controlled researches of drug of Isentress at pregnant women were not conducted therefore Isentress is not recommended to appoint during pregnancy.

There are no data on receipt of a raltegravir in breast milk of the person. However secretion of a raltegravir in milk is found in rats. At administration of drug in a daily dose of 600 mg/kg concentration of a raltegravir in milk exceeded plasma concentration approximately by 3 times. Drug of Isentress should not be appointed during breastfeeding. Besides, breastfeeding is not recommended to HIV-positive mothers in order to avoid post-natal transfer of HIV to children.

Use at abnormal liver functions. With care: liver failure of heavy degree.

Use for children. Perhaps use for children is more senior than 2 years and with body weight higher than 7 kg according to indications.

Special instructions. Patients should be informed that modern anti-retrovirus drugs do not cure HIV infection and do not prevent transfer of HIV to other people with blood or at sexual contacts. During treatment by drug of Isentress patients have to continue to observe the appropriate measures of safety. Also patients have to be informed that at them infections or other states extended among HIV-positive patients (opportunistic infections) can still develop. It is very important to remain iod observation of the doctor during therapy by drug of Isentress.

Raltegravir has rather low genetic barrier to resistance development therefore for increase in efficiency of treatment and decrease in risk of development of resistance to drug ралтегравир it is necessary to appoint in a combination with two other active anti-retrovirus means if it is possible. It is important to explain to patients need to study the application instruction before therapy by drug of Isentress and to re-read се every time when obtaining the next recipe from the doctor. Patients have to be informed on need to report to the doctor about emergence of any unusual symptoms, and also about preservation or deterioration in any known symptom.

Immunity recovery syndrome. At the initial stages of the combined ARVT at HIV-positive patients with a heavy immunodeficiency the so-called syndrome of recovery of immunity, that is inflammatory reaction to asymptomatically current or residual opportunistic infections can develop (the Cytomegaloviral retinitis, the pneumocystic pneumonia caused by Pneumocystis jiroveci disseminated or focal mikobakterialny infections, etc.). It can promote deterioration in a clinical state and strengthening of the available symptoms. Usually such reaction can be observed in the first weeks or months after the beginning of a combination therapy. Any inflammatory symptoms have to be estimated, and if necessary treatment is appointed.

At development of a syndrome of recovery of immunity such autoimmune frustration as Bazedova a disease were described. Nevertheless development of such disturbances can be observed in many months after an initiation of treatment.

Osteonecrosis. In spite of the fact that the etiology of this complication is considered multifactorial (including therapy glucocorticosteroids, alcohol intake, a heavy immunodeficiency, a high index of body weight), cases of development of an osteonecrosis, especially at late stages of HIV infection are described and/or at long reception of the combined ARVT. Patients who had such symptoms as a joint pain, constraint or restriction of mobility need urgent consultation of the specialist.

Heavy reactions from skin and reaction of hypersensitivity. Data on heavy (potentially zhizneugrozhayushchy) and fatal undesirable reactions from skin at the patients accepting drug of Isentress as a part of a combination therapy with other medicines which are associated with these undesirable reactions, such as Stephens-Johnson's syndrome and a toxic epidermal necrolysis are obtained. Also it was reported about hypersensitivity reactions which were shown in the form of rash of generalized character, and sometimes organ dysfunction, including a liver failure. It is necessary to stop immediately use of drug of Isentress and other drugs presumably capable to cause such reactions if there were signs or symptoms of heavy reactions from skin or reaction of hypersensitivity (including the heavy skin rash or rash which is followed by fever, a febricula, weakness, muscle or joints pains, emergence of blisters on skin, damages to an oral cavity, conjunctivitis, a face edema, hepatitis, an eosinophilia, a Quincke's disease, but without being limited only to them). In these cases it is necessary to monitorirovat the clinical status, including activity of hepatic aminotransferases and to begin the corresponding therapy. The untimely termination of therapy by the drug of Isentress or other medicines which are associated with these undesirable reactions after emergence of heavy rash can lead to zhizneugrozhayushy reactions.

