Aptivus

General characteristics. Structure:

Active ingredient: 250 mg of a tipranavir.

Excipients: ethanol, propylene glycol, caprylic acid and capric acid - mono - and diglycerides, a macrogoal глицерилрицинолеат, трометамол, propyl gallate, the water purified.

Capsule covers: gelatin, propylene glycol, sorbitol mix with glycerin (Blend A 810), titanium dioxide (E171), dye ferrous oxide red (E172), water cleared. Ink (Black Opacode NSP 78-17827): SDA 35 alcohol, propylene glycol, dye ferrous oxide black (E172), polyvinyl acetate phthalate, the water purified isopropanol, a macrogoal-400, ammonia of water 28%.

Pharmacological properties:

Pharmacodynamics. The human immunodeficiency virus (VICh-1) codes aspartylprotease which availability is necessary for division and maturing of predecessors of virus proteins. Tipranavir is not peptide inhibitor of VICh-1 protease. Drug inhibits replication of a virus by prevention of maturing of virus particles.

Anti-virus activity of in vitro. Ipranavir inhibits replication of laboratory strains and clinical VICh-1 isolates on models with an acute form of the T-cellular infection; fifty-percentage effective concentration varies from 0.03 to 0.07 µmol (18-42 ng/ml). Anti-virus activity of a tipranavir of in vitro is established concerning a wide range of VICh-1 isolates of group M (And, C, D, F, G, N, CRF01 AE, CRF02 AG, CRF12 BF). Sensitivity of isolates in the vitro O VICh-1 and VICh-2 groups to a tipranavir is reduced. Fifty-percentage effective concentration fluctuate, respectively, from 0.164 to 1 µmol and from 0.233 to 0.522 µmol.

Researches of linkng with proteins showed that anti-virus activity of a tipranavir in case of presence of human serum decreases on average at 3.75 time. When using a tipranavir with other anti-retrovirus drugs in vitro it is established that the combination of a tipranavir with other inhibitors of protease (ампренавир, атазанавир, индинавир, лопинавир, нелфинавнр, ритонавир and саквинавир) rendered from supplementing before antagonistic action; the combination of a tipranavir with nenukleozidny inhibitors of the return transcriptase (делавирдин, эфавиренз and not Virapinum) and nukleozidny inhibitors of the return transcriptase (абакавир, диданозин, эмтрицитабин, ламивудин, ставудин, тенофовир and a zidovudine) usually had the supplementing effect.

Aptivus had synergy effect in case of a combination with HIV fusion inhibitor, enfuvirtidy. In vitro was not noted antagonism of a combination of a tipranavir with adefoviry or with ribaviriny, used in treatment of a viral hepatitis.

Stability. Development of resistance to a tipranavir of in vitro happens slowly and difficult. In vitro is shown that VICh-1 isolate which was emitted in 9 months and had 87-fold stability, to a tipranavir, was characterized by 10 mutations in protease (L10F, I13V, V32I, L33F, M36I, K45I, I54V/T, A71V, V82L, I84V), and also a mutation in CA/P2 polyprotein, in the place of division. In vitro is shown that there is invert correlation between degree of resistance to a tipranavir and ability of viruses to replication. Growth rate of the recombinant viruses having more than 3-fold resistance to a tipranavir makes less than 1% of the growth rate of the natural VICh-1 type in the same conditions.

Using a series of multiple step-by-step regressive analyses of the initial genotypes and genotypes which arose during treatment during clinical trials it was established that 16 amino acids were connected with reduced sensitivity to a tipranavir and/or with reduced effect concerning virus loading in 24 weeks: 10V, 13V, 20M/R/V, 33F/35G, 361, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V. In clinical isolates which were characterized by more than 10-fold decrease in sensitivity to a tipranavir eight came to light or bigger quantity of the mutations connected using a tipranavir.

In clinical trials when studying the genotypes allocated during treatment it is established that mutations of L33F/I, V82T/L HI84V were the prevailing mutations arising during treatment by Aptivus. For decrease in sensitivity the combination of all three mutations usually was required. Mutations in situation 82 arise in two ways: one - from the mutation existing earlier 82A by selection 82T, and another - from natural type 82V by selection 82L. In the research conducted at the patients who were earlier not receiving anti-retrovirus therapy development of stability of protease in patients with a virologic phenomenon of "ricochet" after use of the mode with use Aptivus/ritonavir was studied. At patients at whom initial viruses were studied not imevshiyerany the arisen mutations, stability of viruses to inhibitor of protease did not develop in one case.

In clinical trial among children at whom virologic inefficiency or otsutstvovy effect of treatment, the arising replacements in codons developed of amino acids were similar with observed at adults. As well as at adults, reduced sensitivity to a tipranavir at children was associated with emergence of mutations.

Cross stability. Tipranavir keeps essential anti-virus activity and has, less than 4-fold stability in the relation, the majority clinical, VICh-1 isolates at which after treatment reduced sensitivity to such inhibitors of protease as ампренавир, атазанавир, индинавир, лопинавир, ритонавир, нелфинавир and саквинавир was noted.

More than 10-fold resistance to a tipranavir of the viruses allocated at patients who received a large number of anti-retrovirus means, including various peptide inhibitors of protease was noted infrequently (less than at 2.5% of the studied isolates).

Viruses, steady against tipranavir, the arising in vitro from strains of VICh-1 of natural type, were characterized by the reduced sensitivity to such inhibitors of protease as ампренавир, атазанавир, индинавнр, лопинавир, нелфинавир and ритонавир, but remained sensitive to a sakvinavir.

Studying of an ECG. Aptivus in a combination with ritonaviry in therapeutic doses does not extend an interval of QTI does not exert clinically significant impact on an ECG.

