Fuzeon^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

Roche Diagnostics GmbH (Germany)

Solvent Manufacturer

HAMELN PHARMACEUTICALS, GmbH (Germany)

ATC Code

J05AX07 (Enfuvirtide)

Active Substance

Enfuvirtide (Rec.INN registered by WHO)

Dosage Form

Fuzeon®

Lyophilizate for the preparation of solution for subcutaneous administration 90 mg/1 ml: fl. 60 pcs. in a set with solvent (fl. 60 pcs.), disposable syringes (3 ml 60 pcs.), disposable syringes (1 ml 60 pcs.) and sterile alcohol wipes (180 pcs.)

Dosage Form, Packaging, and Composition

Lyophilizate for the preparation of a solution for subcutaneous administration white or white with a slightly yellowish tint; solvent transparent, colorless; reconstituted solution transparent, colorless or slightly yellowish in color.

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

Solvent water for injections – 2 ml.

Colorless glass vials (60) – cardboard packs (1) in a set with solvent (vials 60 pcs.), disposable syringes with a capacity of 3 ml (60 pcs.), disposable syringes with a capacity of 1 ml (60 pcs.) and sterile alcohol wipes (180 pcs.) – cardboard boxes.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Fusion inhibitor.

Enfuvirtide is the first representative of a class of therapeutic agents called fusion inhibitors. By specifically binding to the gp41 glycoprotein of human immunodeficiency virus 1 (HIV-1) outside the cell and inhibiting its structural rearrangement, it blocks the penetration of the virus into the cell. It does not require intracellular activation. The antiviral activity of enfuvirtide is due to its interaction with another heptad repeat region HR1 in the native gp41 on the virus surface. Antiviral activity in vitro was demonstrated using laboratory and clinical HIV-1 isolates in an example of acute infection in cultures of T-lymphoblast cells, monocyte/macrophage cells, and primary peripheral blood mononuclear cells (PBMC). Selective anti-HIV-1 activity was detected against both prototype and primary viral isolates. When determining sensitivity to enfuvirtide in 612 recombinant HIV samples containing viral RNA env genes using a recombinant phenotyping method using HIV transfer, the geometric mean EC₅₀ (concentration at which half the maximum effect is achieved) of enfuvirtide was 0.259 µg/ml (geometric mean ± 2SD=1.96, µg/ml). These samples were obtained prior to therapy initiation from patients participating in phase III clinical trials. Studies of enfuvirtide in combination with other antiviral agents of various classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors), including zidovudine, lamivudine, nelfinavir, indinavir and efavirenz, showed effects ranging from additive to synergistic and no antagonism. No relationship has been established between the sensitivity of HIV-1 to enfuvirtide in vitro and the inhibition of HIV-1 replication in humans. Due to different target enzymes and presumably due to the activity of enfuvirtide against HIV strains resistant to other classes of antiviral agents, HIV isolates resistant to enfuvirtide should remain sensitive to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors.

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

Resistance in vivo in phase III clinical trials, HIV recombinants containing ENV genes of HIV RNA from samples obtained from 187 patients at 24 weeks of treatment demonstrated more than a 4-fold decrease in sensitivity to enfuvirtide compared to samples taken before the start of therapy. Of these investigated samples, 185 (98.9%) contained specific substitutions in aa 36-45 of gp41 viruses. These substitutions, occurring with decreasing frequency, occurred in aa at positions 38, 43, 36, 40, 42 and 45. Specific single substitutions in the gp41 amino acid residues led to varying degrees of reduction in viral sensitivity to enfuvirtide compared to baseline. The geometric mean fold change in sensitivity ranged from a 15.2-fold decrease for V38M to a 41.6-fold decrease for V38A. The insufficient number of samples containing multiple substitutions does not allow tracking the pattern of these substitutions or their impact on viral sensitivity to enfuvirtide. The relationship of these substitutions with in vivo efficacy has not been established. The degree of reduction in viral sensitivity to enfuvirtide correlated with resistance to baseline antiretroviral therapy prior to treatment initiation (see Table 1).