Mioiatiya and рабдомиолиз. It was reported about development of a myopathy and rabdomioliz. It is necessary to be careful at purpose of drug to patients with a myopathy and rabdomiolizy in the anamnesis or with any factors contributing to their development, in particular, at the accompanying therapy with drugs capable to cause these undesirable reactions.

Abnormal liver function. Safety and efficiency of drug at patients with serious associated diseases of a liver is not established.

It is necessary to be careful at purpose of drug of Isentress to patients with heavy abnormal liver functions.

At patients with the existing liver dysfunction, including chronic hepatitis, the frequency of abnormal liver functions against the background of the combined ARVT increases, and they are subject to monitoring according to standard practice. At emergence in such patients of signs of deterioration in a disease of a liver the question of interruption or the termination of treatment has to be considered.

The patients with chronic hepatitis B or C who are also receiving the combined ARVT enter into risk group of development of heavy and potentially fatal undesirable phenomena from a liver.

Skin rash. At the patients who were earlier receiving ARVT at use of drug of Isentress along with darunaviry skin rash is observed more often than at the patients using drugs separately.

Depressions. The depression, including the suicide ideas and behavior, was observed generally at patients with a depression or psychiatric diseases in the anamnesis. It is necessary to be careful at purpose of drug of Isentress to patients with a pla depression psychiatric diseases in the anamnesis.

Simultaneous use with other medicines. Strong inductors UDF-GT1A1. It is necessary to be careful at purpose of drug of Isentress along with the strong inductors UDF-GT1A1, such as rifampicin, owing to the decrease in plasma concentration of a raltegravir caused by them. In need of carrying out a combination therapy rifampicin and drug of Isentress the dose of drug of Isentress has to be increased twice at adult patients. There are no doses of drugs given for adjustment at simultaneous use of drug of Isentress and rifampicin for patients 18 years are younger.

Antacids. Simultaneous use of drug of Isentress with the antacids containing aluminum or magnesium leads to decrease in concentration of a raltegravir in a blood plasma.

Simultaneous use of drug of Isentress with the antacids containing aluminum or magnesium is not recommended.

Fructose and sorbitol. Drug of Isentress chewable tablets contains fructose and sorbitol in a dosage form. Patients with rare inherited disorders in the form of intolerance of fructose should not accept drug of Isentress.

Fenilketonuriya. Drug of Isentress chewable tablets as a part of the fragrance masking contains phenylalanine as an aspartame component in a dosage form. Each chewable tablet of 25 mg of drug of Isentress contains about 0.05 mg of phenylalanine, and each chewable tablet of 100 mg - about 0.10 mg of phenylalanine. Phenylalanine can do harm to patients with a fenilketonuriya.

Influence on ability to driving of motor transport and to control of mechanisms. Researches but to studying of influence on ability to control of vehicles and use of mechanisms were not conducted. Considering a possibility of development of dizziness, weakness, drowsiness and an illegibility of sight against the background of treatment by drug of Isentress, it is necessary to show extra care during the driving and work with mechanisms.

Side effects:

The profile of safety of drug of Isentress is based on results of the generalized data on safety received during clinical trials with participation of the patients who were earlier receiving anti-retrovirus therapy (ARVT) and the patients who earlier were not receiving ARVT.

In the integrated analysis of results of clinical trials of antiretrovirusiy therapy at the adult patients who were earlier receiving ARVT, the frequency of cancellation of therapy because of undesirable reactions made 3.9% in group of the patients accepting drug of Isentress and the optimized additional therapy (OAT) and 4.6% in group of the patients accepting placebo and ODT. Frequency of cancellation of therapy because of undesirable reactions at the adult patients who earlier were not receiving ARVT made 5.0% in group of the patients accepting drug of Isentress along with emtritsitabiny and tenofoviry, and 10.0% in group of the patients accepting at the same time эфавиренз, эмтрицитабин and тенофовир.

Data on the undesirable phenomena observed in the clinical trials, with various degree of probability connected with drug Isentress or its combination with other ARVT are given below.

The undesirable phenomena are listed according to system and organ classes and classification by frequency: frequent-> 1/100 and <1/10), infrequent-> 1/1000 and <1/100.

