Fuzeon® (Fuzeon®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceEnfuvirtideEnfuvirtide
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  • Fuzeon®
    lyophilizate PC 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbsplyophilizate for the preparation of a solution for subcutaneous administration
    Composition:

    1 bottle with the drug contains: active substance: enfuvirtide-108 mg;

    Excipients: sodium carbonate (anhydrous) - 2.87 mg, mannitol - 27.05 mg, sodium hydroxide - q.s., hydrochloric acid - q.s.

    1 bottle with a solvent contains: water for injection - 2 ml.

    Description:

    Lyophilizate white or white with a slightly yellowish hue.

    Solvent: clear, colorless liquid.

    Reconstituted solution: a clear, colorless or slightly yellowish solution.

    Pharmacotherapeutic group:antiviral [HIV] agent
    ATX: & nbsp

    J.05.A.X.07   Enfuvirtide

    Pharmacodynamics:

    Inhibitor confluence

    Enfuvirtide is the first representative of a class of therapeutic agents called fusion inhibitors. Specifically binding to glycoprocedure gp41 human immunodeficiency virus 1 (HIV-1) outside the cell and inhibiting its structural rearrangement, blocks the penetration of the virus into the cell. Does not require intracellular activation.

    The antiviral activity of enfuvirtide is due to its interaction with the first site containing heptadic repeats (HR1) in natural gp41 on the surface of the virus.

    Antiviral activity in vitro: was demonstrated using laboratory and clinical HIV-1 isolates using the example of acute infection in cell culture Tlymphoblasts, monocyte / macrophage cells and primary peripheral blood mononuclear cells (PMPC). The selective anti-HIV-1 activity was detected both with respect to prototype and primary viral isolates. In determining the sensitivity to enfuvirtide on 612 recombinant HIV samples containing env genes of ribonucleic acid (VPC) of the virus, using the recombinant method of phenotyping using HIV transport, the geometric mean EC50 (the concentration at which half of the maximal effect is achieved) of enfuvirtide was 3.259 μg / ml (geometric mean ± 2SD = 1.96. μg / ml). These samples were obtained prior to initiation of therapy in patients who participated in Phase III clinical trials. Studies of enfuvirtide in combination with other antiviral agents of various classes (nucleoside inhibitors of the image transcriptase, non-nucleoside reverse transcriptase inhibitors and protease inhibitors), including zidovudine, lamivudine, nelfinavir, indinavir and efavirenz, showed the presence of additive and vigorous effects and the absence of antagonism. The relationship between the sensitivity of HIV-1 to enfuvirtide in vitro and inhibition of HIV-1 replication in humans has not been established. Because of the different enzymes and the target is supposed to be due to enfuvirtide activity against HIV strains resistant to other classes of antiviral agents, HIV isolates resistant to enfuvirtide should remain SensitivityNucleoside reverse transcriptase inhibitors, non-nucleoside ingireverse transcriptase inhibitors and protease inhibitors.

    Resistance in vitro: isolated HIV-1 isolates with reduced sensitivity to enfuvirtide and substitutions in the amino acid sequence (aa) 36-38 ectodomain gp41. These changes correlated with different levels of reduced sensitivity to enfuvirtide HIV mutants with site-directed mutations.

    Resistance in vivo: in clinical studies of phase III HIV recombinants containing env genes PNA HIV from samples from 187 patients at week 24 showed a 4-fold decrease in sensitivity to enfuvirtide compared to pre-treatment samples.The samples 185 (98.9%) studied in this experiment contained specific substitutions in aa 36-45 dr41 viruses. These substitutions, which occurred with decreasing frequency, occurred in the context of 38, 43, 36, 40, 42, and 45. Specific single substitutions in amino acid residues gp41 to varying degrees, led to a decrease in the virus sensitivity to enfuvirtide compared with baseline. Deviations from the geometric mean for sensitivity varied from a 15.2-fold decrease for V38M to 41.6-fold decrease for V38A. The insufficient number of samples containing multiple substitutions does not allow us to trace the pattern of these substitutions, as well as lx influence on the viral sensitivity to enfuvirtide. The interrelation of these substitutions with the effectiveness in vivo not installed. The degree of decrease in the virus sensitivity to enfuvirtide correlated with resistance to baseline antiretroviral therapy before initiation of treatment (see Table 1).

    Cross-resistance: thanks to a new viral target enfuvirtide equally active in vitro for wild types of laboratory isolates, clinical isolates and isolates with genotypic resistance to 1,2 or 3 classes of antiviral agents (nucleoside reverse transcriptase inhibitors,non-nucleoside reverse transcriptase inhibitors and protease inhibitors). Conversely, it is assumed that mutations in gp41 aa 36-45, which cause resistance to enfuvirtide, should not cause cross-sensitivity to other classes of antiretroviral agents.

