Telzir (Telzir)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceFosamprenavirFosamprenavir
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  • Telzir
    pills inwards 
    VeeV Helsker United Kingdom Limited     United Kingdom
  • Telzir®
    suspension inwards 
    VeeV Helsker United Kingdom Limited     United Kingdom
    • Dosage form: & nbspcoated tablets
    Composition:

    COMPOSITION for 1 tablet:

    Name of components

    Amount, mg

    Active substance

    Fosamprenavir calcium

    853,2*

    is equivalent to fosamprenavir

    700,0

    Excipients

    Microcrystalline cellulose

    182,9

    Sodium croscarmellose

    57,0

    Povidone K30

    34,2

    Magnesium stearate

    11,4

    Silica colloidal dioxide

    1,4

    Casing of the tablet

    Rape pink *

    34,2

    (Opadry Pink (03K14881))


    * Sheath of Opadrai Pink (Opadry Pink OZK14881) contains:

    Component

    Tablet content, mg

    - Hypromellose (E464)

    23,2

    - Titanium dioxide (E171)

    8,2

    - Triacetin

    2,7

    - Iron oxide red (E172)

    0,05

    * - 853.2 mg of fosamprenavir calcium is equivalent to 700.0 mg of fosamprenavir. In this amount of fosamprenavir calcium is expected to contain 5 moles of water, the exact content of fosamprenavir calcium can be determined from the purity of the original substance.

    Description:

    The tablets covered with a cover, pink color, biconcave, capsular form, with an engraving "GX LL7" on one side of the tablet.

    Pharmacotherapeutic group:Antiviral (HIV) agent, protease inhibitor (PI).
    ATX: & nbsp

    J.05.A.E.   Protease Inhibitors

    J.05.A.E.07   Fosamprenavir

    Pharmacodynamics:

    Mechanism of action

    Fosamprenavir calcium is an inactive precursor of amprenavir. Being a calcium salt of the phosphorether amprenavir, it is hydrolyzed in the body to form an inorganic phosphate and an active metabolite of amprenavir, which is absorbed into the intestine. Amprenavir refers to non-peptide competitive protease inhibitors of the human immunodeficiency virus (HIV), which prevents the cleavage of precursors of polypeptides required for viral replication. Fosamprenavir practically or completely lacks antiviral or enzyme-inhibiting activity, as shown in vitro. Active metabolite - amprenavir is a highly effective selective inhibitor of HIV-1 and HIV-2 replication. In vitro synergism of the action of amprenavir with its combination with nucleoside analogues (including didanosine, zidovudine, abacavir) and the protease inhibitor saquinavir. The additive effect of amprenavir in combination with indinavir, ritonavir and nelfinavir is shown.

    With simultaneous administration of ritonavir with fosamprenavir (fosamprenavir + ritonavir - 700 mg + 100 mg twice a day or 1400 mg + 200 mg once a day) approximately 2 times the area under the pharmacokinetic curve "concentration-time" (AUC) amprenavir, and concentration in blood plasma in an equilibrium state (CT,SS) - in 4-6 times in comparison with these values ​​after reception of not boosted fosamprenavir (1400 mg 2 times a day).

    In experiments in vitro It is shown that the mutation I50V is key in the development of resistance to amprenavir. When there are variants of a virus with a triple mutation I50V+M46I/L+I47V values ​​of 50% inhibitory concentration (1C5o) for amprenavir increased by more than 10 times. This triple mutation does not cause a decrease in sensitivity to other protease inhibitors as in vitro, both in clinical and in clinical settings. Variations of the virus resistant to amprenavir in vitro, kept sensitivity to saquinavir, indinavir and nelfinavir, but their sensitivity to ritonavir decreased by 3-5 times. Recently, additional mutations associated with resistance to amprenavir (I54M and V32I+I47V).

    The profile of resistance to amprenavir in clinical practice differs from the resistance profile to other protease inhibitors. According to the data in vitro the development of resistance to amprenavir during therapy in many cases is associated with a mutation I50V. Three alternative mechanisms of development of resistance to amprenavir, identified in studies in vitro, were also observed in clinical practice with amprenavir. The development of resistance to amprenavir may include either mutations I50V, or I54L/M, or V32I+I47V, or, more rarely, I84V. Each of the four sets of resistance mutations can be accompanied by additional secondary mutations, in particular M46I/L, which leads to the emergence of viruses with reduced susceptibility to amprenavir, some cross-resistance to ritonavir, but sensitivity to indinavir, saquinavir and nelfinavir persists. Patients who had not previously received antiretroviral therapy showed significant differences in resistance to therapy components (both protease inhibitors and nucleoside reverse transcriptase inhibitors), depending on the use of Tetzir-boosted or un-boosted ritonavir, as well as those patients who received nelfinavir.

    The development of cross-resistance between amprenavir and reverse transcriptase inhibitors seems unlikely, since these drugs act on different HIV enzymes. Tselsir is not recommended for use as a monotherapy due to the rapid emergence of resistant viruses.

    Children

    According to two studies on children - APV20002 and APV29005, in which 163 patients participated, 34 patients were confirmed to have virological failure after 48 weeks; paired virological data for determining the resistance developed during treatment were obtained for 22 of 34 patients. In 9 of 22 patients with confirmed virological inefficiency of treatment, who received paired virological data, a virus was detected with a reduced sensitivity to the drug that appeared during treatment. 6 out of 9 patients received fosamprenavir + ritonavir, and 5 had already received antiretroviral therapy, while 3 out of 9 had not previously received antiretroviral therapy and were receiving fosamprenavir without ritonavir. A decrease in susceptibility to amprenavir was detected in 5 of 9 patients, while 6 of 9 had a decrease in sensitivity to non-nucleoside reverse transcriptase inhibitors (NRTIs).The main mutations of resistance to protease are found in the virus obtained from 4 patients with virological inefficiency.

    Pharmacokinetics:

    Fosamprenavir after oral administration quickly and almost completely hydrolyzed to amprenavir and organic phosphate before entering the systemic circulation. The pharmacokinetic properties of amprenavir following simultaneous administration of Talsir and ritonavir were evaluated in healthy volunteers and HIV-infected patients, but there was no significant difference between the two groups.

    Ritonavir inhibits the metabolism of amprenavir by inhibiting the cytochrome isoenzyme CYP3A4, which leads to an increase in the concentration of amprenavir in blood plasma.

    Suction

    With repeated repeated oral administration of Talsir in a dose of 1400 mg 2 times a day amprenavir quickly absorbed. The maximum concentration (CmOh) when the equilibrium state is reached is 4.82 (4.06-5.72) μg / ml, the time to reach the maximum concentration (TmOh) - 1,3 (0,8-4,0) N hours. The average geometric value of the minimum concentration is 0.35 (0.27-0.46) μg / ml for the equilibrium state, the area under the pharmacokinetic curve "concentration-time" (AUC) - 33.0 (27.6-39.2) h mcg / ml in the interval between doses of the preparation. Value AUC the same when receiving on an empty stomach any of the dosage forms of the preparation Telzir®, while the value of CmOh Amprenavir in plasma is 14% higher after taking Talsir® in the form of a suspension for oral administration than after taking Talsir, coated tablets.

    Tselsir, coated tablets, along with fat-rich foods, does not alter the pharmacokinetics of amprenavir in plasma. This drug can be taken regardless of food intake.

    Absolute bioavailability of Telsir preparation in humans is not established.

    Distribution and communication with blood plasma proteins

    The apparent volume of distribution of amprenavir after taking Talsir is approximately 430 liters (6 l / kg, based on body weight of 70 kg). A large volume of distribution is explained by the free penetration of amprenavir into tissues from the systemic blood flow.

    Amprenavir binds to proteins by approximately 90%. He communicates with α1acid glycoprotein (AAG) and albumin, but has a higher affinity for AAG.

