Flebogamma Dif (immune globulin,gamma (IgG)/sorbitol/IgA 0 to 50 mcg/mL)

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibody-Based Therapies/Imlifidase

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Imlifidase is a cysteine protease that cleaves immunoglobulin G (IgG), which results in degradation of all subclasses of human and rabbit IgG. Therapies based on human or rabbit IgG may be inactivated if given concurrently with imlifidase.(1)

CLINICAL EFFECTS: Antibody therapies based on human or rabbit IgG may be inactivated and lead to decreased efficacy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of imlifidase and antibody-based therapies should be closely evaluated for timing of administration to avoid decreased efficacy of the antibody-based therapy.(1) Antibody-based therapies cleaved by imlifidase include, but are not limited to, basiliximab, rituximab, alemtuzumab, adalimumab, denosumab, belatacept, etanercept, rabbit anti-human thymocyte globulin (rATG) and intravenous immunoglobulin (IVIg). The prescribing information recommends the following time intervals for administration of antibody-based therapies after administration of imlifidase: -Equine anti-thymocyte globulin: No time interval needed (may be administered concurrently) -Intravenous immunoglobulin (IVIg): 12 hours -Adalimumab, alemtuzumab, basiliximab, denosumab, etanercept, or rituximab: 4 days -Rabbit anti-human thymocyte globulin (rATG) or belatacept: 1 week In addition, IVIg may contain neutralizing antibodies against imlifidase, which may inactivate imlifidase if IVIg is given before imlifidase. Consider the half-life of IVIg (3-4 weeks) before imlifidase administration to patients treated with IVIg. Eculizumab is not cleaved by imlifidase at the recommended dose level.(1)

DISCUSSION: Imlifidase is a cysteine protease that cleaves IgG, which results in degradation of all subclasses of human and rabbit IgG. Antibody therapies based on human or rabbit IgG may be inactivated if given in connection with imlifidase.(1) IVIg may contain neutralizing antibodies against imlifidase, which may inactivate imlifidase if IVIg is given before imlifidase. In clinical studies, IVIg was not administered within 4 weeks before imlifidase infusion.(1)

Selected Immunoglobulins/Selected Live Viral Vaccines

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Immune globulin(IG) products may prevent the immune system from properly responding to the vaccine.(1-19)

CLINICAL EFFECTS: Administration of selected live viral vaccines after immunoglobulins may impair the efficacy of the vaccine.(1-19) Administration of immunoglobulins within 2-4 weeks after selected live viral vaccines impair the efficacy of the vaccine.(1-4,15)

PREDISPOSING FACTORS: The amount of antigen-specific antibody present in the administered immunoglobulin product determines the duration of this interaction.(15)

PATIENT MANAGEMENT: The recommendations regarding this interaction are conflicting. The Centers for Disease Control and Prevention(CDC) immunization recommendations for spacing of live vaccines and antibody-containing products include the following(15): - Live attenuated influenza vaccine, rotavirus, zoster and Ty21a typhoid vaccines may be given any time before, concurrent, with, or after administration of any immune globulin. Yellow fever vaccine may also be given in areas where donor blood products are unlikely to contain a substantial quantity of yellow fever antibody. - Administration of measles or varicella containing vaccines should be postponed for the following intervals after immunoglobulin therapy: Hepatitis B IG, Tetanus IG - 3 months Rabies IG - 4 months Varicella IG - 5 months Measles prophylaxis IG - 6 months if nonimmunocompromised Botulinum IG Intravenous, CMV IG Intravenous, Hepatitis A IG - 6 months Intravenous Immune Globulin(IVIG) - 8 to 11 months depending upon the dose Monoclonal antibody to RSV F protein (palivizumab) - none - Administration of antibody-containing products should be delayed 2 weeks after administration of live vaccines, except for influenza, rotavirus, zoster and typhoid vaccines as noted above. CDC guidelines state that in circumstances where there is high-risk of vaccine-preventable disease, it is acceptable to administer a dose of vaccine prior to completion of these intervals.(16) Manufacturer recommendations are as follows: Administration of a live viral vaccine should be postponed for at least three months in patients who have received the following immunoglobulin therapy: anthrax immunoglobulin,(19) cytomegalovirus immunoglobulin,(1) hepatitis B immunoglobulin,(5,6) rabies immunoglobulin,(7) tetanus immunoglobulin,(8-11) vaccinia immunoglobulin,(18) and zoster immunoglobulin.(2) Administration of a live viral vaccine should be postponed for at least six months in patients who have received the following immunoglobulin therapy: botulinum neurotoxin a/b immune globulin.(17) The US manufacturer of human immunoglobulin states that live viral vaccines should be postponed for three months in patients who have received human immunoglobulin. The Australian and Canadian manufacturers of human immunoglobulin advise postponing live viral vaccines for 3-6 months in patients who have received human immunoglobulin.(6,12,13,18) The UK manufacturer states that vaccines may be compromised for one year and vaccines should be postponed in children for at least seven months.(14) The US manufacturer of immune globulin-hyaluronidase states that immune response to live attenuated vaccines may be impaired for up to 6 months, or for a year or more in the case of measles vaccine.(15) Cytomegalovirus immunoglobulin(1) or human immunoglobulin(3) should not be administered to patients who have received a live vaccine in the previous two weeks. If a live viral vaccine is given within two weeks of zoster immunoglobulin,(1) repetition of the vaccination three months after the completion of immunoglobulin should be considered.

