OCTAGAM 10%

Drug Overview

Brand name: OCTAGAM 10%

Generic name: Immune Globulin Intravenous (Human)

Drug Class: Human Immune Globulin, Intravenous

Manufacturer: Octapharma Pharmazeutika Produktionsges.m.b.H. (Austria), Octapharma AB Sweden)

Distributor: Pfizer

Approval and Regulatory Status

• Received FDA approval for the treatment of chronic immune thrombocytopenic purpura (ITP) in adults in July 2014.
• Received FDA orphan drug designation for the treatment of dermatomyositis in April 2017.
• Received FDA approval for the treatment of dermatomyositis in adults in July 2021.

Mechanism of Action

The mechanism of action of immunoglobulins in the treatment of chronic ITP or in dermatomyositis has not been fully elucidated.

Intravenous immune globulins have numerous immunomodulatory properties, including:

• Modulation of cytokines (neutralization of pro-inflammatory, augmentation of anti-inflammatory cytokines)
• Neutralization of activated complement compounds
• Regulation of natural killer and dendritic cell activity
• Expansion of regulatory T cells and modulation of effector T cell balance
• Neutralization and enhanced clearance of autoantibodies
• Blocking or modulating affinity of Fcγ receptors

In ITP, Octagam 10% rapidly increases the platelet counts. The mechanism is believed to involve Fc receptor blockade, which prevents antibody-opsonized platelets from being destroyed by Fc receptor-mediated phagocytosis. It may also involve downregulation of antibody production by B cells.

In dermatomyositis, C3 complement activation leads to formation of membrane attack complexes on endomysial capillaries which in turn results in capillary destruction and microangiopathy. The mechanism of Octagam 10% function in dermatomyositis may involve inhibition of complement activation or formation of membrane attack complexes. It may also involve down-regulation of cytokines.

Pharmacokinetics

Pharmacokinetic studies with Octagam 10% have not been performed in patients with chronic ITP nor in patients with dermatomyositis.

Indications and Usage

FDA-Approved Indications: Octagam 10% is indicated:

• For the treatment of chronic immune thrombocytopenic purpura (ITP) to rapidly raise platelet counts to control or prevent bleeding in adults.
• For the treatment of dermatomyositis in adults.
• Off-Label Use: Because of its wide immunomodulatory properties (see Section II), Octagam 10% is used off-label in clinical practice for the treatment many immunological and neurological conditions, including:
• Primary immune deficiency
• Secondary immune deficiency
• Acute antibody mediated rejection
• Desensitization for organ transplantation
• Guillain-Barré syndrome
• Myasthenia Gravis
• Chronic inflammatory demyelinating polyneuropathy
• Stiff person syndrome
• Acute disseminated encephalomyelitis.

Dosage and Administration

Recommended Dosing:

• For chronic TIP: 2 g/kg divided in equal doses given on 2 consecutive days.
• Initial infusion rate: 1.0 mg/kg/min (0.01 mL/kg/min)
• Maintenance infusion rate (if tolerated): up to 12.0 mg/kg/min (Up to 0.12 mL/kg/min)
• For dermatomyositis: 2 g/kg divided in equal doses given over 2-5 consecutive days every 4 weeks.
• Initial infusion rate: 1.0 mg/kg/min (0.01 mL/kg/min)
• Maintenance infusion rate (if tolerated): up to 4.0 mg/kg/min (Up to 0.04 mL/kg/min)

Administration Instructions

• Administer Octagam 10%, which is to be at room temperature, only by the intravenous route.
• Octagam 10% is not supplied with an infusion set. If an in-line filter is used the pore size should be 0.2 - 200 microns.
• Do not use a needle of larger than 16 gauge to prevent the possibility of coring. Insert needle only once, within the stopper area delineated (by the raised ring for penetration). Penetrate the stopper perpendicular to its plane and within the ring.

Rate of Administration

• The recommended rate of administration is shown in the table below.
• Monitor the patient carefully throughout the infusion. Certain adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly. Once the symptoms subside, the infusion may then be resumed at a lower rate.
• Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients at risk of renal dysfunction or thromboembolic events, administer Octagam 10% at the minimum infusion rate practicable, not to exceed 3.3 mg/kg/min (0.03 mL/kg/min). Discontinue Octagam 10% if renal function deteriorates.
• Dosage Forms and Strengths: Solution containing 10% IgG (100 mg/mL).

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Storage

• Store Octagam 10% for 36 months at 2°C to 8°C (36°F to 46°F) from the date of manufacture. Within this shelf-life, Octagam 10% may be stored up to 9 months at ≤25°C (77°F). After storage at ≤25°C (77°F), the product must be used or discarded.
• Do not use after expiration date.
• Do not freeze. Do not use frozen product.
• Dispose of any unused product or waste material in accordance with local requirements.

