Octagam Immune Globulin (Human): Package Insert and Label Information

OCTAGAM IMMUNE GLOBULIN (HUMAN)- human immunoglobulin g solution
Octapharma Pharmazeutika Produktionsgesellschaft m.b.H.

INDICATIONS AND USAGE

Primary Humoral Immunodeficiency Diseases (PI)

Octagam is an immune globulin intravenous (human) 5% liquid indicated for treatment of primary humoral immunodeficiency (PI), such as congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome and severe combined immunodeficiencies.

DOSAGE AND ADMINISTRATION

For intravenously use only

Preparation and handling

• Octagam 5% liquid should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid and/or discoloration is observed.
• Octagam 5% liquid must not be mixed with other medicinal products or administered simultaneously with other intravenous preparation in the same infusion set. Do not mix with immune globulin intravenous (IGIV) products from other manufacturers.
• Do not freeze. Solutions that have been frozen should not be used.
• Octagam 5% liquid bottle is for single use only. Octagam 5% liquid contains no preservative. Any bottle that has been entered should be used promptly. Partially used bottles should be discarded.
• Content of Octagam 5% liquid bottles may be pooled under aseptic conditions into sterile infusion bags and infused within 8 hours after pooling.
• Do not use after expiration date.
• Octagam 5% liquid should not be diluted.

Treatment of Primary Humoral Immunodeficiency

As there are significant differences in the half-life of IgG among patients with primary humoral immunodeficiencies, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response.

The dose of Octagam 5% liquid for replacement therapy in primary humoral immunodeficiency diseases is 300 to 600 mg/kg body weight (6-12ml/kg) administered every 3 to 4 weeks. The dosage may be adjusted over time to achieve the desired trough levels and clinical responses.

If a patient is at risk of measles exposure (ie., outbreak in US or travel to endemic areas outside of the US) and receives a dose of less than 400 mg/kg every 3 to 4 weeks, the dose should be increased to at least 400 mg/kg. If a patient has been exposed to measles, this dose should be administered as soon as possible after exposure.

Missed Doses

If a patient on regular treatment missed a dose, the missed dose should be administered as soon as possible, and then treatment should continue as before.

Administration

Octagam 5% liquid should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid and/or discoloration is observed.

Octagam 5% liquid should be at room temperature during administration. Only administer intravenously.

Any bottle that has been opened should be used promptly. Partially used bottles should be discarded.

Octagam 5% liquid 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). The stopper should be penetrated perpendicular to the plane of the stopper within the ring.

Rate of Administration

It is recommended that Octagam 5% liquid be initially infused at infusion rates stated below, at least until the physician has had adequate experience with a given patient.

Infusion rates: 0.5mg/kg/min (30mg/kg/hr for the first 30 minutes; if tolerated, advance to 1mg/kg/min (60mg/kg/hr) for the second 30 minutes; and if further tolerated, advance to 2mg/kg/min (120mg/kg/hr) for the third 30 minutes. Thereafter the infusion can be maintained at a rate up to, but not exceeding, 3.33mg/kg/min (200mg/kg/hr)

For patients judged to be at risk for developing renal dysfunction, administer Octagam 5% liquid at the minimum infusion rate practicable, not to exceed 0.07 ml/kg (3.3 mg/kg)/minute (200 mg/kg/hour).

Table 1

Rate of Administration	mg/kg/min (mg/kg/hour)	ml/kg/min
first 30 min	0.5 (30)	0.01
next 30 min	1.0 (60)	0.02
next 30 min	2.0 (120)	0.04
Maximum	< 3.33 (<200)	<0.07

Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.

Ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue Octagam 5% liquid if renal function deteriorates.

For patients at risk of renal dysfunction or thromboembolic events, administer Octagam 5% liquid at the minimum infusion rate practicable.

Incompatibilities

Octagam 5% liquid must not be mixed with other medicinal products or administered simultaneously with other intravenous preparations in the same infusion set.

Shelf-life

Octagam 5% liquid may be stored for 24 months at +2°C to + 25°C (36°F to 77°F) from the date of manufacture.

Special Precautions for Storage

Do not freeze. Frozen product should not be used.

