Defibrotide Sodium - Mechanism of Action, Uses, Indications, and Dosage

Overview:

Hepatic veno-occlusive disease is a fatal complication of conditioning for hematopoietic stem cell transplantation. However, it can occur after non-transplant-associated chemotherapy too. Post-HSCT with multi-organ dysfunction (MOD) may be associated with more than 80 % mortality. Defibrotide sodium is prescribed to treat severe hepatic veno-occlusive disease occurring post-HSCT in patients older than one month and hepatic VOD with renal or pulmonary dysfunction post-HSCT. Before the US approval, Defibrotide sodium was used to treat veno-occlusive disease through an expanded-access treatment (T-IND) program.

The hepatic veno-occlusive disease is also called sinusoidal obstruction syndrome (VOD or SOS), which is a potentially life-threatening complication related to hematopoietic stem cell transplantation (HSCT), including reduced-intensity regimens. VOD can also occur as a complication of chemotherapy alone. Post HSCT, VOD with concomitant multi-organ dysfunction has an 80 % mortality rate. The incidence and mortality rate of VOD following nontransplant-associated chemotherapy is not known. Various agents are known to be associated with an increased risk of VOD in the non-HSCT setting, including Inotuzumab, Gemtuzumab Ozogamicin, Vincristine, and Actinomycin.

How Does Defibrotide Sodium Work?

• Defibrotide sodium injection is indicated to treat adults and children with hepatic veno-occlusive disease (VOD), which is blocked blood vessels inside the liver, also known as sinusoidal obstruction syndrome.

• Defibrotide sodium is used as an antithrombotic agent in patients who have undergone hematopoietic stem-cell transplantation and are at risk of developing a veno-occlusive disease or sinusoidal obstruction syndrome, which can result in damage to the kidneys, liver, or lungs. By preventing the formation of blood clots, Defibrotide sodium helps to maintain proper blood flow and reduce the risk of organ damage.

• Defibrotide sodium is an investigational drug that is believed to work by modulating the activity of certain blood-clotting and blood-vessel-related factors in the body, with the aim of preventing or treating certain blood-flow problems. It is thought to work by promoting the breakdown of clots, inhibiting platelet aggregation, and improving blood flow in the microvasculature.

• Defibrotide sodium is being studied as a potential treatment for certain conditions associated with blood-flow problems, such as veno-occlusive disease and sinusoidal obstruction syndrome.

Uses:

• Hepatic Veno-Occlusive Disease - Defibrotide sodium injection is indicated for the treatment of hepatic veno-occlusive disease with renal or pulmonary dysfunction following hematopoietic stem cell transplantation. It works as an antithrombotic agent by preventing the formation of blood clots and promoting the breakdown of clots that have already formed, helping to maintain proper blood flow and reduce the risk of organ damage.

• Circulatory Disorders - Based on the pharmacologic action, the Defibrotide sodium drug is used to treat various circulatory disorders such as thrombophlebitis and leg blood pressure.

• Chronic Venous Insufficiency - Chronic venous insufficiency resulting from deep vein thrombosis (DVT) or reflux can be treated by oral Defibrotide 800 mg/d. In DVT prophylaxis trials in post-surgery patients, Defibrotide also plays a significant role in preventive efficacy and has a similar prophylactic effect when compared to Heparin.

• Peripheral Arterial Disease - In patients with peripheral arterial disease, oral or intravenous Defibrotide treatment is found to improve rheological and hemodynamic parameters of blood flow and increase absolute walking distance.

Dosages:

Recommended Dosage - The recommended dosage of Defibrotide sodium for adult, as well as pediatric patients, is 6.25 mg/kg every six hours, given as a two-hour intravenous infusion.

The dose must be based on the patient’s weight before the preparation for HSCT (hematopoietic stem cell transplantation).

The dose administration is done for a minimum of 21 days. If within 21 days, signs and symptoms of hepatic VOD (veno-occlusive disease) are not resolved, then Defibrotide sodium is continued until resolution of VOD or up to a maximum of 60 days. Prior to the administration of Defibrotide sodium, it must be diluted previously to infusion. Prior to administration of Defibrotide, make sure that the patient is not having significant bleeding and is hemodynamically stable.