Cross-resistance due to the new viral target, Enfuvirtide is equally active in vitro against wild-type 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.

Efficacy

After 48 weeks of therapy, an undetectable level of HIV-1 RNA (less than 400 copies/ml) was noted in 30% of patients receiving Fuzeon^® in combination with optimized background (OB) antiretroviral therapy (ART), compared with 12% in patients receiving only optimized background ART. A more frequent undetectable level of HIV-1 RNA was noted in all patients during therapy with Fuzeon^®, regardless of the baseline level of HIV-1 RNA, CD4 cell count, number of previous or current ART components. At the same time, patients with a CD4 count greater than 100 cells/ml, baseline viral load less than 5 log₁₀ copies/ml, who had previously received less than 10 ART drugs and 1 or more drugs included in the current OB had a better chance of achieving an undetectable level of HIV-1 RNA. Fuzeon^® in combination with optimized background therapy, compared with the use of background therapy alone in HIV-1 infected patients, significantly and statistically significantly changed plasma HIV-1 RNA levels ≥ 1 log₁₀ copies/ml (-1.5 vs -0.6), CD4 cell count (+91 vs +45), percentage of patients with a decrease in HIV RNA of ≥ 1 log or more compared to baseline (37% vs 17%), < 400 copies/ml (30% vs 11%), < 50 copies/ml (18% vs 8%), at 48 weeks. [Based on the results of TORO1 and TORO2 studies, ITT].

Table 1. Proportion of patients with HIV-1 RNA copy levels less than 400 copies/ml and less than 50 copies/ml at 48 weeks in subgroups (pooled data from TORO1 and TORO2, ITT).

¹Discontinuation of treatment or lack of virological response was considered as therapy failure.

²Based on the genotypic sensitivity score (GSS).

Use in children

Data on the efficacy of Fuzeon^® in children over 3 years of age are limited. When conducting combination therapy with Fuzeon^® 60 mg/m² with background antiretroviral therapy in patients aged from 3 to 12 years, by week 48, 43% of patients had a reduction of >1 log₁₀ HIV-1 RNA and 29% of patients had an HIV-1 RNA level below 400 copies/ml. The mean changes in HIV-1 RNA and CD4 cell count were 1.24 log₁₀ copies/ml and 237 cells/µl, respectively.

Preclinical safety data

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

Mutagenesis: Enfuvirtide did not show mutagenic or clastogenic properties in a series of in vivo and in vitro assays, including the Ames reverse mutation test in bacteria, the early gene mutation assay in Chinese hamster ovary AS52 cell line, and the in vivo micronucleus assay in mice.

Impairment of fertility: Enfuvirtide had no adverse effects on fertility in male and female rats at doses exceeding the maximum recommended human daily dose by 0.7, 2.5, and 8.3 times, calculated in mg/kg subcutaneously.

Pharmacokinetics

Absorption

After a single subcutaneous (s.c.) administration of 90 mg enfuvirtide into the anterior abdominal wall area to HIV-1 patients, the maximum concentration (C_max) is 4.59±1.5 µg/ml, the area under the concentration-time curve (AUC) is 55.8±12.1 µg x h/ml and the absolute bioavailability is 84.3±15.5%. When administered subcutaneously in doses from 45 to 180 mg, the bioavailability of enfuvirtide is proportional to the administered dose. Absorption does not depend on the injection site. The mean minimum steady-state plasma concentration of enfuvirtide between two administrations is 2.6-3.4 µg/ml.

Distribution

The mean volume of distribution at steady state after intravenous administration of 90 mg is 5.5±1.1 L. In HIV-infected plasma, Enfuvirtide at concentrations from 2-10 µg/ml is 92% bound to plasma proteins, mainly albumin and, to a lesser extent, α₁-acid glycoprotein.