    Metabolism

    Fosamprenavir in the body is converted into amprenavir, which is metabolized predominantly in the liver with the participation of the cytochrome isoenzyme CYP3A4, less than 1% of amprenavir is excreted by the kidneys unchanged.

    Excretion

    After taking Tselsir, the half-life of amprenavir is 7.7 hours. It is excreted as metabolites through the intestine (about 75%) and kidneys (about 14%).

    Special patient groups

    Children

    The pharmacokinetics of fosamprenavir used in the form of an oral suspension and coated tablets, with or without ritonavir, is characterized in a pharmacokinetic model comprising 212 HIV-infected pediatric patients who participated in 3 studies. Patients aged 2 to 5 years took fosamprenavir without ritonavir from 30 to 40 mg / kg 2 times a day. Fosamprenavir with ritonavir taken according to the following two schemes:

    1. fosamprenavir 30 mg / kg + ritonavir 6 mg / kg once a day in children from 2 to 18 years;

    2. fosamprenavir from 18 to 60 mg / kg + ritonavir from 3 to 10 mg / kg once a day in children from 2 months to 18 years old, having a body weight of 3.2 to 103 kg before the start of treatment.

    The apparent volume of fosamprenavir distribution decreased with increasing body weight and age. The relationship between body weight and apparent volume of distribution was most prevalent in children younger than 4 years, so younger children require more accurate dosing of fosamprenavir depending on body weight.According to the results of the analysis, with the recommended dosing regimen, plasma concentrations in children are the same as in adults. The average geometric (95% confidence interval) of the equilibrium pharmacokinetic parameters of amprenavir in this population, depending on the recommended dosage regimen and age group, are presented below.

    Pharmacokinetic parameters in the equilibrium state for amprenavir in children who received fosamprenavir with ritonavir 2 times a day

    Age

    Dosing regimen (2 times a day)

    FROMmOh

    auc12

    FROM min


    AND

    (μg / ml)

    and

    (μg * h / ml)

    AND

    (μg / ml)


    from

    fosamprenavir

    13

    6,18

    13

    28,6

    30

    2,07


    4 weeks to 2 years

    45 mg / kg plus ritonavir 7 kg / kg


    (3,93; 9,74)


    (17,0, 48,1)


    (1,60; 2,68)

    from 2

    years to 3 years

    fosamprenavir 30 mg / kg + ritonavir 3 mg / kg

    Not studied

    from

    3 to 5 years

    fosamprenavir 23 mg / kg + ritonavir 3 mg / kg

    11

    9,80

    (6,51; 14,7)

    11

    59,7

    (37,1; 96,2)

    15

    3,36

    (2,44;4,63)

    from 6 to 11 years

    fosamprenavir 18 mg / kg + ritonavir 3 mg / kg

    12

    6,40

    (5,02; 8,15)

    12

    48,4

    (38,1,61,4)

    23

    2,42

    (1,90; 3,07)

    from 12 to 18 years

    fosamprenavir 700 mg + ritonavir 100 mg

    13

    4,93

    (3,83; 6,34)

    13

    35,3

    (28,2; 44,1)

    40

    2,01

    (1,74; 2,32)











    * The recommended dosing regimen for children from 2 to 3 years is based on

    pharmacokinetic analysis.

    Elderly patients

    The pharmacokinetics of the Talsir preparation in patients older than 65 years have not been studied. When appointing patients of advanced age, it is necessary to take into account the possibility of impaired liver, kidney or heart function, concomitant diseases,as well as taking other medications.

    Patients with impaired renal function

    Special studies were not conducted. Since a small amount of amprenavir (less than 1% of the therapeutic dose) is excreted unchanged in kidneys, the effect of renal impairment on amprenavir excretion should be minimal. Correction of the dosage regimen of Telsir is not required in this case.

    Patients with impaired hepatic function

    Fosamprenavir in the human body is converted into a amprenavir. For amprenavir, the main way of excretion is the metabolism in the liver. A comparative study of the pharmacokinetics of amprenavir (taking Tselsir with ritonavir for 14 days) in blood plasma in HIV-1-infected adults with impaired liver function and patients with normal liver function was performed. In patients with mild violations of the liver function (5-6 points on the Child-Pugh scale) who received 700 mg of fosamprenavir 2 times a day and a reduced dose of ritonavir (100 mg once a day), a slight increase AUC (by 22%) and similar concentrations in plasma compared to those of patients with normal liver function who received a standard dose of fosamprenavir + ritonavir (700 mg + 100 mg twice daily).

    In patients with moderate hepatic impairment (7-9 on the Child-Pugh scale) receiving fosamprenavir 450 mg twice daily and ritonavir 100 mg once a day, the plasma total amprenavir concentration is approximately 35% lower and the plasma concentration of unbound amprenavir is approximately 67% higher than that found in patients with normal liver function who receive a standard dose fosamprenavir + ritonavir (700 mg + 100 mg) twice daily.

    In patients with moderate liver dysfunction, the use of fosamprenavir 700 mg once daily and ritonavir 100 mg once a day resulted in an average concentration of (Cavg) Amprenavir in blood plasma was 24% lower, Ct 65% lower and Ct unbound amprenavir is almost 42% lower in comparison with patients with normal liver function who received standard therapy with fosamprenavir + ritonavir at a dose of 700 mg + 100 mg twice daily. Thus, in the regimen of using fosamprenavir in the form of tablets in patients with moderate hepatic impairment, comparable pharmacokinetics of amprenavir in blood plasma can not be achieved in comparison with the regimen of administration fosamprenavir + ritonavir in a dose of 700 mg + 100 mg twice a day in patients with normal liver function.Thus, the use of fosamprenavir as a suspension for oral administration to treat this group of patients. In patients with severe impaired liver function (10-13 points on the Child-Pugh scale), taking fosamprenavir 300 mg twice a day and ritonavir 100 mg 1 time per day is accompanied by a decrease in the maximum concentration of amprenavir in blood plasma by 19%, a decrease AUC by 23%, but with a comparable concentration of unbound amprenavir in plasma compared to patients with normal liver function who receive a standard dose of fosamprenavir plus ritonavir (700 mg + 100 mg) twice daily.

    In patients with impaired liver function, an adequate correction of the dosage regimen of Telsir preparation may be required. Fosamprenavir in adults with severe hepatic impairment (10-15 points on the Child-Pugh scale) should be used with caution and in a reduced dose (350 mg 2 times daily without ritonavir). In these patients, Talsir®, a suspension for oral administration, should be used for proper dosing.

    Clinical efficacy and safety

    A comparison of the clinical efficacy of fosamprenavir and nelfinavir (in combination with abacavir and lamivudine, a randomized open trial involving 249 patients over 17 years of age)that at 48 weeks of study, the median plasma HIV-1 RNA concentration decreased by 3.13 log10 copies / ml for fosamprenavir and 3.37 log10 copies / ml of nelfinavir. The study demonstrated a comparable efficacy of fosamprenavir and nelfinavir.

    A similar clinical efficacy of a combination of fosamprenavir and low doses of ritonavir (a single dose) was demonstrated with basal abacavir and lamivudine therapy in patients who had not previously received antiretroviral therapy compared with nelfinavir (2 times a day) with basal abacavir plus lamivudine. In patients with virological inefficiency, fosamprenavir plus ritonavir therapy did not develop primary or secondary mutations of resistance to protease inhibitors, including mutations associated with resistance to ritonavir or amprenavir. The lack of development of resistance to fosamprenavir and ritonavir and cross-resistance to other HIV protease inhibitors against the background of fosamprenavir + ritonavir regimen shows that failure of therapy in this regimen will most likely not affect the therapeutic response to subsequent regimens containing other HIV protease inhibitors.

