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

Active substanceTipranavirTipranavir

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Aptivus

capsules inwards

Boehringer Ingelheim International GmbH Germany

Dosage form: & nbspcapsules

Composition:

1 capsule contains,

Active substance: tipranavir 250 mg

Ethanol 100 mg, propylene glycol 73 mg, caprylic and capric acid mono and diglycerides 75 mg, macrogol glycerylricinoleate 455 mg, trometamol 15 mg, propyl gallate 2 mg, purified water 30 mg.

Capsule shells: gelatin 330.7 mg, propylene glycol 107.1 mg, mixture of sorbitol with glycerol (Blend A 810) 43.6 mg, titanium dioxide (E171) 4 mg, iron dye red oxide (E172) -0 , 45 mg, purified water - up to 733 mg.

Ink (Black Opacode NSP, 78-17827):

- Alcohol SDA 35 - 26.134%, propylene glycol 22.0%, iron dye oxide black, (E172) 20.0%, polyvinyl acetate phthalate 10.913%, purified water 9.803%, isopropanol 8.0%, macrogol- 400 - 2,250%, ammonia water 28% - 0,9%.

Description:

Oval, pink, soft gelatin capsules with black overprint "TPV250". -

The contents of capsules are transparent from light yellow to amber liquid.

Pharmacotherapeutic group:antiviral (HIV) agent

ATX: & nbsp

J.05.A.E.09 Tipranavir

Pharmacodynamics:

The human immunodeficiency virus (HIV-1) encodes aspartyl protease, the presence of which necessary for division and maturation precursors of viral proteins.

Tipranavir is non-peptidic a protease inhibitor of HIV-1. A drug inhibits viral replication by prevention of maturation of viral particles.

Antiviral activity in vitro Tipranavir inhibits replication laboratory strains and clinical of HIV-1 isolates on models with acute form T-cell infection; 50% effective the concentration varies from 0.03 to 0.07 μmol (18-42 ng / ml). Antivirus activity of tipranavir in vitro installed for a wide range of isolates HIV-1 group M (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF).

Sensitivity of isolates of group O HIV-1 and HIV-2 in vitro to tipranavir reduced. 50% effective concentrations fluctuate, respectively, from 0.164 to 1 μmol and from 0.233 to 0.522 μmol.

Studies of protein binding showed that antiviral activity tipranavir in the presence of human serum is reduced in the average of 3.75 times. Using tipranavir with other antiretroviral drugs. drugs in vitro determined that combination of tipranavir with other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) from complementary to antagonistic action; combination tipranavir with non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz and nevirapine) and nucleoside reverse-inhibitor transcriptase (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine) usually provided complementary action.

APTIVUS provided synergistic action in the case of a combination with HIV fusion inhibitor, enfuvirtide.

In vitro no antagonism was noted combination of tipranavir with adefovir or with ribavirin used in treatment viral hepatitis.

Stability. The development of resistance to tipranavir in vitro is slow and complicated. In vitro it was shown that HIV-1 isolate, which was isolated after 9 months and 87-fold resistance to tipranavir, was characterized by 10 mutations in the protease (L10F, 113V, V321, L33F, M36I, K45I, I54V / T, A71V, V82L, I84V), as well as a mutation in the polyprotein CA / P2 at the place of division. In vitro shown, that there is an inverse correlation between degree of resistance to tipranavir and the ability of viruses to replicate.

The growth rate of recombinant viruses, possessing more than 3-fold resistant to tipranavir, is less than 1% of the growth rate of the wild type HIV-1 in the same conditions. Using a series of multiple step-by-step regression analyzes of initial genotypes and genotypes that emerged during the treatment in clinical trials, it was found that with reduced sensitivity to tipranavir and / or reduced effect in relation toin 24 weeks were 16 amino acids are bound: 10V, 13V, 20M / R / V, 33F, 35G, 361, 43T, 46L, 47V, 54A / M / V, 58E, 69K, 74P. 82L / T, 83D and 84V. AT clinical isolates that characterized by more than 10-fold a decrease in sensitivity to tipranavir, eight or more mutations associated with the use of tipranavir.

In clinical studies in the study genotypes isolated during treatment, found that the prevailing mutations that occurred during treatment with the drug APTIVUS, there were mutations L33F / I, V82T / L and I84V. To reduce sensitivity was usually required a combination of all three mutations. Mutations in position 82 arise in two ways: one of the previously existing mutation 82A by selection 82T, and the other from wild type 82V by breeding 82L. AT a study conducted in patients, previously not receiving antiretroviral therapy, the development of resistance protease in patients with virologic phenomenon of "ricochet" after application mode using tipranavir / ritonavir. In patients with which the original viruses did not have before mutations, the resistance of viruses to the protease inhibitor did not develop in eitherbottom case.

In a clinical study among children who developed virological inefficiency or lack of treatment effect, the changes in the codons of amino acids that appeared appeared to be similar to those observed in adults. As in adults, decreased sensitivity to tipranavir in children was associated with the occurrence of mutations.

Cross-resistance. Tipranavir retains significant antiviral activity and has less than 4-fold resistance against the majority of clinical isolates of HIV-1, who, after treatment, showed reduced sensitivity to protease inhibitors such as amprenavir, atazanavir, indinavir, lopinavir. ritonavir, nelfinavir and saquinavir.

BMore than 10-fold resistance to tipranavir viruses. isolated in patients who received a large number of antiretroviral agents, including various peptide protease inhibitors, was infrequent (less than 2.5% studied isolates).

Tipranavir-resistant viruses that occur in vitro from HIV-1 strains of natural type, were characterized by reduced sensitivity to such inhibitors proteases as amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir, but remained sensitive to saquinavir.

ECG study

APTIWUS in combination with ritonavir in therapeutic doses does not extend the interval QT and does not render clinically significant effects on the ECG.

Pharmacokinetics:

The combination of APTIWUS with a low dose of ritonavir (2 times / day) is necessary to achieve an effective concentration tipranavir in plasma. Ritonavir inhibits cytochrome P450 isoenzyme CYP3A at liver, as well as a pump that removes P- glycoprotein (Pgp) from the cells of the intestine, and, possibly, the cytochrome P450 isoenzyme CYP3A in the intestine. Ritonavir increases the value AUC (the area under the curve "concentration-time"), cmax (maximum concentration), C_mi_n(minimum concentration) and reduces clearance of tipranavir. Application of the drug APTIWUS together with a low dose ritonavir (500 mg / 200 mg twice daily) was accompanied by a 29-fold increase mean basal concentration in plasma in the period of steady state pharmacokinetics in comparison with tipranavir, used at a dose of 500 mg 2 times a day without ritonavir.

