Gamma -12

For adults with Chronic Granulomatous Disease (CGD) or Severe Malignant Osteopetrosis (SMO), the dosage is based on Body Surface Area (BSA), which is calculated using the patient's height and weight.

• Standard Adult Dose: 50 mcg/m² (1 million IU/m²) for patients whose BSA is greater than 0.5 m².
• Frequency: The injection is administered subcutaneously three times per week (e.g., Monday, Wednesday, Friday).
• Maximum Dose: The dose should not exceed the calculated BSA-based amount, and adjustments are made as the patient's weight or height changes.

Interferon Gamma-1b is approved for use in children with CGD and SMO. The dosing is also based on Body Surface Area.

• Children with BSA > 0.5 m²: 50 mcg/m² administered subcutaneously three times per week.
• Infants and Children with BSA ≤ 0.5 m²: 1.5 mcg/kg per dose administered subcutaneously three times per week.

Clinical studies have shown that the safety and efficacy profile in pediatric patients is similar to that in adults, though younger children may require more frequent monitoring of growth and development.

Renal Impairment

There are no specific guidelines for dose adjustment in patients with renal (kidney) impairment. However, since the kidneys are involved in the clearance of protein metabolites, healthcare providers should monitor these patients closely for adverse effects. In cases of severe renal failure, the drug should be used with extreme caution.

Hepatic Impairment

Interferon Gamma-1b should be used with caution in patients with known hepatic (liver) disease. If significant elevations in liver enzymes (AST/ALT) occur during treatment, the dose may need to be reduced or temporarily discontinued until levels return to baseline.

Elderly Patients

Clinical trials of Interferon Gamma-1b 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.

Interferon Gamma-1b is administered by subcutaneous injection, usually into the thigh, upper arm, or abdomen.

1. 1Preparation: Remove the vial from the refrigerator and let it reach room temperature (about 15-30 minutes). Do not use external heat sources like a microwave.
2. 2Inspection: Check the liquid; it should be clear and colorless. If it is cloudy or contains particles, do not use it.
3. 3Injection Sites: Rotate injection sites with each dose to prevent skin irritation or the development of hard lumps (lipohypertrophy). Avoid areas that are red, bruised, or scarred.
4. 4Technique: Use a 25- to 27-gauge needle for injection. Pinch the skin and insert the needle at a 45- to 90-degree angle.
5. 5Timing: It is often recommended to administer the injection in the evening to allow the patient to sleep through the most common 'flu-like' side effects.

If a dose is missed, it should be administered as soon as possible. However, if it is almost time for the next scheduled dose, skip the missed dose and return to the regular schedule. Do not 'double up' or administer two doses on the same day. Consistent timing is key to maintaining therapeutic levels in the body.

Symptoms of an overdose of Interferon Gamma-1b may include severe flu-like symptoms (fever, chills, muscle pain), extreme fatigue, dizziness, and significant changes in blood counts (low white blood cells or platelets).

In the event of a suspected overdose, contact a poison control center or seek emergency medical attention immediately. Treatment is generally supportive, focusing on managing symptoms and monitoring vital signs and blood counts.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop the medication without medical guidance, as this could increase your risk of serious infection.

The most frequently reported side effects of Interferon Gamma-1b are known as 'flu-like symptoms.' These are expected biological responses to the interferon protein and usually diminish in intensity as the body adjusts to the medication over several weeks.

• Fever and Chills: Often occurring within a few hours of the injection. These can be managed with acetaminophen (Tylenol) or nonsteroidal anti-inflammatory drugs (NSAIDs) taken before the injection.
• Headache: A dull or throbbing pain that typically lasts for several hours post-injection.
• Fatigue and Malaise: A general feeling of tiredness or being 'unwell.'
• Myalgia (Muscle Pain): Aching in the muscles, similar to what is experienced during a viral infection.
• Injection Site Reactions: Redness, swelling, or tenderness at the spot where the needle entered the skin.

• Gastrointestinal Issues: Nausea, vomiting, diarrhea, or abdominal pain. These are usually mild and transient.
• Arthralgia (Joint Pain): Stiffness or pain in the joints.
• Depression: Some patients may experience changes in mood or feelings of sadness.
• Rash: Mild skin eruptions or itching.

• Neutropenia and Thrombocytopenia: A decrease in the number of white blood cells (neutrophils) or platelets. This can increase the risk of infection or bleeding.
• Elevated Liver Enzymes: Increases in AST or ALT levels, indicating stress on the liver.
• Proteinuria: The presence of excess protein in the urine, which may indicate kidney irritation.

While rare, some side effects require urgent medical intervention.