Infectious and parasitic diseases: infrequent - genital herpes, a folliculitis, a gastroenteritis, a herpes simplex, a herpes infection, shingles, flu, lymph node abscess, a contagious mollusk, a nasopharyngitis, an upper respiratory tract infection.

The high-quality, malignant and not specified new growths (including cysts and polyps): infrequent - a skin papillomatosis.

From blood and lymphatic system: infrequent - anemia, an iron deficiency anemia, morbidity of lymph nodes, a lymphadenopathy, a neutropenia, trombotsitopeniya1.

From immune system: infrequent - an immunity recovery syndrome, hypersensitivity to drug, hypersensitivity reactions.

From a metabolism and food: frequent - a loss of appetite; infrequent - a cachexia, a diabetes mellitus, a dislipidemiya, a hypercholesterolemia, a hyperglycemia, a lipidemia, a hyperphagia, increase in appetite, a polydipsia, disturbance of a lipometabolism.

Disturbances of mentality: frequent - unusual dreams, sleeplessness, nightmares, disturbance povedeniya2, a depression; infrequent - mental disorders, suicide attempts, feeling of alarm, confusion of consciousness, the suppressed mood, big depressive frustration, sleeplessness of the middle of night, change of mood, the panic attacks, sleep disorders, suicide idei1, suicide povedeniye1 (especially at patients with psychiatric diseases in the anamnesis).

From a nervous system: frequent - dizziness, a headache, psychomotor giperreaktivnost2, infrequent - amnesia, a syndrome of a carpal tunnel, cognitive disorders, disturbances of attention, postural dizziness, a disgeziya, a hypersomnia, a hypesthesia, a lethargy, a dysmnesia, migraine, peripheral neuropathy, paresthesias, drowsiness, tension headache, a tremor, decline in quality of a dream.

From an organ of sight: infrequent - decrease in visual acuity.

From an acoustic organ and labyrinth disturbances: frequent - вертиго; infrequent - a sonitus.

From heart: infrequent - a heart consciousness, a sinus bradycardia, ventricular premature ventricular contraction.

From vessels: infrequent - rushes of blood to face skin with feeling of heat, arterial hypertension.

From respiratory system, bodies of a thorax and a mediastinum: infrequent - a dysphonia, nasal bleeding, a nose congestion.

From a GIT: frequent - feeling of a raspiraniye in a stomach, an abdominal pain, diarrhea, a meteorism, nausea, vomiting, dyspepsia; infrequent - gastritis, a sensation of discomfort in a stomach, pain in upper parts of a stomach, morbidity in a stomach, feeling of discomfort in the field of an anus, a lock, dryness in a mouth, a sensation of discomfort in epigastric area, an erosive duodenitis, an eructation, a gastroesophageal reflux, an ulitis, a glossitis, morbidity when swallowing, acute pancreatitis, a round ulcer, rectal bleedings.

From a liver and biliary tract: infrequent - hepatitis, a liver steatosis, alcoholic hepatitis, hepatic nedostatochnost1.

From skin and hypodermic fabrics: frequent - skin rash; infrequent - an acne, an alopecia, acneform rash, a xeroderma, an erythema, a lipoatrophia of the person, a hyperhidrosis, a lipoatrophia, the acquired lipodystrophy, a lipogipertrofiya, night perspiration, пруриго, an itch (local and generalized), macular rash, makulopapulezny rash, pruritic rash, a small tortoiseshell, a xerodermia, other damages of skin, Stephens-Dzhonsona1 syndrome, medicinal rash with an eosinophilia and system simptomami1.

From skeletal and muscular and connecting fabric: infrequent - an arthralgia, arthritis, a dorsodynia, a stitch, a mialgiya, pain in a neck, osteosinging, extremity pain, osteoporosis, polyarthritis, a tendinitis, a myopathy, rabdomioliz1.

From kidneys and urinary tract: infrequent - a renal failure, nephrite, a nephrolithiasis, a nocturia, a kidney cyst, a renal failure, tubulointerstitsialny nephrite.