Pharmacokinetics. The drug combination Aptivus with a low dose of a ritonavir (2 times/days) is necessary for achievement of effective concentration of a tipranavir in plasma. Ritonavir inhibits an isoenzyme of P450 CYP3A cytochrome in a liver, and also the pomp bringing the R-glycoprotein (Pgp) out of intestines cells, and, perhaps, an isoenzyme of P450 CYP3A cytochrome in intestines. Ritonavir increases value AUC, Cmax, Cmin and reduces clearance of a tipranavir. Aptivus's use together with a low dose of a ritonavir (500 mg / 200 mg) was followed by 29-fold increase in average size of basal concentration in plasma in the period of a steady condition of pharmacokinetics in comparison with Aptivus applied in a dose of 250 mg the 2nd time/essence without ritonavir.

Absorption. Absorption of a tipranavir at people is limited, quantitative data on absolute absorption are absent so far. Tipranavir is substrate for the R-glycoprotein (P-gp).

Cmax in plasma is reached during 1-5 h after use of drug and depends on a dose. Concentration of a tipranavir in plasma after repeated use of drug is lower, than it was supposed on the basis of data on use of a single dose, perhaps, owing to induction of enzymes and transport molecules of a liver. The steady condition of pharmacokinetics is reached at most of patients in 7 days of use of drug. The pharmacokinetics of Aptivus who is applied together page a low dose of a ritonavir in the period of a steady state is reflected in the form of linear function.

Average Cmax of a tipranavir in plasma after Aptivus's use together with ritonaviry (500 mg / 200 mg) within 2-4 weeks without restrictions in meal made 94.8±22.8 µmol at female patients and male patients have 77.6±16.6 µmol, and was reached approximately in 3 h.

Average basal concentration (before reception of a morning dose of drug) in the period of a steady condition of pharmacokinetics made 41.6±24.3 µmol at female patients, and male patients have 35.6±16.7 µmol. The size AUC of a tipranavir during a 12-hour interval of dosing averaged 851±309 µmol × h (clearance = 1.15 l/h) at female patients and 710±207 µmol × h (clearance of =1.27 l/h) at male patients.

Average T1/2 made 5.5 h (at women) or 6 h (at men).

Influence of food on absorption of drug after intake. It is established that in case of Aptivus's reception in the form of capsules together with ritonaviry during food (500-682 kcal, fat was a source of 23-25% of calories) clinically significant changes of pharmacokinetic indicators were not noted in comparison with reception of these drugs on an empty stomach. Considering the best portability of a ritonavir in case of its inclusion in time of food and importance of simultaneous use of Aptivus and a ritonavir, Aptivus has to be accepted during food.

When using Aptivus's together with a low dose of a ritonavir together with the liquid antacid containing aluminum and magnesium (20 ml), AUC, Cmax and Cmin value of Aptivus decreased by 25-29%. For prevention of decrease in absorption of a tipranavir it is necessary to divide reception of a tipranavira/ritonavir and antacids.

Distribution. Tipranavir substantially contacts plasma proteins (> 99.9%). Researches of distribution of a tipranavir in spinal and semen at the person were not conducted.

Metabolism. Researches of metabolism in vitro with microsomes of a liver of the person showed that among the CYP isoforms in metabolism there is a tipranavira. the main part is taken by CYP3A4.

The oral clearance of a tipranavir decreased after addition of a ritonavir that can be a consequence of "effect of the first passing" through a GIT and a liver. Metabolism of a tipranavir in the presence of a low dose of a ritonavir is minimum. At use of a 14C-tipranavira/ritonavir (500 mg / 200 in mg a day) it is shown that in 3, 8 or 12 h after their use in plasma prevailed not changed типранавир, making not less than 98.4% of the general dose, marked isotope circulating in plasma. In plasma only the small number of metabolites of a tipranavir is revealed, all of them contained in trace concentration (no more than 0.2% from marked dose isotope). The most part, a marked dose of a tipranavir (about 79.9%) was removed through intestines in not changed look, the main metabolite (about 4.9%), there was hydroxylic derivative a tipranavira. Kidneys removed in an invariable look trace quantities of a tipranavir (about 0.5%), the glyukuronidny conjugate of a tipranavir (about 11%) was the main metabolite.

Removal. Use of a 14C-tipranavir for the patients receiving Aptivus/ritonavir (500 mg / 200 mg a day), showed that in the period of a steady condition of pharmacokinetics the most part marked dose isotope (about 82.3%) was removed by intestines whereas kidneys removed only 4.4% of the general dose. Besides, it is shown that the most part marked was removed by dose isotope (about 56.3%) in an interval between 24 and 96 h after use of drugs. After daily use of Aptivusa/ritonavir (500 mg / 200 mg a day) together with easy food effective average T1/2 of a tipranavira/ritonavir at healthy volunteers and HIV-positive adult patients in the period of a steady condition of pharmacokinetics made, respectively, 4.8 and 6 h.

Use for special groups of patients. Floor: concentration of a tipranavir at women, in general, is higher, than at men. This distinction in concentration does not demand change of a dose.

Race: at men of Caucasian race variability of concentration of a tipranavir is higher, than at men of negroid race. However the most part of data in both races is comparable. At women of any of these races basal concentration of a tipranavir, in general, are higher, than at men.

Dysfunction of kidneys: at patients with dysfunction of kidneys the pharmacokinetics of a tipranavir was not studied. However, as the renal clearance of a tipranavir is small, at patients with a renal failure decrease in the general removal of drug from an organism is not expected.