DISCUSSION: CDC Immunization Recommendations(15)provide discussion, charts, and further details regarding appropriate use and timing of vaccine therapy.(16)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Igg Antibodies And Derivatives/Efgartigimod-Alfa

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Efgartigimod-alfa binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of efgartigimod-alfa states that efgartigimod-alfa should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, efgartigimod-alfa should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with efgartigimod-alfa have not been performed. Efgartigimod-alfa may decrease concentrations of compounds that bind to the human FcRn.(3)

Igg Antibodies And Derivatives/Nipocalimab-Aahu

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Nipocalimab-aahu binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nipocalimab-aahu states that nipocalimab-aahu should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, nipocalimab-aahu should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with nipocalimab-aahu have not been performed. Nipocalimab-aahu may decrease concentrations of compounds that bind to the human FcRn.(3)

Intravenous Immunoglobulin/Pozelimab

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Pozelimab is an IgG4P antibody. Concurrent use of intravenous immunoglobulin which binds to FcRn may interfere with the FcRn recycling mechanism of pozelimab and decrease systemic exposure of pozelimab.(3)

CLINICAL EFFECTS: The levels and effectiveness of pozelimab may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pozelimab states that concomitant use of intravenous immunoglobulin should avoided with pozelimab. If concomitant use cannot be avoided, monitor patients for worsening signs and symptoms of CD55-deficient protein-losing enteropathy.(3)

DISCUSSION: Clinical drug interaction studies with pozelimab have not been performed. Immunoglobulins may interfere with the endosomal FcRn recycling mechanism of monoclonal antibodies like pozelimab and decrease concentrations of pozelimab.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Igg Antibodies And Derivatives/Rozanolixizumab-Noli

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Rozanolixizumab-noli binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medications that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of rozanolixizumab-noli states that concurrent use with medications that bind to the human neonatal Fc receptor (FcRn) should be closely monitored for reduced effectiveness of these medications. If long-term use of such medications is essential for the patient, consider discontinuing rozanolixizumab-noli and use alternative therapies.(3)

DISCUSSION: Clinical drug interaction studies with rozanolixizumab-noli have not been performed. Rozanolixizumab-noli may decrease concentrations of compounds that bind to the human FcRn.(3)

Immune Globulin Iv (IGIV)/Selected Nephrotoxic Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, can cause renal dysfunction, acute renal failure, osmotic nephrosis, and/or death. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-4)

CLINICAL EFFECTS: Concurrent use of Immune Globulin Intravenous (IGIV) products with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, non-steroidal anti-inflammatory agents, tenofovir, and vancomycin may result in renal toxicity.(1-4) Other nephrotoxic agents include capreomycin, gallium nitrate, and streptozocin.