In HIV-infected patients, the level of enfuvirtide in the cerebrospinal fluid is negligible. The drug molecules are probably too large to cross the blood-brain barrier.

Metabolism

Enfuvirtide, being a peptide, undergoes catabolism to its constituent amino acids, followed by their metabolism in the body.

Enfuvirtide is not an inhibitor of cytochrome CYP450 enzymes.

In vitro, hydrolysis of the amide group of the C-terminal amino acid phenylalanine leads to the formation of a deaminated metabolite, and the formation of this metabolite is independent of NADP-H. This metabolite is detected in human plasma after administration of enfuvirtide with an AUC of 2.4-15% of the enfuvirtide AUC.

Excretion

Labeled ³Enfuvirtide is not completely detected in rodent excreta within 7 days after dose administration. Retention of radioactivity was noted in skeletal muscles.

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

Pharmacokinetics in special clinical cases

Patients with hepatic impairment: the pharmacokinetics of enfuvirtide in patients with hepatic impairment has not been studied.

Patients with renal impairment: analysis of plasma concentrations in patients in clinical studies showed that the clearance of enfuvirtide did not show dependence on creatinine clearance in patients with creatinine clearance greater than 35 ml/min. According to a clinical study of patients with renal impairment, the clearance of enfuvirtide decreased by 38% in patients with severe renal impairment and by 14-28% in patients with end-stage renal disease on dialysis, and the AUC of enfuvirtide increased by an average of 43-62% in both groups compared to patients with normal renal function. The results obtained were within the range recorded in large-scale studies conducted in patients with normal renal function. Hemodialysis did not significantly affect the clearance of enfuvirtide. Dose adjustment for patients with renal impairment is not required.

Gender and weight: the clearance of enfuvirtide is 20% lower in women than in men and increases with increasing body weight regardless of gender (20% higher in patients weighing 100 kg and 20% lower in patients weighing 40 kg, relative to a reference patient weighing 70 kg). These changes are not clinically significant and do not require dose adjustment.

Race: no racial differences in drug clearance were found between Blacks and Asians compared to Caucasians after appropriate exposure adjustment for body weight.

Elderly patients: the pharmacokinetics of enfuvirtide in patients aged 65 years and older has not been studied.

Children: in children from 3 to 16 years of age when prescribed at a dose of 2 mg/kg twice daily (not more than 90 mg twice daily), plasma concentrations of enfuvirtide were observed similar to those achieved in adult patients receiving the drug at a dose of 90 mg twice daily.

In children aged 5 to 16 years receiving Enfuvirtide at a dose of 2 mg/kg twice daily, the steady-state AUC is 54.3±23.5 µg x h/ml, C_max is 6.14±2.48 µg/ml and C_min between administrations is 2.93±1.55 µg/ml.

Indications

• Therapy of HIV-1 infection in combination with other antiretroviral agents in case of ineffectiveness of previous therapy.

ICD codes

Dosage Regimen

Standard dosing regimen

The drug should be administered daily, subcutaneously into the shoulder area, anterior thigh, or anterior abdominal wall. It is necessary to change the site of each subsequent injection and administer the drug where there is currently no reaction to the injection.

Adults are prescribed 90 mg twice daily.

Dosing in special cases

Information on the use of the drug in children under 6 years of age is not provided.

Children aged 6-16 years are prescribed 2 mg/kg twice daily. The maximum dose is 90 mg twice daily (see Table 2).

Table 2. Doses recommended in pediatric practice

Dose adjustment of the drug in patients with renal impairment is not required.

Information on the use of the drug in patients with hepatic impairment is not provided.

The dosage regimen for patients over 65 years of age has not been established.

Fuzeon^® does not contain preservatives. The lyophilized powder should be reconstituted with sterile water for injections to obtain a solution. If the prepared solution is not used immediately, it must be stored in the refrigerator (2-8°C (17.6°F)) and used within 24 hours. Before administration, the prepared solution from the refrigerator should be brought to room temperature (for example, by holding it in the hand for about 5 minutes) and it should be checked whether the contents of the vial have completely dissolved. The reconstituted solution should not be used if it contains mechanical particles.