    Efficiency

    After 48 weeks of therapy, an undetectable level PNK HIV-1 (<400 copies / ml) was noted in 30% of patients who received Fuzeon in combination with optimized baseline (OB) antiretroviral therapy (APT), compared with 12% in patients who received only an optimized baseline APT. More often, the undetectable level of HIV-1 RNA was noted in all patients with Fuzeon therapy, regardless of the initial level of HIV-1 RNA, CD4 cells, the number of precursors or components currently being received APT. At the same time, in patients with CD4 more than 100 cells / ml, initial viral load less than 5 log10 copies / ml receiving paless than 10 drugs Apt and 1 or more of the drugs included in the OB in the present, was more likely to reach an undetectable level of HIV-1 RNA (see Table 1). Fuzeon in combination with an optimized basetreatment when compared with the use of only basic therapy in HIV-1 infected patients is significantly better and statistically significantly altered HIV-1 RNA levels in plasma in log10 copies / ml (-1.5 vs. -0.6), the number CD4 cells (+91 vs. +45), the percentage of patients with a decrease PNA BIH in> 1 log and more than the baseline (37% vs 17%), <400 copies / ml (30% vs. 11%), <50 copies / ml (18% vs. 8%), 48 weeks later. [Based on research results TOROl and TORO2, ITT).

    Table 1. Proportion of patients with HIV-1 RNA copies less than 400 copies / ml and less than 50 copies / ml at 48 weeks in subgroups (pooled data TOROl and TORO2, ITT).

    Subgroups

    The copy level of HIV-1 RNA is less than 400 copies / ml

    The copy level of HIV-1 RNA is less than 50 copies / ml

    Fuzeon + ON antiretroviral therapy 90 mg 2 times a day (N = 661)

    Antiretroviral therapy (N = 334)

    Fuzeon + ON antiretroviral therapy 90 mg 2 times a day (N = 661)

    Antiretroviral therapy (N = 334)

    Baseline

    118/269

    26/144

    77 /269

    18/144

    HIV-1 RNA <5.0 log101 copies / ml

    (43.9%)

    (18.1%)

    (28.6%)

    (12.5%)

    Baseline

    83/392

    14/190

    44/392

    8/190

    HIV-1 RNA> 5.0 log101 copies / ml

    (21.2%)

    (7.4%)

    (11.2%)

    (4.2%)

    Total

    100/215

    29/120

    64/215

    19/120

    patients who had previously received <101 drugs Apt

    (46.5%)

    (24.2%)

    (29.8%)

    (15.8%)

    Total

    patients who had previously received> 101 preparations of APT

    101/446

    (22.6%)

    11/214

    (5.1%)

    57/446

    (12.8%)

    7/214

    (3.3%)

    0 active drugs APT initially1,2

    9/112

    (8.0%)

    0/53

    (0%)

    4/112

    (3.5%)

    0/53

    (0%)

    1 active and preparation APT initially1,2

    56/194

    (28.9%)

    7/95

    (7.4%)

    34/194

    (17.5%)

    3/95

    (3.2%)

    > or = 2 active pre-

    of APT parities initially1,2

    130/344

    (37.8%)

    32/183

    (17.5%)

    77/334

    (22.4%)

    22/183

    (12.0%)

    1 The termination of treatment or the absence of a virologic response was considered a failure of therapy.

    2 Based on the index of genotypic sensitivity (GSS).

    Use in children

    Data on the effectiveness of Fuzeon in children older than 3 years are limited.

    When combined therapy with Fuzeon 60 mg / m2 with primary antiretroviral therapy in patients aged 3 to 12 years at week 48, 43% of patients had a decrease> 1 log10 HIV-1 RNA and in 20% of patients the HIV-1 RNA level was below 400 copies / ml. The mean changes in HIV-1 RNA and the number of CD4 cells were 1.24 log10 copies / ml and 237 cells / μl, respectively.

    Pre-clinical safety study data

    Carcinogenesis: long-term studies of carcinogenicity of enfuvirtide in animals have not been conducted.

    Mutagenesis: enfuvirtide did not show mutagenic and clastogenic properties in the series of analyzes in vivo and in vitro, including Ames reverse mutation test in bacteria, analysis of early gene mutation in the AS52 line of Chinese hamster ovary cells and in vivo microscopic analysis in mice.

    Fertility disorder: enfuvirtide did not have undesirable effects on fertility in males and female rats at doses exceeding 0.7,2.5 and 8.3 times the maximum recommended daily dose for humans and calculated in mg / kg subcutaneously.

