Defitelio

DEFITELIO is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

• •Administer DEFITELIO 6.25 mg/kg every 6 hours given as a 2-hour intravenous infusion. (
  2.1 Recommended Dosage

  The recommended dosage of DEFITELIO for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2‑hour intravenous infusion. The dose should be based on patient’s baseline body weight, defined as the patient’s weight prior to the preparative regimen for HSCT.

  Administer DEFITELIO for a minimum of 21 days. If after 21 days signs and symptoms of hepatic VOD have not resolved, continue DEFITELIO until resolution of VOD or up to a maximum of 60 days.
  )
• •Treat for a minimum of 21 days. If after 21 days signs and symptoms of VOD have not resolved, continue treatment until resolution. (
  2.1 Recommended Dosage

  The recommended dosage of DEFITELIO for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2‑hour intravenous infusion. The dose should be based on patient’s baseline body weight, defined as the patient’s weight prior to the preparative regimen for HSCT.

  Administer DEFITELIO for a minimum of 21 days. If after 21 days signs and symptoms of hepatic VOD have not resolved, continue DEFITELIO until resolution of VOD or up to a maximum of 60 days.
  )

Injection: 200 mg/2.5 mL (80 mg/mL) of defibrotide sodium as a clear, light yellow to brown solution in a single-patient-use glass vial.

There are no available data on DEFITELIO 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.

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/m² 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.

• •Hemorrhage: Monitor patients for bleeding. Withhold or discontinue DEFITELIO if significant bleeding occurs. (
  2.3 Treatment Modification

  Treatment modification, including temporary or permanent discontinuation of DEFITELIO, should follow the recommendations in Table 1.

  Table 1: Treatment Modifications for Toxicity or Invasive Procedures

  Discontinue DEFITELIO permanently; do not resume treatment.Withhold DEFITELIO.

  Treat the cause of bleeding and give supportive care as clinically indicated.

  Consider resuming treatment (at the same dose and infusion volume) when bleeding has stopped and the patient is hemodynamically stable.Discontinue DEFITELIO permanently; do not resume treatment.There is no known reversal agent for the profibrinolytic effects of DEFITELIO. Discontinue DEFITELIO infusion at least 2 hours prior to an invasive procedure.

  Resume DEFITELIO treatment after the procedure as soon as any procedure-related risk of bleeding is resolved.

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  Event	Recommended Action
  Hypersensitivity Reaction
  Severe or life-threatening (anaphylaxis)
  Bleeding
  Persistent, severe or potentially life-threatening
  Recurrent significant bleeding
  Invasive Procedures
  ,
  5.1 Hemorrhage

  DEFITELIO increased the activity of fibrinolytic enzymes

  in vitro,

  and it may increase the risk of bleeding in patients with VOD after hematopoietic stem-cell transplantation (HSCT). Do not initiate DEFITELIO in patients with active bleeding. Monitor patients for signs of bleeding. If patients on DEFITELIO develop bleeding, discontinue DEFITELIO, treat the underlying cause, and provide supportive care until the bleeding has stopped

  [see Dosage and Administration (2.3)]

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  Concomitant use of DEFITELIO and a systemic anticoagulant or fibrinolytic therapy (not including use for routine maintenance or reopening of central venous lines) may increase the risk of bleeding. Discontinue anticoagulants and fibrinolytic agents prior to DEFITELIO treatment, and consider delaying the start of DEFITELIO administration until the effects of the anticoagulant have abated

  [see Contraindications (4)]

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• •Hypersensitivity Reactions: If severe or life threatening allergic reaction occurs, discontinue DEFITELIO, treat according to standard of care, and monitor until signs and symptoms resolve. (
  2.3 Treatment Modification

  Treatment modification, including temporary or permanent discontinuation of DEFITELIO, should follow the recommendations in Table 1.

  Table 1: Treatment Modifications for Toxicity or Invasive Procedures

  Discontinue DEFITELIO permanently; do not resume treatment.Withhold DEFITELIO.

  Treat the cause of bleeding and give supportive care as clinically indicated.

  Consider resuming treatment (at the same dose and infusion volume) when bleeding has stopped and the patient is hemodynamically stable.Discontinue DEFITELIO permanently; do not resume treatment.There is no known reversal agent for the profibrinolytic effects of DEFITELIO. Discontinue DEFITELIO infusion at least 2 hours prior to an invasive procedure.

  Resume DEFITELIO treatment after the procedure as soon as any procedure-related risk of bleeding is resolved.

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  Event	Recommended Action
  Hypersensitivity Reaction
  Severe or life-threatening (anaphylaxis)
  Bleeding
  Persistent, severe or potentially life-threatening
  Recurrent significant bleeding
  Invasive Procedures
  ,
  5.2 Hypersensitivity Reactions

  Hypersensitivity reactions have occurred in less than 2% of patients treated with DEFITELIO. These reactions include rash, urticaria and angioedema. One case of an anaphylactic reaction was reported in a patient who had previously received DEFITELIO. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue DEFITELIO, treat according to the standard of care, and monitor until symptoms resolve

  [see Dosage and Administration (2.3)]

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