Suction. Suction of tipranavir limited, quantitative data on Absolute absorption is not yet available. Tipranavir is a substrate for P- glycoprotein (P-gp). Maximum concentration in plasma is reached within 1-5 hours after application of the drug and depends on the dose. Concentration of tipranavir in plasma after repeated use of the drug is lower than this was assumed on the basis of data on application of a single dose, due to the induction of enzymes and transport molecules of the liver. Sustainable the state of pharmacokinetics is achieved in of the majority of patients after 7 days application of the drug. Pharmacokinetics of the drug APTIVUS, used together with a low dose of ritonavir, during the stable state is reflected in the form linear function.

Average maximum concentration tipranavir in plasma after application of the drug APTIWUS together with ritonavir (500 mg / 200 mg twice daily) within 2-4 weeks without restrictions in the intake was 94.8 ± 22.8 μmol in women and 77.6 ± 16.6 μmol in men, and was achieved in about 3 hours. The mean basal concentration (before the morning dose of the drug) during the steady state of pharmacokinetics was 41.6 ± 24.3 μmol in women, and in men 35.6 ± 16.7 μmol. Value AUC (the area under the concentration-time curve) of tipranavir during the 12-hour dosing interval averaged 851 ± 309 μmol-h (clearance = 1.15 L / h) in women and 710 ± 207 μmol-hour (clearance = 1 , 27 l / h) in men. The mean half-life was 5.5 hours in women or 6.0 hours in men.

Effect of food on intake of the drug after ingestion

It was found that in the case of taking tipranavir capsules together with ritonavir during meals (500-682 kcal, fat was the source of 23-25% of calories) clinically significant changes

pharmacokinetic parameters were not observed in comparison with the administration of fastingavir / ritonavir. Given the better tolerability of ritonavir in the case of its intake during meals and the importance of simultaneous application of tipranavir and ritonavir, the APTIWUS should be taken while eating.

When using the drug APTIVUS together with a low dose of ritonavir together with an antacid containing aluminum and magnium (20 ml), the value AUC (the area under the concentration-time curve), Cmax(maximum concentration) and C_mi_n(the minimum concentration) of the drug APTIVUS decreased by 25-29%. To prevent a reduction in the absorption of tipranavir, it is necessary to separate the administration of tipranavir / ritonavir and antacids. Distribution. Tipranavir is largely associated with plasma proteins (> 99.9%).

Studies of the distribution of tipranavir in spinal cord and semen were not performed in humans.

Metabolism. Metabolic Studies in vitro with microsomes of human liver showed that among isoforms CYP in the metabolism of tipranavir, the main CYP3A4.

The total clearance of tipranavir decreased after the addition of ritonavir, which could be a consequence of the "first pass effect" through the gastrointestinal tract and liver. Metabolism of tipranavir in the presence of a low dose of ritonavir is minimal. When using isotope-labeled C-tipranavir / ritonavir (500 mg / 200 mg twice a day), it was shown that 3, 8 or 12 hours after their application in the plasma, the unchanged tipranavir. accounting for at least 98.4% of the total dose isotope-labeled, circulating in plasma. In plasma, only a small number of metabolites of tipranavir, they were all contained in the trace concentrations (no more than 0.2% of the labeled isotope dose).Most of the labeled dose of tipranavir (about 79.9%) was excreted through the intestines in an unchanged form, The main metabolite (about 4.9%) was hydroxyl derivative of tipranavir. Kidneys were excreted unchanged trace amounts of tipranavir (about 0.5%), the main metabolite was gliuronide conjugate of tipranavir (about 11.0%).

Excretion. The use of an isotope labeled 14C-tipranavir in patients who received

APTIWUS / ritonavir (500 mg / 200 mg two times per day), showed that during the period stable state of pharmacokinetics most of the isotope-labeled dose (about 82.3%) was excreted by the intestine, while the kidneys were only 4.4% of the total dose. In addition, it is shown that most of the isotope-labeled dose (about 56.3%) was displayed in the gap between 24 and 96 hours after application tipranavir / ritonavir. After a daily application of tipranavir / ritonavir (500 mg / 200 mg twice daily with light the effective average period half-life of tipranavir / ritonavir y healthy volunteers and HIV- infected adults in period of steady state pharmacokinetics was, respectively, 4.8 and 6.0 hours.

Use in special patient groups

Floor. Concentration of tipranavir in women, in in general, higher than that of men. This difference in concentrations do not require dose changes.

Race. In men of the Caucasoid race variability in tipranavir concentration higher than that of men of Negroid race.

However, most of the data in both races comparable. In women of any of these races Basal concentrations of tipranavir, in in general, higher than that of men.

Renal dysfunction. In patients with renal dysfunction pharmacokinetics tipranavir was not studied. But, since renal clearance of tipranavir is small, in patients with renal insufficiency of speed reduction removal of the drug from the body is not expected.

Liver dysfunction. In patients with lungs impaired liver function changes dose is not required.

Influence of hepatic impairment of moderate severity (class B by(Child-Pugh classification) for pharmacokinetics of tipranavir or ritonavir after multiple application has not been studied. АПТ�?ВУС contraindicated in hepatic insufficiency of moderate and severe severity.

Indications:

'APTIVUS, used in conjunction with a low dose of ritonavir,is indicated for combined antiretroviral therapy in patients previously treated and infected with HIV 1 strains resistant to more than one protease inhibitor.

Contraindications:

Contraindications

hypersensitivity to the active or any auxiliary substance of the drug;

intolerance to fructose, since the drug contains up to 50.4 mg of sorbitol (when using the maximum recommended daily dose);

hepatic insufficiency of moderate and severe severity (class B or C according to Child-Pugh classification);

- the combined use of the drug APTIVUS and a low dose of ritonavir with antiarrhythmic agents (such as, for example, amiodarone, beprideil, quinidine), antihistamines (such as, astemizole, terfenadine), ergot derivatives (such as dihydroergotamine, ergonovin, ergotamine, metergergonovin), agents affecting gastrointestinal motility,(such as, cisapride), antipsychotic agents (such as, pimozide, sertindole and quetiapine), sedatives / hypnotics (such as, midazolam, for oral administration, and triazolam), alpha-1 antagonists adrenoreceptors (alfuzosin) and sildenafil when they are used for treatment of arterial pulmonary hypertension.

Since the above preparations metabolized with the participation of isoenzymes cytochrome CYP3A, joint application of these drugs with tipranavir and low dose of ritonavir can lead to increase in their concentrations in the plasma, which in turn can cause serious and / or life-threatening undesirable phenomena;

- joint application is counter-indicative of the drug APTIVUS and a low dose ritonavir with antiarrhythmic by means of flecainide, propafenone and metoprolol (in the treatment of cardiac insufficiency);

simultaneous application Rifampicin with tipranavir and low dose of ritonavir is contraindicated;

simultaneous application of tipranavir / ritonavir with herbal preparations containing St. John's wort extract is contraindicated, due to the risk of reducing the concentration of tipranavir in plasma and reducing its clinical effect;

joint application of colchicine with tipranavir / ritonavir in patients with impaired liver and / or kidney function contraindicated;

children under 12 years.