Liver dysfunction: with with easy abnormal liver functions of change of a dose it is not required from patients. Influence of moderate abnormal liver functions (a class B on classification of Chayld-Pyyu) on pharmacokinetics of a tipranavir or ritonavir after their repeated use was not studied. Aptivus is contraindicated at moderate and considerable insufficiency of function of a liver.

Indications to use:

Aptivus applied together with a low dose of a ritonavir is shown for the combined anti-retrovirus therapy of the patients who were earlier undergoing treatment and infected with VICh-1 strains, resistant more than to one inhibitor of protease.

Route of administration and doses:

Inside. At adults and children 12 years the recommended dose are more senior makes 500 mg (on 1 capsule of drug Aptivus (250 mg) together with ritonaviry (100 mg) 2 times/days).

General recommendations. Aptivus it is necessary to accept every day in the recommended dose. In case of the admission it is not necessary to accept the doubled dose, and just to accept the following dose as quickly as it is possible.

Aptivus has to be applied to ensuring therapeutic effect with a low dose of a ritonavir.

For information on contraindications, cautions, side effects and potential interactions of a ritonavir, please, address the application instruction of a ritonavir.

Aptivus has to be applied together with a low dose. a ritonavira which needs to be accepted during food to improve portability of a ritonavir.

The accompanying therapy. Aptivus together with a low dose of a ritonavir has to be applied in a combination, at least, with two additional anti-retrovirus drugs. Concerning use of additional anti-retrovirus drugs it is necessary to follow their application instructions.

Features of use:

Use at pregnancy and feeding by a breast. There are no data on use of drug for pregnant women. Aptivus has to be used during pregnancy only if his potential advantage exceeds possible risk for a fruit.

According to the general recommendation, HIV-positive mothers should not nurse children for prevention of risk of post-natal transmission of HIV. Mothers have to stop feeding by a breast if they receive Aptivus.

Use at abnormal liver functions. Before therapy Aptivusy and ritonaviry in a low dose the corresponding laboratory researches have to be conducted, these researches need to be conducted regularly during treatment. More frequent control is required when Aptivus and ритонавир in a low dose are applied at patients with initially increased ACT and ALT levels or in the presence of active hepatitis B or C as in such cases the risk of further increase in level of transaminases or a decompensation of function of a liver can be increased.

In case of asymptomatic increase in the ACT or ALT levels exceeding the upper bound of norm more than by 10 times, therapy by Aptivus should be stopped.

In case of development of clinical signs of hepatitis, therapy by Aptivus should be stopped.

If other reason (for example, an acute hepatitis And, In or With, a disease of a gall bladder, use of other medicines) is established or if the potential advantage exceeds possible risk, then after return of the AST/ALT levels to reference values the question about drug use vozobnovleniye Aptivus can be considered.

There are clinical messages that combined use of Aptivus with a low dose of a ritonavir was followed by development of hepatitis and a decompensation of function of a liver, including from the death. It, as a rule, occurred at the patients with the developed stage of HIV infection accepting the numerous accompanying medicines. The causal relationship using Aptivus and a low dose of a ritonavir did not manage to be established. At patients with signs or symptoms of hepatitis treatment by Aptivus has to be stopped. It is necessary to be careful in case of Aptivus's use to patients who have anamnestic data on increase in enzymes of a liver or on hepatitis.

Tipranavir is preferential metabolized in a liver. It is necessary to be careful in case of use of this drug for patients with abnormal liver functions as concentration of a tipranavir in these cases can increase.

Aptivus is contraindicated to patients with a moderate or considerable liver failure (a class B or C on classification of Chayld-Pyyu).

Use at renal failures. As the renal clearance of a tipranavir is insignificant, increase in concentration of drug in plasma at patients with renal failures is not expected.

Use for children. Prtivopokazan to children up to 12 years.

Use for elderly patients. Clinical trials of drug Aptivus did not include enough patients at the age of 65 years and is more senior that would allow to establish whether the effect of treatment in this age group differs from effect, at younger patients. In general, Aptivus's use for elderly patients has to be carried out with care and under regular control that is caused by higher frequency of abnormal liver functions, kidneys and hearts, and also associated diseases non-use of other medicines in this age group.

Before the choice of the new mode in cases when the previous anti-retrovirus therapy was inefficient, it is necessary to analyze carefully the anamnesis of treatment of the specific patient and types of the mutations connected using various drugs. Whenever possible, it is necessary to carry out resistance tests. Aptivus has to be applied to ensuring therapeutic effect together with a low dose of a ritonavir. Discrepancy to the correct joint mode of use of Aptivus with ritonaviry leads to decrease in level of concentration of a tipranavir in plasma that can be insufficient for achievement of desired anti-virus effect. Patients have to be informed on it.

Aptivus is not capable to cure VICh-1 an infection or AIDS. At patients who receive Aptivus or any other anti-retrovirus therapy opportunistic infections and other complications of VICh-1 of an infection can continue to develop.

Ability of drug to reduce risk of a VICh-1 broadcast is not established to other persons.

Clinical trials of drug Aptivus did not include enough patients at the age of 65 years and is more senior that would allow to establish whether the effect of treatment in this age group differs from effect, at younger patients. In general, Aptivus's use for elderly patients has to be carried out with care and under regular control that is caused by higher frequency of abnormal liver functions, kidneys and hearts, and also associated diseases non-use of other medicines in this age group.

Abnormal liver functions and hepatotoxic. Before therapy Aptivusy and ritonaviry in a low dose the corresponding laboratory researches have to be conducted, these researches need to be conducted regularly during treatment. More frequent control is required when Aptivus and ритонавир in a low dose are applied at patients with initially increased ACT and ALT levels or in the presence of active hepatitis B or C as in such cases the risk of further increase in level of transaminases or a decompensation of function of a liver can be increased.