> Warning: Stop taking Interferon Gamma-1b and call your doctor immediately if you experience any of these:

• Anaphylaxis or Severe Allergic Reactions: Symptoms include hives, swelling of the face, lips, or tongue, difficulty breathing, or a rapid drop in blood pressure. This is a medical emergency.
• Seizures: Interferon Gamma-1b can lower the seizure threshold, particularly in patients with a history of epilepsy.
• Severe Depression or Suicidal Thoughts: Any significant change in mental health, including thoughts of self-harm, must be reported immediately.
• Congestive Heart Failure: Symptoms include shortness of breath (especially when lying down), swelling in the ankles or feet, and unusual weight gain.
• Hepatotoxicity (Liver Damage): Signs include yellowing of the skin or eyes (jaundice), dark urine, and severe upper abdominal pain.

Long-term use of Interferon Gamma-1b is generally well-tolerated in patients with CGD and SMO. However, chronic use requires ongoing monitoring of:

• Growth in Children: While no definitive negative impact on growth has been established, pediatric patients should be monitored regularly.
• Autoimmune Disorders: There are rare reports of interferons triggering or worsening autoimmune conditions, such as lupus-like syndromes or thyroiditis.
• Neutralizing Antibodies: Over time, some patients may develop antibodies against the drug, which could potentially decrease its effectiveness. If a patient who was doing well suddenly experiences more infections, the doctor may test for these antibodies.

There are currently no FDA Black Box Warnings for Interferon Gamma-1b. However, the manufacturer's labeling includes significant warnings regarding hypersensitivity to E. coli-derived products and the potential for severe flu-like symptoms to exacerbate underlying cardiac or neurological conditions.

Report any unusual symptoms to your healthcare provider. Keeping a 'symptom diary' can help your doctor determine if side effects are decreasing over time or if a dose adjustment is necessary.

Interferon Gamma-1b is a powerful immunomodulator that must be used under the close supervision of a specialist (such as an immunologist, hematologist, or infectious disease specialist). It is not a cure for Chronic Granulomatous Disease or Osteopetrosis but a supportive therapy to manage these conditions. Patients must be educated on the importance of maintaining a regular injection schedule and attending all follow-up appointments for laboratory monitoring.

No FDA black box warnings for Interferon Gamma-1b. While it is a high-alert medication due to its biological activity, it does not carry the specific boxed warnings associated with some other interferons (like Interferon Alpha).

• Allergic Reactions / Anaphylaxis Risk: Because Interferon Gamma-1b is produced in E. coli, patients with a known hypersensitivity to E. coli-derived products or to any component of the formulation (such as mannitol or succinate) should not use this drug. Severe allergic reactions, though rare, can occur upon the first dose or after multiple administrations.
• Cardiovascular Disorders: Caution should be exercised in patients with pre-existing cardiac disease, including arrhythmias, heart failure, or ischemia. The acute flu-like symptoms (fever, chills, tachycardia) associated with the injection can place significant stress on the heart and may worsen these conditions.
• Neurological Disorders: Patients with a history of seizure disorders or compromised central nervous system (CNS) function should be monitored closely. Interferons have been known to lower the seizure threshold and, in rare cases, cause encephalopathy (brain dysfunction).
• Bone Marrow Suppression: Interferon Gamma-1b can cause a reversible decrease in white blood cell counts and platelet counts. This is particularly concerning in patients who already have compromised bone marrow function or who are taking other medications that suppress the immune system.
• Hepatic and Renal Function: Patients with severe liver or kidney disease may be at higher risk for toxicity, as these organs are responsible for the clearance and processing of the drug's metabolic byproducts.

Regular laboratory testing is mandatory for patients on Interferon Gamma-1b to ensure safety and detect subclinical side effects. Typical monitoring includes:

• Complete Blood Count (CBC): To monitor for neutropenia (low white cells) and thrombocytopenia (low platelets). This is usually checked before starting therapy and then every 3 months during treatment.
• Liver Function Tests (LFTs): To monitor for elevations in AST, ALT, and bilirubin. These are typically checked at baseline and every 3 months.
• Renal Function Tests: Including serum creatinine and urinalysis (to check for protein) every 3 to 6 months.
• Clinical Assessment: Regular physical exams to check for signs of infection in CGD patients or nerve compression/anemia in SMO patients.

Interferon Gamma-1b may cause dizziness, fatigue, or mental confusion in some patients, especially during the first few weeks of therapy or shortly after an injection. Patients should be advised not to drive or operate heavy machinery until they know how the medication affects them.

There is no direct chemical interaction between alcohol and Interferon Gamma-1b. However, alcohol can worsen certain side effects of the drug, such as dizziness and dehydration. Furthermore, both alcohol and Interferon Gamma-1b can stress the liver. It is generally recommended to limit alcohol consumption while on this therapy.

There is no known 'withdrawal syndrome' associated with stopping Interferon Gamma-1b. However, discontinuing the medication in a patient with CGD significantly increases the risk of life-threatening infections. In patients with SMO, stopping the drug may lead to a rapid progression of bone density issues. Treatment should only be stopped under the direct supervision of a physician.

