наглазим

Overdose

No information provided.

Contraindications

None.

Pharmaceutical form

Undesirable effects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Наглазим was studied in a randomized, double-blind, placebo-controlled trial in which 19 patients received weekly infusions of 1 mg/kg Наглазим and 20 patients received placebo; of the 39 patients 66% were female, and 62% were White, non-Hispanic. Patients were aged 5 years to 29 years. Наглазим-treated patients were approximately 3 years older than placebo-treated patients (mean age 13.7 years versus 10.7 years, respectively).

Serious adverse reactions experienced in this trial include apnea, pyrexia, and respiratory distress. Severe adverse reactions include chest pain, dyspnea, laryngeal edema, and conjunctivitis. The most common adverse reactions requiring interventions were infusion reactions.

Table 1 summarizes the adverse reactions that occurred in the placebo-controlled trial in at least 2 patients more in the Наглазим-treated group than in the placebo-treated group.

Table 1: Adverse Reactions that Occurred in the Placebo-Controlled Trial in at least 2 Patients More in the Наглазим Group than in the Placebo Group

Four open-label clinical trials were conducted in MPS VI patients aged 3 months to 29 years with Наглазим administered at doses of 0.2 mg/kg (n = 2), 1 mg/kg (n = 55), and 2 mg/kg (n = 2). The mean exposure to the recommended dose of Наглазим (1 mg/kg) was 138 weeks (range = 54 to 261 weeks). Two infants (12.1 months and 12.7 months) were exposed to 2 mg/kg of Наглазим for 105 and 81 weeks, respectively.

In addition to those listed in Table 1, common adverse reactions observed in the open-label trials include pruritus, urticaria, pyrexia, headache, nausea, and vomiting. The most common adverse reactions requiring interventions were infusion reactions. Serious adverse reactions included laryngeal edema, urticaria, angioedema, and other allergic reactions. Severe adverse reactions included urticaria, rash, and abdominal pain.

Observed adverse events in four open-label studies (up to 261 weeks treatment) were not different in nature or severity to those observed in the placebo-controlled study. No patients discontinued during open-label treatment with Наглазим due to adverse events.

Ninety-eight percent (53/54) of patients treated with Наглазим and evaluable for the presence of antibodies to galsulfase developed anti-galsulfase IgG antibodies within 4 to 8 weeks of treatment (in four clinical studies). In 19 patients treated with Наглазим from the placebo-controlled study, serum samples were evaluated for a potential relationship of anti-galsulfase antibody development to clinical outcome measures. All 19 patients treated with Наглазим developed antibodies specific to galsulfase; however, the analysis revealed no consistent predictive relationship between total antibody titer, neutralizing or IgE antibodies, and infusion-associated reactions, urinary glycosaminoglycan (GAG) levels, or endurance measures. Antibodies were assessed for the ability to inhibit enzymatic activity but not cellular uptake.

The data reflect the percentage of patients whose test results were considered positive for antibodies to galsulfase using specific assays and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibodies in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to galsulfase with the incidence of antibodies to other products may be misleading.

The following adverse reactions have been identified during postapproval use of Наглазим. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In addition to infusion reactions reported in clinical trials, serious reactions which occurred during Наглазим infusion in the worldwide marketing experience include anaphylaxis, shock, hypotension, bronchospasm, and respiratory failure.

Additional infusion reactions included pyrexia, erythema, pallor, bradycardia, tachycardia, hypoxia, cyanosis, tachypnea, and paresthesia.

During postmarketing surveillance, there has been a single case of membranous nephropathy and rare cases of thrombocytopenia reported. In the case of membranous nephropathy, renal biopsy revealed galsulfase-immunoglobulin complexes in the glomeruli. With both membranous nephropathy and thrombocytopenia, patients have been successfully rechallenged and have continued to receive Наглазим.

Therapeutic indications

Наглазим (galsulfase) is indicated for patients with Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). Наглазим has been shown to improve walking and stair-climbing capacity.

Pharmacodynamic properties

The responsiveness of urinary GAG to dosage alterations of Наглазим is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. No association was observed between antibody development and urinary GAG levels.

