Исентресс®
Producer: Merck Sharp & Dohme Corp. (Merck Sharp and Doum of the Building) USA
Code of automatic telephone exchange: J05AX08
Release form: Firm dosage forms. Tablets.
General characteristics. Structure:
Active ingredient: 400 mg of a raltegravir in 1 tablet.
Excipients: cellulose microcrystallic, lactoses monohydrate, calcium hydrophosphate, a gipromelloz, half-oxameasures 407 *, the sodium stearylfumarating magnesium stearate.
* contains 0,01% of butyl hydroxytoluene as antioxidant. film covering: dye of Opadray II pink (85F94224) 26,06 mg; structure of a film cover: polyvinyl alcohol of 44,75%, macrogoal of 22,0%, talc of 21,415%, titanium dioxide of 11,32%, dye ferrous oxide of red 0,495%, dye ferrous oxide of black 0,02%.
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 α, β, γ 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 Ik5o at concentration from 5 to 12 nmol/l. Raltegravir also suppressed replication of strains of VICh-2 when testing on Semkh174 line cells (IK95=6 nmol/l). At simultaneous introduction to culture of the human T lymphocytes infected with 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 integraza of VICh-1 promoting emergence of virus strains, resistant to a raltegravir (developed or in vitro, or at the patients accepting ралтегравир), generally include replacement of amino acids or Y143 (replacement on With, N or R), or Q148 (replacement by N, To or R), or N155 (replacement by N) plus existence of one more or more additional mutations (for example, L74I/M, E92Q, E138A/K, G140A/S or VI5II). Recombinant viruses with one primary mutation (Q148H, K or R or N155H) 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 any 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 mg to 1600 mg. C124 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, value From 12 h - in favor of insignificant cumulation of drug. In the monotherapy mode on 400 mg 2 times a day value of an average geometrical for AUC0-124 made 14,3 µmol/l x h, C124 value - the 14th 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. In the second research average concentration of a raltegravir in cerebrospinal fluid made 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 of the isoform of enzyme uridinediphosphate-glyukuroniltransferazy (UDF-GT) received by an expression of complementary DNA showed that UDF-GT1A1 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-GT1A1. Duration of a final phase of an elimination half-life of a raltegravir makes about 9 hours, the most part of AUC corresponds to shorter 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 from 18 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. Doses for teenagers and children are more senior than 6 years for treatment of VICh-1 of an infection are recommended that pharmacokinetic parameters of a raltegravir are comparable to those at adult patients.
The pharmacokinetics of a raltegravir 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 heavy degree of a liver failure 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 genetically 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 adults, teenagers and children, since 6 years and with body weight not less than 25 kg as which were earlier receiving, not receiving anti-retrovirus therapy.
Route of administration and doses:
Inside. Drug Isentress® tablets which cannot be chewed, crumbled, broken are appointed regardless of meal.
The doctor having sufficient experience of therapy of HIV infection has to carry out by the drug Isentress® treatment.
The recommended drug Isentress® doses for treatment of VICh-1 of an infection:
- for adults: 400 mg x 2 times a day.
- for children and teenagers (6 years and with body weight not less than 25 kg are more senior): 400 mg x 2 times a day.
Treatment by the drug Isentress® is carried out to combinations with other anti-retrovirus drugs.
Features of use:
Pregnancy and lactation. Controlled researches of the drug 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. The drug Isentress® should not be appointed in the period of a lactation. Besides, breastfeeding is not recommended to HIV-positive mothers in order to avoid post-natal transfer of HIV to children.
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 the infections or other states extended among HIV - the infected patients (opportunistic infections) can still develop. It is very important to remain under observation of the doctor during therapy the drug 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 the drug Isentress® and to re-read its every time when obtaining the next recipe from the doctor. Patients have to be informed about
need to report to the doctor about emergence of any unusual symptoms, either 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 corticosteroids, 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 the drug Isentress® as a part of a combination therapy with other medicines which are associated with these undesirable reactions, such as Stephens's syndrome Are obtained - Johnson and a toxic epidermal necrolysis. 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 the drug 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 Isentress® or other medicines which are associated with these undesirable reactions after emergence of heavy rash can lead to zhizneugrozhayushchy reactions.
