WARNINGS
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. ACTIMMUNE should be used with caution in patients with pre-existing cardiac conditions, including ischemia, congestive heart failure or arrhythmia.
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 mild and reversible within a few days upon dose reduction or discontinuation of therapy. Caution should be exercised 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. Caution should be exercised when administering ACTIMMUNE to patients with myelosuppression.
Hepatic Toxicity
Elevations of AST and /or 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: Dose Modification).
PRECAUTIONS
General
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 but have rarely necessitated treatment interruption.
Information for Patients
Patients being treated with ACTIMMUNE and/or their parents should be informed 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 supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician (see
Information for Patient/Caregiver).
The most common adverse experiences occurring with ACTIMMUNE therapy are "flu-like" or constitutional symptoms such as fever, headache, chills, myalgia or fatigue (see
ADVERSE REACTIONS) which may decrease in severity as treatment continues. Some of the "flu-like" symptoms may be minimized by bedtime administration. Acetaminophen may be used to prevent or partially alleviate the fever and headache.
Laboratory Tests
In addition to those tests normally required for monitoring patients with Chronic Granulomatous Disease and osteopetrosis, the following laboratory tests are recommended for all patients on ACTIMMUNE (Interferon gamma-1b) therapy prior to the beginning of and at three month intervals during treatment (see
WARNINGS: Bone Marrow
and
Hepatic Toxicity).
- 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: Post-Marketing Experience).
- Urinalysis
Drug Interactions
Interactions between ACTIMMUNE and other drugs have not been fully evaluated. Caution should be exercised when administering ACTIMMUNE in combination with other potentially myelosuppressive agents (see
WARNINGS).
Preclinical studies in rodents using species-specific interferon-gamma have demonstrated a decrease in hepatic microsomal cytochrome P-450 concentrations. This could potentially lead to a depression of the hepatic metabolism of certain drugs that utilize this degradative pathway.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenesis
ACTIMMUNE has not been tested for its carcinogenic potential.
Mutagenesis
Ames tests using five different tester strains of bacteria with and without metabolic activation revealed no evidence of mutagenic potential. ACTIMMUNE was tested in a micronucleus assay for its ability to induce chromosomal damage in bone marrow cells of mice following two intravenous doses of 20 mg/kg. No evidence of chromosomal damage was noted.
Impairment of Fertility
Female cynomolgus monkeys treated with daily subcutaneous doses of 30 or 150 mcg/ kg ACTIMMUNE (approximately 20 and 100 times the human dose) exhibited irregular menstrual cycles or absence of cyclicity during treatment. Similar findings were not observed in animals treated with 3 mcg/kg ACTIMMUNE.
Female mice receiving recombinant murine IFN-gamma (rmuIFN-gamma) at 32 times the maximum recommended clinical dose of ACTIMMUNE for 4 weeks via intramuscular injection exhibited an increased incidence of atretic ovarian follicles.
Male cynomolgus monkeys treated intravenously for 4 weeks with 8 times the maximum recommended clinical dose of ACTIMMUNE exhibited decreased spermatogenesis. The impact of this finding on fertility is not known. Male mice receiving rmuIFN-gamma at 32 times the maximum recommended clinical dose of ACTIMMUNE for 4 weeks via intramuscular injection exhibited decreased spermatogenesis.
Male mice treated subcutaneously with rmuIFNgamma from shortly after birth through puberty, with 280 times the maximum recommended clinical dose of ACTIMMUNE exhibited profound yet reversible decreases in sperm counts and fertility, and an increase in the number of abnormal sperm.
The clinical significance of these findings observed following treatment of mice with rmuIFN-gamma is uncertain.
Pregnancy
Teratogenic Effects
Pregnancy Category C
ACTIMMUNE has shown an increased incidence of abortions in primates when given 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 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.
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.
Nursing Mothers
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.
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