Interferon Gamma-1b
Actimmune® | ACTIMMUNE INJECTION
Classification:
• Biologic Response Modifiers
• Interferons
Description, Mechanism of Action, Pharmacokinetics
Description: Interferon gamma-1b (rINFgamma-1b) is a recombinant form of gamma
interferon containing 140 amino acids. Interferon gamma-1b is derived from
genetically engineered Escherichia coli and is supplied as a highly purified
solution with a specific activity of 20 million International Units (IU)/mg. A
unit of activity is based on antiviral activity against encephalomyocarditis
virus. Recombinant gamma interferons are identified by a number indicating the
sequence at position 1 and a letter characterizing position 139. Interferon
gamma-1b has a hydrogen and methionine at position 1 and a hydroxyl group at
position 139. Endogenous interferon gamma is a heterogeneous protein of 166
amino acids encoded on chromosome 12 and is chemically and pharmacologically
distinct from interferon alpha or interferon beta. Interferon gamma-1b is used
to decrease the frequency and severity of infections associated with chronic
granulomatous disease (CGD). Prior to the availability of interferon gamma-1b,
the standard treatment for these patients included surgical drainage of abcesses,
extended use of systemic antimicrobial prophylaxis, and transfusion of white
blood cells. Clinical trials with interferon gamma-1b in the treatment of CGD
were terminated prematurely due to significant benefit over placebo. In the
treatment of osteopetrosis, interferon gamma-1b significantly prolongs the time
to disease progression as compared with treatment with calcitriol (165 days vs.
65 days, respectively). Interferon gamma-1b is currently under investigation for
the treatment of cryptococcal meningitis, multiple-drug resistant tuberculosis,
systemic fungal disease, other mycobacterium infections, and pulmonary fibrosis;
it is no longer under investigation for treatment of atopic dermatitis or renal
cell carcinoma due to lack of benefit. The FDA approved interferon gamma-1b in
December 1990 for the treatment of granulomatous disease. In February 2000,
under fast track review, the FDA approved interferon gamma-1b for delaying the
time to disease progression in patients with severe, malignant osteopetrosis.
InterMune distributes Actimmune® in North America while Boehringer Ingelheim
distributes the product outside of North America (Imukin®).
Mechanism of Action: Interferon gamma belongs to the class of interferons, which
are species-specific proteins produced in response to viruses as well as a
variety of other natural and synthetic stimuli. Interferons regulate immune
response. Interferon gamma is a Type II interferon or immune interferon. As
compared to the other interferons (alpha and beta), interferon gamma is acid
labile, encoded on a different chromosome, and binds to different cell surface
receptors. Similar to interferons alpha and beta, interferon gamma increases the
expression of class I major histocompatibility complex (MHC), enhances the
activity of NK cells, interferes with viral replication, and decreases cell
proliferation. In addition, interferon gamma activates macrophages, increases
expression of MCH class II, and stimulates formation of cytotoxic T lymphocytes.
There are two types of interferon gamma receptors that differ in molecular
weight, acid stability, and regulation of receptor expression. These receptor
differences may explain the various effects of interferon gamma. Interferon
gamma receptors have been found on epithelial and hematopoietic cells and
fibroblasts.[2747] Since interferon gamma is produced by activated T lymphocytes
and regulates the activity of immune cells, it may be more appropriate to
describe interferon gamma as a lymphokine of the interleukin type. There is
evidence that interferon gamma interacts functionally with other interleukin
molecules such as interleukin (IL)-2 and that all of the interleukins form part
of a complex, lymphokine regulatory network. The interaction of interferon gamma
with IL-4 results in suppression of IgE levels as well as inhibition of collagen
production in humans. Interferon gamma also stimulates the release of IL-1,
which is important in the activation of T lymphocytes.
