Actimmune

Name: Actimmune

Missed dose

For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule. Do not double the dose to catch up.

What is the most important information I should know about Actimmune (interferon gamma-1b)?

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).

What should I discuss with my healthcare provider before using Actimmune (interferon gamma-1b)?

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.

Actimmune Pharmacokinetics

Absorption

Bioavailability

Following sub-Q injection, >89% of dose is slowly absorbed; peak plasma concentrations attained 7 hours after dose.1

Elimination

Half-life

5.9 hours following a single sub-Q dose.1

Stability

Storage

Parenteral

Injection

2–8°C; do not freeze.1 Unentered vials may be exposed to room temperature for up to 12 hours prior to use; discard vials not returned to refrigerator or used within 12 hours.1

Avoid shaking or excessively or vigorously agitating vials.1

Actions

  • 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.1 2

  • The exact mechanism(s) of action of interferon gamma-1b in patients with chronic granulomatous disease have not been fully elucidated;1 3 4 5 8 9 10 the drug appears to enhance phagocyte function to allow more effective killing of catalase-positive organisms.1 8 Changes in superoxide levels during therapy with interferon gamma-1b do not predict efficacy and should not be used to assess patient response to therapy.1

  • Mechanisms of action in treatment of osteopetrosis not fully elucidated1 12 15 but may involve enhanced superoxide production in leukocytes and osteoclasts.1 Changes in superoxide levels during therapy with interferon gamma-1b do not predict efficacy and should not be used to assess patient response to therapy.1

Actimmune Dosage and Administration

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

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.

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.

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.

Clinical Studies

Effects in Chronic Granulomatous Disease (CGD)

A randomized, double-blind, placebo-controlled trial of Actimmune (interferon gamma-1b) in patients with CGD, was performed to determine whether Actimmune administered subcutaneously on a three times weekly schedule could decrease the incidence of serious infectious episodes and improve existing infectious and inflammatory conditions in patients with CGD. One hundred twenty-eight eligible patients were enrolled in this trial including patients with different patterns of inheritance. Most patients received prophylactic antibiotics. Patients ranged in age from 1 to 44 years with the mean age being 14.6 years. The study was terminated early following demonstration of a highly statistically significant benefit of Actimmune therapy compared to placebo with respect to time to serious infection (p=0.0036), the primary endpoint of the investigation. Serious infection was defined as a clinical event requiring hospitalization and the use of parenteral antibiotics. The final analysis provided further support for the primary endpoint (p=0.0006). There was a 67 percent reduction in relative risk of serious infection in patients receiving Actimmune (n=63) compared to placebo (n=65). Additional supportive evidence of treatment benefit included a twofold reduction in the number of primary serious infections in the Actimmune group (30 on placebo versus 14 on Actimmune, p=0.002) and the total number and rate of serious infections including recurrent events (56 on placebo versus 20 on Actimmune, p=<0.0001). Moreover, the length of hospitalization for the treatment of all clinical events provided evidence highly supportive of an Actimmune treatment benefit. Placebo patients required three times as many inpatient hospitalization days for treatment of clinical events compared to patients receiving Actimmune (1493 versus 497 total days, p=0.02). An Actimmune treatment benefit with respect to time to serious infection was consistently demonstrated in all subgroup analyses according to stratification factors, including pattern of inheritance, use of prophylactic antibiotics, as well as age. There was a 67 percent reduction in relative risk of serious infection in patients receiving Actimmune compared to placebo across all groups. The beneficial effect of Actimmune therapy was observed throughout the entire study, in which the mean duration of Actimmune administration was 8.9 months/patient.

Effects in Severe, Malignant Osteopetrosis (SMO)

A controlled, randomized trial in patients with SMO was conducted with Actimmune administered subcutaneously three times weekly. Sixteen patients were randomized to receive either Actimmune plus calcitriol (n=11), or calcitriol alone (n=5). Patients ranged in age from 1 month to 8 years, mean 1.5 years. Treatment failure was considered to be disease progression as defined by 1) death, 2) significant reduction in hemoglobin or platelet counts, 3) a serious bacterial infection requiring antibiotics, or 4) a 50 dB decrease in hearing or progressive optic atrophy. The median time to disease progression was significantly delayed in the Actimmune plus calcitriol arm versus calcitriol alone. In the treatment arm, the median was not reached. Based on the observed data, however, the median time to progression in this arm was at least 165 days versus a median of 65 days in the calcitriol alone arm. In an analysis which combined data from a second study, 19 of 24 patients treated with Actimmune plus or minus calcitriol for at least 6 months had reduced trabecular bone volume compared to baseline.

Interferon Gamma-1b Levels and Effects while Breastfeeding

Summary of Use during Lactation

Interferon gamma is a normal component of human milk. No data are available on the use of exogenous interferon gamma 1b during breastfeeding. However, the amounts of the similar drugs, interferon alfa and interferon beta-1a, excreted into milk are very low. Any interferon in breastmilk is probably destroyed in the infant's gastrointestinal tract and not absorbed, except perhaps in neonates. Holder pasteurization (62.5 degrees C for 30 minutes) decreases the concentration of endogenous interferon-gamma by an average about 10%.[1]

Drug Levels

Maternal Levels. Measurements of the colostrum 6 mothers of preterm infants found an average of 2 ng/L of interferon gamma; two mothers of fullterm infants had an average of 2.2 ng/L. At over 30 days postpartum, milk of 3 mothers of preterm infants contained 2.6 ng/L of interferon gamma; the milk of 28 mothers of fullterm infants contained an average of 0.7 ng/L.[2]

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

References

1. Ewaschuk JB, Unger S, O'Connor DL et al. Effect of pasteurization on selected immune components of donated human breast milk. J Perinatol. 2011;31:593-8. PMID: 21330996

2. Srivastava MD, Srivastava A, Brouhard B et al. Cytokines in human milk. Res Commun Mol Pathol Pharmacol. 1996;93:263-87. PMID: 8896040

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