From generative organs and a mammary gland: infrequent - erectile dysfunction, a gynecomastia, menopause symptoms.

The general frustration and disturbances in an injection site: frequent - an adynamy, weakness, fever; infrequent - discomfort in breasts, a fever, a face edema, increase in volume of fatty tissue, a condition of concern, an indisposition, a submaxillary new growth, peripheral hypostases, pain.

Laboratory and tool data: frequent - increase in activity in plasma of alaninaminotranspherase (ALT), aspartate aminotransferase (ACT), lipases and amylases of a pancreas, increase in concentration of triglycerides and quantity of atypical lymphocytes; infrequent - decrease in absolute number of neutrophils of plasma; increase in activity in plasma of an alkaline phosphatase, amylase, a kreatinfosfokinaza. decrease in concentration of albumine; increase in concentration of bilirubin, cholesterol, creatinine, glucose (including defined on an empty stomach), an urea nitrogen, cholesterol of lipoproteins of high density, cholesterol of lipoproteins of low density; increase in value of the international normalized relation; decrease in quantity of thrombocytes and leukocytes in blood; availability of glucose in urine, existence of erythrocytes in urine; increase in a circle of a waist; increase or decrease in body weight.

Injuries, intoxications and complications of manipulations: infrequent - inadvertent overdose.

1 The undesirable phenomena which are not connected using drug of Isentress who were observed in the post-registration period and were not observed during clinical trials.

2 At one patient of children's age the undesirable reactions connected with administration of drug were observed: psychomotor hyperreactivity 3 degrees and behavior disorder; also at this patient sleeplessness was observed.

During clinical trials at the patients who were earlier receiving and not receiving ARVT cases of development of malignant new growths when using a combination of drug of Isentress with other anti-retrovirus means were observed. The characteristic and frequency of malignant new growths corresponded to that for patients with a heavy immunodeficiency. The risk of development of malignant new growths in clinical trials was identical as in groups of the patients accepting drug of Isentress and in groups of the patients accepting comparison drugs.

At the patients accepting drug of Isentress increase in activity of a kreatinfosfokinaza 2-4 degrees was observed. Cases of development of a myopathy and a rabdomioliz were observed. To patients with a myopathy or rabdomiolizy in the anamnesis, and also having other risk factors (including the accompanying therapy), it is necessary to appoint drug with care.

It was reported about cases of development of an osteonecrosis, especially at patients with the conventional risk factors, a late stage of a HIV disease or long influence of the combined ARVT. Frequency of its development is unknown.

In clinical trials at the patients who were earlier receiving ARVT, skin rash regardless of an etiology, it was more often observed at use of drug of Isentress along with darunaviry, than at use of these drugs separately. Nevertheless, the frequency of development of the skin rash connected with administration of drugs was comparable in these groups of treatment. Skin rash was easy and moderate severity and did not influence continuation of ARVT. At the patients who earlier were not accepting ARVT at treatment by drug of Isentress in a combination with emtritsitabiny and tenofoviry development of rash was observed less than at treatment efavirenzy in a combination with emtritsitabiny and tenofoviry.

Patients with coinfection of hepatitis B and/or hepatitis C. In general the profile of safety of drug of Isentress at the patients as who were earlier receiving, not receiving LRVT, to - infected chronic (but not acute) active hepatitis B and/or hepatitis C, was similar to a safety profile at patients without coinfection of hepatitis B and/or hepatitis C though the frequency of a deviation of activities of ALT and ACT was sometimes higher in groups with coinfection of hepatitis B and/or hepatitis C.

Children. By results of clinical trials on use of a raltegravir in the recommended doses in a combination with other anti-retrovirus medicines at VICh-1 of the infected children and teenagers from 2 to 18 years it was established that frequency, the type and expressiveness of the undesirable reactions connected with administration of drug were comparable to those at adults. At one patient the undesirable reactions connected with administration of drug were observed: psychomotor hyperactivity 3 degrees, behavior disorder and sleeplessness. At other patient serious undesirable reaction 2 degrees — allergic rash was observed. At one patient increase in activity of ACT 4 degrees and ALT 3 degrees which was regarded as serious was observed.