    Pharmacokinetics:

    Suction

    After a single subcutaneous (SC) injection of 90 mg of enfuvirtide HIV-1 into the anterior abdominal wall to infected patients, the maximum concentration (CmOh) is 4.59 ± 1.5 μg / ml, the area under the concentration-time curve (AUC) - 55.8 ± 12.1 μg h / ml and absolute bioavailability of 84.3 ± 15.5%. With n / to the introduction of a dose of 45 to 180 mg bioavailability of enfuvirtide is proportional to the administered dose. Absorption does not depend on the place of administration.

    The mean equilibrium plasma concentration when 90 mg of enfuvirtide is administered is shown in Figure 1.

    Figure 1. Equilibrium concentration in plasma with the administration of 90 mg of enfuvirtide twice a day (N = 11)

    Error bar = standard deviation

    The mean minimum equilibrium concentration of enfuvirtide in plasma between two administrations is 2.6-3.4 μg / ml.

    Distribution

    The average volume of distribution in the equilibrium state after intravenous administration of 90 mg is 5.5 ± 1.1 liters. 13 HIV-infected plasma epfivirtide at a concentration of 2-10 μg / ml is 92% associated with plasma proteins, mainly albumin and to a lesser extent with a1acid glycoprotein.

    In HIV-infected patients, the level of enfuvirtide in the cerebrospinal fluid is insignificant. Probably, the molecule of the drug is too large to overcome the blood-brain barrier.

    Metabolism

    Enfuvirtide, being a peptide, undergoes catabolism to the amino acids that make up its composition, followed by a metabolism of the latter in the body.

    Enfuvirtide is not an inhibitor of cytochrome family enzymes CYP450.

    IP vitro hydrolysis of the amide group of the C-terminus of the amino acid phenylalanine leads to the formation of a deaminated metabolite and the formation of this metabolite is independent of 4ADPH. This metabolite is found in human plasma following the administration of enfuvirtide c AUC 2.4-15% of AUC enfuvirtide.

    Allocation

    Labeled 3H-enfuvirtide is not fully detectable in rodent excrement within 7 days after dosing. The delay in radioactivity is noted in skeletal muscles.

    After subcutaneous administration of 90 mg of enfuvirtide, the elimination half-life is 3.8 ± 0.6 hours, and the clearance is 1.7 ± 0.4 l / h.

    Pharmacokinetics the special patient groups

    Patients with hepatic insufficiency: The pharmacokinetics of enfuvirtide in patients with hepatic insufficiency has not been studied.

    Patients with renal insufficiency: analysis of plasma concentrations in patients in clinical studies showed that the clearance of enfuvirtide did not show a dependence on creatinine clearance in patients with creatinine clearance more than 35 ml / min.

    According to a clinical study devoted to the study of patients with renal insufficiency, enfuvirtide clearance was reduced by 38% in patients with severe renal dysfunction and by 14-28% in patients with terminal stage of renal failure who are on dialysis, a AUC enfuvirtide increased by an average of 43-62% in both groups compared with patients with normal renal function. The results were within the limits that were recorded in the framework of large-scale studies conducted on patients with normal renal function. Hemodialysis did not significantly affect the clearance of enfuvirtide. Dose adjustments for patients with impaired renal function are not required.

    Sex and body weight: Enfuvirtide clearance is 20% lower in women than in men and increases with weight gain regardless of sex (20% higher in patients with a body weight of 100 kg and 20% lower in patients with a body weight of 40 kg relative to the comparison patient with a body weight of 70 kg). These changes are not clinically significant and do not require dose adjustment.

    Race: there were no racial differences in clearance between the representatives of the Negroid, Mongoloid race in comparison with the representatives of the European race after appropriate correction of the effect taking into account the body weight.

    Patients of senile age: the pharmacokinetics of enfuvirtide in patients aged 65 years and older have not been studied.

    Children: in children from 3 to 16 years with a dose of 2 mg / kg twice a day (no more than 90 mg twice a day), the concentration of enfuvirtide in plasma was similar to that achieved in adult patients who received the drug in a dose 90 mg twice a day.

    Children aged 5 to 16 years who received enfuvirtide in a dose of 2 mg / kg twice a day, AUC in the equilibrium state is 54.3 ± 23.5 μg h / ml, CmOh - 6.14 ± 2.48 μg / ml and Cmin between the administrations is 2.93 ± 1.55 μg / ml.

    Indications:

    Treatment of HIV-1 infection in combination with other antiretroviral drugs with ineffectiveness of previous regimens containing at least one of the preparations of each of the following groups: protease inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, or intolerance of previously used antiretroviral regimens.