    Patients previously treated with protease inhibitors (after failure of therapy) showed a comparable effectiveness of baseline therapy regimens with two active nucleoside reverse transcriptase inhibitors, with the addition of a combination of fosamprenavir and low doses of ritonavir once (1400 mg +200 mg) or twice (700 mg + 100 mg) per day, as well as a fixed combination of lopinavir + ritonavir (400 mg + 100 mg twice daily). In both groups, a similar degree of suppression of viral replication was noted, defined as the mean area under the curve minus the baseline (AAUCMB) for the concentration of HIV-1 RNA in the blood plasma after 24 weeks of treatment. On average, this indicator was -1.48 log10 copies / ml with a single dose of fosamprenavir + ritonavir, -1,50 log10 copies / ml with a double regimen of fosamprenavir + ritonavir and -1.66 log10 copies / ml for the mode of lopinavir + ritonavir.

    Indications:

    Treatment of infection caused by the human immunodeficiency virus (HIV), as part of combination therapy with other antiretroviral drugs.

    Contraindications:

    Known hypersensitivity to fosamprenavir, amprenavir, or any other ingredient in the formulation.

    Simultaneous use with drugs that have a narrow therapeutic range of concentrations and are substrates of the cytochrome isoenzyme system CYP3A4.

    Simultaneous use with sildenafil in the treatment of pulmonary arterial hypertension.

    The simultaneous use of Telsir in combination with ritonavir and drugs that are highly dependent on metabolism by the cytochrome isoenzyme system CYP2D6, such as flecainide and propafenone.

    Simultaneous use of Talsir with rifampicin.

    Severe hepatic insufficiency (patients need to prescribe Talsir, a suspension for oral administration, because of the impossibility of dose adjustment when taking tablets).

    Children and adolescents with a body weight of less than 39 kg (it is recommended to use the preparation Talsir® in a dosage form for oral administration).

    Carefully:

    The molecule of fosamprenavir contains a sulfonamide group. The possibility of cross-sensitivity to drugs of class sulfonamides and Talsir has not been studied. In the baseline studies of fosamprenavir, there was no evidence of an increased risk of rash in patients with an allergy to sulfonamides in the history,who received fosamprenavir, in comparison with patients without allergy to sulfonamides, who received fosamprenavir. Tselsir should be used with caution in patients with known hypersensitivity to sulfonamide preparations.

    Use of fosamprenavir with ritonavir in doses exceeding registered, may in a number of patients be accompanied by an increase in the level of activity of transaminases, and therefore it is not recommended to exceed the doses indicated in the section "Dosing and Administration".

    Dysfunction of the liver and kidneys

    Metabolism and excretion of amprenavir is carried out mainly in the liver. Tselsir preparation with ritonavir should be used in patients with mild liver function disorder (5-6 points on the Child-Pugh scale) or moderate degree (7-9 on the Child-Pugh scale) with caution and in reduced doses. Patients who have viral hepatitis B or C or an increased activity of transaminases before starting treatment, have the risk of increasing transaminase activity when taking Tselsir. It is necessary to monitor appropriate laboratory parameters before starting therapy and periodically during treatment.

    Ambarenavir kidney clearance is insignificant, therefore, its concentration in plasma is not expected to increase in patients with renal insufficiency. Amprenavir has a high degree of binding to blood plasma proteins, so it is unlikely that the use of hemodialysis and peritoneal dialysis will significantly reduce the concentration of amprenavir.

    Simultaneous application of the combination of Talser with ritonavir and fluticasone propionate or other glucocorticosteroids metabolized by the cytochrome isoenzyme CYP3A4, is not recommended, except when the expected benefit from the appointment exceeds the possible risk of developing systemic effects of glucocorticosteroids, including Cushing's syndrome and suppression of adrenal function. Joint use of Talsir and halofantrine is not recommended because of a possible increase in the concentration of halofantrine and the associated risk of serious adverse events, such as arrhythmia.

    Inhibitors hydroxymethylglutaryl-CoA reductase, metabolized predominantly cytochrome isoenzyme CYP3A4 (lovastatin and simvastatin), is not recommended for use with fosamprenavir and ritonavir because of the likelihood of developing myopathy, including rhabdomyolysis. Also with caution should be applied fosamprenavir simultaneously with atorvastatin, which is less metabolized by the cytochrome isoenzyme CYP3A4. In this situation, the possibility of reducing the dose of atorvastatin should be considered. If treatment with inhibitors of hydroxymethylglutaryl-CoA reductase is indicated, the administration of pravastatin or fluvastatin is recommended.

    Due to amprenavir is an inhibitor of cytochrome isoenzymes CYP3A4 and CYP450, most often responsible for the drug metabolism, and therefore caution is required when taking fosamprenavir and bepridil together, since an increase Concentration of bepridil in blood plasma may increase the risk of life-threatening arrhythmia.

    With the simultaneous administration of fosamprenavir and raltegravir, a significant decrease in the concentrations of amprenavir and raltegravir in blood plasma is observed. In this regard, the joint administration of fosamprenavir and raltegravir is not recommended (see the section "Interaction with other medicinal products").

    Co-administration of fosamprenavir and 5-phosphodiesterase inhibitors (eg sildenafil) is not recommended, as it can lead to a significant increase in the level of 5-phosphodiesterase inhibitors. As a consequence of this interaction, undesirable phenomena may occur, including hypotension, syncopal conditions, visual impairment, and priapism.

    Pharmacokinetics in patients older than 65 years have not been studied.

    Pregnancy and lactation:

    Fertility

    The effect of fosamprenavir on fertility and overall reproductive function was studied in male rats (treated 4 weeks prior to mating at doses providing up to 3 times the expected clinical exposure of amprenavir based on AUC comparative data) and female rats (treated for 2 weeks before mating and up to 21 days after birth in doses providing up to 4-fold expected clinical exposure). The use of fosamprenavir did not interfere with the mating or fertility of male or female rats and did not affect the development and maturation of spermatozoa in rats receiving the drug.

    Pregnancy

    In pregnant female rats and rabbits, no significant effect on embryo-fetal development was found. Systemic exposure in blood plasma (AUC) of amprenavir in these studies was similar (in rats) or lower (in rabbits) compared to exposure in patients in clinical studies using fosamprenavir. Due to the low exposure in rabbits, the potential toxicity of fosamprenavir for the developing organism has not been fully determined.

    Use of Tselsir during pregnancy is possible only if the expected benefit of the application exceeds the possible risk to the fetus.

    Breastfeeding period

    To prevent HIV transmission to a child, HIV-infected women are not allowed to breast-feed, because HIV enters the breast milk.

    Based on data from animals, it is expected that amprenavir can be excreted into human breast milk, although it has not been confirmed in human studies.

    Dosing and Administration:

    Talsir, coated tablets are taken orally, regardless of food intake.

    Tselsir is prescribed only by a doctor with experience in treating patients with HIV infection.

    When using any regimen, the drug should be given in combination with other antiretroviral drugs.

    To increase the pharmacokinetic profile of amprenavir in plasma, low doses of ritonavir can be used. It is not recommended to use a combination of fosamprenavir and ritonavir in doses exceeding the established ones. It is not recommended to use fosamprenavir without low doses of ritonavir in children and adolescents who have previously received antiretroviral therapy. Recommended doses of fosamprenavir without ritonavir or in combination with ritonavir are given below.

    Adults (18 and over)

    Patients who have not previously received antiretroviral therapy

    1400 mg of fosamprenavir (2 tablets of Talsir preparation without ritonavir) 2 times a day; or 1400 mg of fosamprenavir (2 tablets of Talsir preparation) once a day in combination with 100 mg or 200 mg of ritonavir once a day;

    or 700 mg of fosamprenavir (1 tablet of Tselsir preparation) 2 times a day in combination with 100 mg of ritonavir 2 times a day.

    Patients previously treated with protease inhibitors

    700 mg of fosamprenavir (1 tablet of Talsir preparation) 2 times a day in combination with 100 mg of ritonavir 2 times a day.

    A single dosing regimen with Tselsir without ritonavir or in combination with low doses of ritonavir is not recommended in adults who have previously been treated with protease inhibitors.

    All dosing regimens are suitable for combination therapy with other antiretroviral drugs.