In case of asymptomatic increase in the ACT or ALT levels exceeding the upper bound of norm more than by 10 times, therapy by Aptivus should be stopped.

In case of development of clinical signs of hepatitis, therapy by Aptivus should be stopped.

If other reason (for example, an acute hepatitis And, In or With, a disease of a gall bladder, use of other medicines) is established or if the potential advantage exceeds possible risk, then after return of the AST/ALT levels to reference values the question about drug use vozobnovleniye Aptivus can be considered.

There are clinical messages that combined use of Aptivus with a low dose of a ritonavir was followed by development of hepatitis and a decompensation of function of a liver, including from the death. It, as a rule, occurred at the patients with the developed stage of HIV infection accepting the numerous accompanying medicines. The causal relationship using Aptivus and a low dose of a ritonavir did not manage to be established. At patients with signs or symptoms of hepatitis treatment by Aptivus has to be stopped. It is necessary to be careful in case of Aptivus's use to patients who have anamnestic data on increase in enzymes of a liver or on hepatitis.

Tipranavir is preferential metabolized in a liver. It is necessary to be careful in case of use of this drug for patients with abnormal liver functions as concentration of a tipranavir in these cases can increase.

Aptivus is contraindicated to patients with a moderate or considerable liver failure (a class B or C on classification of Chayld-Pyyu).

Renal failures. As the renal clearance of a tipranavir is insignificant, increase in concentration of drug in plasma at patients with renal failures is not expected.

Hemophilia. At patients with hemophilia of type A and B at whom protease inhibitors were applied, it was reported about increase of bleedings, including development of spontaneous hypodermic hematomas and a hemarthrosis. At some patients the factor of VIII was in addition applied. More than at a half of such patients treatment with inhibitors of protease proceeded or resumed (if before it it was stopped). The causal relationship between inhibitors of protease and these adverse phenomena did not manage to be established.

Intracranial bleedings. It is noted that Aptivus's use together with a low dose of a ritonavir for some patients was followed by development of intracranial bleedings from the death and without. At many of these patients associated diseases were observed or other medicines which could be the cause of intracranial bleedings or promote their development were at the same time applied. In general, at patients any certain types of disturbances of hematologic or koagulogichesky indicators, or the disturbances preceding development of intracranial bleedings were not observed. The increased risk of development of intracranial bleedings was observed at patients with the developed stage HIV infection/AIDS, including at the patients receiving Aptivus during clinical trials. The interrelation between Aptivus's use and development of intracranial bleedings is not established.

Influence on aggregation of thrombocytes and blood coagulation. Aptivus applied together with a low dose of a ritonavir has to be used with care at patients with the increased risk of the bleedings arising owing to injuries, surgeries or other reasons or at patients who receive the medicines capable to increase risk of bleedings (for example, antitrombotsitarnyesredstvo and anticoagulants), or high doses of vitamin.

Sugar diabetes / hyperglycemia. On the basis of the review of post-marketing data it was reported that at the HIV-positive patients receiving therapy by protease inhibitors development of a diabetes mellitus or an aggravation of earlier established diabetes mellitus and hyperglycemia was noted. Use of insulin or peroral hypoglycemic means was required from some patients in connection with these phenomena (or correction of their dose). Development of diabetic ketoacidosis was in certain cases noted.

At the patients stopping therapy by protease inhibitors, in certain cases the hyperglycemia remained. The causal relationship between therapy by inhibitors of protease and these phenomena is not established.

Increase in level of lipids. Treatment by Aptivus in a combination with a low dose of a ritonavir and other anti-retrovirus means was followed by increase in level of triglycerides and the general cholesterol in plasma. Level of triglycerides and cholesterol has to be defined before Aptivus's use and throughout therapy. Correction, caused by treatment, increases in level of lipids has to be carried out depending on clinical data.

Fat redistribution. Use of the combined anti-retrovirus therapy for HIV-positive patients led to fat redistribution (lipodystrophy). Long-term effects of these disturbances are not known now. The mechanism of their development is studied not completely. Existence of communication between a visceral lipomatoz and use of inhibitors of protease, and also existence of communication between a lipoatrophia and use of nukleozidny inhibitors of the return transcriptase is supposed. The increased risk of a lipodystrophy is established concerning patients of advanced age, patients receiving long anti-retrovirus therapy and patients with the accompanying metabolic disturbances. During clinical inspection direct assessment of signs of redistribution of fat is necessary. It is necessary to consider levels of lipids in blood serum and blood glucose on an empty stomach. Correction of disturbances of lipidic exchange has to be carried out taking into account, clinical data.

Syndrome of immune reactivation. At the patients receiving the combined anti-retrovirus therapy, including Aptivus, it was reported about development of a syndrome of immune reactivation. During an initial phase of the combined anti-retrovirus therapy at patients with safe immune system inflammatory reaction in response to slow opportunistic infections or on the residual phenomena of these infections can develop (for example, the infection caused by Mycobacterium avium, the pneumonia caused by Pneumocystis carinii, tuberculosis, a cytomegalovirus or reactivation of a virus of a herpes simplex and shingles) that can demand inspection and treatment.

Treatment of the patients who were earlier not receiving anti-retrovirus therapy. Aptivus's use together with a low dose of a ritonavir at the patients infected with HIV of natural type, who were earlier not receiving anti-retrovirus therapy is not recommended.

Cautions concerning simultaneous use of other medicines. Aptivus applied together with ritonaviry can change the content in plasma of other drugs, and other drugs can change the content in plasma of a tipranavir and ritonavir.

Influence on ability to driving of motor transport and to control of mechanisms. Special researches on influence of drug on ability to driving of motor transport and control of mechanisms were not conducted.