    Contraindications:

    Hypersensitivity to enfuvirtide or to any component of the drug.

    Breastfeeding period.

    Children under 6 years.

    Pregnancy and lactation:

    Enfuvirtide had no teratogenic effect in animal studies (rats and rabbits), at a dose of 8.9 times the therapeutic level for humans. Research on the use of Fuzeon® in pregnant women were not conducted.

    Fuzeon® during pregnancy should be avoided. The application is possible only if the potential benefit to the mother exceeds the possible risk to the fetus.

    When introducing a radio-labeled H3-enfuvirtide to rats in the lactation period in milk there is a very low level of radioactivity. Is the enfuvirtide with human breast milk, is unknown. Breastfeeding should be discontinued before therapy, including. and to prevent the transmission of HIV to the child.

    Dosing and Administration:

    Subcutaneously.

    Standard dosing regimen

    Daily, subcutaneously (sc) to the shoulder area, the front surface of the thigh or the anterior abdominal wall. It is necessary to change the place of each subsequent injection and inject the drug there,where there is currently no local reaction to injection.

    Adults and children over 16 years of age: for 90 mg twice a day.

    Dosing in special cases

    Children under 6 years: Data for determining recommendations for the dosage regimen of Fuzeon® in children under 6 years of age are not available.

    Children 6-16 years old: 2 mg / kg twice a day. The maximum dose but 90 mg twice a day (see Table 2).

    Table 2. Doses recommended in pediatric practice.

    Weight, kg)

    The dose (mg / dose) twice a day

    Entered volume (ml) (90 mg of enfuvirtide in ml)

    11 - 15.5

    27

    0.3

    15.6-20

    36

    0.4

    20.1 -24.5

    45

    0.5

    24.6-29

    54

    0.6

    29.1 -33.5

    63

    0.7

    33.6-38

    72

    0.8

    38.1 -42.5

    81

    0.9

    ≥42.6

    90

    1.0

    Renal insufficiency: dose adjustment for patients with impaired renal function is not required.

    Liver failure: data on the dose for patients with hepatic impairment are not provided.

    Patients over 65 years of age: The dosage regimen in patients older than 65 years is not established.

    Fuzeon® contains no preservatives. Liofilizprovapny powder should be diluted with sterile water for injection to obtain a solution. If the finished solution is not used immediately, it must be stored in a refrigerator (2-8 ° C) and used within 24 hours. Before administration, the finished solution from the refrigerator is brought to room temperature (for example, while holding in the hand for about 5 minutes) and check whether the contents of the vial have completely dissolved.The reconstituted solution is not used if it contains mechanical inclusions.

    Information for Patient

    Before the first use of the drug, the physician should instruct patients and caregivers on the rules of preparation for injection, injection and disposal of used syringes and needles.

    Persons caring for patients should immediately consult a doctor if they accidentally prick a needle after injecting the patient.

    Syringes

    The syringes supplied with this medication have a colored protective device attached to the needle that closes it after using the syringe and reduces the risk of needle injuries.

    It is necessary to destroy the used syringes correctly and in accordance with the recommendations of the doctor.

    SAFETY REQUIREMENTS

    - Wash hands thoroughly to reduce the risk of bacterial infections. Do not touch any objects other than the preparation and related materials.

    - Do not touch the needle and the top of the vial plug after they have been treated with an alcoholic napkin.

    - Ensure that the integrity of the packaging of all items necessary for injection is not compromised.Do not use materials if the packaging is damaged.

    - Do not use a syringe with a curved or damaged needle.

    - Do not dilute the drug with plain water.

    - Do not administer Fuzeon® with other injectable medications.

    - The drug is administered only subcutaneously. Solution Fuzeon® can not enter intravenously (directly into the vein) or intramuscularly (directly into the muscle).

    - Do not administer the drug to the place where the reaction remained after the previous injection, change the injection site.

    - Not to miss the injection, a break in treatment leads to the stability of the virus.

    - After use, place the syringe in a separate, closed container in order to safely destroy the material. For safe disposal of used materials, you should contact your doctor.

    PREPARATION FOR INJECTION

    Necessary materials

    To prepare and self-administer the injection, you need:

    - one bottle with Fuzeon®;

    - one bottle of water for injection;

    - one 3 ml syringe with 25 mm needle;

    - one syringe I ml with a 13 mm needle;

    - 3 alcohol wipes;

    - Lockable container for safe disposal of used materials.

    If you need to buy water for injections, 3 ml and 1 ml syringes, alcohol wipes, consult a doctor.

    Open the package with a syringe and remove the caps from the vials.

    - Packaging and lids of vials should be thrown into a trash can.

    - Put the syringes and put the vials on a clean surface.

