Actimmune

Interferon gamma-1b is made from human proteins. Interferons help the body fight viral infections.

Interferon gamma-1b is used to prevent serious infections in people with a condition called chronic granulomatous disease. Interferon gamma-1b is also used to slow the progression of a bone disorder called malignant osteopetrosis.

Interferon gamma-1b may also be used for purposes not listed in this medication guide.

Interferon gamma-1b can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

You should not use this medicine if you are allergic to interferon gamma-1b, or to drug products made from E. coli bacteria.

To make sure interferon gamma-1b is safe for you, tell your doctor if you have:

• kidney disease;
• liver disease;
• heart rhythm problems;
• congestive heart failure;
• a nerve-muscle disorder;
• bone marrow suppression;
• a history of transient ischemic attacks (TIAs), including "mini-stroke";
• a history of seizures; or
• an allergy to rubber.

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

This medicine may affect fertility (your ability to have children), whether you are a man or a woman.

It is not known whether interferon gamma-1b passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Interferon gamma-1b is not approved for use by anyone younger than 1 year old.

Drinking alcohol with this medicine can cause side effects.

This medicine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Other drugs may interact with interferon gamma-1b, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Keep all appointments with your doctor and the laboratory.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

In the U.S.

• Actimmune

Available Dosage Forms:

• Solution

Therapeutic Class: Immunological Agent

Pharmacologic Class: Interferon, Gamma (class)

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Actimmune® to treat CGD in children 1 year of age and older, and to treat SMO in children 1 month and older. However, safety and efficacy have not been established in children to treat CGD younger than 1 year of age, and in newborns with SMO.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Actimmune® in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving Actimmune®.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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:

• Arrhythmia (heart rhythm problem) or
• Congestive heart failure or
• Heart disease (eg, ischemia) or
• Nervous system problems, or history of or
• Seizures—Use with caution. May make these conditions worse.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine.

• Store in a refrigerator. Do not freeze.
• Throw away any part of opened vial not used after use.
• If needed, this medicine can be left out at room temperature for up to 12 hours before use. Throw away any part not used after 12 hours.
• Do not put Actimmune back in the refrigerator after it has been stored at room temperature.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Cardiovascular Disorders

Acute and transient "flu-like" symptoms such as fever and chills induced by Actimmune at doses of 250 mcg/m2/day (greater than 10 times the weekly recommended dose) or higher may exacerbate pre-existing cardiac conditions. Patients with pre-existing cardiac conditions, including ischemia, congestive heart failure or arrhythmia on Actimmune should be monitored for signs/symptoms of exacerbation. Some of the "flu-like" symptoms may be minimized by bedtime administration of Actimmune. Acetaminophen may also be used to ameliorate these effects.

Neurologic Disorders

Decreased mental status, gait disturbance and dizziness have been observed, particularly in patients receiving Actimmune doses greater than 250 mcg/m2/day (greater than 10 times the weekly recommended dose). Most of these abnormalities were reversible within a few days upon dose reduction or discontinuation of therapy. Monitor patients when administering Actimmune to patients with seizure disorders or compromised central nervous system function.

Bone Marrow Toxicity

Reversible neutropenia and thrombocytopenia that can be severe and may be dose related have been observed during Actimmune therapy. Monitor neutrophil and platelet counts in patients with myelosuppression during treatment with Actimmune.

Hepatic Toxicity

Repeated administration of Actimmune to patients with advanced hepatic disease may result in accumulation of interferon gamma-1b. Frequent assessment of liver function in these patients is recommended.

Elevations of aspartate transaminase (AST) and/or alanine transaminase (ALT) (up to 25-fold) have been observed during Actimmune therapy. The incidence appeared to be higher in patients less than 1 year of age compared to older children. The transaminase elevations were reversible with reduction in dosage or interruption of Actimmune treatment. Patients begun on Actimmune before age one year should receive monthly assessments of liver function. If severe hepatic enzyme elevations develop, Actimmune dosage should be modified [see Dosage and Administration (2.3)].