Precautions Before Administration

• Defibrotide sodium should be given by constant intravenous infusion over a two-hour period.

• A diluted solution of Defibrotide should be given with an 0.2-micron in-line filter infusion set.

• The intravenous administration line (peripheral or central) should be washed out with a five percent Dextrose injection or 0.9 % sodium chloride injection immediately before and after the administration.

• Do not administer Defibrotide sodium with any other intravenous drugs concurrently within the same intravenous line.

• Defibrotide 200 mg administered intravenously three times daily for 15 days greatly improves leg blood pressure.

• Defibrotide 800 mg/d (n = 104) or 1200 mg/d (n = 105) significantly improves absolute peripheral arterial disease.

Indications:

Defibrotide sodium is prescribed for the treatment of hepatic veno-occlusive disease (VOD). It is also called sinusoidal obstruction syndrome (SOS). Defibrotide sodium is used in children and adults with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

Warning:

Hemorrhage:

Defibrotide sodium is found to increase fibrinolytic enzyme activity in vitro. It also increases the risk of bleeding in patients with hepatic no-occlusive disease after hematopoietic stem-cell transplantation (HSCT). Patients with signs of bleeding should be monitored. If patients on Defibrotide sodium start bleeding, discontinue it, treat the underlying cause, and provide supportive care until the bleeding has stopped.

Hypersensitivity Reactions:

Hypersensitivity reactions include rash, angioedema, and urticaria. An anaphylactic reaction was also reported in a patient who had previously received Defibrotide sodium. Patients with hypersensitivity reactions, especially if there is a history of previous exposure, should be closely monitored. If a severe hypersensitivity reaction arises, Defibrotide sodium should be discontinued.

For Patients:

Learn About Hepatic Veno-occlusive Disease

• Hepatic veno-occlusive disease with immunodeficiency is a hereditary disorder of the liver and immune system. The signs and symptoms of the disease appear after the first few months of life. Hepatic veno-occlusive disease is a disorder that blocks small veins in the liver, hampering the blood flow in the liver. This can lead to enlargement of the liver (hepatomegaly), a buildup of scar tissue (hepatic fibrosis), and liver failure.

• Children suffering from VODI are predisposed to recurrent infections caused by certain bacteria, viruses, and fungi. The organisms that cause disease in people with this disorder are characterized as opportunistic because, normally, they do not cause disease in healthy people. Such infections are generally serious and can be life-threatening. Patients with VODI infections arise before the hepatic veno-occlusive disease becomes apparent. Patients with VODI generally live only into childhood. However, some affected individuals have survived to early adulthood.

• Hereditary hepatic veno-occlusive disease results from mutations in the SP110 gene. The gene instructs in making a protein called SP110 nuclear body protein, which helps in the normal function of the immune system. The protein helps control the activity of genes required for the body's immune response to foreign organisms such as viruses and bacteria. Mutations in the SP110 gene prevent cells from bringing in functional SP110 nuclear body protein, which harms the immune system's ability to fight against infections.

Learn More About Defibrotide Sodium

Why and When to Start Defibrotide Sodium?

Defibrotide sodium is used to treat adults and pediatrics with hepatic veno-occlusive disease who have kidney or lung problems after acquiring a hematopoietic stem-cell transplant (HSCT). Defibrotide injection is a class of medications called antithrombotic agents that works by preventing the formation of blood clots. Defibrotide injection is available as a solution to be injected intravenously. It is usually injected once every six hours for 21 days. However, it may be given for up to 60 days. The span of the treatment depends on the body’s response to the medication and its side effects.

What Differentiates Defibrotide Sodium From Other Conventional Medicines?

Defibrotide sodium is a drug that is used to treat a rare and severe complication of stem cell transplantation known as a hepatic veno-occlusive disease (VOD). Defibrotide is a complex mixture of single-stranded and double-stranded oligonucleotides derived from porcine mucosal tissue, and it is unique among available therapies as it works by modulating the activity of the endothelium (the inner lining of blood vessels) and by restoring normal blood flow. This mechanism of action sets it apart from other conventional medications used to treat VOD, which often target the underlying cause of the disease, such as infection or tissue damage, rather than its symptoms.