All interferons can induce an antiviral activity in host cells by affecting
attachment, penetration, uncoating, transcription, assembly, and maturation of
viruses. Interferons inhibit viral translation through induction and activation
of 2,5-olgoadenylate synthetase pathway and the eukaryotic protein synthesis
pathway. Induction of 2,5-olgoadenylate synthetase leads to degradation of viral
messenger RNA and activation of protein synthesis initiation factor inhibits
viral translation. Interferon gamma is produced only after T lymphocytes become
activated and is more important in stimulating immune reactions rather than
direct antiviral actions. Interferon gamma induces cellular resistance to
cytomegalovirus, herpes simplex virus, and adenovirus in vitro.[2747]
Interferon gamma is required for macrophage activation. The exact mechanism by
which interferon gamma mediates this is unknown but seems to result from
enhancement of oxidative metabolism in tissue macrophages, as well as,
enhancement of antibody-dependent cellular cytotoxicity and natural killer cell
activity. Enhanced oxidative metabolism results in the production of toxic
oxygen metabolites within phagocytes which allows more efficient killing of
certain fungi, bacteria, and protozoal microbes, including Staphylococcus aureus,
Aspergillus fumigatus, Chlamydia psittaci, Plasmodium falciparum, Leishmania
donovani, Toxoplasma gondii, and Listeria monocytogenes. Interferon gamma also
enhances antigen processing and signaling by antigen-presenting cells by
increasing the expression of MHC class II on the membranes of macrophages. Use
of interferon gamma in patients with chronic granulomatous disease results in a
reduced risk of developing a serious infection. In osteopetrosis, a disorder
characterized by an osteoclast defect leading to bone overgrowth and deficient
macrophage oxidative metabolism, interferon gamma enhancement of superoxide
production by phagocytes has been observed in vitro. Interferon gamma also has
been shown to enhance osteoclast function in vitro.
Pharmacokinetics: Interferon gamma-1b is administered subcutaneously. Available
pharmacokinetic data has been obtained through study of healthy males. Following
administration, approximately 90% of the dose is absorbed. Peak serum
concentrations occur 7 hours after subcutaneous administration with an
elimination half-life of about 5.9 hours. Following intravenous bolus
administration, the half-life of interferon gamma-1b is 25—35 minutes, which
is similar to endogenous interferon gamma.[2748] Accumulation does not occur
following multiple subcutaneous doses. Interferon gamma-1b is not detected in
the urine following administration to healthy adult males.
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Indications
Renal Impairment Dosing
• chronic granulomatous disease
• Mycobacterium avium complex (MAC)†
• pulmonary fibrosis†
• osteopetrosis
†non-FDA-approved indication
Dosage
For the treatment of chronic granulomatous disease:
NOTE: Interferon gamma-1b has been designated an orphan drug by the FDA for this indication.
Subcutaneous dosage:
Adults and children with body surface area (BSA) > 0.5 m[2]: 50 µg/m2 subcutaneously three
times weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy should
be held until the reaction resolves.
Adults and children with body surface area (BSA) <= 0.5 m[2]: 1.5 µg/kg subcutaneously
three times weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy
should be held until the reaction resolves.
For the treatment of severe, malignant osteopetrosis to delay the time to disease
progression:
NOTE: Interferon gamma-1b has been designated an orphan drug by the FDA for this indication.
Subcutaneous dosage:
Children with body surface area (BSA) > 0.5 m[2]: 50 µg/m2 subcutaneously three times
weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy should be
held until the reaction resolves.
Children with body surface area (BSA) <= 0.5 m[2]: 1.5 µg/kg subcutaneously three times
weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy should be
held until the reaction resolves.
