glumine (0, 15, 30, and 45 mg/kg/day) throughoutorganogenesis resulted in decreased fetal body weights at ≥30 mg/kg/day (approximately 10 times the humanexposure at the MRHD based on AUC). The no-observed-adverse-effect-level (NOAEL) for embryofetaldevelopment in rats was 15 mg/kg/day (approximately 7 times the human exposure at the MRHD based onAUC).
In pregnant rabbits, oral administration of tafamidis meglumine (0, 0.5, 2, and 8 mg/kg/day) throughoutorganogenesis resulted in increased embryofetal mortality, reduced fetal body weights, and an increasedincidence of fetal malformations at 8 mg/kg/day (approximately 9 times the human exposure at the MRHDbased on AUC), which was also maternally toxic. Increased incidences of fetal skeletal variations wereobserved at doses ≥0.5 mg/kg/day (approximately equivalent to the human exposure at the MRHD based onAUC).
In the pre- and postnatal study, pregnant rats received oral administration of tafamidis meglumine at doses of 0,5, 15, or 30 mg/kg/day throughout pregnancy and lactation (Gestation Day 7 to Lactation Day 20). Decreasedsurvival and body weights, delayed male sexual maturation and neurobehavioral effects (learning and memory
impairment) were observed in the offspring of dams treated at 15 mg/kg/day (approximately 2 times the MRHDon a mg/m2basis). The NOAEL for pre- and postnatal development in rats was 5 mg/kg/day (approximatelyequivalent to the MRHD on a mg/m2basis).
8.2 Lactation
Risk Summary
There are no available data on the presence of tafamidis in human milk, the effect on the breastfed infant, or theeffect on milk production. Tafamidis is present in rat milk (see Data). When a drug is present in animal milk, itis likely the drug will be present in human milk. Based on findings from animal studies which suggest the
potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is notrecommended during treatment with VYNDAQEL or VYNDAMAX.
Data
Pregnant and lactating female rats were administered repeated daily oral doses of tafamidis meglumine(15 mg/kg/day) followed by a single oral gavage dose of 14C-tafamidis meglumine on Lactation Day 4 or 12.
Radioactivity was observed in milk by 1 hour post-dose and increased thereafter. The ratio of the highestradioactivity associated with 14C tafamidis meglumine in milk (8 hours post-dose) vs. plasma (1 hour post-dose)was approximately 1.6 on Day 12, indicating tafamidis meglumine is transferred to milk after oraladministration.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Based on findings from animal studies, VYNDAQEL and VYNDAMAX may cause fetal harm whenadministered to a pregnant woman [see Use in Specific Populations (8.1)]. Consider pregnancy planning andprevention for females of reproductive potential.
8.4 Pediatric Use
The safety and effectiveness of VYNDAQEL and VYNDAMAX have not been established in pediatricpatients.
8.5 Geriatric Use
No dosage adjustment is required for elderly patients (≥65 years) [see Clinical Pharmacology (12.3)]. Of thetotal number of patients in the clinical study (n=441), 90.5% were 65 and over, with a median age of 75 years.
10. OVERDOSAGE
There is minimal clinical experience with overdose. During clinical trials, two patients accidentally ingested a
single VYNDAQEL dose of 160 mg without adverse events. The highest dose of tafamidis meglumine given tohealthy volunteers in a |
