(dalteparin sodium)
Risk Summary
Available data from published literature and postmarketing reports have not reported a clear association with FRAGMIN and adverse developmental outcomes. There are risks to the mother associated with untreated VTE in pregnancy, and a potential for adverse effects on the preterm infant when FRAGMIN is used in pregnancy (see Clinical Considerations). In animal reproduction studies, there was no evidence of embryo-fetal toxicity or teratogenicity when dalteparin sodium was administered to pregnant rats and rabbits during organogenesis at doses 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 units/kg dalteparin based on the body surface area (see Data). Because animal reproduction studies are not always predictive of human response, FRAGMIN should be used during pregnancy only if clearly needed.
The estimated 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.
Disease-Associated Maternal and/or Embryo/Fetal Risk
Published data describe that women with a previous history of VTE in pregnancy are at higher risk for recurrence during subsequent pregnancies compared to those with no risk factor for VTE (4.5% versus 2.7% respectively, relative risk 1.7, 95% CI: 1.0–2.8).
Fetal/Neonatal Adverse Reactions
Cases of "gasping syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99 mg/kg/day to 404 mg/kg/day). The 3.8 mL multiple-dose vials of FRAGMIN contain 14 mg/mL of benzyl alcohol [see Warnings and Precautions (5.3)].
Animal Data
In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium during organogenesis at intravenous doses up to 2,400 units/kg (14,160 units/m2) (rats) and 4,800 units/kg (40,800 units/m2) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 units/kg dalteparin based on the body surface area. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity.
Risk Summary
Limited published data indicate that dalteparin is present in human milk in small amounts (see Data). No adverse effects on the breastfed infant have been reported. There are no data on the effects of the drug on milk production. Oral absorption of dalteparin is expected to be low, but the clinical implications, if any, of this small amount of anticoagulant activity on a breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FRAGMIN and any potential adverse effects on the breastfed child from FRAGMIN or from the underlying maternal condition.
A study evaluated samples of maternal blood and breast milk in 15 lactating women receiving prophylactic doses of dalteparin in the immediate postpartum period (days 4 to 8 after Cesarean-section). The samples were collected before and 3 hours to 4 hours after daily injections of 2500 units dalteparin. Small amounts of anti-Xa activity (range <0.005 to 0.037 units/mL) in breast milk were detected in 11 of the 15 women. Because this study evaluated colostrum or transitional milk at a single timepoint during the 24 hours dosing interval, the clinical relevance of this data is unclear in regard to passage of drug into mature milk and the quantification of drug exposure to the infant over the full dosing interval.
The safety and effectiveness of FRAGMIN for the treatment of symptomatic venous thromboembolism (VTE) in patients have been established in pediatric patients from birth (gestational age at least 35 weeks) to less than 17 years of age.
Use of FRAGMIN for this indication is supported by evidence from well-controlled studies in adults with additional pharmacokinetic, pharmacodynamic, efficacy, and safety data from two separate prospective studies in pediatric patients aged 1 month and older with symptomatic VTE, and a retrospective study in neonatal patients aged birth (gestational age at least 35 weeks) to 1 month with VTE [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.5]. The frequency, type and severity of adverse reactions observed were generally consistent with those observed in adults.
Use preservative-free FRAGMIN in neonates and infants.
Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low-birth weight infants in the neonatal intensive care unit who received benzyl alcohol preserved medications. In these cases, benzyl alcohol dosages of 99 mg/kg/day to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 mmol/L to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.
When prescribing FRAGMIN multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including FRAGMIN multiple-dose vials (FRAGMIN contains 14 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Warnings and Precautions (5.3)].
The long-term effects of treatment with FRAGMIN in pediatric patients, including effects on growth and bone metabolism, are unknown.
Of the total number of patients in clinical studies of FRAGMIN, 5,516 patients were 65 years of age or older and 2,237 were 75 or older. No overall differences in effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance and literature reports have not revealed additional differences in the safety of FRAGMIN between elderly and younger patients. Give careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) in geriatric patients, particularly in those with low body weight (<45 kg) and those predisposed to decreased renal function [see Warnings and Precautions (5) and Clinical Pharmacology (12)].
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