Carefully:

patients older than 65 years;

patients infected with the hepatitis B or C virus;

patients with impaired liver function;

patients who have anamnestic information about an increase in the level of liver enzymes or about hepatitis;

patients with an increased risk of bleeding.

Pregnancy and lactation:

There are no data on the use of the drug in pregnant women. APTIWUS should be used during pregnancy only if its potential benefit exceeds the possible risk to the fetus.

In accordance with the general recommendation, HIV-infected mothers should not breast-feed their children for the prevention of the risk of .postnatal transmission ~ HIV. Mothers should stop breastfeeding if they get an APTIVUS.

Dosing and Administration:

Inside

Adults and children over 12 years of age:

The recommended daily dose of the drug The APTIVUS is 1000 mg. Two capsules (250 mg) together with 200 mg ritonavir twice daily with meals.

To provide therapeutic effect APTIVUS should be applied with a low dose of ritonavir.The dose of ritonavir is less than 200 mg 2 times a day should not be used, as this may affect the effectiveness of treatment.

For information about contraindications, warnings, side effects and potential interactions ritonavir, please refer to instructions for the use of ritonavir.

General recommendations

ANTIQUE should be taken every day at the recommended dose. When admission for more than 5 hours is not should be taken twice the dose, it is necessary to take the next dose in regular time a combination is adopted APTIWUS / ritonavir. In the event of a miss take less than 5 hours should take the missed dose as quickly as possible. it is possible, then take the next dose at the usual time, which regularly a combination is adopted APTIWUS / ritonavir.

Concomitant therapy

APTIWUS together with a low dose ritonavir should be used in combination with at least two additional antiretroviral preparations. In relation to the application additional antiretroviral drugs must be followed instructions for use.

Special patient groups:

Adolescents over 12 years of age:

During the course of treatment should be carefully monitor the virologic response and tolerability of the drug in this group patients.

Elderly patients:

In general, the use of the drug APTIVUS in elderly patients should with caution and with careful monitoring that is due to a higher frequency violations of the liver, kidney and heart, as well as concomitant diseases or using other medicines in this age group.

Patients with renal insufficiency:

Dose adjustments in patients with impaired kidney function is not required.

Patients with hepatic insufficiency:

Tipranavir is predominantly is metabolized in the liver. Required take care when use of this drug in patients with liver failure severity (class A according to classification Child-Pugh), since the concentration tipranavir in these cases can increase.

APTIVUS is contraindicated in patients with hepatic insufficiency of the middle and severe (grade B or C for Child-Pugh classification).

Side effects:

Have adults:

The most frequent adverse the phenomena were diarrhea, nausea, headache pain, pyrexia, vomiting, fatigue, pain in the abdomen and hyperlipidemia.

Undesirable reactions observed in patients who received tipranavir / ritonavir in placebo- controlled studies, are listed below with their frequency:

very frequent (> 1/10), frequent (from> 1/100 to <1/10), infrequent (from> 1/1000 to <1/100), rare (from> 1/10000 to <1/1000).

From the side of the blood and lymphatic system:

Infrequent - neutropenia, anemia, thrombocytopenia;

From the immune system:

Infrequent - hypersensitivity reactions;

Metabolic and nutritional disorders:

Often - hypertriglyceridemia, hyperlipidemia;

Infrequently, hyperamilazemia. hypercholesterolemia, diabetes mellitus, hyperglycemia, anorexia, decreased appetite, weight loss;

Rarely - dehydration, weight loss;

From the nervous system:

Often - a headache;

Infrequent - dizziness, peripheral neuropathy, drowsiness, insomnia, sleep disturbances;

Rarely - intracranial hemorrhage;

From the respiratory system:

Infrequent - shortness of breath;

From the gastrointestinal tract: Very often - diarrhea, nausea;

Often - vomiting, bloating, abdominal pain, a feeling of stretching, loose stools, indigestion;

Infrequently - gastroesophageal reflux, pancreatitis;

Rarely, an increase in lipase activity;

From the liver and bile excretory ways:

Infrequent - increased enzyme activity liver, impaired function liver, toxic hepatitis;

Rarely - liver failure (including fatal outcome), hepatitis, fatty degeneration of the liver, hyperbilirubinemia;

From the skin and subcutaneous tissues:

Often - a rash;

Infrequently - itching, lipogypertrophy, exanthema, lipoatrophy acquired lipodystrophy;

From the musculoskeletal system:

Infrequently - myalgia, muscle spasms;

From the side of the kidneys and urinary tract:

Infrequent - renal insufficiency;

Common violations:

Often - a malaise;

Infrequent - pyrexia, influenza-like syndrome, weakness.

In clinical studies, reactivation of viral infections, caused by viruses herpes simplex and herpes zoster.

Changes in laboratory indicators

increased activity ACT, ALT, hyperamylasemia, hypercholesterolemia, hypertriglyceridemia, leukopenia.

There is evidence that the risk of an increase in transaminases during the second year of therapy is lower than during the first year.

Description of individual undesirable reactions:

Hepatotoxicity:

In clinical trials in the group of patients taking tipranavir / ritonavir, there was an increase activity ACT and ALS more often than in the group comparison (10% and 3.4% respectively). The risk factor was concomitant hepatitis B or C and a basic insignificant increase in the activity of ALT enzymes and ACT.

Hyperlipidemia:

In clinical trials in the group of patients taking tipranavir / ritonavir. hyperlipidemia was noted more often than in the comparison group (25.2% and 15.6%, respectively).

Bleeding:

It was noted that the use of the drug APTIVUS together with a low dose of ritonavir in some patients was accompanied by the development of intracranial bleeding (VC), with a fatal outcome and without. Many of these patients had comorbid conditions or other medicines that could cause intracranial bleeding or contribute to their development.In general, patients did not have any specific types of violations hematological parameters, coagulogram indices, or violations, preceding the development of intracranial hemorrhages.

An increased risk of intracranial hemorrhage was observed in patients with developed stage HIV-infection / AIDS, including in patients who received APTIVUS in clinical trials. The relationship between the use of tipranavir and the development of intracranial bleeding has not been established.

Skin rash:

In clinical trials, the incidence of rash was comparable in the group patients, host tipranavir / ritonavir, and in the comparison group (16.3% and 12.5%, respectively). Cases of the syndrome Stevens-Johnson and toxic epidermal necrolysis was not recorded.

On background combined antiretroviral therapy, including protease inhibitors, a redistribution of subcutaneous tissue (thinning of the subcutaneous tissue of the face and limbs and increase in subcutaneous tissue in the abdomen, internal organs, breast and abdomen, mammary hypertrophy), hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, as well as increased creatinine phosphokinase, myalgia, myositis, rarely rhabdomyolysis (especially when combined with nucleoside reverse transcriptase inhibitors).

