Data from FDA - Curated by Toby Galbraith - Last updated 18 April 2017

Licensing authority

FDA (Food and Drug Administration, USA)

Indication(s)

INDICATIONS AND USAGE Octagam is an immune globulin intravenous (human), 5 % liquid, indicated for treatment of primary humoral immunodeficiency (PI) (1).

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.

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Advisory information

contraindications

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.

Anaphylactic or severe systemic reactions to human immunoglobulin (4) IgA deficient patients with antibodies against IgA and a history of hypersensitivity (4) Patients with acute hypersensitivity reaction to corn (4)

Adverse reactions

ADVERSE REACTIONS Most common adverse reactions with an incidence of > 5 % during a clinical trial were headache and nausea.

(6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Octapharma at 1-866-766-4860 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 can not 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 48 hrs 72 hrs 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.

Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

Octagam 5 % liquid Postmarketing Experience The following adverse reactions have been identified during post-approval use of Octagam 5 % liquid.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to Octagam 5 % liquid.

Blood and lymphatic system disordersLeukopenia, haemolytic anaemia Immune system disorders Hypersensitivity, anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, angioneurotic oedema, face oedema Metabolic and nutritional disorders Fluid overload Psychiatric disorders Agitation Nervous system disorders Headache, cerebrovascular accident, meningitis aseptic, migraine, dizziness, paraesthesia Cardiac disorders Myocardial infarction, tachycardia, palpitations, cyanosis Vascular disorders Hypotension, thrombosis, peripheral circulatory failure, hypertension Respiratory, thoracic and mediastinal disorders Respiratory failure, pulmonary embolism, pulmonary oedema, bronchospasm, dyspnoea, cough Gastrointestinal disorders Nausea, vomiting, diarrhoea

abdominal pain Skin and subcutaneous tissue disorders Eczema, urticaria, rash, rash erythematous, dermatitis, pruritus, alopecia Musculoskeletal and connective tissue disorders Back pain, arthralgia, myalgia, pain in extremity Renal and urinary disorders Renal failure acute General disorders and administration site conditions Fatigue, injection site reaction, pyrexia, chills, chest pain, hot flush, flushing, hyperhidrosis, malaise Investigations Hepatic enzymes increased, blood glucose false positive General The following adverse reactions have been identified during post-approval use of IGIV products.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to IGIV products: RespiratoryApnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological Coma, loss of consciousness, seizures, tremor Integumentary Steven-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test General/Body as a Whole Pyrexia

rigors Musculoskeletal Back pain Gastrointestinal Hepatic dysfunction, abdominal pain

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION For intravenously use only Intravenous use only (2).

Indication Dose Initial Infusion rate Maintenance infusion rate (if tolerated) PI 300-600 mg/kg 0.5 mg/kg /min 3.33 mg/kg /min Every 3-4 weeks Ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue Octagam 5 % liquid if renal function deteriorates (2.4).

For patients at risk of renal dysfunction or thrombotic events, administer Octagam 5 % liquid at the minimum infusion rate practicable (2.4).

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 (6-12 ml/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: 0.5 mg/kg /min (30 mg/kg/hr for the first 30 minutes; if tolerated, advance to 1 mg/kg /min (60 mg/kg/hr) for the second 30 minutes; and if further tolerated, advance to 2 mg/kg /min (120 mg/kg/hr) for the third 30 minutes.

Thereafter the infusion can be maintained at a rate up to, but not exceeding, 3.33 mg/kg /min (200 mg/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.

Use in special populations

USE IN SPECIFIC POPULATIONS Pregnancy: no human or animal data.

Use only if clearly needed (8.1).

In patients over age 65 or in any person at risk of developing renal insufficiency, do not exceed the recommended dose, and infuse Octagam 5 % liquid at the minimum infusion rate practicable (8.5).

See 17 for PATIENT COUNSELING INFORMATION. Revised: September 2009

_______________________________________________________________________________________________________________________________________

Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Octagam 5 % liquid.

It is also not known whether Octagam 5 % liquid can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Octagam 5 % liquid should be given to a pregnant woman only if clearly needed.

Nursing Mothers Octagam 5 % liquid has not been evaluated in nursing mothers.

Pediatric Use Octagam 5 % liquid was evaluated in 11 pediatric subjects (age range 6 - 16 years).

There were no obvious differences observed between adults and pediatric subjects with respect to pharmacokinetics, efficacy and safety.

No pediatric specific dose requirements were necessary to achieve the desired serum IgG levels.

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 (See Boxed Warnings and Precautions [5.3]).

In the clinical trial only 4 geriatric patients (> 65 years) were enrolled, a number insufficient to determine whether geriatric patients respond differently from younger subjects.

In these 4 patients no particular issues were observed.

Interactions

DRUG INTERACTIONS Admixtures of Octagam 5 % liquid with other drugs and intravenous solutions have not been evaluated.

It is recommended that Octagam 5 % liquid be administered separately from other drugs or medications which the patient may be receiving.

The product should not be mixed with IGIVs from other manufacturers.

The infusion line may be flushed before and after administration of Octagam 5 % liquid with either normal saline or 5 % dextrose in water.

Various passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing.

Antibodies in Octagam 5 % liquid may interfere with the response to live viral vaccines, such as measles, mumps, and rubella.

Physicians should be informed of recent therapy with IGIVs, so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration.

The passive transfer of antibodies may confound the results of serological testing (7).

The passive transfer of antibodies may interfere with the response to live viral vaccines (7).

More information

Category Value
Authorisation number BLA125062
Agency product number 66Y330CJHS
Orphan designation No
Product NDC 67467-843
Date Last Revised 09-09-2009
Type HUMAN PRESCRIPTION DRUG
RXCUI 1809643
Marketing authorisation holder Octapharma Pharmazeutika Produktionsgesellschaft m.b.H.