Myopathy 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 what - or the 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 the drug Isentress® at patients with serious associated diseases of a liver are not established. It is necessary to be careful at purpose of the drug Isentress4’ 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 (see the section SIDE EFFECT).
Depression. 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 the drug Isentress® to patients with a depression or psychiatric diseases in the anamnesis.
Simultaneous use with other medicines. Strong inductors UDF-GT1A1. It is necessary to be careful at purpose of the drug 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 the drug Isentress® the dose of the drug Isentress® has to be increased twice at adult patients. There are no data for a possibility of correction of doses of drugs at simultaneous use of the drug Isentress® and rifampicin for patients 18 years are younger (see the section INTERACTION WITH OTHER MEDICINES).
Antacids. Simultaneous use of the drug Isentress® with the antacids containing aluminum or magnesium leads to decrease in concentration of a raltegravir in a blood plasma. Simultaneous use of the drug Isentress® with the antacids containing aluminum or magnesium is not recommended (see the section INTERACTION WITH OTHER MEDICINES).
Influence on ability to manage vehicles and mechanisms. Researches on 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 the drug Isentress®, it is necessary to show extra care during the driving and work with mechanisms.
Side effects:
The profile of safety of the drug 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 anti-retrovirus 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 the drug 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 the drug 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 clinical trials, with various degree of probability connected with the 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, folliculitis, gastroenteritis, herpes simplex, herpes infection, shingles, flu, lymph node abscess, contagious mollusk, nasopharyngitis, upper respiratory tract infection.
The high-quality, malignant and not specified new growths / including cysts and polyps). Infrequent: skin papillomatosis.
From blood and lymphatic system. Infrequent: anemia, iron deficiency anemia, morbidity of lymph nodes, lymphadenopathy, neutropenia, trombotsitopeniya1.
From immune system. Infrequent: an immunity recovery syndrome, hypersensitivity to drug, and hypersensitivity.
From a metabolism and food. Frequent: loss of appetite. Infrequent: cachexia, diabetes mellitus, dislipidemiya, hypercholesterolemia, hyperglycemia, lipidemia, hyperphagia, increase in appetite, polydipsia, disturbance of a lipometabolism.
Disturbances of mentality. Frequent: unusual dreams, sleeplessness, nightmares, disturbance povedeniya2, 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, headache, psychomotor hyperreactivity. Infrequent: amnesia, syndrome of a carpal tunnel, cognitive disorders, disturbances of attention, postural dizziness, dysgeusia, hypersomnia, hypesthesia, lethargy, dysmnesia, migraine, peripheral neuropathy, paresthesias, drowsiness, tension headache, 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: sonitus.
From heart. Infrequent: heart consciousness, sinus bradycardia, ventricular premature ventricular contraction.
From vessels. Infrequent: "inflows" of blood to face skin with feeling of heat, arterial hypertension. From respiratory system, bodies of a thorax and a mediastinum Infrequent: dysphonia, nasal bleeding, nose congestion.
From digestive tract. 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, 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, skeletal and muscular pain, a mialgiya, pain in a neck, osteosinging, extremity pain, osteoporosis, polyarthritis, a tendinitis, a myopathy, rabdomioliz1.
From kidneys and urinary tract. Infrequent: renal failure, nephrite, nephrolithiasis, nocturia, kidney cyst, renal failure, tubulointerstitsialny nephrite.
From generative organs and a mammary gland. Infrequent: erectile dysfunction, gynecomastia, menopause symptoms.