Hypersensitivity Reactions

Isolated cases of acute serious hypersensitivity reactions have been observed in patients receiving Actimmune. If such an acute reaction develops the drug should be discontinued immediately and appropriate medical therapy instituted. Transient cutaneous rashes have occurred in some patients following injection of Actimmune that have necessitated treatment interruption.

Renal Toxicity

Monitor renal function regularly when administering Actimmune in patients with severe renal insufficiency because the possibility exists that with repeated administration, accumulation of interferon gamma-1b may occur. Renal toxicity has been reported in patients receiving Actimmune.

Allergic Reactions to Natural Rubber

The stopper of the glass vial for Actimmune contains natural rubber (a derivative of latex) which may cause allergic reactions.

Mechanism of Action

Interferons bind to specific cell surface receptors and initiate a sequence of intracellular events that lead to the transcription of interferon-stimulated genes. The three major groups of interferons (alpha, beta, gamma) have partially overlapping biological activities that include immunoregulation such as increased resistance to microbial pathogens and inhibition of cell proliferation. Type 1 interferons (alpha and beta) bind to the alpha/ beta receptor. Interferon gamma binds to a different cell surface receptor and is classified as Type 2 interferon. Specific effects of interferon gamma include the enhancement of the oxidative metabolism of macrophages, antibody dependent cellular cytotoxicity (ADCC), activation of natural killer (NK) cells, and the expression of Fc receptors and major histocompatibility antigens.

CGD is an inherited disorder of leukocyte function caused by defects in the enzyme complex responsible for phagocyte superoxide generation. Actimmune does not increase phagocyte superoxide production even in treatment responders.

In SMO (an inherited disorder characterized by an osteoclast defect, leading to bone overgrowth, and by deficient phagocyte oxidative metabolism), a treatment-related enhancement of superoxide production by phagocytes was observed. Actimmune was found to enhance osteoclast function in vivo.

In both disorders, the exact mechanism(s) by which Actimmune has a treatment effect has not been established. Changes in superoxide levels during Actimmune therapy do not predict efficacy and should not be used to assess patient response to therapy.

Pharmacokinetics

Pharmacokinetic studies in patients with CGD have not been performed. The intravenous, intramuscular, and subcutaneous pharmacokinetics of Actimmune have been investigated in 24 healthy male subjects following single-dose administration of 100 mcg/m2 (twice the recommended dose for CGD and SMO patients). Actimmune is rapidly cleared after intravenous administration (1.4 Liters/minute) and slowly absorbed after intramuscular or subcutaneous injection. After intramuscular or subcutaneous injection, the apparent fraction of dose absorbed was greater than 89%. The mean elimination half-life after intravenous administration of 100 mcg/m2 in healthy male subjects was 38 minutes. The mean elimination half-lives for intramuscular and subcutaneous dosing with 100 mcg/m2 were 2.9 and 5.9 hours, respectively. Peak plasma concentrations, determined by ELISA, occurred approximately 4 hours (1.5 ng/mL) after intramuscular dosing and 7 hours (0.6 ng/mL) after subcutaneous dosing. Multiple dose subcutaneous pharmacokinetic studies were conducted in 38 healthy male subjects. There was no accumulation of Actimmune after 12 consecutive daily injections of 100 mcg/m2.

Interferon gamma was not detected in the urine of healthy human volunteers following administration of 100 mcg/m2 of Actimmune by the intravenous, intramuscular and subcutaneous routes. In vitro perfusion studies utilizing rabbit livers and kidneys demonstrate that these organs are capable of clearing interferon gamma from perfusate.