    Newborns, children and adolescents (from 4 weeks to 17 years)

    Fosamprenavir with ritonavir should be used in newborns born not earlier than 38 weeks of gestation and only from the 28th day of life.

    To more accurately select the dose in children, depending on the body weight, it is recommended to use Talsir®, a suspension for oral administration. And also for adults who are difficult to swallow tablets, the drug dosage form is intended for oral administration.

    Children and adolescents with a body weight of at least 47 kg, previously not receiving antiretroviral therapy and able to swallow the whole tablet

    1400 mg of fosamprenavir (2 tablets of Talsir, without ritonavir) 2 times a day.

    Children and adolescents with a body weight of at least 39 kg,previously untreated with HIV protease inhibitors or having experience with HIV protease inhibitor therapy and able to swallow the whole tablet

    700 mg of fosamprenavir (1 tablet of Talsir preparation) 2 times a day in combination with 100 mg of ritonavir 2 times a day.

    Ritonavir capsules 100 mg can be given to children and adolescents who receive fosamprenavir suspension for ingestion, with a body weight of at least 33 kg, which are able to swallow capsules whole.

    The use of Tselsir without the combined use of low doses of ritonavir is not recommended in adolescents and children who have previously received antiretroviral therapy.

    Special patient groups

    Children under 4 weeks

    Data on efficacy and safety is not sufficient for the use of the drug in this age category.

    Elderly patients

    Pharmacokinetic studies were not performed in patients older than 65 years.

    Patients with impaired renal function

    There is no need to correct the dosage regimen.

    Patients with a mild liver function disorder (5-6 on the Child-Pugh scale)

    The drug should be administered with caution and in a reduced dose.The recommended daily dose of Telsir is 1400 mg divided into 2 doses, without the combined use of ritonavir for patients who have not previously received antiretroviral therapy. It is also possible to combine Telsir in a daily dose of 1400 mg divided into two doses, with ritonavir at a dose of 100 mg once a day for patients who have not previously received antiretroviral therapy or who take HIV protease inhibitors.

    Patients with impaired liver function of moderate degree (7-9 points on the Child-Pugh scale)

    The drug should be administered with caution and in a reduced dose. The recommended daily dose of Telsir is 1400 mg divided into 2 doses, without the combined use of ritonavir for patients who have not previously received antiretroviral therapy. Either the combination of Talsir in a daily dose of 900 mg, divided into two doses (450 mg twice daily), with ritonavir at a daily dose of 100 mg once a day for patients who have not previously received antiretroviral therapy or takenitheir inhibitors of HIV protease. In view of the impossibility of accurately observing the dosage regimen of Telsir in this combination, it is necessary to use Talsir® in the form of a suspension for oral administration.

    Recommendations on the dosage regimen of the drug in children aged 4 weeks to 12 years and adolescents aged 12 to 17 years, with violations of the liver, no.

    Side effects:

    Studies on the safety of fosamprenavir in combination with other antiretroviral drugs have been conducted in controlled clinical trials in adults (n= 166). The most frequent adverse reactions (more than 5% of adult patients) were gastrointestinal disturbances (nausea and diarrhea) and rash.

    Most of the adverse reactions associated with taking fosamprenavir were mild or moderate in severity, were observed at the onset of therapy, and in rare cases restriction of drug use was required. For most of the reported adverse events, there is no single-valued association with the use of the drug, combined therapy, or with the development of the disease itself.

    The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence was determined as follows: very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100), rarely (> 1/10000 and <1 / 1000) and the frequency is unknown.

    Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

    Most of the adverse reactions listed below were recorded during two extensive clinical trials in adults. The list includes the most frequent undesirable reactions associated with the intake of the drug, at least an average degree of severity (grade 2 or higher) and appeared in at least 2% of patients.

    Disorders from the metabolism and nutrition

    Very often: hypercholesterolemia. Often: hypertriglyceridemia.

    Disturbances from the nervous system

    Often: headache, paresthesia of the oral mucosa.

    Heart Disease

    Infrequent: myocardial infarction.

    Disorders from the gastrointestinal tract

    Often: diarrhea, nausea, vomiting. Unknown: pain in the abdomen.

    Disturbances from the skin and subcutaneous tissues

    Often: rash. Rarely: Stevens-Johnson syndrome, angioedema.

    During treatment, erythematous or maculopapular skin rashes may occur with or without itching. The rash usually goes away spontaneously without the need for withdrawal therapy.Receiving Telzir drug should be stopped in case of generalized rash, as well as at moderate rash associated with systemic symptoms or mucosal lesions.

    Disorders from the kidneys and urinary tract

    Infrequently: nephrolithiasis.

    General disorders and disorders at the site of administration

    Often: fatigue.

    Violations from the blood and lymphatic system:

    Unknown: decreased neutrophil count.

    A similar profile of drug safety was noted in the controlled study (n= 534) combinations of fosamprenavir and low doses of ritonavir.

    Some patients treated with HIV protease inhibitors have been observed fat redistribution in the body (lipodystrophy) This reveals a decrease of subcutaneous fat in the periphery and in the face area and increased deposits of visceral fat, hypertrophy of the mammary glands and fat accumulation in the dorsal -cervical region ("buffalo hump"). Also observed metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, and hyperglycemia.

    In patients who received HIV protease inhibitors, development of diabetes mellitus, hyperglycemia or exacerbation of concomitant diabetes mellitus were noted.

    Increased activity of creatine phosphokinase (CK), myalgia, myositis and, rarely, rhabdomyolysis were noted in patients taking HIV protease inhibitors, in particular in combination with nucleoside analogues.

    In patients with hemophilia who received HIV protease inhibitors, cases of increased spontaneous bleeding were noted.

    Clinically significant laboratory changes, possibly associated with fosamprenavir, may include increased transaminase and lipase activity, hypertriglyceridemia, and hypercholesterolemia.

    Children

    The overall safety profile of fosamprenavir with or without ritonavir in children and adolescents was comparable to that in adult clinical trials. Vomiting and neutropenia were more common in children and adolescents than in adults. Vomiting was more frequent in children, especially in those who received fosamprenavir as a monotherapy. In most cases, it was mild, but in a small number of patients, vomiting led to a discontinuation of fosamprenavir.

    Overdose:The antidote to Talsir is unknown.There is also no data on the possibility of removing amprenavir from blood plasma with peritoneal dialysis or hemodialysis. In case of an overdose, monitoring is indicated to detect symptoms of toxic effects and, if necessary, standard symptomatic therapy.
    Interaction:

    Special pharmacokinetic studies of drug interactions between fosamprenavir and other drugs have been carried out. In addition, extensive studies of interactions between amprenavir, the active metabolite of fosamprenavir, and other drugs have been conducted.

    Given that fosamprenavir is exposed in the intestine to the parietal metabolism, rapidly and to a large extent transforming into amprenavir, and that the concentrations of amprenavir in plasma are comparable after taking amprenavir and fosamprenavir. major pharmacokinetic interactions of amprenavir can be extrapolated to fosamprenavir. Pharmacokinetic studies of the properties of fosamprenavir were performed only in adults.

    Metabolic interactions (cytochrome isoenzyme CYP3A4)

    Amprenavir, an active metabolite of fosamprenavir, is mainly metabolized in the liver by the cytochrome CYP3A4 isoenzyme. Drugs that are metabolized in the same way or change the activity of the cytochrome isoenzyme CYP3A4. may alter the pharmacokinetics of amprenavir. The same way fosamprenavir can affect the pharmacokinetics of other drugs, the metabolism of which proceeds along the same path.

    Ritonavir is a potent inhibitor of cytochrome P450 isoenzyme CYP3A. Ritonavir also inhibits the isoenzyme CYP2D6 and stimulates the activity of the isoenzymes CYP3A4, CYP1A2, CYP2C9, as well as glucuronosyl transferase. Amprenavir is a less potent inhibitor of the CYP3A4 isoenzyme compared with ritonavir. If a low dose of ritonavir is needed to improve the pharmacokinetic profile of amprenavir, the complete instructions for the use of ritonavir should be consulted.