Side effects:

At adults. Diarrhea, nausea, a headache, a pyrexia, vomiting, fatigue and an abdominal pain were the most frequent adverse phenomena.

Clinically significant undesirable reactions of any degree of intensity are listed below (gradation 1-4) about which it was reported at the adult patients receiving tipranavir/ritonavir in doses of 500 mg / 200 mg a day during clinical trials a phase II and III.

From blood and lymphatic system: neutropenia, anemia, thrombocytopenia.

From immune system: hypersensitivity.

Disturbances of metabolism and food: gipertriglitseridemiya, lipidemia, hyperamilasemia, hypercholesterolemia, diabetes mellitus, hyperglycemia, anorexia, loss of appetite, decrease in body weight, dehydration, weight loss of the person.

From a nervous system: headache, intracraneal hemorrhage, dizziness, peripheral neuropathy, drowsiness, sleeplessness, sleep disorders.

From respiratory system: asthma.

From digestive tract: diarrhea, nausea, vomiting, abdominal distention, abdominal pain, feeling of stretching, liquid chair, dyspepsia, gastroesophageal reflux, pancreatitis, increase in level of a lipase.

From a liver and biliary tract: increase in activity of enzymes of a liver, cytolytic hepatitis, disturbances
indicators of function of a liver, toxic hepatitis, a liver failure (including death), hepatitis, fatty dystrophy of a liver, a hyperbilirubinemia.

From skin and hypodermic fabrics: rash, an itch, a lipogipertrofiya, a dieback, a lipoatrophia, the acquired lipodystrophy.

From skeletal and muscular system: mialgiya, muscular spasms.

From kidneys and urinary tract: renal failure.

General disturbances: indisposition, pyrexia, grippopodobny syndrome, weakness.

In clinical trials reactivation of the viral infections caused by the herpes simplex and herpes zoster viruses was observed.

Changes of laboratory indicators: increase in the ACT, ALT level, amylase, cholesterol, triglycerides, reduction of leukocytes of blood.

There are data testimonial of the fact that the risk of increase in transaminases within the second year of therapy is lower, than within the first year.

At children. The most frequent adverse reactions were similar observed at adults, at children the tendency to lower frequency of the majority of adverse reactions was noted. At children more often than at adults, vomiting and rash were observed.

The laboratory disturbances contacting treatment were similar observed at adults.

Interaction with other medicines:

Tipranavir is substrate, the inductor and inhibitor of P450 CYP3A cytochrome. However when using together with ritonaviry in the recommended dose the total inhibition of P450 CYP3A is noted. Combined use of Aptivus and a low dose of a ritonavir with the drugs which are generally metabolized with participation of an isoenzyme of CYP3A can lead to change of concentration of a tipranavir or other drugs in plasma that it is capable to affect their therapeutic and side effects.

Drugs which use is contraindicated owing to the expected extent of interaction and possible development of the serious adverse phenomena are listed in the section of the Contraindication.

When using the first dose and in the period of a steady condition of pharmacokinetics of any total influence on activity of an isoenzyme of CYP2C9 or on activity of the R-glycoprotein (P-gp) of a liver it was not noted. After use of the first dose of total influence on activity of an isoenzyme of CYP1A2 it was not observed, but in the period of a steady condition of pharmacokinetics moderate induction of this isoenzyme was noted. After use of the first dose the small inhibition of an isoenzyme of CYP2C19, and in the period of a steady condition of pharmacokinetics - moderate induction was noted. After use of the first dose and in the period of a steady condition of pharmacokinetics the considerable inhibition of an isoenzyme of CYP2D6, and also CYP3A4 and CYP3A5 in a liver and intestines is revealed. Activity R-glikoproteyna was inhibited (P-gp) in intestines after use of the first dose, but did not change in the period of a steady condition of pharmacokinetics.

Tipranavir is metabolized with participation of CYP3A and is substrate for the R-glycoprotein. Combined use of a tipranavir and drugs which induce CYP3A and/or the R-glycoprotein can reduce concentration of a tipranavir and reduce its therapeutic effect. Combined use of Aptivus and medicines which inhibit the R-glycoprotein can increase concentration of a tipranavir in plasma.

Fusion inhibitors. Enfuvirtid. Combined use of an enfuvirtid with Aptivus and a low dose of a ritonavir was followed by increase in basal concentration of a tipranavir in the period of a steady condition of pharmacokinetics approximately for 45%. Change of a dose of a tipranavir or ritonavir is not required.

Inhibitor of transfer of a chain integrazy. Raltegravir. Aptivus/ritonavir in repeated doses had no significant effect on concentration of a raltegravir in serum. At combined use of Aptivusa/ritonavir with raltegraviry change of a dose is not required.

Nukleozidny inhibitors of the return transcriptase. Zidovudine. Aptivus who is applied together with a low dose of a ritonavir reduces AUC value of a zidovudine approximately by 35%. Impact on the level of metabolites of a zidovudine is not noted. Change of a dose of a zidovudine at combined use with Aptivusom/ritonavir is not required.

Didanozin. Aptivus applied together with a low dose of a ritonavir leads to decrease in the size AUC of a didanozin. The clinical importance, reduction of level of a didanozin in plasma is not established. In order to avoid incompatibility of dosage forms, reception of a didanozin in a kishechnorastvorimy dosage form has to be separated from Aptivus's reception and a ritonavir, at least, on 2 h.

Lamivudin and ставудин. Aptivus applied together with a low dose of a ritonavir does not cause essential change of AUC value of a lamivudin or a stavudin. Change of a dose of a lamivudin or stavudin is not required.