For the treatment of idiopathic pulmonary fibrosis† in patients refractory to
corticosteroid therapy:
Subcutaneous dosage:
Adults: In a small, preliminary study, patients were treated with 200 µg interferon gamma-1b SC
three times weekly with prednisone for 12 months. Results of this study indicated that patients
treated with interferon gamma-1b in combination with prednisone had significant improvement in
pulmonary ventilation (lung capacity and force vital capacity) and gas exchange as compared to
those patients receiving prednisone alone.[2749]
As an adjunct to traditional antimycobacterial agents in the treatment of refractory
mycobacterium infection due to Mycobacterium avium complex (MAC)†:
Subcutaneous dosage:
Adults and Children >= 5 years: In a small series of patients with refractory non-tuberculous
mycobacterium infection, the addition of interferon gamma to traditional antimycobacterial therapy
produced both subjective and clinical responses in 7 of 7 patients. The dosage of interferon
gamma-1b was 50 µg SC three times per week and was reduced by half if patients experienced
intolerable adverse effects. The dose was administered for 4—19 months in these 7
patients.[1222]
Patients with renal impairment:
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no
dosage adjustments are needed.
Patients with hepatic impairment:
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that
no dosage adjustments are needed.
†non-FDA-approved indication
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Administration Guidelines
Subcutaneous Administration
•No dilution necessary.
•The activity of interferon gamma-1b is now expressed as International Units (1 million IU/50 µg).
•Premedication with acetaminophen or ibuprofen may decrease the incidence of fever and
headache. Administer at bedtime to minimize some of the flu-like symptoms.
•Store in a refrigerator between 2 and 8 degrees C (36 and 46 degrees F); do not freeze. Do not
shake vial. Discard any unused portions or any vial left at room temperature for > 12 hours.
•Visually inspect parenteral products for particulate matter and discoloration prior to
administration whenever solution and container permit.
Subcutaneous injection:
•Inject subcutaneously into the right or left deltoid or anterior thigh. Care should be taken to avoid
intradermal or intravascular injection. Rotate injection sites.
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Contraindications/Precautions
• angina
• bone marrow suppression
• breast-feeding
• cardiac arrhythmias
• cardiac disease
• E. coli protein hypersensitivity
• females
• heart failure
• infants
• myocardial infarction
• pregnancy
• seizure disorder
• Absolute contraindications are in italics.
Interferon gamma-1b dosage >= 250 µg/m2 may cause neutropenia. Interferon gamma-1b should
be administered with caution to patients with pre-existing bone marrow suppression. At doses
listed in the package insert, interferon gamma-1b is not usually myelosuppressive.
Interferon gamma-1b is classified as FDA pregnancy category C. It is recommended that the
drug not be used in pregnant women because the safety of interferon gamma-1b during pregnancy
has not been established. Females of childbearing age should use effective methods of birth
control while receiving interferon gamma-1b.
It is unknown whether interferon gamma-1b is excreted into breast milk, therefore, it is
recommended that breast-feeding be discontinued while the mother is receiving interferon
gamma-1b.
The safe and effective use of interferon gamma-1b in infants (< 1 year of age) for the treatment of
chronic granulomatous disease has not been established, therefore, use in these patients is not
recommended by the manufacturer. In clinical trials for osteopetrosis, children aged 1 month to 8
years (mean age 1.5 years) were treated safely. The long-term effects of interferon gamma-1b
therapy on growth, development, or other parameters are not known.
Interferon gamma-1b should be used cautiously in patients with pre-existing cardiac disease
including ischemia (i.e., angina or myocardial infarction), congestive heart failure, or cardiac
arrhythmias. No direct cardiotoxic effects have been noted, but it is possible that the transient,
acute flu-like symptoms (i.e., fever and chills) associated with interferon gamma-1b doses >= 250
µg/m2 may exacerbate the cardiac condition.
Interferon gamma-1b should be used with caution in patients with seizure disorders or
compromised CNS function. Adverse CNS reactions such as decreased mental status, gait
disturbance, and dizziness have been reported with interferon gamma-1b, particularly in patients
receiving doses >= 250 µg/m2.
Interferon gamma-1b is contraindicated in patients with a prior history of E. coli protein
hypersensitivity.