Interaction with other medicines:

In the researches in vitro it was shown what ралтегравир is not substrate of isoenzymes of system of P450 cytochrome and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A. Besides, in vitro ралтегравир ие induces CYP3A4 and is not inhibitor of the R-glikoprotein-oposredovannogo transport. On the basis of these data it is possible to draw a conclusion that Isentress does not influence pharmacokinetic parameters of medicines which are substrates of the specified enzymes or the R-glycoprotein.

As showed the researches in vitro and in vivo, ралтегравир it is removed generally by means of metabolism (glyukuronirovaniye) on UDF-GT1A1 - the mediated way. Though the researches in vitro showed what ратгегравир is not UDF-GT1A1 and 2V7 inhibitor, in one clinical trial some signs of inhibition of UDF-GT1A1 of in vivo on the basis of observed influence on a bilirubin glyukuronirovaniye were revealed. Nevertheless it is improbable that this effect leads to clinically significant intermedicinal interactions.

In pharmacokinetics of a raltegravir also intraindividualny variability was observed significant inter-. Information on interaction given below with medicines is based on average geometrical values; the effect at the certain patient precisely cannot be predicted.

Influence of a raltegravir on pharmacokinetics of other medicines. In researches on studying of medicinal interaction ралтегравир did not exert clinically significant impact on pharmacokinetics of an etravirin, a maravirok, a tenofovir, hormonal contraceptives, methadone and midazolam.

In some researches at simultaneous use of drug of Isentress with darunaviry insignificant decrease in concentration of a darunovir in a blood plasma was observed. The mechanism of this phenomenon is unknown. Nevertheless influence of a raltegravir on concentration of a darunavir in a blood plasma is not considered clinically significant.

Influence of other medicines on pharmacokinetics of a raltegravir. It is necessary to be careful at simultaneous use of drug of Isentress with the strong inductors UDF-GT1A1 (for example, rifampicin), considering what ралтегравир is metabolized generally by means of UDF-GT1A1. Rifampicin reduces concentration of a raltegravir in a blood plasma. Influence on efficiency of a raltegravir is unknown. Nevertheless, if simultaneous use with rifampptsiny cannot be avoided, it is possible to double a dose of drug of Isentress at adults. Data on simultaneous use of drug of Isentress and rifampicin at patients are younger than 18 years are absent.

Influence of other strong inductors of the izrferment metabolizing medicines, such as Phenytoinum and phenobarbital on the UDF-GT1A1 system is unknown. Less strong inductors (for example, эфавиренз, not Virapinum, этравирин, рифабутин, glucocorticosteroids, the St. John's Wort which is made a hole пиоглитазон) can be used along with drug of Isentress in the recommended dose.

Simultaneous use of drug of Isentress with strong UDF-GT1A1 inhibitors (for example, atazanaviry) can increase concentration of a raltegravir in a blood plasma. Less strong UDF-GT1A1 inhibitors (for example, индинавир and саквинавир) can also increase concentration of a raltegravir in a blood plasma, but to a lesser extent in comparison with atazanaviry. Besides, тенофовир can increase concentration of a raltegravir in a blood plasma, however the mechanism of this influence is unknown.

The safety profile observed at the patients receiving атазанавир and/or тенофовир, in general is identical to a profile of patients who did not accept these drugs therefore dose adjustment is not required.

Simultaneous use of drug of Isentress with the antacids containing bivalent ions of metals can reduce absorption of a raltegravir by chelation that leads to decrease in concentration of a raltegravir in a blood plasma. As reception of the antacids containing aluminum or magnesium in 2 hours after administration of drug of Isentress leads to considerable decrease in concentration of a raltegravir in a blood plasma, simultaneous use of drug of Isentress and antacids containing aluminum or magnesium is not recommended.

Simultaneous use of drug of Isentress with the antacids containing calcium carbonate reduces concentration of a raltegravir in a blood plasma, however this interaction is not considered as clinically significant. Thereof at simultaneous use of drug of Isentress with the antacids containing calcium carbonate, dose adjustment is not required.