Abakavir. Aptivus applied together with a low dose of a ritonavir reduces AUC value of an abakavir approximately by 40%. The clinical importance of reduction of level of an abakavir is not established therefore change of a dose of an abakavir is not required.

Nucleotide inhibitors of the return transcriptase. Tenofovir. Aptivus applied together with a low dose of a ritonavir did not cause essential change, concentration of a tenofovir in plasma. Change of a dose of a tenofovir is not required.

Nenukleozidny inhibitors of the return transcriptase. Not Virapinum. Essential interaction between Aptivus applied together with a low dose of a ritonavir, and not Virapinum was not observed. Therefore change of a dose is not required.

Efavirenz. Efavirenz applied by 1 times/days in a dose of 600 mg in a phase of a steady condition of pharmacokinetics when sharing with Aptivusy and ritonaviry in a low dose (500/200 mg) did not make essential impact on AUC value and the maximum concentration of a tipranavir (reduction of these indicators, respectively, for 8.3% and 2.9% was noted). Aptivus applied together with a low dose of a ritonavir significantly did not influence AUC value and the minimum concentration of an efavirenz.

Protease inhibitors. Altrenavir, атазанавир, лопинавир, саквинавир. Simultaneous use of Aptivus and a low dose of a ritonavir with protease inhibitors amprenaviry, atazanaviry, lopinaviry or sakvinaviry (each of them was applied together with a low dose of a ritonavir) led to essential decrease in concentration of inhibitors of protease in plasma. The combination of above-mentioned inhibitors of protease with Aptivusom/ritonavir is not recommended.

At the patients receiving Aptivus's combination and an amprenavir (both drugs are used together with a low dose of a ritonavir), the risk of increase in level of hepatic can increase. transaminases. If this combination therapy is considered absolutely necessary, change of a dose is not recommended.

Data on Aptivus's interaction and a low dose of a ritonavir with other inhibitors of protease (except stated above) are absent now.

Antagonists α1-адренорецепторов. Alfuzozin. Simultaneous use of a tipranavir and alfuzozin leads to increase in concentration of an alfuzozin and can cause hypotension.

Anticonvulsants. Carbamazepine, phenobarbital and Phenytoinum have to be used in a combination with Aptivusom/ritonavir with care. Simultaneous use of carbamazepine in a dose of 200 mg/days with Aptivusom/ritonavir led to increase in concentration of carbamazepine in plasma and to reduction of the minimum concentration of a tipranavir that can be the cause of decrease in its efficiency.

Antifungal drugs. Flukonazol. Aptivus applied together with a low dose of a ritonavir significantly does not influence pharmacokinetics of a flukonazol in the period of a steady state. Flukonazol increases AUC value and the minimum concentration of a tipranavir, respectively, for 56% and 104%. Change of a dose is not required. Use of a flukonazol in a dose more than 200 mg/days is not recommended.

Itrakonazol and кетоконазол. Aptivus applied together with a low dose of a ritonavir can increase concentration of a ketokonazol or itrakonazol. Itrakonazol and кетоконазол have to be used with care at combined use with Aptivusom/ritonavir. Use of an itrakonazol and ketokonazol in a dose more than 200 mg/days is not recommended.

Vorikonazol. Owing to a large number of systems of isoenzymes of CYP participating in metabolism of a vorikonazol to predict its interaction with Aptivus applied together with a low dose of a ritonavir, difficult.

Anti-gouty drugs. Colchicine. Treatment of a gouty attack: use of colchicine for the patients receiving Aptivus/ritonavir is carried out as follows: 0.6 mg once, then in 1 h 0.3 mg. Reception of colchicine can repeat not earlier than in 3 days.

Antagonists of receptors to endothelin. Bozentan. At the patients receiving Aptivus/ritonavir within at least 10 days, the initial dose of a bozentan has to make 62.5 mg and be accepted every day or every other day depending on individual portability. At the patients who are not receiving Aptivus/ritonavir yet, reception of a bozentan has to stop at least for 36 h prior to Aptivusa/ritonavir's use. After the beginning of use of Aptivusa/ritonavir during at least, 10 days reception of a bozentan is resumed in a dose of 62.5 mg every day or every other day depending on individual portability.

GMG-KOA-reduktazy inhibitors. Atorvastatin, симвастатин, ловастатин. Inhibitors hydroxymethylglutaryl coenzyme A (GMG-KOA) of reductase, симвастатин and ловастатин, are metabolized with active participation of isoenzymes of CYP3A4 cytochrome. Simultaneous use by these drugs of Aptivus and a low dose of a ritonavir is not recommended owing to the increased risk of development of a myopathy, including рабдомиолиз. If Aptivus together with a low dose of a ritonavir is applied together with atorvastatiny which is metabolized with smaller participation of CYP3A4, it is necessary to be careful and use an atorvastatin in the smallest doses. It is necessary to take into account a possibility of use of other inhibitors of GMK-KOA-reduktazy (except an atorvastatin), such as правастатин, флувастатин or розувастатин.

Rozuvastatin and правастатин. Aptivus (together with a low dose of a ritonavir) increases AUC value of a rozuvastatin by 37% and the maximum concentration of a rozuvastatin for 123%. Simultaneous use of Aptivusa/ritonavir and a rozuvastatin should be begun with the smallest dose of a rozuvastatin (5 mg/days), raising it gradually depending on effect of treatment and carrying out careful clinical monitoring concerning by-effects of a rozuvastatin thus as it is specified in the instruction for its use.

Considering similarity in removal of a pravastatin and rozuvastatin, use of a pravastatin is also recommended to be begun with the smallest dose (10 g/days), carefully watching by-effects according to the application instruction of a pravastatin.