The general frustration and disturbances in an injection site Frequent: 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 without existence of relationship of cause and effect using the drug Isentress® which were observed in the post-registration period of observation 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 earlier not receiving ARVT, cases of development of malignant new growths when using a combination of the drug 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 the drug Isentress® and in groups of the patients accepting comparison drugs.
At the patients accepting the drug 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 the drug 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 all three groups of treatment. Skin rash was easy and moderate
severity also did not influence continuation of ARVT. At the patients who earlier were not accepting ARVT at treatment by the drug 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 the drug Isentress® at the patients as who were earlier receiving, not receiving ARVT, 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 adult patients.
At one patient the following 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:
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Medicine taking into account a therapeutic scope |
Interaction (the mechanism if it is known) |
Recommendations about correction of the mode of dosing |
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Anti-retrovirus medicines |
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Protease inhibitors (SP |
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atazanavir/ritonavir (ралтегравир 400 mg 2 times a day) |
ралтегравир % AUC↑41 ралтегравир C 12 h ↑ 77% ралтегравир Cmax ↑ 24% (UDF-GT1A1 inhibition) |
Dose adjustment of the drug Isentress® is not required. |
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tipranavir/ritonavir (ралтегравир 400 mg 2 times a day) |
ралтегравир AUC ↓ 24% ралтегравир S12ch ↓55% ралтегравир C max ↓18% (induction of UDF-GT1A1) |
Dose adjustment of the drug Isentress® is not required. |
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Nenukleozidny inhibitors of the return transcriptase (NNIOT) |
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эфавиренз (ралтегравир 400 mg of 1 times a day) |
ралтегравир AUC ↓ 36% ралтегравир S12ch ↓21% ралтегравир C max ↓36% (induction of UDF-GT1A1) |
Dose adjustment of the drug Isentress® is not required. |
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этравирин (ралтегравир 400 mg 2 times a day) |
ралтегравир AUC ↓ 10% ралтегравир S12ch ↓34% ралтегравир Cmax of ↓11% (induction of UDF-GT1A1) этравирин AUC ↑ 10% этравирин S12ch ↑ 17% этравирин C max ↑4% |
Correction of doses of the drug Isentress® or etravirin is not required. |
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Nukleozidny inhibitors of the return transcriptase (ниот) |
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тенофовир (ралтегравир 400 mg 2 times a day) |
ралтегравир % AUC↑49 ралтегравир S12Ch ↑3% ралтегравир % Cmax↑64 (the mechanism of interaction is unknown) тенофовир % AUC↓10 тенофовир S24Ch ↓13% тенофовир Cmax of ↓23% |
Correction of doses of the drug Isentress® or tenofovir of a dizoproksil of a fumarat is not required. |
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Antagonists of hemokinovy receptors of CCR5
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Contraindications:
• Hypersensitivity to any of drug components;
• Children's age up to 6 years;
• Body weight is up to 25 kg;
• Pregnancy;
• Lactation period.
Исентресс® contains lactose therefore patients with a rare hereditary lactose intolerance, deficit of lactase or the broken absorption glyukozo-galactoses should not accept this drug.
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 the drug 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 the drug Isentress® to patients with a depression or psychiatric diseases in the anamnesis.
Overdose:
Specific symptoms of overdose of the drug Isentress® are not revealed. Raltegravir was well had by healthy volunteers in the mode of 1600 mg x 1 times to days and 800 mg x 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 for
vital signs, including an ECG, purpose of symptomatic therapy. There are no data on efficiency of dialysis at overdose by the drug Isentress®.
Storage conditions:
At a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 2,5 years. Not to use after the period of validity specified on packaging.
Issue conditions:
According to the recipe
Packaging:
Tablets, coated 400 mg. Packaging: on 60 tablets in the bottle from polyethylene of high density soldered by a protective membrane and closed by a plastic cover with the device against opening of a bottle by children and a container with silica gel. On 1 bottle together with the application instruction in a cardboard pack.