    Prohibited combinations

    Fosamprenavir should not be administered concomitantly with cytochrome P450 ZA4 isoenzyme substrates (CYP3A4), which have a narrow therapeutic range of concentrations. The combined use of such drugs and Tselsir can lead to competitive inhibitionmetabolism of these drugs and potentially create conditions for serious and / or life-threatening adverse reactions such as cardiac arrhythmia (eg, terfenadine, astemizole, cisapride and pimozide), arterial hypotension (eg alpha-blocker alfuzosin), prolonged sedation or respiratory function suppression (eg, triazolam, midazolam, diazepam, flurazepam, quetiapine), spasm of peripheral vessels or ischemia (eg, ergotamine, dihydroergotamine, ergonovin and methylergonovine).

    Do not use fosamprenavir concomitantly with alfuzosin, flecainide, propafenone, delavirdine, St. John's wort perforated.

    Do not use fosamprenavir simultaneously with sildenafil in the treatment of pulmonary arterial hypertension. There is an increased risk of serious unwanted reactions associated with the use of sildenafil.

    Concomitant use of rifampicin with amprenavir reduces AUC and Cmin Amprenavir in blood plasma by 82% and 92%, respectively. Co-administration of Talsir with rifampicin is contraindicated in connection with the expected decrease in the concentration of amprenavir in blood plasma.

    Interaction with antiretroviral drugs

    Non-nucleoside reverse transcriptase inhibitors

    Efavirenz: in adults efavirenz reduces the values ​​of Cmax, Cmin, ss and AUC of amprenavir by approximately 40%. There are no recommendations on the combined use of fosamprenavir and efavirenz.

    Co-administration of efavirenz (600 mg once daily) with fosamprenavir and ritonavir (fosamprenavir 1400 mg once a day and ritonavir 200 mg once a day) reduces the AUC value of amprenavir by 13%, Cmin-by 36%. An increase in the dose of ritonavir up to 300 mg once a day maintains the concentration of amprenavir in blood plasma. When efavirenz (600 mg once a day) is prescribed together with fosamprenavir and ritonavir 2 times a day (fosamprenavir 700 mg and ritonavir 100 mg), the concentration of amprenavir in plasma did not change significantly.

    Nevirapine: with the simultaneous administration of fosamprenavir (1400 mg twice daily) and nevirapine (200 mg twice daily), AUC, Cmah and Cmin amprenavir decreased by 33%, 25% and 35%, respectively. In this case, AUC, Cmah and Cmin nevirapine increased by 29%. 25% and 34%, respectively. It is not possible to formulate recommendations on the dosing regimen of a combination of fosamprenavir and nevirapine.When combined, these drugs should be used with caution, since the efficacy of fosamprenavir may decrease due to a lower and potentially sub-therapeutic concentration in the blood plasma.

    With the combined administration of fosamprenavir (700 mg twice daily), ritonavir (100 mg twice daily), and nevirapine (200 mg twice daily), the effect of nevirapine on the pharmacokinetic parameters of fosamprenavir is partially compensated by ritonavir, which results in a less significant decrease in AUC and Cmin amprenavir by 11% and 19% respectively, Cmax does not change. In this case, AUC, Cmax and Cmin nevirapine increased by 14%, 13% and 22%, respectively. Thus, with the recommended combination, dosage adjustment is not required.

    A single-dose regimen of fosamprenavir and ritonavir was not studied. Joint use of nevirapine and fosamprenavir without ritonavir is not recommended.

    E etravirine: when co-administered with etravirine fosamprenavir + ritonavir, AUC, Cmin and Cmax amprenavir increased by 69%, 77% and 62%, respectively. Indicators AUC, Сmin and Сmax etravirin did not significantly change (but compared with the available control data).

    When using Telsir, you may need to adjust the dosage regimen (you should consider the appointment of the preparation Telzir® in the form of a suspension for oral administration).

    Delavirdine: AUC, Cmah and Cmin delavirdine decreased, respectively, by 61%, 47% and 88% with concomitant administration with amprenavir. AUC. FROMmah and Cmin amprenavir increased by 130%, 40% and 125%, respectively. Due to a significant reduction in delavirdine concentrations, simultaneous administration of fosamprenavir and delavirdine is not recommended. It is not possible to formulate recommendations for doses of delavirdine when combined with fosamprenavir. With the joint use of these drugs should be careful, because the efficacy of delavirdine may decrease due to a lower and potentially sub-therapeutic concentration in the blood plasma.

    Nucleoside and / or nucleotide reverse transcriptase inhibitors

    When combined with fosamprenavir with the following antiretroviral drugs: zidovudine, didanosine, stavudine, lamivudine, abacavir and tenofovir there is no need to correct the dosage regimen.

    HIV protease inhibitors

    There are no specific recommendations for a dosing regimen using fosamprenavir in combination with other HIV protease inhibitors, except for ritonavir.

    Ritonavir: The dose of fosamprenavir should be reduced when used in combination with ritonavir (see "Dosage and Administration"). It is also necessary to read the instructions for the use of ritonavir for more information on drug interactions.

    Lopinavir + ritonavir: indicators Cmah, AUC and Cmmin For lopinavir remained unchanged when receiving the combination lopinavir + ritonavir (533 mg + 133 mg twice daily for 2 weeks) together with fosamprenavir (1400 mg twice a day for 2 weeks) when compared with the standard regimen combinations lopinavir + ritonavir (400 mg + 100 mg twice daily). At the same time, the Cmah, AUC AND Cmin for combination with amprenavir were 13%, 26% and 42% less, respectively, but compared to the values ​​obtained by taking the combination fosamprenavir + ritonavir (700 mg + 100 mg twice daily for 2 weeks). The optimal dose of this combination in terms of safety and efficacy is not established.Simultaneous use is not recommended.

    Indinavir: with combined use of amprenavir (750 mg or 800 mg 3 times daily) and indinavir (800 mg 3 times a day on an empty stomach) for 2 weeks, the value of Cmah, AUC and Cmin in the equilibrium state for amprenavir increased by 18%. 33% and 25%, respectively. Cmax, AUC and Cmin indinavir in a state of equilibrium decreased by 22%, 38% and 27%. respectively.

    Saquinavir: with combined use of amprenavir (750 mg or 800 mg 3 times daily) and saquinavir (800 mg 3 times daily after meals) for 2 weeks, the value of Cmah, AUC and Cmin amprenavir in the equilibrium state decreased by 37%. 32% and 14%, respectively. FROMmIn the equilibrium state, saquinavir increased by 21%. and the values ​​of AUC and Cmin saquinavir in the equilibrium state decreased by 19% and 48%. respectively.

    Nelfinavir: with the combined use of amprenavir (750 mg or 800 mg 3 times daily) and nelfinavir (750 mg 3 times daily after meals) for 2 weeks, the value of Cmah and Cmin Amprenavir in the equilibrium state decreased by 14% and increased by 189%, respectively. FROMmah, AUC and Cmin of nelfinavir in the equilibrium state increased by 12%, 15% and 14%, respectively.

    Atazanavir: a joint fosamprenavir + ritonavir(700 mg + 100 mg twice daily) and atazanavir (300 mg once a day) for 10 days did not affect the equilibrium pharmacokinetics of amprenavir. Area under the pharmacokinetic curve "concentration-time" at the end of the dosing period (AUC(0-t)) atazanavir in blood plasma decreased by 22%, Cmah - by 24%, and Ct remained unchanged compared to the values ​​obtained for the combination atazanavir + ritonavir (300 mg + 100 mg once a day).

    HIV integrase inhibitors

    Raltegravir: with the simultaneous administration of fosamprenavir (1400 mg twice daily) and raltegravir (400 mg twice daily), amprenavir concentrations decreased in healthy volunteers (Cmin decreased by 33%) and raltegravir (Cmin decreased by 68%) in blood plasma (values ​​obtained when taking on an empty stomach).