Inhalation beta-agonists. Salmeterol. Simultaneous use of Aptivusa/ritonavir is not recommended. The combination of these drugs can increase risk of the undesirable reactions from cardiovascular system caused salmeteroly including lengthening of an interval of QT, heartbeat and sinus tachycardia.

Inductors of isoenzymes of CYP. Rifabutin. Aptivus (applied together with a low dose of a ritonavir) increases concentration of a rifabutin in plasma no more, than by 3 times, and concentration 25-O-dezatsetil-rifabutina (an active metabolite) no more, than by 20 times. Rifabutin increases the minimum concentration of a tipranavir by 16%. Reduction of a usual dose of a rifabutin (300 mg/days), at least, for 75% is recommended (for example, 150 mg every other day or three times a week). The patients receiving рифабутин together with Aptivusom/ritonavir have to be observed carefully concerning the possible adverse phenomena connected with therapy rifabutiny. There can be necessary a further dose decline.

Rifampicin (Rifampinum). Simultaneous use of Aptivus and rifamptsin (Rifampinum) contraindicated. At simultaneous use of inhibitors of protease, including Aptivusa with rifampicin (rifampiiy) is expected considerable decrease in concentration of inhibitor of protease. Decrease in levels of a tipranavir to suboptimal values can lead to loss of virologic effect and to development of resistance of a virus to Aptivus or to all group of inhibitors of protease.

Inhibitors of isoenzymes of CYP. Klaritromitsin. Aptivus applied together with a low dose of a ritonavir increases AUC value and the minimum concentration of a klaritromitsin, respectively, for 19% and 68%, and reduces AUC value of an active metabolite of a klaritromitsin more than by 95%. These changes are not considered as clinically significant. Klaritromitsin increases the minimum concentration of a tipranavir more than by 100%. This essential increase can be clinically significant. The patients using кларитромицин in the doses exceeding 500 mg of 2 times/days have to be observed carefully concerning toxicity signs. At patients with dysfunctions! kidneys the following changes of a dose have to be taken into account: if the clearance of creatinine makes 30-60 ml/min., the dose of a klaritromitsin has to be reduced by 50%; if the clearance of creatinine makes less than 30 ml/min., the dose of a klaritromitsin has to be reduced by 75%. With normal function of kidneys of changes of a dose it is not required from patients.

Analog of nucleosides - DNA polymerase inhibitor. Valatsiklovir. Simultaneous use of a valatsiklovir with Aptivusom/ritonavir was not followed by clinically significant influences on pharmacokinetics. Therefore these drugs can be used jointly without dose adjustment.

Peroral contraceptive means / are oestrogenic. Aptivus applied together with a low dose of a ritonavir reduces AUC value and the maximum concentration of ethinylestradiol by 150%, but significantly does not change norethindrone pharmacokinetics. In case of use of oral contraceptives which basis is made by estrogen together with Aptivusy and ritonaviry in a low dose have to be used, an alternative or additional birth control. The patients using replacement hormonal therapy have to be observed for the purpose of identification of signs of deficit of estrogen. At the women accepting estrogen the risk of developing of the rash which is not relating to the category of serious complications can increase.

Phosphodiesterase-5 inhibitors. Tadalafil. Simultaneous use of a tadalafil with Aptivusy and ritonaviry in - a low dose after the first reception of Aptivusa/ritonavir led to increase in influence of a tadalafil by 2.3 times though in the period of a steady state - Aptivusa/ritonavir's pharmacokinetics of changes, influence of a tadalafil was not noted. If tadalafit it is used during reception of the first dose of Aptivusa/ritonavir, use of a tadalafil in the lowest dose is necessary. But after 7-10 days of reception of Aptivusa/ritonavir when the steady condition of a pharmakonetika of a tipranavir and a ritonavir is reached, the dose of a tadalafil can increase (if it is clinically necessary).

Sildenafil. The safe and effective dose of this drug in case of combined use with Aptivusom/ritonavir is not established. There is a probability of emergence of undesirable reactions; caused sildenafily (to which the vision disorder, hypotension, a priapism and a syncope belongs).

Inhibitors of a protonew pomp. Omeprazol. Aptivus applied together with a low dose of a ritonavir reduces AUC value and the maximum concentration of an omeprazol respectively by 71% and for 73%. Essential clinical changes of properties of a tipranavira/ritonavir in the period of a steady condition of pharmacokinetics are not noted. When using an omeprazol together with Aptivusy and ritonaviry increase in a dose of an omeprazol can be required.

Drugs of a plant origin. The drugs of a plant origin containing extract of the St. John's Wort which is made a hole should not be applied along with Aptivusy and ritonaviry. In case of a combination of extract of the St. John's Wort which is made a hole with protease inhibitors including with Aptivus, considerable decrease in concentration of inhibitor of protease is expected. Decrease in level of a tipranavir to suboptimal values can lead to loss of virologic effect and to development of resistance of a virus to Aptivus or to all group of inhibitors of protease.

Other drugs. Buprenorphine/Naloxonum. Simultaneous use of buprenorphine/Naloxonum with Aptivusy and ritonaviry did not lead to change of clinical effect of buprenorphine/Naloxonum. When using this combination of drugs the minimum concentration of a tipranavir decreased by 39%. Clinical value of such change of concentration of a tipranavir in plasma is unknown.

Bupropion. Aptivus applied together with ritonaviry in small doses brought into the period of a steady condition of pharmacokinetics to decrease in values of the maximum concentration and AUC of a bupropion approximately for 50%. When using a combination of these three drugs careful clinical control is necessary.