In HIV-infected patients with severe immunodeficiency at the onset of a combined antiretroviral therapy can develop inflammatory responses to opportunistic infections. Autoimmune diseases can also develop (eg, a basic disease), but such diseases can occur several months after the start of treatment, and the reactivation of viruses herpes simplex and herpes zoster.

Cases of osteonecrosis have been documented, especially in patients with an advanced stage of HIV infection or long-term combined antiretroviral therapy. Frequency of occurrence osteonecrosis is unknown.

Dchildren

The most frequent adverse reactions were similar to those observed inadults. In children more often than in adults, there was vomiting and rash and fever. Laboratory disorders associated with treatment were similar to those observed in adults.

Overdose:

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

Treatment: -

The antidote is not known. Treatment of overdose should consist of applying general supportive measures, including removing the unabsorbed drug from the gastrointestinal tract by washing the stomach and prescribing 'coal'

activated.

Interaction:

Tipranavir is a substrate, inducer and inhibitor of cytochrome P450 CYP3A. However, when used in conjunction with ritonavir, total inhibition of P450 CYP3A. Joint use of the drug APTIWUS and low-dose ritonavir with drugs. basically metabolized with the participation of isoenzyme CYP3A, can lead to a change in the concentration of tipranavir or other drugs in the plasma, which can affect their therapeutic and side effects.

Preparations, the use of which contraindicated due to expected drug interactions and the possible development of seriousadverse events are listed in the "Contraindications" section.

When using the first dose and in the period of ystable state of pharmacokinetics of any total effect on isoenzyme activity CYP2C9 or on athe activity of P-glycoprotein (P-gp) liver was not noted. After applying the first dose of the total effect on the activity of the isoenzyme CYP1A2 was not observed, but in the period of steady state

pharmacokinetics, there was a moderate induction of this isoenzyme. After the first dose, a slight inhibition of the isoenzyme CYP2C19. and in the period of steady state pharmacokinetics - moderate induction. After the application of the first dose and during the steady state of pharmacokinetics, a significant inhibition of the isoenzyme CYP2D6, and CYP3A4 and CYP3A5 in the liver and intestines. P-glycoprotein activity (P-gp) in the intestine was inhibited after the first dose, but did not change during the steady state of pharmacokinetics.

Tipranavir is metabolized with CYP3A and is a substrate for P-glycoprotein. Joint use of tipranavir and drugs that induce CYP3A and / or P-glycoprotein, can reduce the concentration of tipranavir and reduce its therapeutic effect.The combined use of tipranavir and drugs that inhibit P-glycoprotein may increase the concentration of tipranavir in plasma.

Antiretroviral drugs: Inhibitors of fusion:

Enfuvirtide. Joint use of enfuvirtide with the drug APTIVUS and low dose of ritonavir was accompanied by an increase in the basal concentration of tipranavir during the steady state of pharmacokinetics by approximately 45%. A change in the dose of tipranavir or ritonavir is not required.

Inhibitor integrals

Raltegravir. APTIVUS / ritonavir in multiple doses did not have a significant effect on the concentration of raltegravir in serum. When joint use of tipranavir / ritonavir with raltegravir, dose changes are not required.

Nucleoside reverse transcriptase inhibitors

Zidovudii. APTIVUS, used together with a low dose of ritonavir, reduces the value AUC (area under the concentration-time curve) of zidovudine by approximately 35%. There is no effect on the concentration of zidovudine metabolites. Changing the dose of zidovudine when combined with tipranavir / ritonavir is not required. Didanosia. APTIVUS, used withTogether with a low dose of ritonavir, AUC (area under the concentration-time curve) didanosine. The clinical significance of decreasing didanosine concentration in plasma has not been established. To avoid drug interactions, the intake of didanosine in an enteric-soluble dosage form should be separated from the administration of tipranavir / ritonavir for at least 2 hours.

Lamivudine, stavudine and emtricitabine. APTIVUS, applied together with a low dose of ritonavir. does not cause a significant change in the value AUC (area under the concentration-time curve) of lamivudine, stavudine, and emtricitabine. A change in the dose of lamivudine, stavudine, and emtricitabine is not required.

Abacavir. APTIVUS, used together with a low dose of ritonavir, reduces the value of AUC (area under the concentration-time curve) of abacavir by approximately 40%. The clinical significance of reducing the concentration of abacavir is not established, therefore, a change in the dose of abacavir is not required. Nucleotide reverse transcriptase inhibitors:

Teiofovir. APTIWUS. applied together with a low dose of ritonavir, did not causea significant change in the concentration of tenofovir in plasma. A change in the dose of tenofovir is not required.

Non-nucleoside reverse transcriptase inhibitors:

Nevirapine. Significant interaction between the drug APTIVUS,

applied together with a low dose of ritonavir, and nevirapine was not observed. Therefore, a dose change is not required. Efavirenz. Efavirenz used once a day at a dose of 600 mg in the phase of steady state pharmacokinetics when used in conjunction with tipranavir and ritonavir in low dose (500/200 mg twice a day) had no significant effect on the value AUC (area under the concentration-time curve) and Cm_Oh(maximum concentration) of tipranavir (there was a decrease in these indicators, respectively, by 8.3% and 2.9%). APTIVUS, used together with a low dose of ritonavir, did not significantly affect the value AUC (the area under the concentration-time curve) and C_min (minimum concentration) of efavirenz.

Etravirine. APTIVUS / ritonavir decreases 76% AUC (the area under the concentration-time curve) of etravirine, which significantly reduces the effectiveness of etravirine.Joint application of tIpranavir / ritonavir with etravirine is not recommended.

Rilpiviria. The interaction of rilpinivir and tipranavir has not been studied. Co-administration with ritonavir / darunavir or ritonavir / lopinavir resulted in an increased plasma rilpivirin concentration, however, dose changes when rilpivirin is combined with ritonavir / darunavir or

ritonavir / lopinavir was not required. When combined

tipranavir / ritonavir with rilpivirin requires careful monitoring of the concentration of drugs in the plasma, as may require a correction of their dose. Protease inhibitors:

Amprenavir, atazapavir, lottavir, saquiavir. Simultaneous use of the drug APTIVUS and low dose of ritonavir with protease inhibitors amprenavir, atazanavir, lopinavir or saquinavir (each of which was used together with a low dose of ritonavir) led to a significant decrease in the concentration of protease inhibitors in plasma. The combination of the above protease inhibitors with tipranavir / ritonavir is not recommended.

Patients receiving a combination of nmedicines and amprenavir (both drugs are used together with a low dose of ritonavir), the risk of an increase in hepatic transaminase activity may increase. If this combination therapy is considered absolutely necessary, a dose change is not recommended.

