Defibrotide

Risk Summary

There are no available data on defibrotide use in pregnant women. When administered to pregnant rabbits during the period of organogenesis at doses that were comparable to the recommended human dose based on body surface area, defibrotide sodium decreased the number of implantations and viable fetuses. Advise pregnant women of the potential risk of miscarriage.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Data

Animal Data

Embryo-Fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses. Pregnant rats were administered defibrotide sodium from gestational day (GD) 6 to 15 at 0, 240, 1200, and 4800 mg/kg/day by continuous intravenous infusion over 24 hours or at 60, 120, and 240 mg/kg/day by 2-hour infusions 4 times per day. Pregnant rabbits were administered defibrotide sodium at 0, 30, 60, or 120 mg/kg/day from GD 6 to 18 by 2-hour infusions 4 times per day.

In another study in pregnant rabbits, 3 separate subgroups of animals were treated with doses of 80 mg/kg/day defibrotide sodium administered by 2-hour infusions 4 times per day for 5 days each in a staggered manner during the organogenesis period. The dose of 80 mg/kg/day is approximately equivalent to the recommended clinical dose on a mg/m ² basis. Subgroup 1 was dosed from GD 6 to 10, subgroup 2 was dosed from GD 10 to 14, and subgroup 3 was dosed from GD 14 to 18. An increased incidence of unilateral implantation was observed in defibrotide sodium-treated animals. Treatment with defibrotide sodium resulted in a decreased number of implantations and viable fetuses.

Risk Summary

There is no information regarding the presence of defibrotide in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with defibrotide.

No carcinogenicity studies have been conducted with intravenous administration of defibrotide sodium.

Defibrotide sodium was not mutagenic in vitro in a bacterial reverse mutation assay (Ames assay). Defibrotide sodium was not clastogenic in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells or an in vivo micronucleus assay conducted in bone marrow from rats administered defibrotide sodium by intravenous infusion.

Studies of fertility were not conducted with defibrotide sodium administered by the intravenous route. In repeat dose general toxicology studies, when defibrotide sodium was administered intravenously to rats and dogs for up to 13 weeks, there were no effects on male or female reproductive organs.

• Hemorrhage
• Hypersensitivity Reactions

Clinical 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.

The safety of defibrotide was determined in 176 adult and pediatric patients with hepatic VOD with pulmonary and/or renal dysfunction following HSCT who were treated with defibrotide 6.25 mg/kg every 6 hours. Patients were excluded from these trials if at time of study entry they had significant acute bleeding, active grades B-D graft-versus-host disease, or a requirement for multiple vasopressors to provide blood pressure support. For the purposes of adverse event recording in the clinical trials, events were not required to be reported if they were related to the hepatic VOD, or if they were expected to occur after hematopoietic stem-cell transplantation (HSCT), unless they were serious or Grade 4-5.

The median age of the safety population was 25 years (range: 1 month to 72 years), and 63% were ≥17 years of age. A total of 60% of patients were male, 78% were white, 89% had undergone allogeneic HSCT, and the underlying diagnosis was acute leukemia for 43%. At study entry, 13% were dialysis dependent and 18% were ventilator dependent. Defibrotide was administered for a median of 21 days (range: 1 to 83 days).

Information about adverse reactions resulting in permanent discontinuation of defibrotide was available for 102 patients, and 35 (34%) of these patients had an adverse reaction with permanent discontinuation. Adverse reactions leading to permanent discontinuation included pulmonary alveolar hemorrhage in 5 (5%) patients; pulmonary hemorrhage, hypotension, catheter site hemorrhage, and multi-organ failure, each in 3 (3%) patients; and cerebral hemorrhage and sepsis, each in 2 (2%) patients.

Information about adverse reactions of any grade was available for all 176 patients. The most common adverse reactions (incidence ≥10% and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis. The most common serious adverse reactions (incidence ≥5% and independent of causality) were hypotension (11%) and pulmonary alveolar hemorrhage (7%). Hemorrhage events of any type and any grade were reported for 104 (59%) of the patients, and the events were grade 4-5 in 35 (20%).

The following table presents adverse reactions independent of causality ≥10% any grade or Grade 4/5 ≥2% reported in patients treated with defibrotide.

Adverse Reactions ^a ≥10% or Grade 4-5 Adverse Reactions ≥2%:

^aExcludes events considered to be due to the underlying disease: multi-organ failure, veno-occlusive disease, respiratory failure, renal failure, and hypoxia
^b Adverse reactions considered life-threatening or fatal
^c Cerebral hemorrhage has been included in the table due to clinical relevance