Narcotic analgetics (methadone, Meperidinum). Combined use of Aptivus and a low dose of a ritonavir with a single dose of methadone leads to reduction of the maximum concentration of methadone approximately for 50%. Therefore observation of patients in the development plan for a withdrawal of opiates is necessary. Increase in a dose of methadone can be required. It is expected that Aptivus in combination with a low dose of a ritonavir will lead to reduction of concentration of Meperidinum and to increase in concentration of a metabolite of a normeperidin. Increase in a dose and long use of Meperidinum together with Aptivus and a low dose of a ritonavir are not recommended owing to increase in concentration of a metabolite of a normeperidin which has analgetic effect and the stimulating influence on TsNS (including causes spasms).

Midazolam. Simultaneous use of midazolam. for intake and Aptivusa/ritonavir contraindicated. Ritonavir is active inhibitor of an isoenzyme CYP3A and therefore influences pharmacokinetics of the drugs which are metabolized by means of this isoenzyme. Concentration of the midazolam applied once intravenously together with Aptivusom/ritonavir (in the period of a steady condition of pharmacokinetics), increased by 2.8 times. If Aptivus/ritonavir is applied together with parenterally used midazolam, careful monitoring of patients concerning respiratory depression and/or lengthenings of sedative action is necessary; it is necessary to take possible change of a dose into account.

Immunodepressants (cyclosporine, такролимус, сиролимус). When using these drugs together with Aptivusom/ritonavir monitoring of concentration of immunodepressants is recommended.

Warfarin and other peroral anticoagulants. The result of combined use of Aptivusa/ritonavir and S-warfarin was characterized by increase in influence of S-warfarin by 18% after use of the first dose of Aptivusa/ritonavir. and reduction of influence of S-warfarin by 12% in the period of a steady condition of pharmacokinetics of Aptivusa/ritonavir. In case of the combined use of these medicines control is recommended clinical and biological (MHO definition).

Theophylline. Aptivus/ritonavir can reduce concentration of theophylline that, in turn, increase in a dose of theophylline can demand.

Desipramine. Aptivus applied by page a low dose of a ritonavir can increase concentration of desipramine. Reduction of a dose of desipramine and monitoring of its concentration is recommended.

Loperamide. The pharmacokinetic analysis showed that at combined use of Aptivusa/ritonavir of AUC value and maksiamalny concentration of loperamide decreased, respectively, by 51% and 61%, the minimum concentration of a tipranavir decreased by 26%. The clinical importance of these changes is unknown.

Disulfiramum/metronidazole. Soft gelatin capsules of Aptivus contain alcohol which can cause disulfiramopodobny reactions in case of combined use with Disulfiramum or other drugs causing this reaction (for example, with metronidazole).

Flutikazona propionate. In post-market researches it was reported that when using a ritonavir at the patients receiving a flutikazon propionate it is inhalation or intranazalno system effects of corticosteroids, including Cushing's syndrome and suppression of function of adrenal glands were noted. Therefore combined use of a flutikazon of propionate and Aptivusa/ritonavir it is not recommended if only the potential advantage for the patient does not exceed risk of system side effects of corticosteroids.

Trazodonum. Simultaneous use of Trazodonum with Aptivus and a low dose of a ritonavir can increase concentration of Trazodonum in plasma. After simultaneous use of Trazodonum and a ritonavir such side effects as nausea, dizziness, hypotension and a faint were observed. When using Trazodonum in a combination with Aptivusom/ritonavir it is necessary to be careful and consider the possibility of use of a smaller dose of Trazodonum.

Contraindications:

— intolerance of fructose as drug contains up to 50,4 mg of sorbitol (when using of the maximum recommended daily dose);

— moderate or considerable insufficiency of function of a liver (a class B or C on classification of Chayld-Pyyu);

— combined use of Aptivus and a low dose of a ritonavir with antiarrhytmic means (Amiodaronum, bepridil/flekainid, пропафенон, quinidine), antihistamines (астемизол, терфенадин), ergot derivatives (dihydroergotamine, эргоновин, ergotamine, метилэргоновин), the means influencing motility of a GIT (цизаприд), neuroleptics (Pimozidum) sedative / hypnagogues (midazolam and to triazoles), antagonists α1-адренорецепторов (альфузозин) and sildenafily when it is used for treatment of pulmonary arterial hypertension. As above-mentioned drugs are metabolized with participation of isoenzymes of CYP3 A cytochrome, with Aptivus and a low dose of a ritonavir can lead combined use of these drugs to increase in their concentration in plasma that in turn can become the reason of the serious and/or life-threatening adverse phenomena;

— simultaneous use of rifampicin (Rifampinum) with tipranaviry and a low dose of a ritonavir;

— during Aptivus's reception with a low dose of a ritonavir the vegetable drugs containing extract of the St. John's Wort which is made a hole owing to risk of decrease in concentration of a tipranavir in plasma and reduction of its clinical effect should not be used;

— children's age up to 12 years;

— hypersensitivity to active or any excipient of drug.

With care:

— patients are more senior than 65 years;

— the patients infected with a virus of hepatitis B or C;

— patients, with abnormal liver functions;

— patients who have anamnestic data on increase in level of enzymes of a liver or on hepatitis.

Overdose:

Specific symptoms of overdose are unknown. Presumably, the overdose can lead to increase in frequency and weight of side effects.

Treatment: the antidote is not known. Treatment of overdose has to consist in use of general measures of the supporting character, including removal of not absorbed drug of a GIT, by a gastric lavage and purpose of absorbent carbon.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature of 2-8 °C (in the refrigerator). To store the opened bottle at a temperature not above 25 °C. Posde of opening a bottle should be used within 90 days. Period of validity 3 years.

Issue conditions:

According to the recipe

Packaging:

On 120 capsules in bottles, on 1 bottle in a cardboard pack.