Simultaneous use of drug of Isentress with other medicines increasing values рН a gastric juice (for example, омепразол or famotidine), can increase the speed of absorption of a raltegravir and, respectively, concentration of a raltegravir in a blood plasma. In clinical trial the safety profile in subgroup of the patients accepting inhibitors of the proton pump or blockers histamine _{H2 receptors} was comparable to a safety profile in subgroup of the patients who were not accepting these medicines. Dose adjustment of drug of Isentress is not required at simultaneous use with inhibitors of the proton pump or blockers histamine _{H2 receptors}.

All researches of interaction of medicines were conducted with participation of adult patients.

Table 2. Data on pharmakokinstichesky interaction of medicines at adult patients.

Medicine taking into account a therapeutic scope	Interaction (the mechanism if it is known)	Recommendations about correction of the mode dosing
Anti-retrovirus medicines
Protease inhibitors
atazanavir/ritonavir (ралтегравир 400 mg of 2 times/days)	ралтегравир AUC ↑ 41% ралтегравир S12ch ↑ 77% ралтегавир Cmax ↑ 24% (UDF-GT1A1 inhibition)	Dose adjustment of drug of Isentress is not required
tipranavir/ritonavir (ралтегравир 400 mg of 2 times/days)	ралтегравир AUC ↓ 24% ралтегравир S12ch ↓ 55% ралтегавир Cmax ↓ 18% (induction of UDF-GT1A1)	Dose adjustment of drug of Isentress is not required
Nenukleozidny inhibitors of the return transcriptase (NNIOT)
эфавиренз (ралтегравир 400 mg of 1 times/days)	ралтегравир AUC ↓ 36% ралтегравир S12ch ↓ 21% ралтегавир Cmax ↓ 36% (induction of UDF-GT1A1)	Dose adjustment of drug of Isentress is not required
этравирин (ралтегравир 400 mg of 2 times/days)	ралтегравир AUC ↓ 10% ралтегравир S12ch ↓ 34% ралтегавир Cmax ↓ 11% (induction of UDF-GT1A1) этравирин AUC ↑ 10% этравирин S12ch ↑ 17% этравирин Cmax ↑ 4%	Correction of doses of drugs of Isentress or etravirin is not required
Antagonists of hemokinovy receptors of CCR5
maravirok (ралтегравир 400 mg of 2 times/days)	ралтегравир AUC ↓ 37% ралтегравир S12ch ↓28% ралтегавир Cmax ↓ 33% (the mechanism of interaction is unknown) AUC maravirok ↓ 14% maravirok S12ch ↓ 10% Cmax maravirok ↓ 21%	Correction of doses of drugs of Isentress or maravirok is not required
Medicines against a hepatitis C virus
Hepatitis C virus NS3/4A protease inhibitors
боцепревир (ралтегравир 400 mg of 1 times/days)	ралтегравир AUC ↑ 4% ралтегравир S12ch ↓ 25% ралтегавир Cmax ↑ 11% (the mechanism of interaction is unknown)	Correction of doses of drugs of Isentress or botseprevir is not required
Antimicrobic drugs
Antitubercular drugs
rifampicin (ралтегравир 400 mg of 1 times/days)	ралтегравир AUC ↓ 40% ралтегравир S12ch ↓ 61% ралтегавир Cmax ↓ 38% (induction of UDF-GT1A1)	Rifampicin reduces concentration of a raltegravir in a blood plasma. If the combination therapy with rifampicin cannot be avoided, it is necessary to consider the possibility of increase in a dose of Isentress twice.
Sedative drugs
midazolam (ралтегравир 400 mg of 2 times/days)	AUC midazolam ↓ 8% Cmax midazolam ↑ 3%	Correction of doses of drugs of Isentress or midazolam is not required. The obtained data indicate that they ралтегравир do not yavleitsya by the inductor or CYP3A4 inhibitor and that ралтегравир does not influence pharmacokinetics of the medicines which are CYP3A4 substrates.
Antacids
The antacids containing aluminum or magnesium (ралтегравир 400 mg of 2 times/days)	Along with raltegraviry ралтегравир AUC ↓ 49% ралтегравир S12ch ↓63% ралтегавир Cmax ↓ 44% For 2 h before reception of a raltegravir ралтегравир AUC ↓ 51% ралтегравир S12ch ↓56% ралтегавир Cmax of ↓51% In 2 h after reception of a raltegravir ралтегравир AUC ↓ 30% ралтегравир S12ch ↓57% ралтегавир Cmax of ↓22% (chelation by cations of metals)	The antacids containing aluminum or magnesium reduce concentration of a raltegravir in a blood plasma. Simultaneous use of drug of Isentress and antacids containing aluminum or magnesium is not recommended.
The antacids containing calcium a carbonate (ралтегравир 400 mg of 2 times/days)	ралтегравир % AUC↓55 ралтегравир S12ch ↓32% ралтегавир Cmax of ↓52% (chelation by cations of metals)	Dose adjustment of drug of Isentress is not required
Blockers histamine H2 receptors and inhibitors of the proton pump
омепразол (ралтегравир 400 mg of 2 times/days)	ралтегравир AUC ↑ 37% ралтегравир S12ch24% ралтегравир % Cmax↑51 (increase in solubility)	Dose adjustment of drug of Isentress is not required
famotidine (ралтегравир 400 mg of 2 times/days)	ралтегравир AUC ↑ 44% ралтегравир S12ch6% ралтегравир % Cmax↑60 (increase in solubility)	Dose adjustment of drug of Isentress is not required
Hormonal contraceptives
ethinylestradiol норэлгестромин (ралтегравир 400 mg 2 times a day)	% AUC↓2 ethinylestradiol % Cmax↑6 ethinylestradiol норэлгестромин AUC ↑ 14% норэлгестромин % Cmax↑29	Correction of doses of drug of Isentress or hormonal contraceptives (estrogen and/or progestagensoderzhashchy) is not required
Opioid analgetics
methadone (ралтегравир 400 mg 2 times a day)	AUC methadone ↔ Cmax methadone ↔	Correction of doses of drugs of Isentress or methadone is not required.

