DESCRIPTION SECTION

11 DESCRIPTION

ACTIMMUNE (Interferon gamma-1b), an interferon gamma, is a single-chain polypeptide containing 140 amino acids. Production of ACTIMMUNE is achieved by fermentation of a genetically engineered Escherichia coli bacterium containing the DNA which encodes for the recombinant protein. Purification of the product is achieved by conventional column chromatography. ACTIMMUNE is a highly purified sterile solution consisting of non-covalent dimers of two identical 16,465 Dalton monomers; with a specific activity of 20 million International Units/mg (2 × 106 International Units/0.5 mL) which is equivalent to 30 million units/mg.

ACTIMMUNE is a sterile, clear, colorless solution filled in a single-dose vial for subcutaneous injection. Each 0.5 mL of ACTIMMUNE contains: 100 mcg (2 million International Units) of interferon gamma-1b formulated in disodium succinate hexahydrate (0.37 mg), mannitol (20 mg), polysorbate 20 (0.05 mg), succinic acid (0.14 mg) and Sterile Water for Injection. Note that the above activity is expressed in International Units (1 million International Units/50 mcg). This is equivalent to what was previously expressed as units (1.5 million units/50 mcg).

INDICATIONS & USAGE SECTION

Highlight: ACTIMMUNE is an interferon gamma indicated for:

Reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease (CGD) (1)
Delaying time to disease progression in patients with severe, malignant osteopetrosis (SMO) (1)

1 INDICATIONS AND USAGE

ACTIMMUNE is indicated for reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease (CGD).
ACTIMMUNE is indicated for delaying time to disease progression in patients with severe, malignant osteopetrosis (SMO).

DOSAGE & ADMINISTRATION SECTION

Highlight: * For subcutaneous use only (2.1)

The recommended dose is 50 mcg/m2 for patients whose body surface area is greater than 0.5 m2 and 1.5 mcg/kg/dose for patients whose body surface area is equal to or less than 0.5 m2 three times weekly. (2.1)
Monitor hematology, blood chemistries and urinalysis prior to the beginning of treatment and at 3-month intervals. (2.1)
If severe reactions occur, reduce dose by 50 percent or discontinue therapy until the adverse reaction abates. (2.3)

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

The recommended dosage of ACTIMMUNE administered subcutaneously, for the treatment of patients with CGD and SMO is shown in Table 1 below:

Table 1: Recommended Dosage for ACTIMMUNE for the Treatment of Patients with CGD and SMO

Body Surface Area (m2)	Dose (mcg/m2)	Dose (International Units/m2)*	Frequency
Note that the above activity is expressed in International Units (1 million International Units/50 mcg). This is equivalent to what was previously expressed as units (1.5 million units/50 mcg).
Greater than 0.5 m2	50 mcg/m2	1 million International Units/m2	Three times weekly (For example, Monday, Wednesday and Friday)
Equal to or less than 0.5 m2	1.5 mcg/kg/dose	------------	Three times weekly (For example, Monday, Wednesday and Friday)

Prior to the beginning of treatment and at three-month intervals during treatment the following laboratory tests are recommended for all patients on ACTIMMUNE (interferon gamma-1b) therapy [see Warnings and Precautions (5.3, 5.4, 5.6)]:
- Hematologic tests – including complete blood counts, differential and platelet counts
- Blood chemistries – including renal and liver function tests. In patients less than 1 year of age, liver function tests should be measured monthly [see Adverse Reactions (6.2)].
- Urinalysis

2.2 Important Administration Instructions

The optimum sites of subcutaneous injection are the right and left deltoid and anterior thigh.
ACTIMMUNE can be administered by a physician, nurse, family member or patient when appropriately counseled in the administration of subcutaneous injections.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ACTIMMUNE is a clear, colorless solution.
ACTIMMUNE is for a single dose only. Discard any unused portion. ACTIMMUNE does not contain a preservative.
ACTIMMUNE should not be mixed with other drugs in the same syringe.
Administer ACTIMMUNE using either sterilized glass or plastic disposable syringes.

2.3 Dose Modification

If severe reactions occur, the dosage should be reduced by 50 percent or therapy should be interrupted until the adverse reaction abates.
Safety and efficacy has not been established for ACTIMMUNE given in doses greater or less than the recommended dose of 50 mcg/m2. Higher doses (i.e., greater than 50 mcg/m2) are not recommended. The minimum effective dose of ACTIMMUNE has not been established.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Injection**:** 100 mcg (2 million International Units) of Interferon gamma-1b in 0.5 mL solution in a single dose vial. (3)

3 DOSAGE FORMS AND STRENGTHS

Injection: 100 mcg (2 million International Units) per 0.5 mL solution in a single-dose vial. ACTIMMUNE (interferon gamma-1b) is a sterile, clear, colorless solution filled in a single-dose vial for subcutaneous injection.