Warnings and Precautions

Black Box Warnings: The Octagam 10% prescribing information includes a Black Box Warning for the following:

• Thrombosis may occur with immune globulin intravenous (IGIV) products, including Octagam 10%. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.
• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive IGIV products, including Octagam 10%. Patients predisposed to renal dysfunction include those with a degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV product containing sucrose. Octagam 10% does not contain sucrose.
• For patients at risk of thrombosis, renal dysfunction or acute renal failure, administer Octagam 10% at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Other Warnings and Precautions

The Octagam 10% prescribing information lists the following additional warnings and precautions:

• Hypersensitivity: Severe hypersensitivity reactions may occur. In case of hypersensitivity, discontinue Octagam 10% infusion immediately and institute appropriate treatment.
• Blood Glucose Monitoring: Some glucose monitoring systems give falsely elevated glucose readings because they interpret the maltose in Octagam 10% as glucose. Monitor glucose levels in diabetic patients with a glucose-specific method only.
• Hyperproteinemia, Increased Serum Viscosity and Hyponatremia: Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving Octagam 10% therapy. It is clinically critical to distinguish true hyponatremia from pseudohyponatremia related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and a higher risk of thromboembolic events.
• Hemolysis: Octagam 10% may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin test (Coombs’ test) result and hemolysis. Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours post infusion.
• Aseptic meningitis syndrome (AMS): AMS may occur with Octagam treatment. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae.
• Transfusion-Related Acute Lung Injury (TRALI): Noncardiogenic pulmonary edema (TRALI) may occur in patients administered IVIG. Monitor recipients of Octagam 10% for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-HLA and anti-neutrophil antibodies in the product.
• Transmission of Infectious Agents: Because Octagam 10% is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease agent.
• Monitoring Laboratory Tests: After infusion of immunoglobulin, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation.

Adverse Reactions

Clinical Trials Experience:

• In clinical trial of Octagam 10% for the treatment of chronic ITP, the most common drug-related adverse reactions (AEs) were headache (25%), fever (15%), and increased heart rate (11%).
• In clinical trial of Octagam 10% for the treatment of dermatomyositis, the most common drug-related AEs were headache (42%), pyrexia (19%), nausea (16%), vomiting (8%), chills (7%), musculoskeletal pain (7%), and increased blood pressure (6%).

Postmarketing Experience:

• The following adverse reactions have been identified during post-approval use of Octagam:
• Blood and lymphatic system disorders: Leucopenia, hemolytic anemia
• Immune system disorders: Hypersensitivity, anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, angioedema, face edema
• Metabolic and nutritional disorders: Fluid overload, hyponatremia, pseudohyponatremia
• Psychiatric disorders: Agitation, confusional state, anxiety, nervousness
• Nervous system disorders: Cerebrovascular accident, loss of consciousness, speech disorder, aseptic meningitis, migraine, dizziness, paresthesia, hypoesthesia, tremor, photophobia
• Eye disorders: Visual impairment
• Cardiac disorders: Myocardial infarction, angina pectoris, bradycardia, tachycardia, palpitations, cyanosis
• Vascular disorders: Hypotension, thrombosis, circulatory collapse, peripheral circulatory failure, hypertension, phlebitis, pallor
• Respiratory, thoracic and mediastinal disorders: Respiratory failure, pulmonary embolism, pulmonary edema, bronchospasm, dyspnea, cough, hypoxia
• Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain
• Skin and subcutaneous tissue disorders: Eczema, skin exfoliation, urticaria, rash, rash erythematous, dermatitis, erythema, pruritus, alopecia
• Musculoskeletal and connective tissue disorders: Back pain, arthralgia, myalgia, pain in extremity, neck pain, muscle spasms, muscular weakness, musculoskeletal stiffness
• Renal and urinary disorders: Acute renal failure, renal pain
• General disorders and administration site conditions: Fatigue, edema, injection site reaction, pyrexia, influenza-like illness, chills, chest pain, chest discomfort, hot flush, flushing, feeling hot, feeling cold, hyperhidrosis, malaise, lethargy, asthenia, burning sensation
• Investigations: Hepatic enzymes increased, falsely elevated blood glucose level
• Injury, poisoning and procedural complications: Transfusion-related acute lung injury

Drug Interactions

Drug admixtures: Admixtures of Octagam 10% with other drugs and intravenous solutions have not been evaluated. It is recommended that Octagam 10% be administered separately from other drugs or medications which the patient may be receiving. Do not mix the product.

IVIG mixtures: Do not mix Octagam 10% with IGIVs from other manufacturers.

Serological testing: Passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing.

Vaccines: Antibodies in Octagam 10% may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Inform physicians of recent therapy with Octagam 10%, so that administration of live viral vaccines, if indicated, can be appropriately delayed for 3 or more months from the time of Octagam 10% administration.

Clinical Trials

Chronic ITP: The safety and efficacy of Octagam 10% for the treatment of chronic ITP was assessed in one prospective, open-label, single-arm, multicenter study in 116 subjects with tentative newly diagnosed or chronic ITP and a platelet count of 20 × 109/L or less.