PREDISPOSING FACTORS: Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs.(1-4) Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose.(3-4)

PATIENT MANAGEMENT: For patients at risk of renal dysfunction or renal failure, the US manufacturers of Immune Globulin Intravenous (IGIV) products recommends administration at the minimum dose and infusion rate practicable; ensure adequate hydration in patients before administration; and monitor renal function and urine output with assessment of blood urea nitrogen (BUN) and serum creatinine before initial infusion and at regular intervals during therapy.(1-3) Concurrent administration of potentially nephrotoxic agents should be avoided.(1) Review prescribing information for IGIV product to be administered for sucrose content. If concurrent therapy is warranted, monitor renal function closely. In high risk patients, consider selecting an IGIV product that does not contain sucrose.

DISCUSSION: The safety of Immune Globulin Intravenous (IGIV) has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is a major toxicity of IGIV products.(1-3) A review of the FDA renal adverse events (RAEs) (i.e. acute renal failure or insufficiency) from June 1985 to November 1998 identified 120 reports worldwide associated with IGIV administration. In the US, the FDA received 88 reports of cases with clinical and/or laboratory findings consistent with RAE (i.e. increased serum creatinine, oliguria, and acute renal failure). Patient cases involved a median age of 60.5 years and 55% were male. Of the 54 patients who developed acute renal failure, 65% were greater than 65 years, 56% had diabetes, and 26% had prior renal insufficiency; 59% had one, 35% had two, and 6% had three of these conditions. Upon review of the IGIV product received, 90% of cases received sucrose-containing IGIV products with the remaining patients receiving either maltose- or glucose-containing products. Approximately 40% of affected patients required dialysis and RAE may have contributed to death in 15% of patients.(4)

Intravenous Immunoglobulin Therapies/Eculizumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concomitant use of eculizumab products in patients on intravenous immunoglobulin treatment (IVIg) can reduce eculizumab concentrations.(1-2)

CLINICAL EFFECTS: The effectiveness of eculizumab may be decreased.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients with generalized myasthenia gravis, the manufacturer of eculizumab states a supplemental dose of eculizumab is required with concomitant use of IVIg treatment. Acute IVIg rescue treatment: No supplemental eculizumab dose needed. IVIg treatment equal to or more frequent than every 4 weeks: -If the most recent eculizumab dose was 900 mg or more, administer a supplemental eculizumab dose of 600 mg at the same scheduled eculizumab dose. -If the most recent eculizumab dose was 600 mg or less, administer a supplemental eculizumab dose of 300 mg at the same scheduled eculizumab dose. IVIg treatment less frequently than every 4 weeks: -If the most recent eculizumab dose was 900 mg or more, administer a supplemental eculizumab dose of 600 mg at the next scheduled eculizumab dose after the last IVIg cycle. -If the most recent eculizumab dose was 600 mg or less, administer a supplemental eculizumab dose of 300 mg at the next scheduled eculizumab dose after the last IVIg cycle.

DISCUSSION: Clinical drug interaction studies with eculizumab have not been performed. IVIg treatment may decrease concentrations of eculizumab.(1)

Selected Human Immunoglobulins/Estrogens

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of human immunoglobulin with estrogens may have additive effects on clotting mechanisms.(1)

CLINICAL EFFECTS: Concurrent use of human immunoglobulin with estrogens may increase the risk of thrombosis. Thrombosis may occur regardless of the route of administration of the immunoglobulin.(1)

PREDISPOSING FACTORS: Additional risk factors include advanced age, prolonged immobilization, hypercoagulable states, history of arterial or venous thrombosis, indwelling central vascular catheter, hyperviscosity and cardiovascular risk factors (e.g. coronary artery disease, hypertension, diabetes).(1)

PATIENT MANAGEMENT: For patients at risk of thrombosis, administer the minimum concentration of immunoglobulin available at the minimum rate of infusion practicable. Ensure that patients are adequately hydrated before immunoglobulin is infused. Patients should be monitored for signs and symptoms of thrombosis. Assess blood viscosity in patients at risk for hyperviscosity. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis.(1)

DISCUSSION: Thrombosis has been associated with the use of human immunoglobulin and may occur without the presence of risk factors and regardless of the route of administration of the immunoglobulin. Risk factors known to increase the risk of thrombosis include the use of estrogens, advanced age, prolonged immobilization, hypercoagulable states, history of arterial or venous thrombosis, indwelling central vascular catheter, hyperviscosity and cardiovascular risk factors (e.g. coronary artery disease, hypertension, diabetes). For patients at risk of thrombosis, administer the minimum concentration of immunoglobulin available at the minimum rate of infusion practicable. Ensure that patients are adequately hydrated before immunoglobulin is infused. Patients should be monitored for signs and symptoms of thrombosis. Assess blood viscosity in patients at risk for hyperviscosity. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis.(1)

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There are no contraindication contraindications for this drug.