Pharmacokinetic properties

The pharmacokinetic parameters of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg /kg of Наглазим as a weekly 4-hour infusion for 24 weeks. The pharmacokinetic parameters at Week 1 and Week 24 are shown in Table 2.

Table 2: Pharmacokinetic Parameters (Median, Range)

Galsulfase pharmacokinetic parameters listed in Table 2 require cautious interpretation because of large assay variability. Development of anti-galsulfase antibodies appears to affect galsulfase pharmacokinetics, however, the data are limited.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Anaphylaxis and severe allergic reactions have been observed in patients during and up to 24 hours after Наглазим infusion. Some of the reactions were life-threatening and included anaphylaxis, shock, respiratory distress, dyspnea, bronchospasm, laryngeal edema, and hypotension. If anaphylaxis or other severe allergic reactions occur, Наглазим should be immediately discontinued, and appropriate medical treatment should be initiated. In patients who have experienced anaphylaxis or other severe allergic reactions during infusion with Наглазим, caution should be exercised upon rechallenge; appropriately trained personnel and equipment for emergency resuscitation (including epinephrine) should be available during infusion.

Type III immune complex-mediated reactions, including membranous glomerulonephritis have been observed with Наглазим, as with other enzyme replacement therapies. If immune-mediated reactions occur, discontinuation of the administration of Наглазим should be considered, and appropriate medical treatment initiated. The risks and benefits of re-administering Наглазим following an immune-mediated reaction should be considered. Some patients have successfully been rechallenged and have continued to receive Наглазим under close clinical supervision.

Caution should be exercised when administering Наглазим to patients susceptible to fluid volume overload; such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness, or patients with compromised cardiac and/or respiratory function, because congestive heart failure may result. Appropriate medical support and monitoring measures should be readily available during Наглазим infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.

Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes. Evaluation of airway patency should be considered prior to initiation of treatment. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use.

Consider delaying Наглазим infusions in patients who present with an acute febrile or respiratory illness because of the possibility of acute respiratory compromise during infusion of Наглазим.

Because of the potential for infusion reactions, patients should receive antihistamines with or without antipyretics prior to infusion. Despite routine pretreatment with antihistamines, infusion reactions, some severe, occurred in 33 of 59 (56%) patients treated with Наглазим. Serious adverse reactions during infusion included laryngeal edema, apnea, pyrexia, urticaria, respiratory distress, angioedema, and anaphylactoid reaction. Severe adverse reactions included urticaria, chest pain, rash, dyspnea, apnea, laryngeal edema, and conjunctivitis.

The most common symptoms of drug-related infusion reactions were pyrexia, chills, rash, urticaria, dyspnea, nausea, vomiting, pruritis, erythema, abdominal pain, hypertension, and headache. Respiratory distress, chest pain, hypotension, angioedema, conjunctivitis, tremor, and cough were also reported. Infusion reactions began as early as Week 1 and as late as Week 146 of Наглазим treatment. Twenty-three of 33 patients (70%) experienced recurrent infusion reactions during multiple infusions though not always in consecutive weeks.

Symptoms typically abated with slowing or temporary interruption of the infusion and administration of additional antihistamines, antipyretics, and occasionally corticosteroids. Most patients were able to complete their infusions. Subsequent infusions were managed with a slower rate of Наглазим administration, treatment with additional prophylactic antihistamines, and, in the event of a more severe reaction, treatment with prophylactic corticosteroids.

If severe infusion reactions occur, immediately discontinue the infusion of Наглазим and initiate appropriate treatment. The risks and benefits of re-administering Наглазим following a severe reaction should be considered.

No factors were identified that predisposed patients to infusion reactions. There was no association between severity of infusion reactions and titer of anti-galsulfase antibodies.

Spinal or cervical cord compression (SCC) with resultant myelopathy is a known and serious complication of MPS VI. SCC is expected to occur in the natural history of the disease, including in patients on Наглазим. There have been post-marketing reports of patients treated with Наглазим who experienced the onset or worsening of SCC requiring decompression surgery. Patients with MPS VI should be monitored for signs and symptoms of spinal/cervical cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care.

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with galsulfase.