Subjects received a 2 g/kg dose of Octagam 10% administered as two daily 1 g/kg intravenous doses, given on 2 consecutive days.

The study was designed to determine:

• The response rate defined as the percentage of subjects with an increase in platelet count to at least 50 × 109/L within 7 days after the first infusion (responders):
• Of the 66 subjects with chronic ITP in the efficacy analysis, 54 (82%) responded to Octagam 10% with a rise in platelet counts to at least 50 × 109/L within 7 days after the first infusion. The lower bound of the overall 95% confidence interval for the response rate (73%) is above the predefined response rate of 70%.
• The maximum platelet count:
• The mean maximum platelet count achieved in the 66 subjects with chronic ITP was 227 × 109/L.
• The time to reach a platelet count of at least 50 × 109/L within the first 7 days:
• The median time to reach a platelet response of at least 50 × 109/L was 2 days after the first infusion.
• The duration of the response (ie, the number of days the platelet count remained in excess of 50 × 109/L):
• The duration of platelet response was analyzed for the 54 subjects with chronic ITP who achieved a response within 7 days after the first infusion: the median duration of platelet response in these subjects was 12 days (range: 1 to 79 days).
• The regression of hemorrhages in subjects who had bleeding at baseline were observed:
• In 35 of the 45 subjects with chronic ITP (78%) who had bleeding at baseline, the hemorrhages had completely resolved by Day 7. A decrease in the severity of hemorrhage from baseline to Day 7 was observed in 38 of 45 subjects (84%) with chronic ITP.

Dermatomyositis: The safety and efficacy of Octagam 10% for the treatment of myositis was assessed in one prospective, double-blind, randomized, placebo-controlled, multicenter study in 95 adults with dermatomyositis.

Forty-seven subjects received Octagam 10% and 48 subjects received placebo in an initial 16-week, double-blind First Period, followed by a 6-month, open-label Extension Period.

Efficacy in this study was based on the proportion of responders at Week 16 (end of First Period). The table below shows the proportion of responders in the Octagam 10% and the placebo groups, and the difference in responder rate between the two groups at Week 16.

The median time to response was 35 days in the Octagam 10% group.

Efficacy was further supported by an improvement in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) total activity score, with a mean decrease of 9.4 (standard deviation: 10.5) points from baseline to Week 16 in the Octagam 10% group versus 1.2 (standard deviation: 7.0) point in the placebo group.

The Octagam 10% group maintained their improvement in TIS (32/45, 71.1%) during the 6-month Extension Period. Among the 46 subjects who switched from placebo to Octagam 10% in the Extension Period, 69.6% (32/46) were classified as responders at the end of the 6-month Extension Period.

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Specific Populations

Pediatric Use: The safety and effectiveness of Octagam 10% has not been established in pediatric patients with ITP or dermatomyositis.

Geriatric Use: Patients > 65 years of age may be at increased risk for developing certain adverse reactions such as thromboembolic events and acute renal failure. Do not exceed recommended doses in this population, and the applied infusion rate should be the minimum practicable.

Pregnancy: No human data are available to indicate the presence or absence of drug-associated risk. Animal reproduction studies have not been conducted with Octagam 10%. It is not known whether Octagam 10% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. Octagam 10% should be given to pregnant women only if clearly needed.

Lactation: No human data are available to assess the presence or absence of Octagam 10% in human milk, the effects of Octagam 10% on the breastfed child, and the effects of Octagam 10% on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Octagam 10% liquid and any potential adverse effects on the breastfed infant from Octagam 10% liquid or from the underlying maternal condition. Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate.

Patient Counseling Information

General Information: Inform patients of the signs and symptoms of hypersensitivity reactions including urticaria, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis, and to contact their physicians immediately if allergic symptoms occur.

Inform patients to immediately report the signs and symptoms of the following conditions to their physician:

• renal failure, such as decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath
• aseptic meningitis, such as headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting
• hemolysis, such as fatigue, increased heart rate, yellowing of the skin or eyes, and dark-colored urine
• TRALI, such as troubled breathing, chest pain, blue lips or extremities, and fever. TRALI typically occurs within 1 to 6 hours following transfusion.

Thrombosis: Instruct patients to immediately report symptoms of thrombosis. These symptoms may include: pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body.

Inform patients that Octagam 10% is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses, and, theoretically, the CJD agent), and that the risk of infectious agent transmission has been reduced by (a) screening plasma donors for prior exposure to certain viruses, (b) testing the donated plasma for certain viral infections and (c) inactivating and/or removing certain viruses during manufacture.

Inform patients that administration of Octagam 10% may interfere with the response to live viral vaccines such as measles, mumps and rubella, and to notify their immunizing physician of their therapy with Octagam 10%.

Useful Resources

• American Society of Hematology 2019 guidelines for immune thrombocytopenia
• British Society for Rheumatology guideline on management of pediatric, adolescent and adult patients with idiopathic inflammatory myopathy
• Consult the ClinicalTrials.gov website for ongoing trials of Octagam 10%