Data on the interaction of the drug APTIVUS with a low dose of ritonavir with other protease inhibitors (other than those mentioned above) are currently not available.

Other protease inhibitors:

There is currently no data on the interaction of tipranavir / ritonavir with other (not listed above) protease inhibitors.

The antagonist of alpha-1 adrenergic receptors is Alfuzosin. The simultaneous use of tipranavir and alfuzosin leads to an increase in the concentration of alfuzosin and may cause hypotension.

The simultaneous use of tipranavir with alfuzosin, when used for the treatment of pulmonary arterial hypertension, is contraindicated.

Antipsychotics:

Pimozide, sertindole and quetiapine. Joint use of tipranavir / ritonavir with pimozide, sertindole and quetiapine is contraindicated, since inhibition of the isoenzyme CYP3A

tipranavir / ritonavir, can lead to serious life threatening conditions, including to whom.

Anticonvulsants: Carbamazepine, phenobarbital and phenytoin should be used in combination with tipranavir / ritonavir with

caution. Simultaneous

the use of carbamazepine at a dose of 200 mg per day with tipranavir / ritonavir resulted in an increase in carbamazepine plasma concentration and a decrease in the minimum concentration (C_min) tipranavir, which may be the reason for the decrease in its effectiveness. Antifungal preparations:

Fluconazole. APTIVUS, used together with a low dose of ritonavir, does not significantly affect the pharmacokinetics of fluconazole during the steady state of pharmacokinetics. Fluconazole increases the value AUC (the area under the concentration-time curve) and C_mi_n(minimum concentration) of tipranavir, respectively, by 56% and 104%. A dose change is not required. Do not use fluconazole at a dose of more than 200 mg / day.

Itraconazole and ketoconazole. APTIWUS, nWhen taken with a low dose of ritonavir, it can increase the concentration of ketoconazole or itraconazole. Itraconazole and ketoconazole should be used with caution when combined with tipranavir / ritonavir. Do not use itraconazole and ketoconazole at a dose of more than 200 mg / day. Voriconazole. Due to the large number of isoenzyme systems CYP, involved in the metabolism of voriconazole. predict its interaction with the drug APTIVUS, used in conjunction with a low dose of ritonavir, is difficult. It is necessary to avoid simultaneous administration with voriconazole of tipranavir / ritonavir. Anti-gouty drugs Colchicine is a substrate of isoenzyme CYP3A and glycoprotein-P. When colchicine is used together with tipranavir / ritonavir in patients with normal liver and kidney function, a dose reduction or colchicine can be required. Treatment of a gouty attack: the use of colchicine in patients receiving APTIVUS / ritonavir is as follows: 0.6 mg (1 tablet) once, then after 1 hour 0.3 mg (half tablet). Reception of colchicine can be repeated no earlier than 3 days later.

In patients with impaired hepatic function

and / or kidney joint application

colchicine with tipranavir / ritonavir

it is contraindicated.

Drugs used for treatment

hepatitis C

Boceprevir

In pharmacokinetic studies, there was

shown, that boceprevir reduced

exposure to ritonavir; lopinavir,

ritonavir-boosted; atazanavir,

enhanced by ritonavir, and darunavir,

ritonavir-boosted. Impact

Bocetreviir decreased by 45% and 32%

when combined with lopinavir,

enhanced ritonavir, and with darunavir,

enhanced ritonavir. These medicinal

interactions can reduce

effectiveness of HIV protease inhibitors

and / or boceprevir, so the joint

use of bocetrevir and

tipranavir / ritonavir is not recommended.

Telaprevir.

Joint use of the drug

APTIWUS and telaprevir have not been studied.

Telaprevir is metabolized in the liver

isoenzymes CYP3A and is

substrate for glycoprotein-P; also

other isoenzymes may take

participation in the metabolism of telaprevir. When The combined use of ritonavir-enhanced protease inhibitors and telaprevir plasma concentrations of telaprevir and protease inhibitors used with ritonavir may "concentration-time") of hydroxyl metabolites, approximately, by 85%. Atorvastatin has no significant impact on indicators AUC, Stakh and Cmin tipranavir. The simultaneous use of atorvastatin with the drug APTIVUS and a low dose of ritonavir is not recommended. In those cases where

joint use is necessary, it should be borne in mind that the daily dose of atorvastatin should not exceed 10 mg. It is recommended to start therapy with

the lowest dose of atorvastatin with careful clinical control

tolerability, or use other inhibitors of GMC-CoA reductase, such as pravastatin, fluvastatin or rosuvastatin. Simvastatin and lovastatin

metabolized with the active participation of cytochrome isoenzymes CYP3A4. Simvastatin / lovastatin should be avoided simultaneously with tipranavir and low-dose ritonavir due to an increased risk of myopathy, including rhabdomyolysis.

Rosuvastatin and pravastatin. APTIWUS (together with a low dose of ritonavir) increases the value AUC (area under the concentration-time curve) and Cm_Oh(maximum concentration) of rosuvastatin by 37% and 123%, respectively.

Simultaneous use of tipranavir / ritonavir and rosuvastatin should be started with the lowest dose of rosuvastatin (5 mg / day), increasing it gradually depending on the effect of the treatment and conducting a thorough clinical monitoring for the side effects of rosuvastatin in the manner described in the instructions for its use. Given the similarity in the excretion of pravastatin and rosuvastatin, the use of pravastatin also

it is recommended to start with the lowest dose (10 mg / day), carefully observing side effects in accordance with the instruction on the use of pravastatin. Inhalation beta-agonists Salmeterol. The simultaneous use of tipranavir / ritonavir is not recommended. The combination of these drugs can increase the risk of cardiovascular adverse reactions caused by salmeterol, including the lengthening of the interval QT, heartbeat and sinus tachycardia.

Inductors of isoenzymes CYP:

Rifabutin. APTIVUS (used together with a low dose of ritonavir) increases the concentration of rifabutin in the plasma by no more than 3 times, and the concentration of 25-O-deacetyl-rifabutin (active metabolite) is not more than 20 raz. Rifabutin increases the minimum concentration (C_mi_n) of tipranavir by 16%.It is recommended that the usual dose of rifabutin (300 mg / day) be reduced by at least 75% (eg, 150 mg every other day or three times a week). Patients receiving rifabutin together with tipranavir / ritonavir, should be carefully monitored for possible adverse events associated with rifabutin therapy. It may be necessary to further reduce the dose.

Rifampicin. The simultaneous use of the drug APTIVUS and rifampicin is contraindicated. With the simultaneous use of protease inhibitors, including the drug APTIVUS, with rifampicin, a significant decrease in the concentrations of the protease inhibitor is expected. Reducing the concentration of tipranavir to suboptimal values can lead to a loss of virologic effect and to the development of virus resistance to the drug APTIVUS or to the whole group of protease inhibitors.