CONTRAINDICATIONS SECTION

Highlight: Known hypersensitivity to interferon gamma, E. coli derived products, or any component of the product (4)

4 CONTRAINDICATIONS

ACTIMMUNE is contraindicated in patients who develop or have known hypersensitivity to interferon gamma, E. coli derived products, or any component of the product.

WARNINGS AND PRECAUTIONS SECTION

Highlight: * Cardiovascular Disorders: Pre-existing cardiac conditions may be exacerbated. (5.1)

Neurologic Disorders: Reduce dose or discontinue if decreased mental status, gait disturbance, dizziness occur. (5.2)
Bone Marrow Toxicity: Monitor for neutropenia and thrombocytopenia particularly when administering ACTIMMUNE in combination with other potentially myelosuppressive agents. (5.3)
Hepatic Toxicity: Reduce dose or discontinue to reverse severe elevations of aspartate transaminase (AST) and/or alanine transaminase (ALT); monitor liver function monthly in patients less than 1 year old. (5.4)
Hypersensitivity Reactions: If serious hypersensitivity reactions occur, discontinue and institute appropriate medical therapy. (5.5)
Renal Toxicity: Monitor renal function regularly when administering ACTIMMUNE to patients with severe renal insufficiency (5.6)

5 WARNINGS AND PRECAUTIONS

5.1 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.

5.2 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.

5.3 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.

5.4 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)].

5.5 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.

5.6 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.

5.7 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.

USE IN SPECIFIC POPULATIONS SECTION

Highlight: Based on animal data, may cause fetal harm. (8.1)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies in pregnant women. ACTIMMUNE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

ACTIMMUNE has shown an increased incidence of abortions in primates when given from gestation day 20 to 80 in doses approximately 100 times the human dose. A study in pregnant primates treated with subcutaneous doses 2 – 100 times the human dose failed to demonstrate teratogenic activity for ACTIMMUNE.

Female mice treated subcutaneously with recombinant murine IFN-interferon gamma (rmuIFN-gamma) at 280 times the maximum recommended clinical dose of ACTIMMUNE from shortly after birth through puberty but not during pregnancy had offspring which exhibited decreased body weight during the lactation period. The clinical significance of this finding observed following treatment of mice with rmuIFN-gamma is uncertain. For lower doses, there is no evidence of maternal toxicity, embryotoxicity, fetotoxicity or teratogenicity in preclinical studies.

8.2 Lactation

Risk Summary

It is not known whether ACTIMMUNE is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ACTIMMUNE, a decision should be made whether to discontinue nursing or to discontinue the drug, dependent upon the importance of the drug to the mother.

8.3 Females and Males of Reproductive Potential

Infertility

Based on the information available, it cannot be excluded that the presence of higher levels of interferon gamma may impair male fertility and that in certain cases of female infertility increased levels of interferon gamma may have played a role [see Nonclinical Toxicology (13.1)].

In younger patients, the long-term effect on fertility is also not known.

8.4 Pediatric Use

The safety and effectiveness of ACTIMMUNE has been established in pediatric patients aged 1 year and older in CGD patients and 1 month and older in SMO patients [see Clinical Studies (14)]. There are no data available for pediatric patients below the age of 1 month.

8.5 Geriatric Use

Clinical studies of ACTIMMUNE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

OVERDOSAGE SECTION

10 OVERDOSAGE

Central nervous system adverse reactions including decreased mental status, gait disturbance and dizziness have been observed, particularly in patients receiving doses greater than 100 mcg/m2/day by intravenous or intramuscular administration. These abnormalities were reversible within a few days upon dose reduction or discontinuation of therapy. Reversible neutropenia, elevation of hepatic enzymes and of triglycerides, and thrombocytopenia have also been observed.

INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient and/or their parents or caregivers to read the FDA-approved patient labeling (Information for Patient/Caregiver).

Inform patients and/or their parents or caregiver regarding the potential benefits and risks associated with treatment. If home use is determined to be desirable by the physician, instructions on appropriate use should be given, including review of the contents of the Information for Patient/ Caregiver. This information is intended to aid in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects.
If home use is prescribed, a puncture resistant container for the disposal of used syringes and needles should be used by the patient and/or parents or caregivers. Instruct patients thoroughly on the importance of proper disposal and caution the patient and/or patient or caregiver against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician.
Advise the patients and/or their parents or caregivers that the most common adverse reactions occurring with ACTIMMUNE therapy are "flu-like" or constitutional symptoms such as fever, headache, chills, myalgia or fatigue [see Adverse Reactions (6.1)] which may decrease in severity as treatment continues. Some of the "flu-like" symptoms may be minimized by bedtime administration of ACTIMMUNE. Acetaminophen may also be used to prevent or partially alleviate the fever and headache.
Advise patients and/or their parents or caregivers that they may experience undesirable effects such as fatigue, convulsion, confusional state, disorientation or hallucination during treatment. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience any of these events, they should avoid potentially hazardous tasks such as driving or operating machinery. This effect may be enhanced by alcohol.