> Important: Discuss all your medical conditions with your healthcare provider before starting Interferon Gamma-1b. Provide a full list of all medications, including over-the-counter drugs and supplements.

There are no absolute drug-drug contraindications listed in the official FDA labeling for Interferon Gamma-1b. However, it should never be used in patients who have had a life-threatening allergic reaction to other interferon products or E. coli-derived proteins.

• Myelosuppressive Agents: Drugs that lower blood cell counts (such as certain chemotherapies, hydroxyurea, or zidovudine) can have an additive effect when used with Interferon Gamma-1b. This increases the risk of severe neutropenia (low white blood cells) or thrombocytopenia (low platelets). If these drugs must be used together, frequent blood count monitoring is essential.
• Hepatotoxic Drugs: Medications known to cause liver damage (such as high-dose acetaminophen, methotrexate, or certain anti-fungals) should be used cautiously. Since Interferon Gamma-1b can elevate liver enzymes, the combination may increase the risk of liver injury.
• Neurotoxic Drugs: Drugs that affect the central nervous system or lower the seizure threshold (such as certain antidepressants or antipsychotics) should be monitored, as the interferon may exacerbate neurological side effects.

• CYP450 Substrates: While Interferon Gamma-1b is not a CYP enzyme substrate, studies have shown that interferons can reduce the activity of certain cytochrome P450 enzymes in the liver. This could potentially increase the blood levels of other drugs metabolized by these enzymes (e.g., theophylline, warfarin, or certain anti-seizure medications). While the effect with Gamma-1b is less pronounced than with Alpha interferons, patients on drugs with a narrow therapeutic index should be monitored.
• Vaccines: The use of live-attenuated vaccines (such as MMR or Varicella) should be discussed with a doctor. While Interferon Gamma-1b stimulates the immune system, the underlying condition (CGD) or the drug's effects on immune signaling may alter the body's response to the vaccine.

There are no known interactions between Interferon Gamma-1b and specific foods. Because it is an injectable medication, absorption is not affected by the contents of the stomach. However, maintaining good hydration is recommended to help manage the flu-like side effects (fever and muscle aches).

• Echinacea and Other Immunostimulants: Many herbal supplements claim to 'boost the immune system.' Since Interferon Gamma-1b is already a potent immune modulator, combining it with these supplements could theoretically lead to an overactive immune response or unpredictable side effects.
• St. John's Wort: While primarily an issue for drugs metabolized by the liver, St. John's Wort can affect many metabolic pathways. Patients should consult their doctor before using any herbal products.

Interferon Gamma-1b does not typically interfere with the chemical analysis of laboratory tests, but it does cause physiological changes that will be reflected in lab results:

• CBC: May show decreased white blood cell, neutrophil, or platelet counts.
• Liver Function: May show increased levels of AST, ALT, or Alkaline Phosphatase.
• Urinalysis: May show increased protein (proteinuria).

For each major interaction, the mechanism involves either shared pathways of toxicity (pharmacodynamic) or the drug's effect on the body's ability to process other chemicals (pharmacokinetic). The management strategy usually involves more frequent blood work and clinical monitoring rather than complete avoidance.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. Even 'natural' products can interact with biological therapies like Interferon Gamma-1b.

There are specific circumstances where Interferon Gamma-1b must NEVER be used due to the risk of life-threatening complications:

1. 1Hypersensitivity to Interferon Gamma-1b: Any patient who has had a previous severe allergic reaction (anaphylaxis, angioedema) to this specific medication.
2. 2Hypersensitivity to E. coli-Derived Products: Since the drug is manufactured in E. coli bacteria, it contains trace amounts of bacterial proteins. Patients with a known allergy to other E. coli-derived drugs (such as certain types of insulin, filgrastim, or pegaspargase) are at high risk for a reaction.
3. 3Hypersensitivity to Components: Allergy to any inactive ingredients in the vial, including sodium succinate, mannitol, or polysorbate 20.

These are conditions where the drug may be used, but only after a careful risk-benefit analysis by the healthcare provider:

• Pre-existing Seizure Disorders: Because interferons can lower the seizure threshold, the risk of a breakthrough seizure must be weighed against the benefit of preventing infections in CGD.
• Severe Cardiac Disease: Patients with unstable angina, recent myocardial infarction (heart attack), or severe congestive heart failure. The physiological stress of the flu-like syndrome (fever/tachycardia) may be dangerous.
• Severe Hepatic or Renal Insufficiency: The drug's safety has not been fully established in patients with end-stage organ failure.
• Autoimmune Disease: Patients with conditions like Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis, as interferons may theoretically trigger a 'flare' of the autoimmune response.