Do not use after expiration date.

DOSAGE FORMS AND STRENGTHS

Octagam 5% liquid is supplied in 1.0 g, 2.5 g, 5 g , 10 g or 25 g single use bottles (See How Supplied/Storage and Handling [16]).

CONTRAINDICATIONS

Octagam 5% liquid is contraindicated in patients who have acute severe hypersensitivity reactions to human immunoglobulin.

Octagam 5% liquid contains trace amounts of IgA (not more than 0.2 mg/ml in a 5% solution). It is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity (See Description [11]).

Octagam 5% liquid is contraindicated in patients with acute hypersensitivity reaction to corn. Octagam 5% liquid contains maltose, a disaccharide sugar which is derived from corn. Patients known to have corn allergies should avoid using Octagam 5% liquid.

WARNINGS AND PRECAUTIONS

Sensitivity

Severe hypersensitivity reactions may occur [ 1 ] (See Contraindications [4.1]). In case of hypersensitivity, Octagam 5% liquid infusion should be immediately discontinued and appropriate treatment instituted. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction. IgA deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactoid reactions when administered Octagam 5% liquid (See Contraindications [4.2]). Patients known to have corn allergies should avoid using Octagam 5% liquid (See Contraindications [4.3]).

Renal Failure

Assure that patients are not volume depleted prior to the initiation of the infusion of Octagam 5% liquid.

Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure. Renal function, including a measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of Octagam 5% liquid and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered (See Patient Counselling Information [17])

For patients judged to be at risk for developing renal dysfunction and/or at risk of developing thrombotic events, it may be prudent to reduce the amount of product infused per unit time by infusing Octagam 5% liquid at a maximum rate less than 0.07 ml/kg (3.3 mg/kg)/minute (200 mg/kg/hour) (See Boxed Warning, and Dosage and Administration [2.4]).

Blood Glucose Monitoring

Blood Glucose Testing [ 2 ] :some types of blood glucose testing systems (for example, those based on the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods) falsely interpret the maltose contained in Octagam 5% liquid as glucose. This has resulted in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering Octagam 5% liquid, the measurement of blood glucose must be done with a glucose-specific method. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products.

Hyperproteinemia

Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV therapy. The hyponatremia is likely to be a pseudohyponatremia as demonstrated by a decreased calculated serum osmolality or elevated osmolar gap. Distinguishing true hyponatremia from pseudohyponatremia is clinically critical, as treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and a disposition to thromboembolic events [ 3 ].

Thrombotic events

Thrombotic events have been reported in association with IGIV therapy [ 4 ],[ 5 ],[ 6 ]. Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization and/or known or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia / markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

Aseptic meningitis syndrome

Aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following IGIV treatment and rapid infusion. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cu mm, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. It appears that patients with a history of migraine may be more susceptible. [ 7 ] (See Patient Counselling Information [17]).

Hemolysis

IGIV products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis [ 8 ]. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration [See ADVERSE REACTIONS] [ 9 ]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis. If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done (See Patient Counseling Information [17]).

Transfusion-Related Acute Lung Injury (TRALI)

There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV [ 10 ]. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1-6 hours after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.

IGIV recipients should be monitored for pulmonary adverse reactions (See Patient Counseling Information [17]). If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum.

General

Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Octapharma. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient (See Patient Counseling Information [17]).

Laboratory Tests

If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done.

If TRALI is susppected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum.

Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most serious adverse reactions observed with Octagam 5% Liquid treatment have been immediate anaphylactic reactions, aseptic meningitis, and hemolytic anemia.

The most common adverse reactions observed with Octagam 5% Liquid treatment during clinical trial (> 5%) were headache and nausea.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in clinical practice.

The clinical trial database includes a multi-center, open-label, single arm study in 46 children and adults with PI. Subjects participated in the study for a mean of 346 days and received 300 to 450 mg/kg every 21 days or 400 to 600 mg/kg every 28 days. Infusions were initiated at a rate of 30 mg/kg/hour for the first 30 minutes, and, if tolerated, could be advanced to a maximum tolerated rate not exceeding 200 mg/kg/hour. Over half of the subjects were male (n=28; 61%), and more than half were on the 28-day infusion schedule (n=27; 59%). The mean age of subjects was 31.5 years.