Contraindications:

— hypersensitivity to any of drug components;

— the children's age up to 2 years and body weight is less than 7 kg;

— pregnancy;

— lactation period;

— deficit of invertase/isomaltase, intolerance of fructose, glyukozo-galaktozny malabsorption

— fenilketonuriya.

With care: a myopathy and рабдомиолиз (including in the anamnesis), existence of the states and factors contributing to their development; liver failure of heavy degree; simultaneous use with the strong inductors UDF-GT1A1 (rifampicin); simultaneous use of drug of Isentress with the antacids containing aluminum or magnesium; the depression, including the suicide ideas and behavior, was observed generally at patients with a depression or psychiatric diseases in the anamnesis. It is necessary to be careful at purpose of drug of Isentress to patients with a depression or psychiatric diseases in the anamnesis.

Overdose:

Specific symptoms of overdose of drug of Isentress are not revealed. Raltegravir was well had by healthy volunteers in the mode of 1600 mg of 1 times to days and 800 mg 2 times a day, without any manifestations of toxicity. The single dose of a dose of 1800 mg a day in the researches II/III of a phase did not make toxic impact. On the basis of the available data it is possible to conclude that ралтегравир two times are well transferred to days in doses to 800 mg, and also at reception with the drugs increasing its exposure by 50-70% (for example, tenofoviry and atazanaviry). Raltegravir has the broad therapeutic range therefore the potential of toxic action as a result of overdose is limited.

In case of overdose it is necessary to follow standard recommendations, such as removal of not soaked up drug from digestive tract, observation of vital signs, including an ECG, purpose of symptomatic therapy. There are no data on efficiency of dialysis at overdose by drug of Isentress.

Storage conditions:

In the dry place at a temperature not above 30 °C in densely closed original packaging with the moisture absorbing agent. To store in the place, unavailable to children. A period of validity - 2 years. Not to use on expiry date, specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 60 pieces of tablets - bottles polyethylene (1) - packs cardboard.