    Joint administration of fosamprenavir (without ritonavir) and raltegravir is not recommended, as this may lead to a decrease in the content of amprenavir in the blood plasma to subtherapeutic concentrations. Reduction of concentrations of amprenavir Cmin by 19-33% and raltegravir Cmin by 36-54% was observed when the combination was combined fosamprenavir + ritonavir (700 mg + 100 mg twice daily) and raltegravir (400 mg twice daily). Decreased concentrations of amprenavir Cmin by 17-50% and raltegravir Cmin by 25-41% was observed after the combined administration of the combination fosamprenavir + ritonavir (1400 mg + 100 mg once a day) and raltegravir (400 mg twice daily). The clinical significance of this decline is unknown.

    Significant reduction in exposure and Cmin, established for both amprenavir and raltegravir, (especially when taking a beggar) may lead to virologic failure in patients.

    CCR5 chemokine receptor antagonists

    Maraviroc: a decrease in the concentration of amprenavir in blood plasma after 12 hours Cmin 36% were observed with the following treatment regimen: 700 mg of fosamprenavir and 100 mg of ritonavir 2 times a day in combination with maraviroc 300 mg twice daily. As well as a decrease in the concentration of amprenavir in the blood plasma after 24 hours of C2411 by 15% with fosamprenavir 1400 mg and ritonavir 100 mg once a day in combination with maraviroc 300 mg once a day. Clinical studies have shown comparative efficacy between a combination of fosamprenavir + ritonavir and maraviroc 150 mg twice daily and other HIV protease inhibitors in conjunction with ritonavir and maraviroc 150 mg twice daily. The exposure of the maraviroc increases approximately 2-fold with the combination fosamprenavir + ritonavir. When assigning a combination fosamprenavir + ritonavir with maraviroc is recommended maraviroc in a dose of 150 mg 2 times a day. Dose adjustment for combination fosamprenavir + ritonavir not required.

    Simultaneous application of maraviroc in a dose of 300 mg 2 times a day and combination fosamprenavir + ritonavir Not recommended. There is a significant decrease in Cmin amprenavir, which can lead to virological failure in patients.

    Medicines against hepatitis C

    Telaprevir: The combined use of fosamprenavir in combination with ritonavir and telaprevir leads to a decrease in the concentration of amprenavir and telaprevir in the blood plasma. The mechanism of interaction is unknown. The combined use of fosamprenavir in combination with ritonavir and telaprevir is not recommended.

    Boceprevir: not studied. Based on the results of a study comparing the use of boceprevir with other HIV protease inhibitors, the joint use of bocetrevir with a combination of fosamprenavir + ritonavir, is likely to lead to subtherapeutic levels of bocepreviram and amprenavir. Joint application boceprevir with fosamprenavir and ritonavir is not recommended.

    Antibiotics and / or antifungal medications

    Clarithromycin: ritonavir increases the concentration in the blood plasma of clarithromycin. A decrease in the dose of clarithromycin should be considered with the appointment of a combination fosamprenavir + ritonavir in patients with renal insufficiency.

    Erythromycin: a pharmacokinetic study of fosamprenavir in combination with erythromycin has not been conducted. However, the concentrations of both drugs in the blood plasma can increase with a combined appointment.

    Ketoconazole or itraconazole: amprenavir increases the concentration of ketoconazole in the blood plasma and, presumably, also increases the concentration of itraconazole. Do not use high doses of ketoconazole and itraconazole (more than 200 mg per day) concomitantly with taking fosamprenavir without first assessing the benefit-risk ratio.

    Rifampicin: rifampicin is a strong inducer of the cytochrome isoenzyme CYP3A4. Co-administration with amprenavir leads to a decrease in Cmin and AUC of amprenavir by 92% and 82%, respectively. Rifampicin is contraindicated in conjunction with fosamprenavir.

    Rifabutin: The combined use of amprenavir and rifabutin increases rifabutin concentrations in blood plasma by 200% (AUC) and increases the amount of unwanted reactions associated with rifabutin. With the simultaneous administration of ritonavir and rifabutin, the concentration of rifabutin can increase significantly. It is recommended to reduce the dose of rifabutin by at least 50% of the recommended dose with simultaneous appointment with fosamprenavir and at least 75% of the recommended dose when taking fosamprenavir in combination with ritonavir. Careful medical follow-up is necessary, further reduction of the dose may be required.

    Other medications

    Antacids: a decrease in AIJC and Cmax amprenavir by 18% and 35%, respectively, with a simultaneous increase in Cmin (C12h) by 14% when taking a single dose of 1400 mg of fosamprenavir together with a single intake of 30 ml of an antacid suspension (equivalent to 2.75 g of aluminum hydroxide and 1.8 g of magnesium hydroxide).

    Correction of a dose of any of the listed preparations at combined application is not required.

    Antagonists H2-histamine receptors: the concentration of amprenavir in the blood may decrease with the combined use of antagonists H2-histamine receptors (for example, ranitidine and cimetidine). Joint use of ranitidine (a single dose of 300 mg) with fosamprenavir (a single dose of 1400 mg) reduces the AUC of amprenavir in blood plasma by 30% and Cmah - by 51%.

    However, the amprenavir Cmin (C12h) remains unchanged. Dose adjustments for co-administration for any of the drugs indicated herein are not required.

    Proton pump inhibitors: the combined use of fosamprenavir (1400 mg twice daily) and esomeprazole (20 mg once daily) for 14 days did not result in a change in AUC, Cmax or Cmin of amprenavir in blood plasma increased esomeprazole AUC in blood plasma by 55% and tmax by 1 hour, without affecting CmOh. The combined use of esomeprazole (20 mg once daily) and fosamprenavir (700 mg twice daily) in combination with ritonavir (100 mg twice daily) for 14 days did not result in a change in AUC, Cmax or Cmin Amprenavir in blood plasma and AUC or Cmah esomeprazole, tmax extended by 1 hour. Dose adjustments for co-administration for any of the drugs indicated herein are not required.

    With the simultaneous use of fosamprenavir with drugs such as amiodarone, quinidine, lidocaine (systemic route of administration), tricyclic antidepressants and warfarin, it is required to control the concentrations of these drugs in the blood plasma in connection with the possibility of developing life-threatening conditions. For warfarin, it is necessary to monitor the international normalized relationship (INR).

    The following list of drugs is an example of substrates, inhibitors or inducers of the cytochrome isoenzyme CYP3A4, which can interact with fosamprenavir when used simultaneously. The list is not exhaustive. The clinical significance of these potential interactions is unknown and is not fully understood. In this regard, special attention should be paid to monitoring the toxic effects of these drugs while taking them with fosamprenavir.

    Colchicine: patients with impaired renal or hepatic function should not apply colchicine together with fosamprenavir and ritonavir.

    Boszentan: The joint administration of bosentan to patients receiving fosamprenavir Patients receiving fosamprenavir at least 10 days, bosentan should be prescribed at a dose of 62.5 mg I once a day or every other day, depending on individual tolerability.

    The co-administration of fosamprenavir to patients receiving bosentan Stop taking bosentan at least 36 hours before taking fosamprenavir. After at least 10 days from the start of taking fosamprenavir, resume bosentan at a dose of 62.5 mg once a day or every other day, depending on individual tolerability.

    Alfuzosin: Serum concentration in the blood serum may increase, which can lead to an increased risk of developing hypotension. Simultaneous assignment is not recommended.

    Anticonvulsants: simultaneous administration of anticonvulsants, enzyme inducers (phenytoin, phenobarbital, carbamazepine), with fosamprenavir without combined administration with low doses of ritonavir can lead to a decrease in the concentration of amprenavir in blood plasma.