    Wash hands thoroughly!

    - After washing your hands, you should not touch anything, except for the injection site and the necessary means.

    - Rub rubber plugs of each bottle with one separate new alcoholic napkin. Allow them to air dry.

    - Do not touch the rubber plugs, otherwise they must be wiped off again.

    PREPARATION OF FOUEON® / dilution /

    Set in a syringe of water for long injections

    - Take large syringe 3 ml. With your index finger, bend the colored needle guard to the side of the syringe.

    - Make sure that the needle is firmly attached to the syringe. To do this, hold the transparent plastic cap with your fingers, secure the needle, carefully turning the cap clockwise. Do not apply too much force, as the needle can be broken.

    - To remove the transparent plastic cap, first press the cap in the direction of the syringe, and then remove it by pulling in the opposite direction.

    - Draw 1.1 ml of air into the syringe.

    - Puncture the syringe with a rubber stopper of the vial with water for injection and inject air from the syringe into the vial by pressing the piston.

    - Turn the bottle upside down. Make sure that the end of the needle is constantly in the water to avoid the formation of air bubbles in the syringe.

    - Slowly pull the plunger until there is slightly more in the syringe than 1.1 ml of water.

    - Holding the syringe with the needle up, gently tap with the finger on the syringe so that the air bubbles gather at the top of the syringe.

    - Gently push the piston to remove excess air from the syringe, leaving 1.1 ml of water for injection.

    - Remove the needle from the vial, Do not touch it with your fingers or other objects.

    - The bottle with water for injection should be thrown into the waste basket, since it is intended for single use only.

    Addition of water for injection to Fuzeon® powder

    - Carefully knock on the bottle with Fuzeon® to loosen the powder.

    - Puncture the rubber stopper of the vial with Fuzeon® (pre-treated with an alcoholic napkin) with a syringe needle with water for injection at a small angle.

    - Slowly and gently press the plunger of the syringe into the vial. Do not inject water quickly and do not direct a strong jet of water onto the powder, as this can cause the formation of the yen and require more time to completely dissolve the powder.

    - After the introduction of all the water into the bottle with Fuzeon®, remove the needle from the vial.

    - Holding the syringe in one hand, press slightly flat surface a colored needle guard until it closes the needle. You should hear a click. Do not press the needle guard with your hand.

    - Place the syringe in a separate, closed waste container.

    DISSOLUTION OF PREPARATION OF FUZEON®

    - Lightly tap the tip of the finger on the vial until the powder dissolves. Carefully twist the bottle between the palms. Put the bottle. Do not shake or flip the bottle, as this creates a foam. It may take up to 45 minutes to completely dissolve the powder and obtain a solution.

    - If you accidentally touch the rubber stopper, then it must be wiped off with a new alcoholic napkin.

    - Make sure that the powder is completely dissolved. It should not contain any particles or air bubbles. If air bubbles persist, you must gently knock on the vial.

    - If foreign matter or bubbles are detected in the solution, do not use this vial. You should place this vial in a separate closable waste container or contact the pharmacy where you purchased it.

    - Repeat the dilution procedure with a new bottle of Fuzeon®.

    - PThe prepared solution should be immediately used or stored in the refrigerator for no more than 24 hours. In the latter case, the solution must be brought to room temperature before administration.

    - If you are preparing both daily doses, then for each dose you need to use separate syringes, bottles of water for injection and bottles with Fuzeon®.

    PREPARATION FOR INJECTION

    Injections are produced under the skin in the abdomen, hip and shoulder area.

    It is necessary to perform injections daily at the same time and distribute them evenly throughout the day (in the morning and in the evening with an interval of 12 hours).

    Places for injections

    Each time you change the injection site.Do not inject the medication into birthmarks, scar tissue, hematoma or in the navel, in places with seals and / or reaction after previous administration of the drug. Also avoid areas that can be irritated by a belt or belt of clothing.

    Preparation of injection site

    - Carefully wipe the skin at the injection site with an alcoholic napkin in a circular motion from the center to the periphery. Wait until the treated area dries.

    Set of Fuzeon® in a 1 ml syringe

    - Again, wipe the bottle stopper with Fuzeon® with an alcohol wipe.

    - Take in hand syringe 1 ml. With your index finger, bend the colored needle guard to the side of the syringe.

    - Make sure that the needle is firmly attached to the syringe. To do this, hold the transparent plastic cap with your fingers, secure the needle with the cap, gently turning the cap clockwise.

    - To remove the transparent plastic cap from the needle, first push it in the direction of the syringe, and then in the opposite direction remove the cap.

    - Draw 1 ml of air into the syringe. Do not pull the piston too fast, as it can pass through the 1 ml mark and / or pop out of the syringe.