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Drug Interactions
• Fosphenytoin
• Phenytoin
• Theophylline, Aminophylline
• Warfarin
The interaction of interferon gamma-1b with other drugs has not been fully determined. Studies in
rodents have demonstrated alterations in the levels of the hepatic cytochrome P450
concentrations. Drugs metabolized by this system, including warfarin, theophylline, and
phenytoin, may be susceptible to drug interactions with interferon gamma-1b. Until additional
human data is available, interferon gamma-1b should be used cautiously in patients receiving
phenytoin or fosphenytoin, theophylline, or warfarin.
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Adverse Reactions
• arthralgia
• ataxia
• chills
• confusion
• diaphoresis
• dizziness
• elevated hepatic enzymes
• erythema
• fatigue
• fever
• headache
• injection site reaction
• maculopapular rash
• myalgia
• nausea/vomiting
• neutropenia
• rash (unspecified)
• urticaria
The most common adverse reactions with interferon gamma-1b involve flu-like symptoms. The
symptoms may include fever (52%), headache (33%), chills (14%), and fatigue (14%).
Arthralgia, myalgia, and night time diaphoresis may also occur. Premedication with
acetaminophen or ibuprofen may prevent or partially alleviate the fever and headache.
Nausea/vomiting (10%/13%) and diarrhea (14%) have also been reported. In patients receiving
interferon gamma-1b for indications other than chronic granulomatous disease, pancreatitis and GI
bleeding have been recorded.
Rash (unspecified) may develop (17%) or patients may develop an injection site reaction with
erythema and tenderness around the injection site (14%). Maculopapular rash or urticaria has
been reported. Acute hypersensitivity reactions have not been reported with interferon gamma-1b.
In interferon gamma-1b doses >= 250 µg/m2/day, reversible neutropenia and elevated hepatic
enzymes can be dose limiting. Thrombocytopenia and proteinuria have also been seen rarely at
these doses.
Interferon gamma-1b-induced central nervous system toxicity including altered mental status,
ataxia, confusion, and dizziness has been observed, particularly in patients receiving dosages
>= 250 µg/m2/day. Parkinsonian symptoms, disorientation, seizures, and hallucinations have also
been reported. Neurotoxic effects are usually reversible after withdrawal of interferon gamma-1b.
Additional adverse reactions have been reported in patients receiving interferon gamma-1b at
dosages > 100 µg/m2/day for indications other than chronic granulomatous disease. These
reactions include bronchospasm, deep vein thrombosis, heart block, heart failure, hypotension,
interstitial pneumonitis, myocardial infarction, pulmonary embolism, reversible renal insufficiency,
syncope, tachyarrhythmia, and tachypnea.
Neutralizing antibodies to interferon gamma-1b have not been reported in patients treated for
chronic granulomatous disease.
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Patient Education
Interferon Gamma-1b injection
What does interferon gamma-1b injection do?
INTERFERON Gamma-1b (Actimmune®) is a man-made drug that acts like a substance in your
body called interferon gamma. Interferon gamma helps your immune system work better. In
patients with chronic granulomatous disease, interferon gamma helps to fight infections. In children
with osteopetrosis, interferon gamma helps to slow the progression of the disease. Interferon
gamma is also being studied in the treatment of other infections and diseases. Generic interferon
gamma-1b injections are not available.
What should my health care professional know before I receive interferon gamma-1b?
They need to know if you have any of these conditions:
•blood disorders
•heart disease, especially heart failure or an irregular heart beat
•seizure disorder
•an unusual or allergic reaction to interferon, proteins, other medicines, foods, dyes, or
preservatives
•pregnant or trying to get pregnant
•breast-feeding
How should I use this medicine?
Interferon gamma-1b is for injection under the skin. A health-care professional can give it, or you
may be able to give yourself the injections. Before you try to use this injection, carefully read the
instructions provided. Make sure you understand how to prepare, inject, and store interferon
gamma-1b. Before preparing an injection always wash your hands well with soap and water. Do
not shake the solution before measuring or injecting a dose. Do not use more than the prescribed
dose. Using larger or more frequent doses increases the risk of getting serious side effects.