Information for the patient

Syringes

The syringes supplied with this medicinal product have a colored safety device attached to the needle that covers it after the syringe is used and reduces the risk of needle stick injuries.

Used syringes must be disposed of properly and in accordance with the doctor’s recommendations.

Safety requirements

Wash hands thoroughly to reduce the risk of bacterial infections.

Do not touch the needle and the top of the vial stopper after they have been wiped with an alcohol wipe.

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

Do not use a syringe with a bent or damaged needle.

Do not reconstitute the medicinal product with plain water.

Do not administer Fuzeon^® together with other injectable medicinal products.

The drug is administered only subcutaneously. The Fuzeon^® solution must not be administered intravenously (directly into a vein) or intramuscularly (directly into a muscle).

Do not inject the drug into a site where there is a reaction from a previous injection; rotate injection sites.

Do not miss an injection; a break in treatment leads to virus resistance.

For questions regarding the safe disposal of used materials, consult your doctor.

Preparation for injection

Necessary materials

For the preparation and self-administration of the injection, the following are required:

1 vial with Fuzeon^®;

1 vial with water for injections;

1 syringe 3 ml with a 25 mm needle;

1 syringe 1 ml with a 13 mm needle;

3 alcohol swabs.

If it is necessary to purchase water for injections, 3 ml and 1 ml syringes, or alcohol swabs, contact your doctor.

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

The packaging and vial caps should be discarded into a waste bin.

Place the syringes and stand the vials on a clean surface.

Wash hands thoroughly!

After washing hands, do not touch anything except the injection site and the necessary supplies.

Wipe the rubber stoppers of each vial with a separate new alcohol swab. Allow them to air dry.

Do not touch the rubber stoppers; otherwise, they must be wiped again.

Preparation of Fuzeon^® (reconstitution)

Drawing water for injections into the syringe

Take the large 3 ml syringe. Use your index finger to bend the colored needle protection device towards the syringe.

Ensure the needle is firmly attached to the syringe. To do this, while holding the transparent plastic cap with your fingers, secure the needle by gently turning the cap clockwise. Do not apply excessive force, as the needle attachment may be damaged.

To remove the transparent plastic cap from the needle, first press the cap towards the syringe, then pull it off in the opposite direction.

Draw 1.1 ml of air into the syringe.

Pierce the rubber stopper of the water for injections vial with the syringe needle and inject the air from the syringe into the vial by pressing the plunger.

Turn the vial upside down. Ensure the tip of the needle remains in the water to avoid forming air bubbles in the syringe.

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

Holding the syringe with the needle up, gently tap the syringe with your finger so that air bubbles collect at the top of the syringe.

Gently press the plunger to expel the remaining air from the syringe, leaving exactly 1.1 ml of water for injections in it.

Remove the needle from the vial, without touching it with your fingers or any other objects.

Discard the water for injections vial into the trash, as it is for single use only.

Adding water for injections to the Fuzeon^® powder

Gently tap the Fuzeon^® vial to loosen the powder.

Pierce the rubber stopper of the Fuzeon^® vial (previously cleaned with an alcohol swab) with the needle of the syringe containing water for injections, at a slight angle.

Slowly and carefully press the syringe plunger to inject the water into the vial**, do not inject the water quickly or direct a strong stream of water onto the powder,as this may cause foaming and require more time for the powder to dissolve completely.

After injecting all the water into the Fuzeon^® vial, remove the needle from the vial.

Holding the syringe in one hand, gently press the flat surface of the colored needle protection device until it covers the needle. You should hear a click. Do not press the needle protection device with your hand.