    - Using the needle of the syringe, pierce the rubber stopper of the vial (pre-treated with an alcoholic napkin) with Fuzeon® and, pushing the piston, push the air out of the syringe. Carefully turn the bottle upside down.

    Make sure, that the end of the needle is constantly in solution, To avoid the formation of air bubbles in the syringe.

    - Slowly pull the piston and draw a little more 1.0 ml of the solution into the syringe. Do not pull the piston too fast, as it can pass through the 1 ml mark and / or pop out of the syringe body.

    - Carefully knock on the syringe so that air bubbles gather at the top of the syringe.

    - Smoothly press the plunger to remove air from the syringe into the vial, while in the syringe should remain 1.0 ml of solution or Goth volume, which is appointed by the doctor.

    - Remove the needle from the vial.

    INTRODUCTION OF THE PREPARATION

    Do not skip the injection! A break in treatment leads to the stability of the virus!

    The doctor will help you choose the technique for administering the drug that is convenient for you personally.

    - One hand collect the skin in a crease

    - Until the end, insert the needle under the skin at an angle of 45 ° degrees, release the fold of the skin and position this hand on the syringe to fix it in a stationary position and prevent the displacement.

    - Press the thumb of the hand holding the syringe onto the plunger and inject the medication.

    - After the entire dose is introduced, remove the needle from the skin.

    - Holding the syringe in one hand, press slightly flat surface a colored needle guard until the holes close the needle. You should hear a click. Do not press the needle guard with your hand.

    - In case of the appearance of blood at the injection site, use a patch.

    DESTRUCTION OF MATERIALS USED

    All used syringes must be placed in a separate, closed container. Always keep the lid of the container tightly closed, keep the container out of the reach of children.

    Vials with Fuzeon® are for single use only. Used napkins and vials, including those with drug residues or water for injection, must be disposed of with precautions.

    The used materials (napkins and empty vials), with the exception of syringes, can be thrown into the trash can in the absence of visible traces of blood.

    In the presence of traces of blood, such materials should be placed in a closed container.

    For safe disposal of used materials, contact your doctor
    Side effects:

    Local Reactions

    Pain, discomfort at the injection site, compaction, erythema, node, cyst, itching, ecchymosis; 1.5% of patients had abscess and phlegmon.

    Table 3. Local responses (% of patients).

    n = 663

    The frequency of cancellation of treatment due to the development of local reactions

    4%

    Reaction

    Fuzeon® + ABOUT

    antiretroviral therapy

    % of reactions with 3

    severity

    % of reactions with 4

    severity

    Pain / discomfort b

    96.1%

    11%

    0%

    Erythema from

    90.8%

    23.8%

    10.5%

    Sealing d

    90.2%

    43.5%

    19.4%

    Nodules and cysts e

    80.4%

    29.1%

    0.2%

    Itching f

    65.2%

    3.9%

    not indicated

    Ecchymosis g

    51.9%

    8.7%

    4.7%

    a Any degree of severity.

    b Degree 3 = severe pain requiring the use of analgesics (or narcotic analgesics for <72 hours) and / or restriction of normal activities; Degree 4 = severe pain requiring hospitalization or prolongation, leading to death, or to sustained or significant disability / inability to service yourself, life-threatening, or clinically significant.

    from Degree 3 = average diameter> 50 mm, but the average diameter is <85 mm; Degree 4: average diameter> 85 mm.

    d Degree 3 = average diameter> 25 mm, but the average diameter is <50 mm; Degree 4: average diameter> 50 mm.

    e Degree 3 => 3 cm; Degree 4 = if drainage is carried out.

    f Degree 3 = refractory to local treatment or requiring oral or parenteral treatment; The degree 4 = is not defined.

    g Degree 3 => 3 cm, but <5 cm; The degree of 4 => 5 cm.

    Other undesirable phenomena, observed in at least 2 adult patients with an undesirable phenomenon for 100 patients-years who received combined treatment with Fuzeon® with an optimized baseline (OB) APT.

    Cabout the side of the nervous system: headache, peripheral neuropathy, dizziness, impaired taste, insomnia, depression, anxiety, nightmares, irritability, hypoesthesia, attention disturbances, tremor.

    Co the side of the respiratory system: cough.

    Infections: candidiasis of the oral mucosa, herpes simplex, skin papilloma, influenza, sinusitis, folliculitis, otitis media, pneumonia, sinusitis, ear infections.

    From the skin and subcutaneous fat: itching, night sweats, dry skin, excessive sweating, seborrheic eczema, erythema, acne.

    From the musculoskeletal system: myalgia, arthralgia, back pain, pain in the limbs, muscle spasm.