Anti-malarial drugs Halofantrine, lumepantria With the simultaneous use of tipranavir / ritonavir and antimalarial drugs increasing the concentration of the latter.

There is a possibility of

adverse reactions caused by antimalarial drugs.Joint use of tipranavir / ritonavir with halofantrine and lumefantrine is not recommended.

Inhibitor inhibitors CYP: Clarithromycin. APTIVUS, applied together with a low dose of ritonavir, increases the value of AUC (area under the concentration-time curve) and Cmin (minimum concentration) of clarithromycin, respectively, by 19% and 68%, and decreases the value AUC (area under the concentration-time curve) of the active metabolite of clarithromycin by more than 95%. These changes are not considered clinically significant. Clarithromycin increases the C_mi_n (minimal concentration) of tipranavir by more than 100%. This is a significant increase in Cmincan be clinically significant. Patients using clarithromycin in doses exceeding 500 mg 2 times a day, should be observed for signs of toxicity.

In patients with impaired renal function, the following dose changes should be taken into account: if the clearance toof reatinin is 30-60 ml / min, the dose of clarithromycin should be reduced by 50%; if the creatinine clearance is less than 30 ml / min, the dose of clarithromycin should be reduced by 75%. In patients with normal renal function, dose changes are not required.

Kobitsystat and preparations containing it: APTIWUS / ritonavir should not be administered in conjunction with the cobicystate and preparations containing it. Kobitsystat significantly inhibits hepatic enzymes. When combined with tipranavir and kobitsistata, the effectiveness of both drugs is much lower than when they are used separately.

The nucleoside analogue - DNA polymerase inhibitor

Valaciclovir. The simultaneous use of valaciclovir with tipranavir / ritonavir was not accompanied by clinically significant effects on their pharmacokinetics. Therefore, these drugs can be used together without dose adjustment.

Oral contraceptives / estrogens:

APTIVUS, used together with a low dose of ritonavir, lowers the value of AUC (area under the concentration-time curve) and Cm_Oh (maximum concentrationethanol estradiol by 50%, but significantlye changes the pharmacokinetics of norethindrone. In the case of the use of oral contraceptives, which are based on estrogens, alternative or additional contraceptive measures should be used in conjunction with the drug APTIVUS and ritonavir in a low dose.Patients using hormone replacement therapy should be observed to identify signs of estrogen deficiency. Women taking estrogens may have a higher risk of developing a rash that does not belong to the category of serious complications.

Inhibitors of phosphodiesterase-5

Vardenafil

When combined combination of the drug APTIVUS and a low dose of ritonavir with vardenafil should be taken care, as the use of this combination can significantly increase the concentration of vardenafil and, as a consequence, lead to an increase in the frequency of such adverse reactions as hypotension, visual impairment, priapism caused by vardenafil.

Tadalafil. Simultaneous use of tadalafil with tipranavir and ritonavir in a low dose already after the first administration of tipranavir / ritonavir resulted in the magnitude of the effect of tadalafil 2.3 times, although no changes in the effect of tadalafil were observed during the period of stable pharmacokinetics of tipranavir / ritonavir.

If tadalafil used during reception the first doses

tipranavir / ritonavir, is necessary

the use of tadalafil in the lowest dose.But after 7-10 days of taking tipranavir / ritonavir, when a stable state of the pharmaconetics of tipranavir and ritonavir is achieved. the dose of tadalafil may increase (if it is clinically necessary).

Sildenafil

A safe and effective dose of sildenafil in the case of combined use with the drug APTIVUS and ritonavir is not established. There is a possibility of undesirable reactions caused by sildenafil (which include visual impairment, hypotension, priapism and syncope). The joint use of tipranavir / ritonavir with sildenafil, used for

treatment of pulmonary arterial hypertension, contraindicated.

H2 receptor antagonists

No interaction data Tipranavir / ritonavir with H2 antagonistsof the acceptors. Reduction of the pH of the stomach, in as a result of the intake of H2 receptor antagonists, does not affect the concentration tipranavir.

Antiarrhythmic drugs Simultaneous use of amiodarone, beprinid, quinidine with the drug

APTIWUS and a low dose of ritonavir are contraindicated. When using this combination, a significant increase in the concentration of amiodarone is expected, Beprinid, quinidine.

Simultaneous use of flecainide, propafenone. metoprolol (with heart failure) with the drug APTIVUS and a low dose of ritonavir is contraindicated. When using this combination, a significant increase in the concentration of flecainide, propafenone and metoprolol is expected.

Aitigistamine preparations The simultaneous use of astemizole and terfenadine with the drug APTIVUS and a low dose of ritonavir is contraindicated. When using this combination, a significant increase in the concentration of astemizole and terfenadine is expected.

Alkaloids of ergot

Simultaneous application dihydroergotamine, ergonovine, ergotamine, methylergonovine with the drug APTIVUS and A dose of ritonavir is contraindicated. When using these combinations, a significant increase in the concentration of dihydroergotamine is expected,

ergonovine, ergotamine, methylergonovine. Antacids:

When using the drug APTIVUS together with a low dose of ritonavir together with antacids containing aluminum and magnesium (20 ml), the value AUC (the area under the concentration-time curve), Cm_Oh(maximum concentration) and C_mi_n(minimum concentration) of tipranavir decreased by 25-29%. To prevent decrease the absorption of tipranavir it is necessary to separate the reception tipranavir / ritonavir and antacids for at least two hours.

Proton Pump Inhibitors:

Omeprazole. APTIVUS applied together with a low dose of ritonavir. reduces the AUC and Cm_Oh omeprazole, respectively, by 71% and 73%. Significant clinical changes in the concentration of tipranavir / ritonavir in the period of steady state pharmacokinetics are not noted. When using omeprazole in conjunction with the drug APTIVUS and ritonavir, an increase in the dose ofmeprazole.

Vegetable preparations: Preparations of plant origin containing St. John's wort extract

perforated, should not be used concomitantly with tipranavir / ritonavir. In the case of a combination of St. John's wort extract with protease inhibitors, including with the drug APTIVUS, a significant decrease in the concentration of the protease inhibitor is expected.

Reducing the concentration of tipranavir to suboptimal values can lead to a loss of virologic effect and to the development of virus resistance to the drug APTIVUS or to the whole group of protease inhibitors.

Other drugs:

Cisapride

Simultaneous use of cisapride with the drug APTIVUS and a low dose of ritonavir is contraindicated. When use of this combination is expected to significantly increase the concentration of cisapride.

Triazolam

The simultaneous use of triazolam with the drug APTIVUS and a low dose of ritonavir is contraindicated. When use of this combination is expected to significantly increase toon the concentration of triazolam.

Buprenorphine / naloxone. The simultaneous use of buprenorphine / naloxone with tipranavir and ritonavir did not change the clinical effect of buprenorphine / naloxone. When

Using this combination of drugs, the minimal concentration of tipranavir decreased by 39%. The clinical significance of this change in the concentration of tipranavir is unknown.