• Predisposition to thrombosis
• Thromboembolic disorder

• Atherosclerotic cardiovascular disease
• Bed-ridden
• Diabetes mellitus
• Hemolytic anemia
• Hypertension
• Hypovolemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Monoclonal gammopathy
• Sepsis
• Transfusion related acute lung injury

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More Frequent

• Tachycardia

Less Frequent

• Dyspnea
• Wheezing

Rare or Very Rare

• Acute myocardial infarction
• Anaphylaxis
• Angioedema
• Bronchospastic pulmonary disease
• Bullous dermatitis
• Cerebrovascular accident
• Chest pain
• Cyanosis
• Disseminated intravascular coagulation
• Erythema multiforme
• Hemolysis
• Hemolytic anemia
• Hyperproteinemia
• Hypertension
• Hypotension
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Migraine
• Non-infective meningitis
• Pancytopenia
• Pseudohyponatremia
• Pulmonary edema
• Pulmonary thromboembolism
• Renal failure
• Seizure disorder
• Stevens-johnson syndrome
• Thromboembolic disorder
• Thrombotic disorder
• Transfusion related acute lung injury

More Frequent

• Acute abdominal pain
• Arthralgia
• Chills
• Cough
• Diarrhea
• Dizziness
• Earache
• Edema
• Fatigue
• Fever
• Headache disorder
• Injection site sequelae
• Nausea
• Pharyngitis
• Skin rash
• Upper respiratory infection
• Vomiting

Less Frequent

• Aphthous stomatitis
• Asthma
• Cramps
• Extravasation injury
• Injection site pain
• Malaise
• Nasal congestion
• Pain in extremities
• Pain in oropharynx
• Symptoms of anxiety

Rare or Very Rare

• Acute cognitive impairment
• Agitation
• Back pain
• Body fluid retention
• Flushing
• General weakness
• Hematuria
• Hypoesthesia
• Myalgia
• Paresthesia
• Photophobia
• Pruritus of skin
• Tremor
• Urine discoloration
• Urticaria

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Animal reproduction studies have not been performed with IGIM, IGIV, or immune globulin subcutaneous and it is not known whether immune globulins can cause fetal harm when administered to pregnant women. Some manufacturers state that immune globulin should be used during pregnancy only when clearly needed.

ACIP states that there are no known risks associated with use of immune globulins for passive immunization in pregnant women.

Intact immune globulins, such as those contained in IGIV, cross the placenta in increasing amounts after 30 weeks of gestation. Results of studies in pregnant women with ITP who received IGIV prior to delivery indicate that the platelet response and clinical effects of IGIV were similar in the mother and neonate.

Animal reproduction studies have been performed with the recombinant human hyaluronidase component of immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia(R)). In mice and rabbits, antibodies to recombinant human hyaluronidase (anti-rHuPH20 antibodies) that developed in the mother were not associated with adverse effects on pregnancy; these antibodies crossed the placenta and were transferred to offspring in utero. It is not known whether anti-recombinant human hyaluronidase antibodies that develop in women cause fetal harm. The manufacturer states that Hyqvia(R) should be used during pregnancy only if clearly needed,

IGIV and immune globulin subcutaneous have not been evaluated in nursing women.

It is not known whether immune globulin is distributed into milk following IM, IV, or subcutaneous administration, affects milk production, or affects the breast-fed infant.

Immune globulin should be used with caution in nursing women. The benefits of breast-feeding and the importance of immune globulin to the woman should be considered along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

The manufacturer of immune globulin subcutaneous 10% with recombinant human hyaluronidase (Hyqvia(R)) states that data are not available regarding use in nursing women. In lactating animals, maternal antibodies bound to recombinant human hyaluronidase (anti-rHuPH20 antibodies) were transferred to nursing offspring; no adverse effects on pregnancy or offspring development were associated with these antibodies. The possible effects of these antibodies to recombinant human hyaluronidase that may be transferred to infants are unknown.

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