    Phenytoin: AUC and Cmin amprenavir increased by 20% and 19%. respectively. here Cmah did not change with the simultaneous use of fosamprenavir (700 mg twice a day) in combination with ritonavir (100 mg twice a day) and phenytoin (300 mg once a day). AUC. FROMmax AND Cmin phenytoin decreased by 22%, 20% and 29%, respectively.Thus, the use of fosamprenavir and ritonavir in combination with phenytoin does not require a change in the dosage regimen of fosamprenavir and ritonavir. However, it is recommended to monitor the concentration of phenytoin in the blood plasma and, if necessary, increase the dose of phenytoin. The mode of application of fosamprenavir and ritonavir was not examined once a day.

    Benzodiazepines (alprazolam, clorazepam, diazepam, flurazepam, midazolam, triazolam): it is possible to increase their concentrations in the serum, which may lead to an increase in their activity.

    Tricyclic antidepressants (desipramine, nortriptyline): not studied. An increase in concentration is expected (moderate inhibition of ritonavir CYP2D6). It is recommended to carefully monitor the therapeutic and undesirable reactions of tricyclic antidepressants.

    Calcium channel blockers (amlodipine, diltiazem, felodipine, izradipine, nicardipine, nifedipine, nimodipine, nisoldipine and verapamil): it is possible to increase their concentrations in the serum, which can lead to an increase in their activity and toxicity.

    Dexamethasone: can induce the cytochrome CYP3A4 isoenzyme and lower the concentration of amprenavir in the blood plasma.

    Inhibitors of phosphodiesterase-5: not studied.According to these other HIV protease inhibitors, the concentration of phosphodiesterase-5 inhibitors (eg, sildenafil) in plasma may increase significantly with the simultaneous use of fosamprenavir. which can increase the incidence of adverse reactions of other phosphodiesterase-5 inhibitors. It is not recommended to use together with phosphodiesterase-5 inhibitors for the treatment of erectile dysfunction or pulmonary arterial hypertension (arterial hypotension, visual impairment, priapism). The simultaneous use of fosamprenavir and sildenafil, tadalafil and vardenafil is not recommended.

    Fluticasone propionate (interaction with ritonavir): in healthy volunteers with simultaneous application within 7 days of 200 μg fluticasone propionate intranasally once a day and 100 mg ritonavir capsule 2 times a day, a significant increase in the concentrations of fluticasone propionate in blood plasma and a decrease in the level of endogenous cortisol by approximately 86%. An increased risk of developing systemic adverse reactions associated with the inhalation of fluticasone propionate is expected.Reports on the development of systemic adverse reactions include Cushing's syndrome, suppression of adrenal function in patients receiving ritonavir and fluticasone propionate by inhalation or intranasal route. Such an interaction is predicted for all glucocorticosteroids metabolized by cytochrome CYP3A4 isoenzyme. Thus, the combined use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient exceeds the risk of systemic corticosteroid reactions.

    Halofantrine: The concentration of halophthrin in the blood plasma may increase when combined with fosamprenavir. which can lead to an increase in the incidence of adverse reactions associated with the use of halofantrine, such as cardiac arrhythmia. The combined use of these drugs is not recommended.

    Inhibitors of hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase): when combined with fosamprenavir, a marked increase in plasma concentrations of HMG-CoA reductase inhibitors, such as lovastatin and simvastatin, the metabolism of which largely depends on the isoenzyme of cytochrome CYP3A4. Since an increase in the concentration of HMG-CoA reductase inhibitors can lead to myopathy, including rhabdomyolysis, the use of these drugs in combination with fosamprenavir is not recommended. FROMmah and AIJC atorvastatin increased by 304% and 130%. respectively, and Cmin decreased by 10% with the simultaneous use of atorvastatin (10 mg once a day for 4 days) and fosamprenavir (1400 mg twice a day for 2 weeks). FROMmah, AUC and Cmin amprenavir decreased by 18%. 27% and 12%, respectively. When combined with fosamprenavir, doses of atorvastatin should not be administered at a dose greater than 20 mg / day, while ensuring thorough control of the toxicity of atorvastatin. The same recommendations apply to the use of atorvastatin and fosamprenavir in combination with ritonavir. Metabolism of pravastatin and fluvastatin does not depend on the isoenzyme of cytochrome CYP3A4, and therefore interactions with HIV protease inhibitors are not expected. If treatment with HMG-CoA reductase inhibitors is indicated, the use of pravastatin or fluvastatin is recommended.

    Immunosuppressive drugs: you can expect an increase in the concentration in the blood plasma of cyclosporine, rapamycin and tacrolimus with a simultaneous appointment with fosamprenavir.For this reason, frequent monitoring of therapeutic concentrations is recommended until the levels become stable.

    Salmeterol: the joint administration of salmeterol and fosamprenavir is not recommended. This combination can lead to an increased risk of adverse cardiovascular reactions associated with salmeterol administration. such as QT interval elongation, heart palpitations and sinus.

    Bepridil: the simultaneous administration of a combination of fosamprenavir + ritonavir and bepripid should be avoided due to the fact that amprenavir and ritonavir are inhibitors of the cytochrome CYP3A4 isoenzyme involved in the metabolism of bepridil, which can lead to an increase in concentrations of bepridil in the blood and increase the risk of life-threatening arrhythmia.

    Methadone: The combined use of a combination of fosamprenavir 700 mg with ritonavir 100 mg twice daily and methadone once a day (at a dose of <200 mg) for 14 days resulted in a decrease in AUC (0-t) and Cmax of the active (K) -enantiomer of methadone by 18% and 21%. The unbound fraction of R-methadone increased after 2 hours (12.4% compared to 8.5%) and after 6 hours (11.5% compared to 9.3%), but the concentration of unbound R-methadone (active) through 2 hours and 6 hours did not change significantly.Based on comparative historical data, methadone does not change the pharmacokinetics of amprenavir. A similar effect on the concentration of methadone was observed with the simultaneous use of amprenavir (without ritonavir) and methadone. Based on these data, when a methadone with fosamprenavir is co-administered, dose adjustment is not required. As a precaution, the possible development of withdrawal symptoms in patients should be monitored.

    Paroxetine: paroxetine concentrations in the blood plasma can be significantly reduced with simultaneous administration with fosamprenavir and ritonavir, therefore an adequate correction of the paroxetine dosage regimen is required depending on the clinical effect and tolerability.

    Steroid drugs: the combined use of fosamprenavir in a dose of 700 mg 2 times a day in combination with ritonavir at a dose of 100 mg 2 times a day and the drug Brevinor (ethinyl estradiol (EE) 0.035 mg / norethisterone (NE) 0.5 mg) once a day reduced AUC (0-t) and Cmax EE in blood plasma by 37% and 28%. accordingly, and reduced AUC (O-t), FROMmah and Ct NEs by 34%, 38% and 26%. respectively. Co-administration with Brevinor significantly did not affect the pharmacokinetic (PK) parameters of amprenavir in plasma in equilibrium: however, AUC (0-t) and Cmax ritonavir were 45% and 63% higher, respectively, compared with the data obtained earlier in female patients receiving only a combination fosamprenavir + ritonavir. In addition to reducing the concentration of the hormonal contraceptive, the combined use of fosamprenavir in combination with ritonavir and Brevinor caused a clinically significant increase in liver transaminase activity in some healthy patients. Thus, it is recommended that women capable of childbearing use alternative non-hormonal methods of contraception.

    Preparations containing St. John's wort: the concentration of amprenavir in the blood may decrease due to the concomitant use of preparations containing St. John's wort (Hypericum perforatum). In this regard, preparations of St. John's wort should not be used simultaneously with therapy Telsir. The induction effect of St. John's wort can persist for 2 weeks after its cancellation.

    Quetiapine: In connection with the inhibition of fosamprenavir by the isozyme CYP3A, an increase in the concentration of quetiapine is expected. Contraindicated in the combined use of fosamprenavir and quetiapine, as this may lead to an increase in toxicity associated with the use of quetiapine.An increase in the concentration of quetiapine in the blood plasma can lead to coma.