Bupropion. APTIVUS, used together with ritonavir in small doses, resulted in a steady state of pharmacokinetics to a decrease in C_max(maximum concentration) and AUC (the area under the concentration-time curve) of bupropion by about 50%. When using a combination of these three drugs, careful clinical monitoring is necessary.

Narcotic analgesics: methadone, meperidine. Joint use of tipranavir and a low dose of ritonavir with a single dose of methadone leads to a decrease in the maximum concentration of methadone (Cma_x) by about 50%. Therefore, patients should be monitored for the development of opiate withdrawal syndrome. It may be necessary to increase qoases of methadone. It is expected that APTIWUS combined with a low dose of ritonavir will lead to a decrease in the concentration of meperidine and an increase in the concentration of the metabolite of normeperidine. Increasing the dose and prolonged use of meperidine together with tipranavir and a low dose of ritonavir are not recommended due to an increase in the concentration of metabolite normeperidine, which has an analgesic effect and a stimulating effect on the central nervous system.

Midazolam. The simultaneous use of midazolam for oral administration and tipranavir / ritonavir is contraindicated. Ritonavir is an active inhibitor of isoenzyme CYP3A and therefore affects the pharmacokinetics of drugs,

metabolized by this isoenzyme. The concentration of midazolam, administered once intravenously with tipranavir / ritonavir (in the period of steady state

pharmacokinetics) increased by 2.8 times.If APTIVUS / ritonavir is used in conjunction with parenteral midazolam, careful monitoring of patients with respiratory depression and / or lengthening of sedation is necessary; a possible dose change should be taken into account.

Immunosuppressive agents (ciclosporin,

tacrolimus, sirolimus). When using these drugs in conjunction with tipranavir / ritonavir, concentration monitoring

immunosuppressants.

Warfarin and other oral anticoagulants. The result of joint use of tipranavir / ritonavir and S- warfarin was characterized by increased exposure S-warfarin by 18% after the first dose

tipranavir / ritonavir, and reduced exposure S-warfarin by 12% during the stable state of pharmacokinetics of tipranavir / ritonavir. When

combined use of these

It is recommended to use clinical drugs (definition of MNO) for control of drugs. Theophylline. APTIVUS, used in conjunction with ritonavir, may reduce the concentration of theophylline, which in turn may require an increase in the dose of theophylline.

Desipramine. APTIVUS, used with a low dose of ritonavir, can increase the concentration of desipramine. It is recommended to reduce the dose of desipramine and monitor its concentration.

Loperamide. Pharmacokinetic analysis showed that when combined use of tipranavir / ritonavir and loperamide values AUC (the area under the concentration-time curve) and C_thatx

(maximum concentration) of loperamide decreased, respectively, by 51% and 61%, and C _{] n}in (minimal concentration) of tipranavir decreased by 26%. The clinical significance of these changes is unknown. Disulfiram / Metronidazole The drug contains alcohol, which can cause disulfiram-like reactions in the case of combined use with disulfiram or other drugs that cause this reaction (for example, with metronidazole).

Fluticasone propionate In postmarketing studies, it was reported that when using ritonavir in patients who received fluticasone propionate by inhalation or intranasal, systemic effects of corticosteroids, including Cushing's syndrome and suppression of adrenal function. Therefore, joint the use of fluticasone propionate and tipranavir / ritonavir is not recommended unless the potential benefit of using fluticasone propionate for the patient does not exceed the risk of systemic side effects of corticosteroids.

Digoxin

It is necessary to control the concentration digoxin in plasma before reaching stable state of pharmacokinetics tipranavir.

Trazodone

Simultaneous use of trazodone with tipranavir and low-dose ritonavir can increase the concentration of trazodone in plasma. After simultaneous application trazodone and ritonavir side effects like nausea, dizziness, hypotension and syncope. When use trazodone in combination with tipranavir / ritonavir be careful and consider possibility of using a smaller dose trazodone.

Special instructions:

Before choosing a new regimen in cases where prior antiretroviral therapy was ineffective, a careful analysis of the patient's treatment history and the types of mutations associated with the use of different drugs should be carefully considered. If possible, it is necessary to conduct resistance tests.

To ensure therapeutic effect, APTIVUS should be used together with a low dose of ritonavir. Nonconformity correct joint regime application of the drug APTIWUS with ritonavir leads to a decrease concentration of tipranavir in plasma, which may not be sufficient for achieve the desired antivirus effect. Patients should be informed about this.

APTIWUS is unable to cure HIV-1 infection or AIDS. Patients who receive APTIWUS or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.

The ability of the drug to reduce the risk of transmission of HIV-1 to others has not been established.

Clinical studies of the drug APTIVUS did not include a sufficient number of patients aged 65 years and older, which would establish whether the effect of treatment in this age group differs from the effect in younger patients. In general, the use of the drug APTIVUS in elderly patients should be carried out with caution and with careful monitoring, which is due to a higher incidence of violations of the liver, kidney and heart, as well as concomitant diseases or nThe use of other medicines in this age group.

Dysfunction of the liver and hepatotoxicity

Before beginning therapy with the drug APTIVUS and ritonavir in a low dose, appropriate laboratory tests should be conducted, these studies should be performed regularly during treatment. More frequent monitoring is required when APTIWUS and ritonavir in a low dose are used in patients with initially increased activity ACT and ALT, or in the presence of active hepatitis B or C, since in such cases the risk of further increase in the activity of transaminases or decompensation of liver function may be increased.

Therapy with the drug APTIVUS should not be started in patients with initial activity ACT or ALT is more than 5 times higher than the upper limit of the norm (until it steadily decreases to a level less than 5 times the upper limit of the norm). In the case of an asymptomatic increase in activity ACT or ALT, which exceeds the upper limit of the norm by more than 10 times, therapy with the drug APTIVUS should be discontinued.

In case of development of clinical signs Hepatitis therapy with the drug APTIVUS should be discontinued.

If another cause (eg, acute hepatitis A, B or C, gall bladder disease, use of other drugs) is established or if the potential benefit from the use of tipranavir exceeds the possible risk, then after the return of ACT / ALT activity to baseline values, the issue of resumption application of the drug АПТ�?ВУС.

There are clinical reports that joint use of tipranavir with a low dose of ritonavir was accompanied by the development of hepatitis and decompensation of liver function, including fatal. This, as a rule, occurred in patients with a developed stage of HIV infection, taking numerous concomitant medications. The causal relationship with the use of the drug APTIVUS and a low dose of ritonavir was not established. In patients with signs or symptoms of hepatitis, treatment with APTIVUS should be stopped. Care should be taken when using APTIWUS in patients who have anamnestic information on the increase of aliver enzymes or hepatitis.