How Effective Is Defibrotide Sodium?

The effectiveness of Defibrotide sodium in treating hepatic veno-occlusive disease (VOD) has been demonstrated in clinical trials and observational studies. In phase III clinical trial, treatment with Defibrotide sodium was shown to result in a significant improvement in the complete response rate (CRR) compared to best supportive care alone. The CRR was defined as the resolution of VOD symptoms and normalization of liver function.

However, the evidence base for Defibrotide sodium is limited, as VOD is a rare condition, and the majority of studies on the drug are small or have a retrospective design. Further large, well-designed clinical trials are needed to confirm the efficacy and safety of Defibrotide sodium for the treatment of VOD.

Overall, Defibrotide sodium has shown promise as a treatment for VOD and may be an effective alternative for patients who do not respond to other available therapies. However, it is always recommended to consult a healthcare provider for an individual assessment and to weigh the potential benefits and risks of treatment.

Things to Do After One Starts Taking Defibrotide Sodium:

After starting treatment with Defibrotide sodium, it is important to do the following:

1. Take the Medication as Directed: It is important to follow the recommended dosage and administration instructions provided by the healthcare provider and to take the medication at the same time.

2. Report Any Side Effects: If a patient experiences any side effects, such as nausea, vomiting, bleeding, or diarrhea, it is important to immediately report them to the healthcare provider.

3. Regular Check-Ups: Regular check-ups with the healthcare provider are important to monitor the progress and ensure that the medication is working as intended.

4. Monitor for Bleeding: As Defibrotide sodium can cause serious bleeding, it is important to be aware of any signs of bleeding, such as unusual bruising, prolonged bleeding from cuts, or red or dark-colored urine.

5. Avoid Activities That May Increase the Risk of Bleeding: During treatment with Defibrotide sodium, it is important to avoid activities that may increase the risk of bleeding, such as contact sports or using power tools.

6. Keep a Healthcare Provider Informed: It is important to keep the healthcare provider informed of any changes in the medical history, medications, or symptoms, as well as any new medications that must be started during treatment.

7. Follow a Healthy Lifestyle: In addition to taking the medication as directed, following a healthy lifestyle, such as eating a balanced diet, getting regular exercise, and managing stress, may help improve overall health and well-being during treatment with Defibrotide sodium.

Look Out for the Side Effects:

Defibrotide sodium can cause side effects. Consult a doctor immediately if any of the following symptoms appear:

• Vomiting.

• Dizziness.

• Nausea.

• Diarrhea.

• Nose bleeding.

• Rash.

• Itching.

• Hives.

• Swelling of the tongue, lips, face, or throat.

• Bleeding or bruising.

• Headache.

• Blood in stool or urine.

• Confusion.

• Vision changes.

• Slurred speech.

• Fever, cough, or other signs of infection.

For Doctors

Indication:

Defibrotide sodium is indicated for the treatment of hepatic veno-occlusive disease in patients undergoing stem cell transplantation, and it may be an effective alternative for patients who do not respond to other available therapies. VOD is a rare and potentially life-threatening complication that can occur following stem cell transplantation and is characterized by occlusion of the small veins in the liver, leading to liver dysfunction and symptoms such as jaundice, abdominal swelling, and weight gain. Defibrotide sodium is a unique drug that works by modulating the activity of the endothelium and restoring normal blood flow, and it has been shown to improve the complete response rate in patients with VOD compared to the best supportive care alone.

Pharmacology and Mechanism Of Action:

Defibrotide sodium help to prevent the formation of blood clots and help dissolve blood clots by increasing the levels of prostaglandin I2, E2, and prostacyclin, increasing tissue plasminogen activator function, and altering platelet activity. At certain concentrations, it inhibits platelet aggregation. Moreover, the drug delivers additional useful anti-inflammatory and anti-ischemic activities.

Pharmacodynamics:

Defibrotide sodium has illustrated a half-life of approximately 10 to 13 minutes and bioavailability of about 58 % in animal studies with excretion, especially in urine. The oral, intramuscular, and intravenous formulations of Defibrotide sodium are developed, with similar half-lives. Parenteral administration is used for VOD and may have other applications in fairly short-term regimens. In contrast, oral administration may be chosen for long-term treatments to increase patient comfort and acceptability. Defibrotide sodium's half-life is 0.47 (0.10) hours, and the total plasma clearance is 9.629 (1.175) L/h.