Patients who have had allergic reactions to Interferon Alpha (used for Hepatitis or Cancer) or Interferon Beta (used for Multiple Sclerosis) may be at an increased risk of cross-sensitivity to Interferon Gamma-1b. While they are different types of interferons, they share some structural similarities. Any history of reaction to biological 'interferon' products must be disclosed to the prescribing physician.

> Important: Your healthcare provider will evaluate your complete medical history, including any history of allergies to biological medicines, before prescribing Interferon Gamma-1b.

Interferon Gamma-1b is classified as Pregnancy Category C (under the older FDA system). There are no adequate and well-controlled studies in pregnant women. Animal studies have shown that very high doses can increase the risk of miscarriage (abortifacient effect) in primates.

• Clinical Consideration: Interferon Gamma-1b should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If a patient becomes pregnant while on this medication, they should notify their doctor immediately. It is not typically used in fertility treatments.

It is not known whether Interferon Gamma-1b 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, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. However, since the drug is a large protein, it is likely to be digested in the infant's stomach if any small amounts were present in breast milk.

Interferon Gamma-1b is specifically approved for use in children with CGD and SMO.

• Approved Age: It has been used safely in infants as young as 1 month old for SMO and in young children for CGD.
• Growth and Development: Long-term studies have not shown significant negative impacts on linear growth or pubertal development, but regular monitoring of growth charts is standard clinical practice.
• Dosing: For children with a BSA of 0.5 m² or less, dosing is based on weight (1.5 mcg/kg) rather than surface area.

There is limited data on the use of Interferon Gamma-1b in patients over age 65. Because elderly patients are more likely to have underlying heart disease or reduced kidney function, they should be monitored more frequently for side effects like tachycardia (fast heart rate) or changes in blood counts. The risk of falls may be increased if the patient experiences significant dizziness or fatigue from the medication.

No specific dose adjustments are provided in the manufacturer's labeling for renal impairment. However, in patients with a GFR (Glomerular Filtration Rate) of less than 30 mL/min, the drug should be used with extreme caution. Dialysis does not significantly clear the drug because it is a large protein that is metabolized within the tissues.

In patients with liver impairment (Child-Pugh Class B or C), there is an increased risk of drug-induced liver injury. Healthcare providers may choose to reduce the dose or increase the frequency of LFT monitoring. If AST or ALT levels rise to more than 5 times the upper limit of normal, the drug is typically paused until levels recover.

> Important: Special populations require individualized medical assessment. Pediatric and pregnant patients, in particular, must be managed by specialists familiar with these rare genetic conditions.

Interferon Gamma-1b is a recombinant version of the naturally occurring cytokine, interferon gamma. It is a homodimeric glycoprotein that binds to the IFN-gamma receptor (IFNGR) complex. This complex consists of two subunits: IFNGR1 (the ligand-binding chain) and IFNGR2 (the signal-transducing chain).

Upon binding, the receptor-associated kinases JAK1 and JAK2 are activated. These kinases phosphorylate the receptor, creating a docking site for STAT1 (Signal Transducer and Activator of Transcription 1). STAT1 is then phosphorylated, forms a homodimer, and translocates to the nucleus. In the nucleus, it binds to GAS (Gamma-Activated Site) elements in the promoter regions of specific genes. This results in the transcription of genes that enhance the 'oxidative burst' in phagocytes, increase the expression of MHC molecules, and promote the differentiation of T-cells.

The pharmacodynamic effects of Interferon Gamma-1b include a transient decrease in white blood cell counts and a temporary increase in body temperature (fever) following each dose. The onset of biological activity (gene transcription) occurs within hours, but the clinical effect (reduction in infections) may take several weeks of consistent dosing to become apparent. There is no evidence of 'tolerance' development; the drug remains effective for many years in patients with CGD.

| Parameter | Value |

|---|---|

| Bioavailability | >89% (Subcutaneous) |

| Protein Binding | Negligible |

| Half-life | 3-6 hours (Subcutaneous) |

| Tmax | 4-12 hours |

| Metabolism | Proteolysis (Proteins to Amino Acids) |

| Excretion | Renal (minimal unchanged drug) |

• Molecular Formula: C734H1216N204O221S5 (approximate for the 140 amino acid protein)
• Molecular Weight: Approximately 16,465 Daltons.
• Solubility: Highly soluble in the provided sterile water/succinate buffer.
• Structure: It consists of 140 amino acids. It is non-glycosylated (unlike the natural human form) because it is produced in E. coli.

Interferon Gamma-1b belongs to the class of Interferons, specifically Type II Interferon. It is the only member of this class used clinically. It is distinct from Type I Interferons (Alpha and Beta), which are primarily used for viral infections (Hepatitis) and Multiple Sclerosis. Its unique ability to activate macrophages makes it a specialized tool for specific primary immunodeficiencies and bone disorders.