Hydrolytic Lysosomal Glycosaminoglycan-specific Enzyme

Vimizim

Approved 14 Feb 2014InjectionInjectable

Indications

VIMIZIM (elosulfase alfa) is indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). VIMIZIM is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). ( 1 )

Contraindications

None. None. ( 4 )

Warnings and precautions

Risk of Acute Respiratory Complications: Patients with acute febrile or respiratory illness may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient's clinical status prior to administration of VIMIZIM and consider delaying the VIMIZIM infusion. ( 5.2 )

5.1Hypersensitivity Reactions Including Anaphylaxis

Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with enzyme replacement therapies, including VIMIZIM. In premarketing clinical trials, 18 of 235 (7.7%) patients treated with VIMIZIM experienced signs and symptoms consistent with anaphylaxis. These 18 patients experienced 26 anaphylactic reactions during infusion with signs and symptoms including cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and gastrointestinal symptoms (e.g., nausea, abdominal pain, retching, and vomiting) in conjunction with urticaria.

These cases of anaphylaxis occurred as early as 30 minutes from the start of infusion and up to three hours after infusion. Anaphylaxis occurred as late into treatment as the 47 th infusion. In clinical trials with VIMIZIM, 44 of 235 (18.7%) patients experienced hypersensitivity reactions, including anaphylaxis. Hypersensitivity reactions have occurred as early as 30 minutes from the start of infusion but as late as six days after infusion.

Frequent symptoms of hypersensitivity reactions (occurring in more than 2 patients) included anaphylactic reactions, urticaria, peripheral edema, cough, dyspnea, and flushing. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of VIMIZIM should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.

Warnings and precautions

5.1Hypersensitivity Reactions Including Anaphylaxis

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Available data from published case reports, a registry with a pregnancy sub-study and pharmacovigilance reports with VIMIZIM use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Limitations of the available data include a small number of exposed cases and missing data. In animal reproduction studies, no effects on embryo-fetal development were observed in rats given daily administration of elosulfase alfa up to 33 times the human steady-state AUC (area under the concentration-time curve) at the recommended human weekly dose pre-mating and through the period of organogenesis.

No effects on embryo-fetal development were observed in rabbits given daily administration of elosulfase alfa at doses up to 8 times the human steady-state AUC at the recommended weekly dose during organogenesis, which produced maternal toxicity. A dose-dependent increase in stillbirths was observed when elosulfase alfa was administered daily in rats during organogenesis through lactation at doses 5 times the human steady-state AUC at the recommended human weekly dose.

An increase in pup mortality was observed at doses producing maternal toxicity. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Disease-associated maternal and embryo/fetal risk Pregnancy can exacerbate preexisting clinical manifestations of MPS and lead to adverse outcomes for both mother and fetus. Data Animal Data All reproductive studies with rats included pre-treatment with diphenhydramine to prevent or minimize hypersensitivity reactions. The effects of elosulfase alfa were evaluated based on comparison to a control group treated with diphenhydramine alone.

Daily intravenous administration of up to 20 mg/kg elosulfase alfa in rats (33 times the human steady-state AUC at the recommended weekly dose of 2 mg/kg) during a 15-day pre-mating period, mating, and the period of organogenesis, produced no maternal toxicity or effects on embryo-fetal development. Daily intravenous administration of up to 10 mg/kg in rabbits (8 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis had no effects on embryo-fetal development.

However, maternal toxicity (gross changes in liver) was observed in rabbits given doses of 1 mg/kg/day and higher (0.1 times the human steady-state AUC at the recommended weekly dose). Elosulfase alfa produced an increase in the percentage of stillbirths when administered daily to rats at intravenous doses of 6 mg/kg and higher (5 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis through lactation.

Daily intravenous administration of 20 mg/kg (33 times the human steady-state AUC at the recommended weekly dose) produced maternal toxicity and an increase in mortality of offspring during the lactation period. This study lacked a full evaluation of neurodevelopmental milestones; however, no effects of elosulfase alfa were noted in tests for learning and memory .

Adverse reactions

The following serious adverse reactions are described below and elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] . Risk of Acute Respiratory Complications [see Warnings and Precautions (5.2) ] . Spinal or Cervical Cord Compression [see Warnings and Precautions (5.3) ] . Most common adverse reactions (≥10%) are: pyrexia, vomiting, headache, nausea, abdominal pain, chills, and fatigue.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin at 1-866-906-6100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

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 in the clinical trials of another drug and may not reflect the rates observed in practice. A 24-week, randomized, double-blind, placebo-controlled clinical trial of VIMIZIM was conducted in 176 patients with MPS IVA, ages 5 to 57 years old. Approximately half of the patients (49%) were male.

Of the 176 patients, 65% were White, 23% Asian, 3% Black, and 10% Other race. The majority of patients (78%) were non-Hispanic. Patients were randomized to three treatment groups: VIMIZIM 2 mg/kg once per week (n=58), VIMIZIM 2 mg/kg once every other week (n=59), or placebo (n=59). All patients were treated with antihistamines prior to each infusion. Table 3 summarizes the most common adverse reactions that occurred in the placebo-controlled trial with an incidence of ≥ 10% in patients treated with VIMIZIM 2 mg/kg once per week and with a higher incidence than in the placebo-treated patients.

Table 3: Adverse Reactions That Occurred in the Placebo-Controlled Trial in At Least 10% of Patients in the VIMIZIM 2 mg/kg Once Per Week Group and with a Higher Incidence than in the Placebo Group Adverse Reaction VIMIZIM 2 mg/kg once per week Placebo N= 58 n (%) N= 59 n (%) Pyrexia 19 (33%) 8 (14%) Vomiting 18 (31%) 4 (7%) Headache 15 (26%) 9 (15%) Nausea 14 (24%) 4 (7%) Abdominal pain 12 (21%) 1 (2%) Chills 6 (10%) 1 (2%) Fatigue 6 (10%) 2 (3%) Extension Trial An open-label extension trial was conducted in 173 patients who completed the placebo-controlled trial [see Clinical Studies (14) ] .

No new adverse reactions were reported.

6.2 Immunogenicity As with all therapeutic proteins, including VIMIZIM, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies in other studies or to other elosulfase alfa products may be misleading. All patients treated with VIMIZIM 2 mg/kg once per week in the placebo-controlled trial developed anti-drug antibodies by Week 4. Anti-drug antibody titers were sustained or increased for the duration of VIMIZIM treatment. Because all patients developed anti-drug antibodies, associations between antibody titers and reductions in treatment effect or the occurrence of anaphylaxis or other hypersensitivity reactions could not be determined.

All patients treated with VIMIZIM 2 mg/kg once per week tested positive for neutralizing antibodies capable of inhibiting the drug from binding to the mannose-6-phosphate receptor at least once during the trial. Binding to this receptor is required for VIMIZIM to be taken into cells where it is active. Neutralizing antibody titers were not determined in the patients. Therefore, the possibility of an association between neutralizing antibody titer and treatment effect cannot be assessed.

Vimizim

Indications

Contraindications

Warnings and precautions

5.1Hypersensitivity Reactions Including Anaphylaxis

Two medicines in one question?

Vimizim

Indications

Contraindications

Warnings and precautions

5.1Hypersensitivity Reactions Including Anaphylaxis

Two medicines in one question?

5.2Risk of Acute Respiratory Complications Patients

5.3Spinal or Cervical Cord Compression Spinal

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

Composition

Official product information

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