Absorption:

The bioavailability of Defibrotide sodium is 58 to 70 % after pursuing oral administration, compared to parenteral forms (i.v. and i.m. = 100%).

Elimination:

Defibrotide sodium is primarily metabolized and excreted in the urine. Its total clearance ranges from 3.4 to 6.1 L/h, and its elimination half-life is less than two hours. In clinical trials with VOD patients, multiple-dose administration of 6.25 mg/kg every six hours for five days did not result in accumulation. This suggests that Defibrotide sodium is eliminated from the body relatively quickly and does not build up to high concentrations.

Metabolism:

Though the accurate pathway of Defibrotide sodium degradation in plasma is unknown, it has been suggested that nucleosidases, nucleotidases, deaminases, and phosphorylases metabolize polynucleotides progressively to nucleotides, oligonucleotides, nucleosides, and then to the free bases. The biotransformation of defibrotide sodium does not undergo observable metabolism by human hepatocyte cells.

Excretion:

Post administration of 6.25 mg/kg to 15 mg/kg doses of Defibrotide sodium as two-hour infusions, around five to 15 % of the total dose is excreted in urine as Defibrotide sodium, with the bulk excreted during the first four hours.

Contraindications:

The use of Defibrotide sodium is contraindicated under the following conditions:

• Concomitant Regime with Systemic Anticoagulant or Fibrinolytic Therapy: Concomitant use of Defibrotide sodium and a systemic anticoagulant or fibrinolytic therapy not containing usage for routine maintenance. Conclude anticoagulants and fibrinolytic agents prior to Defibrotide treatment, and evaluate postponing the start of the Defibrotide regime until the effects of the anticoagulant have lessened.

• Known hypersensitivity to Defibrotide Sodium: Defibrotide sodium may cause hypersensitivity reactions in some patients, with an incidence of less than two percent. These reactions include rash, hives, swelling, and in rare cases, anaphylaxis. Patients with a history of hypersensitivity should be monitored for symptoms, and if a severe reaction occurs, the treatment should be discontinued, and standard measures should be taken until symptoms subside.

• Use of Defibrotide Sodium in Pregnancy and Lactation: The use of Defibrotide sodium in pregnancy and lactation has not been studied in humans. Animal studies have not shown any teratogenic effects, but the safety of Defibrotide in pregnancy has not been established. Women who are pregnant or planning to become pregnant should consult with their healthcare provider before using Defibrotide.

The safety of Defibrotide sodium in lactation has not been established. It is not known if Defibrotide is excreted in human milk. Women who are breastfeeding should consult with their healthcare provider before using Defibrotide.

Geriatric Use

The use of Defibrotide sodium in geriatric patients has not been extensively studied. As with any drug, caution should be exercised when using Defibrotide in older adults, as they may have age-related decreases in kidney function and increased sensitivity to the drug. Close monitoring and individualized dosing may be necessary. The safety and efficacy of Defibrotide in geriatric patients should be evaluated by a healthcare provider.

Pediatric Use

Defibrotide has been demonstrated to have both safety and effectiveness in pediatric patients, based on results from adequate and well-controlled studies and a dose-finding study in both adult and pediatric patients with veno-occlusive disease and renal or pulmonary dysfunction after hematopoietic stem cell transplantation. The efficacy and safety outcomes were found to be consistent between pediatric and adult patients in the clinical trials.

Drug Interactions:

• Abciximab - The threat or severity of bleeding can be raised when Abciximab is combined with Defibrotide.

• Abrocitinib - The risk or severity of bleeding and thrombocytopenia can rise when Defibrotide sodium is combined with Abrocitinib.

• Aceclofenac - The severity of bleeding and risk of hemorrhage ca n be increased when Aceclofenac is combined with Defibrotide.

• Acemetacin - The severity of bleeding and hemorrhage when Defibrotide is combined with Acemetacin is increased.

• Diclofenac - The risk or severity of bleeding and hemorrhage when Alclofenac is combined with Defibrotide is increased.