Dissolution of Fuzeon^®

Gently tap the vial with your fingertip until the powder begins to dissolve. Gently roll the vial between your palms. Set the vial down. Do not shake or invert the vial, as this will create foam. It may take up to 45 minutes for the powder to dissolve completely and for the solution to be ready.

If you accidentally touch the rubber stopper, it must be wiped again with a new alcohol swab.

Ensure the powder has dissolved completely. There should be no particles or air bubbles present. If air bubbles persist, gently tap the vial.

If foreign particles or bubbles are visible in the solution, do not use this vial and contact the pharmacy where you purchased it.

Repeat the reconstitution procedure with a new vial of Fuzeon^®.

The prepared solution must be used immediately 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 at once, you must use separate syringes, vials of water for injections, and vials of Fuzeon^® for the preparation of each dose.

Preparation for injection

Injections are administered subcutaneously in the abdomen, thigh, and upper arm areas. Injections must be performed daily at the same time and evenly distributed throughout the day (morning and evening with a 12-hour interval).

Injection sites

Do not administer the drug injections into the same spot. Do not inject the medication into birthmarks, scar tissue, hematomas, or the navel, into areas with indurations and/or reactions from previous injections. Also, avoid areas that may be irritated by a belt or clothing waistband.

Preparing the injection site

Thoroughly wipe the skin at the injection site with an alcohol swab using circular motions from the center to the periphery. Wait for the treated area to dry.

Drawing Fuzeon^® into the 1 ml syringe

Wipe the stopper of the Fuzeon^® vial again with an alcohol swab.

Take the 1 ml syringe in your hand. Use your index finger to bend the colored needle protection device towards the syringe.

To remove the transparent plastic cap from the needle, first press it towards the syringe, then pull it off in the opposite direction.

Draw 1 ml of air into the syringe. Do not pull the plunger back too quickly, as it may go past the 1 ml mark and/or come out of the syringe.

Pierce the rubber stopper of the Fuzeon^® vial (previously cleaned with an alcohol swab) with the syringe needle and, by pressing the plunger, push the air out of the syringe. Carefully turn the vial upside down.

Ensure the tip of the needle remains in the solution to avoid forming air bubbles in the syringe.

Slowly pull back the plunger and draw slightly more than 1 ml of solution into the syringe. Do not pull the plunger back too quickly, as it may go past the 1 ml mark and/or come out of the syringe barrel.

Gently tap the syringe so that air bubbles collect at the top of the syringe.

Smoothly press the plunger to expel the air from the syringe back into the vial, leaving 1 ml of solution or the volume prescribed by your doctor in the syringe.

Remove the needle from the vial.

Drug administration

Do not miss an injection! A break in treatment leads to virus resistance!

With one hand, pinch the skin to form a fold.

Insert the needle completely under the skin at a 45°C (113°F) angle, release the skin fold, and place that hand on the syringe to hold it steady and prevent movement.

Using the thumb of the hand holding the syringe, press the plunger and inject the medication.

After administering the entire dose, remove the needle from the skin.

Holding the syringe in one hand, gently press the flat surface of the colored needle protection device until it covers the needle. You should hear a click. Do not press the needle protection device with your hand.

If blood appears at the injection site, use a bandage.

Disposal of used materials

All used syringes must be collected and stored in places inaccessible to children. Consult your doctor for disposal rules.

Fuzeon^® vials are for single use only. Used swabs and empty vials can be discarded in the trash if there are no visible traces of blood. If blood traces are present, such materials should be stored together with used syringes (see above).

For questions regarding the safe disposal of used materials, consult your doctor.

Adverse Reactions

Adverse events reported in at least 2 adult patients per 100 patient-years with an adverse event receiving Fuzeon^® in combination with an optimized background (OB) ART regimen

Nervous system and peripheral nervous system disorders headache, peripheral neuropathy, dizziness, taste disturbance, insomnia, depression, anxiety, nightmares, irritability, hypoesthesia, attention disturbances, tremor.

Gastrointestinal system disorders nausea, upper abdominal pain, constipation, diarrhea, pancreatitis.