Contraindications

Hypersensitivity to interferon gamma or E. coli-derived products

Cautions

Immunocompromised patients

Potential for hepatotoxicity

If severe reactions occur, decrease dose 50% or withhold until side effects subside

Caution in cardiovascular disease; pre-existing cardiac conditions may be exacerbated

Reduce dose or discontinue if decreased mental status, gait disturbance, dizziness occur

Monitor for neutropenia and thrombocytopenia particularly when administering in combination with other potentially myelosuppressive agents

Reduce dose or discontinue to reverse severe elevations of aspartate transaminase (AST) and/or alanine transaminase (ALT); monitor liver function monthly in patients <1 year old

If serious hypersensitivity reactions occur, discontinue and institute appropriate medical therapy

Monitor renal function regularly when administering therapy to patients with severe renal insufficiency

Refrigerate vials-do not freeze or shake

The stopper of the glass vial contains natural rubber (a derivative of latex) which may cause allergic reactions

May cause flu-like symptoms

No preservatives-discard unused portions

Applies to interferon gamma-1b: solution

Along with its needed effects, interferon gamma-1b (the active ingredient contained in Actimmune) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking interferon gamma-1b:

• Chills
• fever

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• confusion
• cough or hoarseness
• loss of balance control
• lower back or side pain
• mask-like face
• painful or difficult urination
• pinpoint red spots on the skin
• shuffling walk
• sore throat
• stiffness of the arms or legs
• trembling and shaking of the hands and fingers
• trouble breathing
• trouble speaking or swallowing
• trouble thinking or concentrating
• trouble walking
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness

• Abdominal or stomach pain or tenderness
• change in walking and balance
• clay colored stools
• clumsiness or unsteadiness
• dark urine
• decreased appetite
• decreased frequency or amount of urine
• general feeling of discomfort or illness
• headache
• increased thirst
• itching or skin rash
• joint or muscle pain
• loss of appetite
• lower back or side pain
• muscle aches and pains
• nausea and vomiting
• numbness or tingling of the face, hands, or feet
• painful or difficult urination
• pale skin
• redness and soreness of the eyes
• runny nose
• shivering skin
• sweating
• swelling of the face, fingers, or lower legs
• trouble sleeping
• weight gain
• yellow eyes or skin

Some side effects of interferon gamma-1b may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea
• redness or tenderness at the injection site

• Back pain
• dizziness
• weight loss

Applies to interferon gamma-1b: subcutaneous solution

General

General flu-like side effects have been reported most frequently. These have included fever (52%), headache (33%), chills (14%), fatigue (14%), myalgia (6%), and arthralgia (2%). Chest discomfort has been reported.[Ref]

Gastrointestinal

Gastrointestinal side effects have been reported frequently. These have included diarrhea (14%), vomiting (13%), and nausea (10%). Gastrointestinal bleeding has been reported rarely.[Ref]

Dermatologic

Dermatologic side effects have included rash (17%).[Ref]

Local

Local side effects have included erythema or tenderness at the site of injection (14%).[Ref]

Cardiovascular

Cardiovascular side effects have been reported rarely. These have included hypotension, syncope, tachyarrhythmia, heart block, heart failure, and myocardial infarction.[Ref]

Nervous system

Nervous system side effects have been reported rarely. These have included confusion, disorientation, gait disturbance, Parkinsonian symptoms, seizure, hallucinations, and transient ischemic attacks.[Ref]

Respiratory

Respiratory side effects have included tachypnea, bronchospasm, and interstitial pneumonitis.[Ref]

Hematologic

Hematologic side effects have been reported rarely. These have included deep venous thrombosis and pulmonary embolism.[Ref]

Renal

Renal side effects have included renal insufficiency which was reversible.[Ref]

Metabolic

Metabolic side effects have included hyponatremia, hyperglycemia, and hypertriglyceridemia.[Ref]

Immunologic

Immunologic side effects have included increased autoantibodies and lupus-like syndrome.[Ref]

Some side effects of Actimmune may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Substance Name

Interferon Gamma-1b

CAS Registry Number

98059-61-1

Drug Class

Immunologic Adjuvants