    From the genitourinary system: concrements in the kidneys, hematuria.

    From the respiratory, thoracic and mediastinal: nasal congestion.

    From the gastrointestinal tract: nausea, pain in the upper abdomen, constipation, diarrhea, pancreatitis, gastroesophageal reflux disease.

    From the side of the eye: conjunctivitis.

    From the organ of hearing: Vertigo.

    Co side of the system of hematopoiesis: lymphadenopathy.

    From the side of metabolism and nutrition: hypertriglyceridemia, decreased appetite, anorexia, diabetes mellitus.

    Hypersensitivity reactions: rash, itching, fever, nausea and vomiting, chills, tremors, decreased blood pressure, increased activity of "hepatic" transaminases in the serum, the primary reaction of immune complexes, respiratory distress syndrome, glomerulonephritis. Other: weakness, weight loss, asthenia, sore throat, flu-like syndrome. Laboratory indicators

    In most patients, the severity of the change in any laboratory indicator of ns changed during the study.

    During 48 weeks of therapy, eosinophilia (above the upper limit of normal (VGN) 0.7x109/ l) was more common in patients who received combination therapy with Fuzeonto with optimized baseline therapy, compared with those who received only optimized basal therapy (12.9 patients compared with 5.6 patients per 100 patient-years).

    Table 4. Laboratory disorders of grade 3 and 4, occurring in 2 patients with a side effect on 100 patients-years who received a combination of Fuzeon® with optimized baseline therapy or only optimized basal therapy.

    INDEX

    Fuzeon® + ABOUT

    ABOUT

    Full exposure (patient-years)

    n = 557

    n = 162.1

    Alanine aminotransferase

    3 severity (more than 5-10 x VG11)

    4.8

    4.3

    4 severity (more than 10 x VGP)

    1.4

    1.2

    Krsatininphosphokinase

    3 severity (more than 5-10 x VG11)

    8.3

    8.0

    4 severity (more than 10 x VGP)

    3.1

    8.6

    Hemoglobin

    3 degree of severity (6.5-7.9 g / l)

    2.0

    1.9

    4 degree of severity (less than 6.5 g / l)

    0.7

    1.2

    Laboratory disorders without a causal relationship with Fuzeon®, observed in> 2% of patients, and also more often in the group of patients receiving Fuzeon® + OB, compared with the group of patients receiving only OB: increased activity of gamma-glutamyltransferase, amylase, lipase, aspartate aminotransferase.

    Children

    The profile of side effects in children is similar to that of adults.

    Overdose:

    There is no information about an overdose of Fuzeon® in humans.

    The maximum dose was 180 mg in the form of a single subcutaneous injection.Side-effects, other than those occurring when the recommended dose was administered, were not noted. There is no specific antidote for an overdose of Fuzeon®. Treatment is symptomatic.

    Interaction:

    Clinically significant pharmacokinetic interactions between enfuvirtide and drugs, the metabolism of which occurs with the participation of enzymes of the P450 family, has not been established.

    Enfuvirtide at the recommended dose of 90 mg 2 times a day does not inhibit the metabolism of isoenzyme substrates CYP3A4 (dapsop), CYP2D6 (debrisoquine), CYP1A2 (caffeine), CYP2C19 (mephenytoin) and CYP2E1 (chlorosoxazone).

    The introduction of Fuzeon ® in combination with ritonavir, saquinavir and rifamycin did not lead to clinically significant pharmacokinetic interactions. Enfuvirtide It is not displaced from the sites of its binding to the protein with saquinavir, nelfinavir, loyinavir, efavirenz, nevirapine, amnievievir, itraconazole, midazolam or warfarin. Enfuvirtide does not replace warfarin, midazolam, amprenavir or efavirenz in their binding sites with protein.

    Fuzeon® should not be mixed with other drugs, except for the supplied solvent (water for injections).

    Special instructions:

    Fuzeon® is prescribed only in combination with other antiretroviral drugs. Patients with symptoms of a suspected systemic hypersensitivity reaction should stop treatment and immediately undergo a medical examination. Do not resume treatment after the occurrence of systemic reactions, possibly associated with taking the drug. The risk factors that may predetermine the development or severity of the hypersensitivity reaction to Fuzeon® are not established.

    When therapy with Fuzeon® marked increased incidence of bacterial pneumonia (6.6 patients with pneumonia compared with 0.6 per 100 patient-years in the groups receiving combined drug therapy Fuzeon® and OH and only ON, respectively, included in the analysis and bronchopneumonia associated phenomena) .

    Risk factors for the development of pneumonia include a low baseline CD4 lymphocytes, a high initial viral load, intravenous administration of drugs, smoking and lung disease in the anamnesis.

