There are no data on the developmental risk associated with the use of inotersen in pregnant women. Inotersen treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking inotersen. Vitamin A is essential for normal embryofetal development; however, excessive levels of Vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by inotersen and of vitamin A supplementation are unknown.
In animal studies, subcutaneous administration of inotersen to pregnant rabbits resulted in premature delivery and reduced fetal body weight at the highest dose tested, which was associated with maternal toxicity. No adverse developmental effects were observed when inotersen or a pharmacologically-active surrogate was administered to pregnant mice.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Subcutaneous administration of inotersen (0, 3, 15, or 25 mg/kg) or a rodent-specific surrogate (15 mg/kg) to male and female mice every other day prior to and during mating and continuing in females throughout the period of organogenesis produced no adverse effects on embryofetal development.
Subcutaneous administration of inotersen (0, 2.5, 5, or 15 mg/kg) to pregnant rabbits every other day throughout the period of organogenesis resulted in premature delivery and reduced fetal body weight at the highest dose tested, which was associated with maternal toxicity (reduced body weight and food consumption).
Subcutaneous administration of inotersen (0, 2.9, 11.4, or 22.9 mg/kg) or a rodent-specific surrogate (11.4 mg/kg) to mice every other day throughout pregnancy and lactation produced no adverse effects on pre- or postnatal development.
There is no information regarding the presence of inotersen in human milk, the effects on the breast-fed infant, or the effects on milk production. A study in lactating mice has shown excretion of inotersen in milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for inotersen and any potential adverse effects on the breastfed infant from inotersen or from the underlying maternal condition.
In a 26-week carcinogenicity study in transgenic (TgRasH2) mice, weekly subcutaneous administration of inotersen (0, 10, 30, or 80 mg/kg) or a rodent-specific (pharmacologically active) surrogate (30 mg/kg) did not result in an increase in tumors.
Inotersen was negative for genotoxicity in in vitro (bacterial mutagenicity, chromosomal aberration in Chinese hamster lung) and in vivo (mouse bone marrow micronucleus) assays.
Subcutaneous administration of inotersen (0, 3, 15, or 25 mg/kg) or a rodent-specific surrogate (15 mg/kg) to male and female mice every other day prior to and during mating and continuing in females throughout the period of organogenesis produced no adverse effects on fertility.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of inotersen cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.
A total of 112 adult patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) received inotersen in Study 1 and 60 patients received placebo. The, mean age of the study patients was 59 years (27 to 78 years of age). Of the inotersen-treated patients, 69% were male and 94% were Caucasian, with a mean exposure of 385 days, and median exposure of 449 days. Baseline disease characteristics were largely similar in inotersen-treated patients and patients in the placebo control group. Sixty-seven percent of patients were in Stage 1 of the disease at baseline, and 33% in Stage 2. Fifty-two percent of patients had Val30Met mutations in the TTR gene, with the remaining 48% comprised of 26 different other point mutations.
Table 1 presents common adverse reactions that occurred in at least 5% of inotersen-treated patients and that occurred at least 5% more frequently or two times more frequently than on placebo.
The most common adverse reactions that occurred in at least 20% of inotersen-treated patients and more frequently than on placebo were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever. Serious adverse reactions were more frequent in inotersen-treated patients (32%) than in patients on placebo (21%). The most common adverse reactions leading to discontinuation were thrombocytopenia and cachexia.
Table 1. Adverse Reactions Reported in At Least 5% Inotersen-Treated Patients and that Occurred At Least 5% More Frequently or At Least Two Times More Frequently than Placebo Patients (Study 1):
| Inotersen (N=112) % | Placebo (N=60) % | |
|---|---|---|
| Injection site reactions a | 49 | 10 |
| Nausea | 31 | 12 |
| Headache | 26 | 12 |
| Fatigue | 25 | 20 |
| Thrombocytopenia | 24 | 2 |
| Fever | 20 | 8 |
| Peripheral edema | 19 | 10 |
| Chills | 18 | 3 |
| Anemia | 17 | 3 |
| Vomiting | 15 | 5 |
| Myalgia | 15 | 10 |
| Decreased renal function | 14 | 5 |
| Arrhythmia b | 13 | 5 |
| Arthralgia | 13 | 8 |
| Pre-syncope or syncope | 13 | 5 |
| Decreased appetite | 10 | 0 |
| Paresthesia | 10 | 3 |
| Dyspnea | 9 | 3 |
| Elevated liver function test | 9 | 3 |
| Orthostasis | 8 | 2 |
| Influenza-like illness | 8 | 3 |
| Contusion | 7 | 2 |
| Bacterial infection c | 7 | 3 |
| Eosinophilia | 5 | 0 |
| Dry mouth | 5 | 2 |
a Includes bruising, erythema, hematoma, hemorrhage, induration, inflammation, mass, edema, pain, pruritus, rash, swelling, and urticaria.
b Includes arrhythmia, atrial fibrillation, atrial flutter, bradyarrhythmia, bradycardia, extrasystoles, sinus arrhythmia, sinus bradycardia, supraventricular extrasystoles, tachycardia, and ventricular extrasystoles.
c Includes bacteremia, cellulitis staphylococcal, clostridium difficile infection, conjunctivitis bacterial, cystitis Escherichia, Helicobacter gastritis, Helicobacter infection, Staphylococcal infection.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, 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 to inotersen in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In Study 1, 30% of inotersen-treated patients tested positive for anti-drug antibodies (ADA) following 65 weeks of treatment. However, the assay measured only IgG isotypes and the existence of other isotypes may be possible. In many cases adverse reactions occurred in patients with ADA, although the available data are too limited to make definitive conclusions about the relationship.
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