Chemical formula: C₂₅₈₀H₃₉₁₈N₆₈₀O₇₂₇S₁₇
The limited available data on taliglucerase alfa use in pregnant women are not sufficient to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations]. In animal reproduction studies when pregnant rats and rabbits were administered taliglucerase alfa at intravenous doses up to 5 times the recommended human dose (RHD), there was no evidence of embryo-fetal toxicity [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. 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.
Women with Type 1 Gaucher disease have an increased risk of spontaneous abortion if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Type 1 Gaucher disease manifestations may lead to adverse pregnancy outcomes, including hepatosplenomegaly which can interfere with the normal growth of a fetus and thrombocytopenia which can lead to increased bleeding and possible postpartum hemorrhage requiring transfusion.
Reproduction studies have been performed with taliglucerase alfa administered during the period of organogenesis in rats and rabbits. In rats, intravenous doses up to 55 mg/kg/day (about 5 times the RHD of 60 units/kg based on the body surface area) did not cause any adverse effects on embryo-fetal development. In rabbits, intravenous doses up to 27.8 mg/kg/day (about 5 times the RHD of 60 units/kg based on the body surface area) did not show any embryo-fetal toxicity.
There are no data on the presence of taliglucerase alfa in human milk, the effects on the breast fed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for taliglucerase alfa and any potential adverse effects on the breastfed child from taliglucerase alfa or from the underlying maternal condition.
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with taliglucerase alfa. In a male and female fertility study in rats, taliglucerase alfa did not cause any significant adverse effect on male or female fertility parameters up to a maximum dose of 55 mg/kg/day (about 5 times the recommended human dose of 60 units/kg based on the body surface area).
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.
The safety of taliglucerase alfa at dosages of either 30 units/kg (n=16) or 60 units/kg (n=16) every other week was assessed in 32 adult treatment-naïve patients (aged 19 to 74 years) with Type 1 Gaucher disease in a 9-month double-blind, randomized clinical trial.
Table 1. Adverse Reactions in ≥5% of Treatment-Naïve Adult Patients Treated with Taliglucerase alfa:
| Preferred Term | Treatment-Naïve Adults (N=32) n (%) |
|---|---|
| Headache | 6 (19) |
| Arthralgia | 4 (13) |
| Fatigue | 3 (9) |
| Nausea | 3 (9) |
| Dizziness | 3 (9) |
| Abdominal pain | 2 (6) |
| Pruritus | 2 (6) |
| Flushing | 2 (6) |
| Vomiting | 2 (6) |
| Urticaria | 2 (6) |
The safety of taliglucerase alfa at dosages of either 30 units/kg (n=4) or 60 units/kg (n=5) every other week was assessed in 9 pediatric treatment-naïve patients (aged 2 to 13 years) with Type 1 Gaucher disease in a 12-month randomized clinical trial.
The most common adverse reaction (≥10%) was vomiting, which occurred in 4 of 9 patients. Two patients developed hypersensitivity reactions; one patient experienced severe vomiting and gastrointestinal inflammation, and 1 experienced mild throat irritation and chest discomfort. Both patients responded to treatment with antihistamines and continued taliglucerase alfa treatment.
The safety of taliglucerase alfa was assessed in 31 patients (26 adult and 5 pediatric patients), ages 6 to 66 years old, with Type 1 Gaucher disease who had previously been receiving treatment with imiglucerase for a minimum of 2 years. Taliglucerase alfa was administered for 9 months at the same number of units as each patient’s previous imiglucerase dose.
Table 2. Adverse Reactions in ≥10% of Patients Switched from Imiglucerase to Taliglucerase alfa (after 9 months on treatment):
| Preferred Term | Patients Switched from Imiglucerase (N=31; 26 adults and 5 children) n (%) |
|---|---|
| Arthralgia | 4 (13) |
| Headache | 4 (13) |
| Pain in extremity | 3 (10) |
As with all therapeutic proteins, 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 the studies described below with the incidence of antibodies in other studies or to other taliglucerase alfa products may be misleading.
In a clinical trial of treatment-naïve adults, 17 (53%) of 32 patients developed ADA during treatment with taliglucerase alfa, and 2 (6%) of 32 patients tested positive for ADA at baseline prior to taliglucerase alfa treatment. Of the 17 patients who developed ADA during taliglucerase alfa treatment, 6 patients (35%) developed hypersensitivity reactions, 2 of whom met criteria for anaphylaxis. Two of the 17 patients who developed ADA during taliglucerase alfa treatment discontinued treatment due to hypersensitivity reactions, one of whom had met criteria for anaphylaxis. Of the 2 patients who tested positive for ADA prior to initiation of taliglucerase alfa treatment, one patient developed a hypersensitivity reaction during the first dose of taliglucerase alfa and withdrew from the study. The second patient did not experience a hypersensitivity reaction.
In a clinical trial of treatment-naïve pediatric patients, 2 (22%) of 9 patients developed ADA during treatment with taliglucerase alfa, and one of 9 patients was ADA-positive prior to initiation of taliglucerase alfa. Two of these 3 patients experienced hypersensitivity reactions (1 who developed ADA during treatment and became negative after Week 12 and 1 who was ADA-positive at baseline and became ADA negative after Week 8) and continued treatment with taliglucerase alfa. The third patient who developed ADA during treatment and continued to be ADA-positive until study completion at Week 52 did not experience a hypersensitivity reaction.
In clinical trials of 31 patients (26 adult and 5 pediatric patients) who switched from imiglucerase to taliglucerase alfa treatment, 5 adults (16% of patients) developed ADA during treatment with taliglucerase alfa. Four additional patients (13%, 2 adults and 2 children) tested positive for ADA at baseline but became ADA-negative after the switch to taliglucerase alfa; one of these adult patients subsequently developed ADA to taliglucerase alfa. Two adult patients (1 patient who developed ADA after the switch and 1 who was ADA positive at baseline) experienced hypersensitivity reactions. Both patients continued treatment with taliglucerase alfa.
The relationship between ADA and hypersensitivity reactions is not fully understood. Monitoring for ADA to taliglucerase alfa may be useful in ADA positive patients or in patients who have experienced hypersensitivity reactions to taliglucerase alfa or other enzyme replacement therapies.
Thirty (30) of the 31 adult and pediatric patients who developed ADA to taliglucerase alfa during treatment or tested positive for ADA at baseline were evaluated for neutralizing activity of the ADA in the mannose receptor binding and enzyme activity assays. Nineteen (63%) of the 30 patients had neutralizing antibodies capable of inhibiting mannose receptor binding of taliglucerase alfa. Eight of these 19 patients had neutralizing antibodies capable of inhibiting the enzymatic activity of taliglucerase alfa. Available data do not indicate a clear relationship between the presence of mannose receptor binding neutralizing antibodies or neutralizing antibodies capable of inhibiting the enzymatic activity of taliglucerase alfa and the therapeutic response to taliglucerase alfa.
Nine (29%) of the 31 adult and pediatric patients who developed ADA to taliglucerase alfa during treatment or tested positive for ADA at baseline also developed antibodies against plant-specific glycans in taliglucerase alfa.
The following adverse reactions have been identified during post-approval use of taliglucerase alfa. Because these reactions include those reported voluntarily from a population of uncertain size in addition to those from postmarketing studies, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
Gastrointestinal disorders: Vomiting, diarrhea
General disorders and administration site conditions: Fatigue
Immune system disorders: Anaphylaxis, Type III immune-mediated fixed drug eruption
Musculoskeletal and connective tissue disorders: Back pain
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