    Because the causal relationship between an increase in the incidence of bacterial pneumonia and therapy with Fuzeon® has not been established,A follow-up study was conducted with the participation of HIV-1 infected patients (the observation in the treatment group with Fuzeon® was 2,045 patients-years, and in the control group, 3501 patients-years).

    This study assessed the risk of pneumonia with Fuzeon®, while simultaneously controlling other known risk factors.

    As a result of this extensive study, there were no significant differences in the incidence of pneumonia in patients treated with Fuzeon® compared to patients who did not receive it (the effects of unbalanced risk factors were adjusted when compared). The adjusted risk ratio for pneumonia was 0.989 for a confirmed diagnosis of pneumonia, 1.228 for a confirmed diagnosis or suspected pneumonia, with a lower limit of 95% confidence interval of 0.437 and 0.862, respectively.

    The most frequent side effects (according to the results of studies TOR01 and TOR02) with Fuzeon® therapy, there were reactions at the site of administration (98%). The withdrawal of therapy was required only in 4% of patients.The vast majority of local reactions (85%) of mild and moderate severity are observed during the first week of treatment and do not lead to restriction of normal activities. The severity of the pain syndrome and discomfort during the continuation of treatment do not increase. The number of local lesions observed at the planned visit to the clinician during the clinical trial was less than 5 in 72% of patients with such events.

    The administration of Fuzeon® to persons who are not infected with HIV-1 (eg, after prophylaxis) may cause the appearance of anti-enfuvirtide antibodies that cross-react with HIV gp41. This can lead to a false-positive HIV test when carrying out ELISA with HIV antibodies.

    When choosing a new regimen of therapy, it is necessary to carefully evaluate the previous therapy, the presence of possible mutations associated with previous treatment. If possible, conduct a study of resistance.

    Syndrome of immune reactivation (synonyms - immune reactivation syndrome, immune reconstitution disease, inflammatory immune reconstitution syndrome) was observed in patients who received complex antiretroviral therapy, including Fuzeon ®.At the onset of comprehensive antiretroviral therapy, patients may develop an inflammatory response to opportunistic infections (such as infection caused by Mycobacterium avium; cytomegalovirus infection; pneumonia caused by Pneumocystis jirovecii; tuberculosis and others), which may require immediate diagnosis and treatment.

    The immune reactivation syndrome may also manifest itself in the development of autoimmune disorders (eg, Graves' disease and Pshena Barre's syndrome) that develop at different times of therapy. The development of autoimmune disorders is possible many months after the initiation of therapy. In patients with advanced HIV infection and / or prolonged use of complex antiretroviral therapy, osteonecrosis has been reported (despite the different etiology of osteonecrosis (eg, glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index)). When joint pain occurs, feelings of aches, stiffness and movement restrictions, patients are advised to consult a doctor.

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

    There is no evidence that Fuzeon ® can affect the ability to drive and operate machinery, but it is necessary to take into account the side effects that occur with the administration of Fuzeon ® (see the "Side effect" section).

    Form release / dosage:Lyophilizate for the preparation of a solution for subcutaneous administration of 90 mg / ml
    Packaging:

    Lyophilizate: 108 mg of enfuvirtide (corresponds to the concentration of enfuvirtide in the reconstituted solution of 90 mg / 1 ml) in a bottle of colorless glass of hydrolytic class I (EF), sealed with a butyl rubber stopper, laminated with a fluoropolymer film, crimped with an aluminum cap with a plastic lid.

    60 bottles with lyophilizate are placed in a cardboard bundle with partitions.

    Solvent: 2 ml of water for injection into a bottle of colorless glass of hydrolytic class 1 (EF), sealed with a plug of butyl rubber, laminated with a fluoropolymer film, crimped with an aluminum cap with a plastic lid.

    For 60 bottles of solvent are placed in a cardboard bundle with partitions.

    Set:

    1 cardboard pack with 60 bottles of lyophilizate;

    1 cardboard pack with 60 bottles of solvent;

    1 cardboard bundle with 60 sterile packaged disposable syringes with a capacity of 3 ml;

    1 cardboard bundle with 60 sterile packaged disposable syringes with a capacity of 1 ml;

    180 sterile napkins impregnated with alcohol, packed one by one in a sachet of aluminum foil with a polyethylene coating and laminated paper with instructions for use in a cardboard box.
    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    After reconstitution, the solution is stored at a temperature of 2-8 ° C for 24 hours in a dark place.

    Keep out of the reach of children.

    Shelf life:

    4 years. Do not use the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LS-000270
    Date of registration:15.12.2009
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp29.11.2015
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