Six subjects experienced a total of 12 SAEs (abdominal pain (2 occurrences), cardiac arrest, pneumonia, cellulitis, coxsackie viral infection, renal calculus (2 occurrences), blood culture positive, ketonuria, gastroenteritis, and colitis pseudomembranosus). Eleven of the 12 SAEs were not suspected to be related to study drug; the other SAE was noted before the subject began receiving the next scheduled infusion, and it was not temporally related to the previous infusion.

Pre-medications were used in 165 (25.2%) out of 654 infusions and in 14 (30.4%) out of 46 patients. Infusions were slowed or interrupted in 9 out of 489 infusions (1.84%) without pre-medication and in 10 out of 165 infusions (6.06%) with pre-medication. Five out of 32 (15.63%) patients who never received any pre-medication had at least one slowed or interrupted infusion, whereas 9 out of 14 (64.29%) patients who received pre-medication at least once also had a slowed or interrupted infusion.

Six of the 46 subjects in the trial (13%) were withdrawn from the study: 2 on the subjects’ request; 1 because of investigator’s decision (non-compliance); 1 because of loss to follow-up; 1 death (cardiac arrest, not suspected to be related to study drug); and 1 by error of the study coordinator.

All adverse events in trial OCTA-06, irrespective of the causality assessment, reported by at least 5% of subjects during the 12-months treatment are given in the table below.

Table 2: Subjects and Infusions with at least one Adverse Event Irrespective of Causality (Study OCTA-06)

	Octagam	5% liquid
	No. of subjects (%)	No. of infusions (%)
Total	46 (100%)	654 (100%)
Nasal congestion	24 (52%)	39 (6%)
Sinusitis NOS	23 (50%)	45 (7%)
Headache NOS	22 (48%)	62 (9%)
Cough	20 (43%)	46 (7%)
Sore throat NOS	16 (35%)	25 (4%)
Fever	15 (33%)	19 (3%)
Vomiting NOS	12 (26%)	15 (2%)
Diarrhoea NOS	11 (24%)	22 (3%)
Bronchitis NOS	10 (22%)	14 (2%)
Abdominal pain upper	9 (20%)	11 (2%)
Arthralgia	9 (20%)	15 (2%)
Nasopharyngitis	8 (17%)	14 (2%)
Rhinorrhoea	8 (17%)	9 (1%)
Upper respiratory tract infection NOS	8 (17%)	13 (2%)
Fatigue	7 (15%)	9 (1%)
Nausea	7 (15%)	8 (1%)
Pain in limb	7 (15%)	10 (2%)
Sinus congestion	7 (15%)	9 (1%)
Back pain	5 (11%)	10 (2%)
Injection site reaction NOS	5 (11%)	11 (2%)
Wheezing	5 (11%)	8 (1%)
Asthma NOS	4 (9%)	5 (0.8%)
Asthma aggravated	4 (9%)	10 (2%)
Chest pain NEC	4 (9%)	4 (0.6%)
Conjunctivitis NEC	4 (9%)	4 (0.6%)
Dyspepsia	4 (9%)	5 (0.8%)
Earache	4 (9%)	6 (0.9%)
Ecchymosis	4 (9%)	7 (1%)
Fungal infection NOS	4 (9%)	4 (0.6%)
Injection site pain	4 (9%)	4 (0.6%)
Insomnia NEC	4 (9%)	4 (0.6%)
Sinusitis acute NOS	4 (9%)	8 (1%)
Urinary tract infection NOS	4 (9%)	8 (1%)
Vaginal candidiasis	4 (9%)	7 (1%)
Abdominal pain NOS	3 (7%)	3 (0.5%)
Dizziness (exc vertigo)	3 (7%)	4 (0.6%)
Dyspnoea NOS	3 (7%)	3 (0.5%)
Epistaxis	3 (7%)	5 (0.8%)
Eye discharge	3 (7%)	3 (0.5%)
Eye irritation	3 (7%)	3 (0.5%)
Hypertension NOS	3 (7%)	5 (0.8%)
Otitis media NOS	3 (7%)	4 (0.6%)
Pain NOS	3 (7%)	4 (0.6%)
Postnasal drip	3 (7%)	3 (0.5%)
Productive cough	3 (7%)	3 (0.5%)
Rigors	3 (7%)	4 (0.6%)
Throat irritation	3 (7%)	3 (0.5%)
Urticaria NOS	3 (7%)	8 (1%)

The adverse reactions in trial OCTA-06 reported by at least 5% of subjects during the 12-month treatment are given in the table below.

