Defitelio

• Jazz Pharmaceuticals, Inc.

Serious side effects have been reported with Defitelio. See the “Defitelio Precautions” section.

Common side effects of Defitelio include the following:

• low blood pressure
• diarrhea
• vomiting
• nausea
• nose bleeds

This is not a complete list of Defitelio side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Before taking Defitelio, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Defitelio or to any of its ingredients
• have an active bleed
• are taking anti-thrombotic medications such as blood thinners
• have a surgery planned
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are breastfeeding or plan to breastfeed.

There is no information regarding the presence of Defitelio 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, breastfeeding is not recommended during treatment with Defitelio.
 

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Active bleeding—Should not be given in patients with this condition.

• Bleeding problems—Use with caution. May make these conditions worse.

You should not use defibrotide if you are allergic to it, or if:

• you have active bleeding;

• you also take a blood thinner such as warfarin (Coumadin, Jantoven); or

• you use any medication to treat or dissolve blood clots such as streptokinase or urokinase.

To make sure defibrotide is safe for you, tell your doctor if you have:

• a bleeding or blood clotting disorder.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether defibrotide passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Defibrotide is injected into a vein through an IV. This medicine must be given slowly, and the IV infusion can last at least 2 hours.

You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used.

Defibrotide is usually given for at least 21 days, to a maximum of 60 days if symptoms have not fully improved.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Defibrotide must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

Do not mix defibrotide with other medicines in the same IV line. Follow your doctor's instructions about flushing your IV line after each injection.

Prepare your dose only when you are ready to give an injection. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

After mixing defibrotide with a diluent, store in the refrigerator and use within 24 hours.

Mixed medicine must be used within 4 hours if you keep it at room temperature.

Each single-use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

A nurse or other trained health professional will give you or your child this medicine in a hospital. This medicine is given through a needle placed in one of your veins. The medicine must be injected slowly, so your IV tube will need to stay in place for 2 hours.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Very bad dizziness or passing out.
• Very bad headache.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.

Antithrombotic Agents

Defitelio may enhance the pharmacodynamic activity of antithrombotic/fibrinolytic drugs such as heparin or alteplase. Concomitant use of Defitelio with antithrombotic or fibrinolytic drugs is contraindicated because of an increased risk of hemorrhage [see Contraindications (4)].

The efficacy of Defitelio was investigated in three studies: two prospective clinical trials (Study 1 and Study 2), and an expanded access study (Study 3).

Study 1 enrolled 102 adult and pediatric patients in the Defitelio treatment group with a diagnosis of VOD according to the following criteria (bilirubin of at least 2 mg/dL and at least two of the following findings: hepatomegaly, ascites, and weight gain greater than 5% by Day+21 post-HSCT) with an associated diagnosis of multi-organ dysfunction (pulmonary, renal, or both) by Day+28 post-HSCT. Defitelio was administered to the treatment group at a dose of 6.25 mg/kg infused every 6 hours for a minimum of 21 days and continued until patient was discharged from the hospital. Patients enrolled in the Defitelio treatment group were not permitted to receive concomitant medications such as heparin, warfarin, or alteplase because of an increased risk of bleeding.

Study 2 included adult and pediatric patients with a diagnosis of hepatic VOD and multi-organ dysfunction following HSCT, with 75 patients treated with Defitelio at a dose of 6.25 mg/kg infused every 6 hours. The planned minimum duration of treatment was 14 days. The treatment could be continued until signs of hepatic VOD resolved.

Study 3 is an expanded access program for Defitelio for the treatment of adult and pediatric patients with hepatic VOD. The efficacy of defibrotide was evaluated in 351 patients who had received a HSCT and developed hepatic VOD with renal or pulmonary dysfunction. All patients received Defitelio at a dose of 6.25 mg/kg infused every 6 hours.

Baseline demographic information and details for patients treated in these studies are provided below in Table 3.

Table 3: Baseline Demographics of Patients Treated with Defitelio at 6.25 mg/kg Every 6 Hours

The efficacy of Defitelio was based on survival at Day + 100 after HSCT. In Study 1, the survival rate was 38% (95% CI: 29%, 48%) at 100 days after transplantation. In Study 2 the survival rate was 44% (95% CI: 33%, 55%) at 100 days after transplantation. In Study 3, the Day + 100 survival was 45% (95% CI: 40%, 51%).

Based on published reports and analyses of patient level data for individuals with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than Defitelio, the expected Day +100 survival rates are 21% to 31%.

Get emergency medical help if you have signs of an allergic reaction: hives, itching, skin rash; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• easy bruising, unusual bleeding;
• blood in your urine or stools;
• confusion, headaches;
• vision problems, slurred speech; or
• a light-headed feeling, like you might pass out.

Your treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

• nausea, vomiting, diarrhea;
• dizziness; or
• nosebleeds.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.