    Special instructions:

    The patient should strictly adhere to all recommendations regarding the dosage regimen of the drug.

    The patient should be informed that combined antiretroviral therapy, including Telsir, does not cure HIV infection, so opportunistic infections or other complications of HIV infection may develop with therapy. It has not been proven that antiretroviral drugs known to date, including combination therapy with Telsir, are able to prevent the transmission of HIV to others through sexual contact or through blood. Therefore, appropriate precautions should be taken. Pharmacokinetics, safety and efficacy of fosamprenavir in children under 4 weeks of age have not been established. In patients with concomitant hepatitis B or C or in patients with initially increased activity of transaminases, the risk of an increase in the activity of transaminases increases. In such patients, appropriate laboratory tests should be performed prior to initiation of therapy, and then at regular intervals during treatment.

    Since renal clearance of amprenavir does not play a significant role in drug clearance, it is unlikely that patients with renal insufficiency will experience an increase in plasma concentration. It is unlikely that hemodialysis or peritoneal dialysis can significantly amprenavir because of its high degree of binding to plasma proteins.

    Amprenavir, like other HIV protease inhibitors, is an inhibitor of the enzyme ZA4 cytochrome P450. Do not use fosamprenavir simultaneously with drugs that have a narrow therapeutic range and are substrates for the cytochrome isoenzyme CYP3A4. There are other drugs, the use of which can lead to serious and / or life-threatening drug interactions, and therefore caution should be exercised when using fosamprenavir together with medications that are stimulants, inhibitors or substrates of the cytochrome isoenzyme CYP3A4.

    The combined use of fosamprenavir and delavirdine is not recommended, as there is a significant decrease in delavirdine concentration.

    Hepatitis C Virus (HCV) protease inhibitors: HCV protease inhibitors have a structural similarity to HIV protease inhibitors, and there is evidence to suggest that they share a common metabolic pathway. The combined use of fosamprenavir in combination with ritonavir and telaprevir leads to a stable decrease in the exposure of amprenavir and telaprevir at an equilibrium concentration, with the possibility of achieving a subtherapeutic concentration. The combined use of fosamprenavir in combination with ritonavir and telaprevir is not recommended.

    There have been reports of a pharmacokinetic interaction between bocetrevir and some HIV protease inhibitors in combination with ritonavir, which led to a decrease in the concentration of HIV protease inhibitors and, in some cases, a decrease in the concentration of bocetrephir. Despite the fact that the interaction with fosamprenavir in combination with ritonavir has not been investigated, there is a likelihood of a similar interaction. Thus, the combined use of boceprevir and fosamprenavir in combination with ritonavir is not recommended.

    Serious and / or life-threatening drug interactions are possible between amprenavir and amiodarone, lidocaine (systemic), tricyclic antidepressants, quinidine, and warfarin. It is recommended to monitor the concentration (warfarin control of the International normalized relationship) of these drugs, as this will minimize the risk of a potential security risk in a joint application.

    Joint use of amprenavir and rifabutin leads to an increase in the concentration of rifabutin in the blood plasma (AUC) on 200%. It is recommended to reduce the dosage of rifabutin by at least 50% of the recommended dose when combined with fosamprenavir. When combined with ritonavir, an even greater increase in the concentration of rifabutin is expected. It is recommended to reduce the dosage of rifabutin by at least 75% of the recommended dose when administered with fosamprenavir and ritonavir. Clinical observation of patients is necessary.

    The combined use of fosamprenavir and preparations containing Hypericum perforatum (also known as St. John's wort).The results of the study of pharmacokinetics using indinavir show that Hypericum perforatum can reduce the serum concentration of amprenavir in a joint application.

    In connection with the possible increased risk of an increase in the activity of transaminases and a change in the level of hormones with the joint use of fosamprenavir, ritonavir and oral contraceptives, it is recommended that women capable of childbearing use nonhormonal methods of contraception.

    There is no data on the combined use of fosamprenavir and ritonavir with estrogens and / or progestogens as hormone replacement therapy. The efficacy and safety of these therapies with fosamprenavir and ritonavir has not been established.

    Hypersensitivity reactions

    Admission of the drug with the development of skin rashes of mild or moderate severity and in the absence of severe systemic manifestations of hypersensitivity can be continued with the simultaneous use of antihistamines. Severe life-threatening skin reactions, including Stevens-Johnson syndrome, have been observed in clinical studies in less than 1% of patients.Tselsir should be withdrawn without resuming admission if the following symptoms develop:

    - severe skin rash;

    - skin rash of moderate severity, accompanied by other systemic manifestations of hypersensitivity or rashes on the mucous membranes.

    Patients with hemophilia

    There were registered frequent cases of bleeding, including spontaneous intradermal hematomas and hemarthroses, in patients with hemophilia A and B receiving treatment with HIV protease inhibitors. Some of these patients received treatment with coagulation factor VIII. In more than half the cases, treatment with HIV protease inhibitors has been continued or resumed (if the treatment was interrupted). A causal relationship is possible, despite the fact that the mechanism of action is not explained. Therefore, patients with hemophilia should be informed of the possible increase in bleeding.

    Hemolytic anemia

    There were reports of the development of acute hemolytic anemia in a patient who received amprenavir.

    Hyperglycaemia

    The incidence of diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been observed in patients receiving antiretroviral therapy, including HIV protease inhibitors.Some patients required the onset of insulin therapy or the correction of the dose of insulin or oral hypoglycemic drugs for the relief of these phenomena. In some cases, diabetic ketoacidosis has been documented. The causal relationship between therapy of HIV protease inhibitors and these phenomena has not been established.

    Redistribution of subcutaneous fat

    Combined antiretroviral therapy, including HIV protease inhibitors, in some cases resulted in the redistribution and / or accumulation of subcutaneous fat. The causal relationship between these phenomena has not been established.

    Increase in lipid content

    Treatment with fosamprenavir led to an increase in the concentration of triglycerides and cholesterol. It is necessary to determine the initial concentration of triglycerides and cholesterol before the start of therapy, and then regularly monitor these indices during treatment with fosamprenavir. Treatment of dyslipidemia should be based on clinical manifestations.

    Immunodeficiency Syndrome

    In HIV-infected patients with severe immunodeficiency in the early stages of antiretroviral therapy, inflammatory responses in response to asymptomatic or residual opportunistic infections and cause serious clinical manifestations or worsening of the patient's condition (cytomegalovirus retinitis, generalized and / or local mycobacterial infections and pneumocystis pneumonia). Typically, such reactions are observed during the first few weeks or months after initiation of therapy. If any signs of inflammation should immediately begin appropriate therapy.

    Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were also observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after initiation of therapy and have an atypical course.

    Renal stone disease

    During post-registration follow-up, reports of cases of kidney stone disease in patients with HIV-1 were received, fosamprenavir. Since these messages were sent voluntarily in the clinical practice, it is impossible to assess the frequency of occurrence of these phenomena. If there are signs or symptoms of kidney stone disease, you can consider the possibility of temporary suspension or completediscontinuation of treatment.

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

    No studies have been conducted, however, the safety profile of the preparation and undesirable reactions that can develop against the background of Telsir preparation should be taken into account.

    Form release / dosage:

    The tablets covered with a cover, 700 mg.

    Packaging:60 tablets per bottle of high-density polyethylene, sealed with a screw cap with a plastic seal, with the control of the first autopsy and the device against opening the bottle by children. On the lid is a scheme for opening the vial. The bottle is equipped with a membrane of paper and aluminum foil with logos of the company in English. 1 bottle with instructions for use in a cardboard box.
    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LS-002473
    Date of registration:30.06.2010
    The owner of the registration certificate:VeeV Helsker United Kingdom LimitedVeeV Helsker United Kingdom Limited United Kingdom
    Manufacturer: & nbsp
    Representation: & nbspVIIV Chelskea UK Limited VIIV Chelskea UK Limited United Kingdom
    Information update date: & nbsp23.01.2015
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