If you will be giving interferon gamma-1b at home, make sure you receive a puncture resistant
container for the disposal of used syringes and needles. Do not reuse needles or syringes.
What if I miss a dose?
If you miss a dose, use it as soon as you can. Reschedule your next dose about 48 hours later.
Contact your prescriber or health care professional if you have questions about adjusting your
schedule.
What other medicines can interact with interferon gamma-1b?
•phenytoin
•theophylline
•warfarin
Tell your prescriber or health care professional about all other medicines that you are taking,
including non-prescription medicines, nutritional supplements, or herbal products. Also tell your
prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol,
if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check
with your health care professional before stopping or starting any of your medicines.
What side effects may I notice from receiving interferon gamma-1b?
Side effects that you should report to your prescriber or health care professional as soon as
possible:
•skin rash, itching
•unusual weakness or tiredness
Side effects that usually do not require medical attention (report to your prescriber or health care
professional if they continue or are bothersome):
•fever, chills, or flu-like symptoms
•headache
•increased sweating
•muscle aches
•nausea, vomiting
•redness, swelling, tenderness, and irritation at the injection site
What do I need to watch for while I receive interferon gamma-1b?
Visit your prescriber or health care professional for regular checks on your progress. Females of
child-bearing age should use a reliable method of birth control. If you do get pregnant, stop using
interferon gamma-1b at once and contact your prescriber or health care professional.
Reactions at the site of injection may occur. Ask your prescriber or health care professional to
suggest a series of injection sites, so that you do not have to use the same site repeatedly. You can
use an injection site again after one week, providing the skin is not tender, red, or hard.
Flu-like symptoms are common with interferon gamma-1b therapy. Using this medicine at night
can reduce the impact of these symptoms. After checking with your prescriber or health care
professional and getting their approval, you may also take acetaminophen (Tylenol®) or ibuprofen
(Advil®, Motrin®) before your injection to help lessen any fever or headache.
Use disposable syringes only once, and throw away syringes and needles in a closed container to
prevent accidental needle sticks.
Where can I keep my medicine?
Keep out of the reach of children.
Store in a refrigerator between 2 and 8 degreesC (36 and 46 degreesF); do not freeze. Use within
12 hours of taking out of the refrigerator. Throw away any unused vials if they have been out of
the refrigerator longer than 12 hours. Do not use any vials after the expiration date.
NOTE: This information is not intended to cover all possible uses, precautions, interactions, or
adverse effects for this drug. If you have questions about the drug(s) you are taking, check with
your health care professional.
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Costs and Monitoring
Relative Drug Costs
• generic not available
Monitoring Parameters
• CBC with differential: baseline and every 3 months
• LFTs
• serum creatinine/BUN
• urinalysis
Total Cost of Therapy
• 100 µg SC: $200.00—299.99/ea.
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Product Information
More information about the following products is available:
• ACTIMMUNE INJECTION
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References
2. Lombroso PJ, Scahill L, King RA et al. Risperidone treatment of children and adolescents with
chronic tic disorders. J Am Acad Child Adolesc Psych 1995;34:1147—52.
1222. Holland SM, Eisenstein EM, Kuhns DB et al. Treatment of refractory disseminated
nontuberculous mycobacterial infection with interferon gamma. N Engl J Med
1994;330:1348—55.
2747. Bolinger AM, Taeubel MA. Recombinant gamma interferon for the treatment of chronic
granulomatous disease and other disorders. Clin Pharm 1992;11:834—50.
2748. Kurzrock R, Rosenblum MG, Sherwin SA, et al. Pharmacokinetics, single-dose tolerance,
and biologic activity of recombinant gamma-interferon in cancer patients. Cancer Res
1985;45:2866—72.
2749. Zieche R, Hofbauer E, Wittmann K, et al. A preliminary study of long-term treatment with
interferon gamma-1b and low-dose prednisone in patients with idiopathic pulmonary fibrosis. N
Engl J Med 1999;341;1264—9.