Urinary system disorders: kidney stones, hematuria.

Hematopoietic system disorders lymphadenopathy.

Respiratory system disorders cough.

Musculoskeletal system disorders myalgia, arthralgia, back pain, limb pain, muscle spasm.

Infections oral candidiasis, herpes simplex, skin papilloma, influenza, sinusitis, folliculitis, otitis, pneumonia.

Skin and subcutaneous tissue disorders pruritus, night sweats, dry skin, hyperhidrosis, seborrheic eczema, erythema, acne.

Eye disorders conjunctivitis.

Ear and labyrinth disorders: vertigo.

Hypersensitivity reactions rash, pruritus, fever, nausea and vomiting, chills, rigors, arterial hypotension, elevated serum hepatic transaminase levels, primary immune complex reaction, respiratory distress syndrome, glomerulonephritis.

General disorders and administration site conditions weakness, weight decreased, decreased appetite, anorexia, asthenia, sore throat, flu-like syndrome.

Laboratory findings

In most patients, the severity grade of the laboratory parameter change did not change during the study.

Over 48 weeks of therapy, eosinophilia (above the upper limit of normal (ULN) 0.7×10⁹/L) occurred more frequently in patients receiving Fuzeon^® combination therapy with optimized background therapy compared to those receiving optimized background therapy alone (12.9 patients compared to 5.6 patients per 100 patient-years).

Table 3: Grade 3 and 4 laboratory abnormalities occurring in 2 patients with adverse events per 100 patient-years receiving Fuzeon^® in combination with optimized background therapy or optimized background therapy alone.

Local reactions: pain, injection site discomfort, induration, erythema, nodule, cyst, pruritus, ecchymosis; rarely (1.5%) – abscess and cellulitis.

Table 4. Local reactions (% of patients).

*Any severity grade

^bGrade 3 = severe pain requiring analgesic use (or narcotic analgesics for ≤72 hours) and/or limiting usual activities; Grade 4 = severe pain requiring hospitalization or prolongation of hospitalization, resulting in death, or persistent or significant disability/incapacity, life-threatening, or clinically significant.

^cGrade 3 = mean diameter ≥50 mm, but mean diameter <85 mm; Grade 4: mean diameter ≥85 mm.

^dGrade 3 = mean diameter ≥25 mm, but mean diameter <50 mm; Grade 4: mean diameter ≥50 mm.

^eGrade 3 = ≥3 cm; Grade 4 = if drainage is performed.

^fGrade 3 = refractory to topical treatment or requiring oral or parenteral treatment; Grade 4 = not defined.

^gGrade 3 = >3 cm, but <5 cm; Grade 4 = > 5 cm.

The adverse event profile in children is similar to that in adults.

Contraindications

• Breastfeeding;
• Hypersensitivity to enfuvirtide or to any component of the drug.

Use with caution – pregnancy.

Use in Pregnancy and Lactation

Enfuvirtide showed no teratogenic effects in animal studies (rats and rabbits) at a dose 8.9 times the human therapeutic dose. Adequate and well-controlled clinical studies on the safety of the drug during pregnancy have not been conducted. Use of the drug during pregnancy is only possible if the anticipated benefit for the mother outweighs the potential risk to the fetus.

When radiolabeled H³-enfuvirtide was administered to lactating rats, very low levels of radioactivity were present in the milk. If it is necessary to use the drug during lactation, breastfeeding should be discontinued before starting therapy due to the lack of data on the excretion of the active substance in breast milk, as well as to avoid transmission of HIV to the child.

Use in Hepatic Impairment

Information on the use of the drug in patients with hepatic impairment is not available.

Use in Renal Impairment

Dosage adjustment in patients with renal impairment is not required.

Pediatric Use

Information on the use of the drug in children under 6 years of age is not available.

Children aged 6-16 years are prescribed 2 mg/kg twice daily. The maximum dose is 90 mg twice daily.

