ACTIMMUNE

ACTIMMUNE- interferon gamma-1b injection, solution
HZNP USA, Inc.

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).

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 use 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.

3 DOSAGE FORMS AND STRENGTHS

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

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.

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.

6 ADVERSE REACTIONS

The following adverse reactions are described below and elsewhere in the warnings and precautions section of the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following data on adverse reactions are based on the subcutaneous administration of ACTIMMUNE at a dose of 50 mcg/m2 , three times weekly, in patients with CGD during a clinical trial in the United States and Europe.

The most common adverse reactions observed in patients with CGD are shown in the following table:

Table 2: Adverse Reactions Occurring in 2 % or Greater of CGD Patients Receiving ACTIMMUNE in Clinical Trials
Adverse Reactions Percent of Patients
ACTIMMUNECGD (n=63) PlaceboCGD (n=65)
Fever 52 28
Headache 33 9
Rash 17 6
Chills 14 0
Injection site erythema or tenderness 14 2
Fatigue 14 11
Diarrhea 14 12
Vomiting 13 5
Nausea 10 2
Myalgia 6 0
Arthralgia 2 0

Similar safety data were observed in 34 patients with SMO.

The clinical and laboratory toxicity associated with multiple dose studies of ACTIMMUNE is dose, route and schedule-dependent.

The most common adverse reactions include constitutional symptoms such as fever, headache, chills, myalgia or fatigue which may decrease in severity as treatment continues.

Less Common Adverse Reactions

The following adverse reactions are assessed as potentially related to ACTIMMUNE (interferon gamma-1b) therapy:

Blood and Lymphatic System—neutropenia (reversible), febrile neutropenia, leukopenia, and thrombocytopenia.

Cardiovascular— angina pectoris, arrhythmia, atrial fibrillation, atrioventricular block, cardiac failure (including congestive cardiac failure), tachyarrhythmia, heart block, (acute) myocardial infarction, myocardial ischemia, syncope, and tachycardia.

Gastrointestinal—abdominal pain, dyspepsia, gastrointestinal bleeding, granulomatous colitis, hepatic insufficiency, and pancreatitis, including pancreatitis with fatal outcome.

General Disorders and Administration Site Conditions—asthenia, chest pain/discomfort, influenza-like illness/flu-like symptoms, injection site hemorrhage, injection site pain, malaise, rigors, and weakness.

Hepatobiliary Disorders—hepatic insufficiency and hepatomegaly.

Immunological—hypersensitivity, increased autoantibodies, lupus-like syndrome (including systemic lupus erythematosus-flares and drug-induced lupus erythematosus), and Stevens-Johnson syndrome.

Infections and Infestations—upper respiratory tract infection.

Investigations—blood alkaline phosphatase increased, liver function tests abnormal/ elevation of hepatic enzymes, increased triglycerides, and weight decreased.

Metabolic—hyponatremia, hypokalemia, hyperglycemia, and hypertriglyceridemia.

Musculoskeletal—back pain, clubbing, and muscle spasms.

Nervous System—dizziness (excluding vertigo), gait disturbance, headache, Parkinsonian symptoms, convulsion/seizure (including grand mal convulsions), and transient ischemic attacks.

Psychiatric—confusion, depression, disorientation, hallucinations, mental status changes, and mental status decreased.

Pulmonary—tachypnea, bronchospasm, pulmonary edema, and interstitial pneumonitis.

Renal—acute renal failure (which may be reversible) and proteinuria.

Skin and Subcutaneous Tissue Disorders—atopic dermatitis, (exacerbation of) dermatomyositis, transient cutaneous rash, and urticaria.

Vascular Disorder—deep venous thrombosis, hypotension, pulmonary embolism.

Abnormal Laboratory Test Values: Elevations of ALT and AST have been observed [see Warnings and Precautions (5.4)].

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