Manufactured by:
Horizon Therapeutics Ireland DAC
Dublin, Ireland
U.S. License No. 2022

Distributed by:
Horizon Therapeutics USA, Inc.
Lake Forest, IL 60045

ACT-US-PI-001

SPL PATIENT PACKAGE INSERT SECTION

Information for the Patient/Caregiver

ACTIMMUNE® (Interferon gamma-1b)

DO NOT ADMINISTER** ACTIMMUNE**** UNTIL YOUR PHYSICIAN HAS THOROUGHLY TRAINED YOU IN THE PROPER TECHNIQUES.**

ACTIMMUNE is supplied in single-dose vials. The unused portion of each vial should be disposed of as instructed by your physician.DO NOT SHAKE.

Your physician will tell you what size needle and syringe to use and also give you instructions on sterile technique. Keep all used syringes and needles out of the reach of children. Follow your physician's instructions on the safe disposal of used syringes and needles.

MEASURING THE DOSE

In measuring the correct dose for injection, be sure to check that the ACTIMMUNE solution is clear. If the solution is cloudy or hazy, do not inject it, but return the ACTIMMUNE vial to your pharmacist or prescribing physician.

	1. Wash your hands thoroughly with soap and water before preparing the medication. This helps prevent infection.
	2. Check the date on the ACTIMMUNE vial to be sure the drug has not expired.
	3. Remove the protective plastic cap and wipe the rubber stopper located on top of the ACTIMMUNE vial with an alcohol swab.
	4. Draw air into the syringe by pulling back on the plunger. The amount of air should be equal to the ACTIMMUNE dose.
	5. Remove and save the needle guard. Slowly insert the needle straight through the center of the rubber stopper into the ACTIMMUNE vial.
	6. Gently push the plunger to discharge the air into the vial.
	7. Turn the vial upside down with the syringe needle still in it and hold it in one hand. Be sure the tip of the needle is in the solution. Using your other hand slowly pull back on the plunger in a continuous motion until the correct amount of ACTIMMUNE solution is in the syringe. Each vial contains enough ACTIMMUNE for removal of up to 0.5 mL, with a small additional amount present for ease of withdrawal.
	8. Remove the needle from the ACTIMMUNE vial and replace the needle guard until time of administration or injection. Administration should be as soon after filling the syringe as possible; do not store ACTIMMUNE in the syringe.
SELECTING THE INJECTION SITE
Your doctor or nurse will teach you how to locate appropriate injection sites. It is very important that you rotate the site of an injection each time you give the medication. Even if you or your child develop a preference for one site – as often happens – you still should rotate the injection site.
Following are the injection sites most often recommended:
	Upper Arm
	Abdomen
	Thigh
GIVING THE MEDICATION
Your doctor or nurse will provide you with hands-on training on how to give an injection. Needles and syringes should be used only once to insure sterility of both the needle and the syringe. The following is a review of the steps involved in giving the medication:
	1. Cleanse the injection site with an alcohol-saturated cotton ball or cotton swab.
	2. Remove the needle guard from the syringe filled with the proper dose of solution and hold the syringe the way you would hold a pencil. Double check that the correct amount of ACTIMMUNE solution is in the syringe.
	3. Squeeze the skin between your fingers before and during the injection. Insert the needle into the skin at a 45° angle with a quick, firm motion. This hurts less than pushing the needle in slowly.
4. After the needle is in, pull back very slightly with one hand on the plunger to see if blood comes into the syringe. This is to be sure that the needle has not entered a blood vessel. If blood does come into the syringe, do not inject the ACTIMMUNE solution. Withdraw the needle and insert at another location.
	5. If blood does not come into the syringe, slowly (within a few seconds) inject the solution by gently pushing the plunger until the syringe is empty.
	6. Withdraw the needle quickly, pulling it straight out, and apply pressure over the injection site with a dry gauze pad or cotton ball. A drop of blood may appear. Put a Band-Aid® on the injection site if desired.
	7. To prevent injury, safely dispose of all used needles and syringes after a single dose as instructed by your physician by following these simple steps:
Place all used needles and syringes in a hard, plastic container with a screw-on cap, or a metal container with a plastic lid, such as a coffee can properly labeled as to content. If a metal container is used, cut a small hole in the plastic lid and tape the lid to the metal container. When the metal container is full, cover the hole with tape and throw it away. If a hard, plastic container is used, always screw the cap on tightly after each use. When the plastic container is full, tape around the cap and throw it away. Do not use glass or clear, plastic containers, or any container that will be recycled or returned to a store. Always store the container out of the reach of children. Please check with your doctor, nurse or pharmacist for other suggestions. There may be special state and local laws that they will discuss with you.
8. Occasionally a problem may develop at the injection site. If you notice any of the following signs or symptoms, contact your doctor or nurse: A lump or swelling that doesn't go away Bruising that doesn't go away Any signs of infection or inflammation at an injection site (pus, persistent redness, surrounding skin that is hot to the touch, persistent pain after the injection)