Table 3: Subjects and Infusions with At Least One Adverse Reaction (Study OCTA-06)

	Octagam	5% liquid
	No. of subjects (%)	No. of infusions (%)
Total	46 (100%)	654 (100%)
Headache NOS	7 (15%)	18 (3%)
Nausea	3 (7%)	4 (0.6%)

The following table provides an overview on the temporally associated adverse events (TAAEs) during and within different time-points after the end of Octagam infusion.

Table 4: Overview on TAAEs Occurring During and Over a Specified Number of Hours after the End of Infusion, Irrespective of Causality (Study OCTA-06)

Total # of infusions (N=654)	Time-Points
	24 hrs	48hrs	72hrs
Total # of TAAEs	172	183	189
Proportion of infusions with TAAEs	26.3%	28.0%	28.9%
Upper bound 1 sided 97.5% CI for proportion of TAAEs	29.7%	31.4%	32.4%

All temporally associated adverse events (TAAEs) in trial OCTA-06, irrespective of the causality assessment, reported by at least 5% of subjects within 72 hours after the end of the infusion are given in the table below.

Table 5: TAAEs During and Over 72 Hours After End of Infusion, Irrespective of Causality (Study OCTA-06)

TAAE	Subjects (%)n=46	Infusion (%)N=654
Headache NOS	15 (32.6%)	28 (4.3%)
Sinusitis NOS	12 (26.1%)	13 (2.0%)
Nasal congestion	10 (21.7%)	11 (1.7%)
Arthralgia	7 (15.2%)	10 (1.5%)
Cough	7 (15.2%)	7 (1.1%)
Injection site reaction NOS	5 (10.9%)	11 (1.7%)
Sore throat NOS	5 (10.9%)	5 (0.8%)
Vomiting NOS	5 (10.9%)	5 (0.8%)
Back pain	4 (8.7%)	6 (0.9%)
Diarrhoea NOS	4 (8.7%)	5 (0.8%)
Ecchymosis	4 (8.7%)	5 (0.8%)
Injection site pain	4 (8.7%)	4 (0.6%)
Nausea	4 (8.7%)	5 (0.8%)
Upper respiratory tract infection NOS	4 (8.7%)	5 (0.8%)
Wheezing	4 (8.7%)	6 (0.9%)
Asthma aggravated	3 (6.5%)	4 (0.6%)
Eye irritation	3 (6.5%)	3 (0.5%)
Fungal infection NOS	3 (6.5%)	3 (0.5%)
Pain in limb	3 (6.5%)	5 (0.8%)
Rhinorrhoea	3 (6.5%)	3 (0.5%)
Urinary tract infection NOS	3 (6.5%)	3 (0.5%)

The subset of drug related temporally associated adverse events (TAAEs) in trial OCTA-06 reported by at least 5% of subjects within 72 hours after the end of the infusion is given in the table below.

Table 6: Drug-Related TAAEs During and Over 72 Hours After End of Infusion (Study OCTA-06)

TAAE	Subjects (%)n=46	Infusion (%)N=654
Headache NOS	6 (13.0%)	15 (2.3%)
Nausea	3 (6.5%)	4 (0.6%)

Laboratory Abnormalities

Standard clinical laboratory evaluations were performed Study OCTA-06. Three subjects (7%) had incidences of AST (>2.5 x ULN) which were all assessed as clinically non-significant. Four subjects (9%) had incidences of serum creatinine increases being stable throughout the course of the study. Therefore, these observations were not regarded as indicative of acute renal dysfunction.