Galsulfase at intravenous doses up to 3.0 mg/kg (about 0.5 times the recommended human dose of 1 mg/kg based on body surface area) was found to have no effect on the fertility and reproductive performance of male and female rats.

Adequate and well-controlled studies have not been conducted with Наглазим in pregnant women. Reproduction studies have been performed in rats at intravenous doses up to 3 mg/kg/day (about 0.5 times the recommended human dose of 1 mg/kg based on the body surface area) and in rabbits at intravenous doses up to 3 mg/kg/day (about 0.97 times the recommended human dose of 1 mg/kg based on the body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to Наглазим. Наглазим should be used during pregnancy only if clearly needed.

Pregnant women with MPS VI who are treated with Наглазим should be encouraged to enroll in the MPS VI Clinical Surveillance Program at 800-983-4587.

It is not known whether Наглазим is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Наглазим is administered to a nursing mother. Nursing mothers with MPS VI who are treated with Наглазим should be encouraged to enroll in the MPS VI Clinical Surveillance Program at 800-983-4587.

Clinical studies with Наглазим were conducted in 56 patients, ages 5 to 29 years, with the majority of these patients in the pediatric age group. In addition, an open-label study was conducted in four infants (3 months to 12.7 months) treated with 1 mg/kg (n = 2) or 2 mg/kg (n = 2) of Наглазим. Safety results in infants were consistent with results observed in patients 5 to 29 years old.

Clinical studies of Наглазим did not include patients older than 29 years of age. It is not known whether older patients respond differently from younger patients.

Dosage (Posology) and method of administration

The recommended dosage regimen of Наглазим is 1 mg per kg of body weight administered once weekly as an intravenous infusion.

Pretreatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion.

The total volume of the infusion should be delivered over a period of time of no less than 4 hours. Наглазим should be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 250 mL and delivered by controlled intravenous infusion using an infusion pump. The initial infusion rate should be 6 mL per hour for the first hour. If the infusion is well tolerated, the rate of infusion may be increased to 80 mL per hour for the remaining 3 hours. The infusion time can be extended up to 20 hours if infusion reactions occur.

For patients 20 kg and under or those who are susceptible to fluid volume overload, physicians may consider diluting Наглазим in a volume of 100 mL. The infusion rate (mL per hour) should be decreased so that the total infusion duration remains no less than 4 hours.

Each vial of Наглазим provides 5 mg of galsulfase (expressed as protein content) in 5 mL of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, using aseptic techniques. Prepare Наглазим using low-protein-binding containers and administer the diluted Наглазим solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 μm in-line filter. There is no information on the compatibility of diluted Наглазим with glass containers.

Prepare and use Наглазим according to the following steps. Use aseptic techniques.

1. Determine the number of vials to be used based on the patient's weight and the recommended dose of 1 mg per kg:
   Patient's weight (kg) x 1 mL/kg of Наглазим = Total number of mL of Наглазим
   Total number of mL of Наглазим ÷ 5 mL per vial = Total number of vials
   Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not allow vials to remain at room temperature longer than 24 hours prior to dilution. Do not heat or microwave vials.
2. Before withdrawing the Наглазим solution from the vial, visually inspect each vial for particulate matter and discoloration. The Наглазим solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution.
3. From a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP, withdraw and discard a volume equal to the volume of Наглазим solution to be added. If using a 100 mL infusion bag, this step is not necessary.
4. Slowly withdraw the calculated volume of Наглазим from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature Наглазим, rendering it biologically inactive.
5. Slowly add the Наглазим solution to the 0.9% Sodium Chloride Injection, USP, using care to avoid agitation of the solutions. Do not use a filter needle.
6. Gently rotate the infusion bag to ensure proper distribution of Наглазим. Do not shake the solution.
7. Administer the diluted Наглазим solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 μm in-line filter.

Наглазим does not contain preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution must be stored refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 48 hours from the time of dilution to completion of administration. Other than during infusion, do not store the diluted Наглазим solution at room temperature. Any unused product or waste material must be discarded and disposed of in accordance with local requirements.

Наглазим must not be infused with other products in the infusion tubing. The compatibility of Наглазим in solution with other products has not been evaluated.