Geriatric Use

The dosage regimen for patients over 65 years of age has not been established.

Special Precautions

Fuzeon^® should be prescribed only in combination with other antiretroviral drugs.

Patients with symptoms suggestive of a systemic hypersensitivity reaction should discontinue treatment and seek immediate medical evaluation. Treatment should not be resumed after the occurrence of systemic reactions potentially associated with the drug. Risk factors that may predispose to the development or severity of hypersensitivity reactions to Fuzeon^® have not been identified.

During therapy with Fuzeon^®, an increased incidence of bacterial pneumonia was observed (6.6 patients with pneumonia compared to 0.6 per 100 patient-years in the groups receiving Fuzeon^® combination therapy with OB and OB alone, respectively; the analysis included bronchopneumonia and related events), which was fatal in some cases. The incidence of pneumonia during Fuzeon^® therapy was similar to that in the general patient population (literature data), but was lower in the control group. A causal relationship between pneumonia and Fuzeon^® therapy has not been established. Risk factors for pneumonia include low baseline CD4 lymphocyte count, high viral load, intravenous drug use, smoking, and a history of lung disease. Patients should be carefully monitored for signs and symptoms of infection, especially if they have risk factors for pneumonia.

The most frequent adverse events (based on the results of the TORO1 and TORO2 studies) during Fuzeon^® therapy were injection site reactions (98%). However, treatment discontinuation was required in only 4% of patients. The vast majority of local reactions (85%) were mild to moderate in severity, occurred during the first week of treatment, and did not lead to limitations in usual activities. The severity of pain and discomfort did not increase with continued treatment. The number of local lesions observed at scheduled physician visits during the clinical study was less than 5 in 72% of patients with such events.

Administration of Fuzeon^® to individuals not infected with HIV-1 (e.g., for post-exposure prophylaxis) may lead to the development of anti-Enfuvirtide antibodies that cross-react with HIV gp41. This may lead to a false-positive HIV test when using an HIV antibody ELISA.

Immune reconstitution syndrome (synonyms – immune reactivation syndrome, immune restoration disease, inflammatory immune reconstitution syndrome) has been observed in patients receiving combination antiretroviral therapy, including Fuzeon^®. At the initiation of combination 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.

Effect on ability to drive and operate machinery

There is no evidence that Fuzeon^® may affect the ability to drive and operate machinery; however, consideration should be given to adverse effects that may occur during the administration of Fuzeon^® (see the “Adverse Reactions” section).

Information on the use of the drug in children under 6 years of age is not available.

Overdose

There is no information on overdose of Fuzeon^® in humans.

The maximum dose administered was 180 mg as a single subcutaneous injection. No cases of overdose have been described when following the recommended dosage regimen.

Treatment is symptomatic. There is no specific antidote for Fuzeon^® overdose.

Drug Interactions

No clinically significant pharmacokinetic interactions between enfuvirtide and drugs metabolized by cytochrome P450 enzymes have been established.

Enfuvirtide is not an inhibitor of 3A4, 2D6, 1A2, 2C19, 2E1 enzymes and therefore does not affect the metabolism of drugs involving these enzymes.

Co-administration of Fuzeon^® with ritonavir, saquinavir, and rifampicin did not lead to clinically significant pharmacokinetic interactions.

Enfuvirtide is not displaced from its protein binding sites by saquinavir, nelfinavir, lopinavir, efavirenz, nevirapine, amprenavir, itraconazole, midazolam, or warfarin. Enfuvirtide does not displace warfarin, midazolam, amprenavir, or efavirenz from their protein binding sites.

The drug Fuzeon^® should not be mixed with other medicinal products, except for the supplied solvent (water for injections).

Storage Conditions

List B. The drug should be stored out of the reach of children, at a temperature not exceeding 30°C (86°F).

After reconstitution, the solution should be stored at a temperature of 2-8°C (17.6°F) for 24 hours, protected from light.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.