Tipranavir is mainly metabolized in the liver. Caution should be exercised when using this drug in patients with impaired hepatic function and with mild liver failure (class A according to Child-Pugh classification), since the concentration of tipranavir in these cases may increase.

APTIVUS is contraindicated in patients with hepatic insufficiency of moderate to severe severity (class B or C according to Child-Pugh classification).

Impaired renal function. Because the renal clearance of tipranavir is insignificant, an increase in plasma concentration in patients with impaired renal function is not expected. Hemophilia. Patients with haemophilia type A and B who had protease inhibitors reported increased bleeding, including the development of spontaneous subcutaneous hematomas and hemarthrosis. In some patients, factor VIII was additionally applied. In more than half of these patients, treatment with protease inhibitors continued or resumed (if it was discontinued before). The causal relationship between protease inhibitors and these unfavorable events could not be established.

Intracranial hemorrhages. It was noted that the use of the drug APTIVUS together with a low dose of ritonavir in some patients was accompanied by the development of intracranial bleeding (VC), with a fatal outcome and without. Many of these patients had comorbid conditions or concomitantly used other medications that could cause intracranial bleeding or contribute to their development. In general, patients did not have any specific types of hematologic disorders or disorders of the coagulogram, or disorders preceding the development of intracranial bleeding.

An increased risk of intracranial hemorrhage was observed in patients with advanced HIV infection / AIDS, including patients who received APTIVUS in clinical trials. The relationship between the use of the drug APTIVUS and the development of intracranial hemorrhages is not established.

Effect on platelet aggregation and withblood clotting.

APTIVUS, used in conjunction with a low dose of ritonavir, should be used with caution in patients with an increased risk of bleeding,surgical operations or other causes, or in patients who receive medications that can increase the risk of bleeding (eg, antiplatelet agents and anticoagulants), or high doses of vitamin E.

Diabetes mellitus / hyperglycemia. Based on a review of post-marketing data, it was reported that HIV-infected patients receiving protease inhibitor therapy had a history of diabetes mellitus or exacerbation of previously established diabetes mellitus and hyperglycaemia. Some patients in connection with these phenomena required the use of insulin or oral hypoglycemic agents (or correction of their dose). In some cases, the development of diabetic ketoacidosis was noted.

In patients who stopped therapy with protease inhibitors. in some cases, hyperglycemia persisted. The causal relationship between therapy andprotease inhibitors and these phenomena have not been established.

Increase in lipid levels. Treatment with the drug APTIVUS in combination with a low dose of ritonavir and other antiretroviral agents was accompanied by an increase in the level of triglycerides and total cholesterol in the plasma.The level of triglycerides and cholesterol should be determined before the use of the drug APTIVUS and in the continuation of therapy. Correction of lipid metabolism disorders should be carried out taking into account clinical data.

Redistribution of fat. The use of combined antiretroviral therapy in HIV-infected patients led to a redistribution of fat (lipodystrophy). The long-term consequences of these violations are currently unknown. The mechanism of their development is not fully understood. It is assumed that there is a link between visceral lipomatosis and the use of protease inhibitors, as well as a link between lipoatrophy and the use of nucleoside reverse transcriptase inhibitors. An increased risk of lipodystrophy is established for older patients, patients receiving long-term antiretroviral therapy and patients with concomitant metabolic disorders. During the clinical examination, a direct evaluation of the signs of fat redistribution is necessary. It is necessary to take into account the level of lipids in blood serum and fasting blood glucose. Correction of lipid metabolism disorders should be carried out taking into account clinical data.

Syndrome of restoration of immunity. Patients who received combined antiretroviral therapy, including APTIVUS, were informed of the development of immune reconstitution syndrome. During the initial phase of combined antiretroviral therapy, patients with a safe immune system may develop an inflammatory response in response to slow-onset opportunistic infections or the residual effects of these infections (for example, Mycobacterium avium, PCP, tuberculosis, cytomegalovirus or reactivation of herpes simplex viruses and herpes zoster), which may require examination and treatment. Autoimmune diseases (eg, Based's disease) can also be noted in the case of immune reconstitution syndrome. However, such diseases can occur through several months after the start of treatment. Skin rash

In clinical trials, cases of mild skin and mild skin rash, including urticaria, rose-olympic rash, photosensitivity were recorded. Also, there were cases of skin rash accompanied by pain or stiffness of the joints, a feeling of compression in the throat, itching.In clinical trials involving adolescents, rash cases were more common than in adults.

Osteonecrosis

The etiology of osteonecrosis is multifactorial (use of glucocorticosteroids, alcohol consumption, severe immunosuppression, increase in body mass index), cases of osteonecrosis have also been observed with tipranavir, especially in patients with advanced HIV infection and / or long-term combined antiretroviral therapy. Patients should be warned about the need to consult a doctor in case of aches and pains in the joints, joint stiffness or difficulty in moving.

Treatment of patients who have not previously received antiretroviral therapy Use of the drug APTIWUS withTogether with low-dose ritonavir in patients infected with wild-type HIV who have not previously received antiretroviral therapy, it is not recommended.

Cautions regarding the simultaneous use of other medications. APTIVUS, used in conjunction with ritonavir, may affect the concentration of other drugs in the plasma, and other drugs may affect the concentration in the plasma of tipranavir and ritonavir.Description of the established and potential mechanisms of interactions of tipranavir, is given in the section "Interactions with other drugs". Capsules of the drug АПТ�?ВУС contain ethanol (7% v / v). This should be taken into account when appointing women during pregnancy and breastfeeding, children, patients with liver disease, epilepsy, patients with alcoholism.

Effect on the ability to drive transp. cf. and fur:Special studies on the effect of tipranavir / ritonavir on the ability to drive vehicles and mechanisms were not conducted. However, in thewith the possible development of dizziness, drowsiness and fatigue, care must be taken when operating vehicles and mechanisms. In case of fatigue, dizziness or drowsiness, such potentially hazardous activities as transpo-means and mechanisms.

Form release / dosage:Capsules 250 mg

Packaging:

For 120 capsules in a plastic bottle of white, sealed with foil and ukuporenny, screwed.plastic, cover with the control of the first opening; Vial with instructions for use in a cardboard box.

Storage conditions:

At a temperature of 2-8 ° C (in the refrigerator).

The opened vial should be stored at a temperature not exceeding 25 ° C.

Keep out of the reach of children!

Shelf life:

3 years.

After opening the vial, use the drug for 90 days.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-001124

Date of registration:03.11.2011

The owner of the registration certificate:Boehringer Ingelheim International GmbHBoehringer Ingelheim International GmbH Germany

Manufacturer: & nbsp

Boehringer Ingelheim Roxan Inc.

Representation: & nbspBehringer Ingelheim, LLCBehringer Ingelheim, LLC

Information update date: & nbsp11.09.2015

Illustrated instructions

Instructions

Aptivus (Aptivus)