Gammaplex

Dosage Forms And Strengths

Gammaplex is a liquid solution containing 5% IgG (50 mg/mL).

Storage And Handling

Gammaplex is supplied in a single use, clear Type II glass bottle, closed with a stopper and oversealed with a tamper-evident cap.

The components used in the packaging for Gammaplex are latex free.

The following presentations of Gammaplex are available:

Each vial has a label with a peel-off strip showing the product name and batch number.

When stored between 2 °C [35.6 °F] and 25 °C [77 °F]), Gammaplex has a shelf life of 24 months.

Keep Gammaplex in its original carton to protect it from light.

DO NOT FREEZE.

Manufactured by: Bio Products Laboratory Limited, Dagger Lane, Elstree, Hertfordshire, WD6 3BX United Kingdom. Distributor: BPL Inc., 8601 Six Forks Road, Suite 400, Raleigh North Carolina 27615. U.S.A.  Bio Products Laboratory Limited, Dagger Lane, Elstree, Herts., WD6 3BX, U.K. Tel: 1-866-398-0825. Revised: July 2015.

Serious adverse reactions (ARs) observed in clinical trial subjects with primary humoral immunodeficiency (PI) were thrombosis and chest pain. The one event of thrombosis (1 subject, 2%) was reported in an adult who also had a diagnosis of antiphospholipid syndrome which results in increased clotting tendency [see WARNINGS AND PRECAUTIONS].

Serious ARs observed in clinical trial subjects with immune thrombocytopenic purpura (ITP) were headache, vomiting and dehydration. In addition following a review of the data, 4 subjects (11%) were considered to have experienced asymptomatic suspected treatment-emergent hemolysis [see Clinical Trials Experience].

The following potential serious ARs are described above and/or elsewhere in the labeling:

• Thrombotic Events [see WARNINGS AND PRECAUTIONS]
• Hemolysis [see WARNINGS AND PRECAUTIONS]

The most common ARs observed in the PI clinical trials were headache (29 subjects, 39%), pyrexia (11 subjects, 15%), nasal congestion/edema (10 subjects, 13%), fatigue (9 subjects, 12%), nausea (7 subjects, 9%), hypertension (6 subjects, 8%), rash (6 subjects, 8%), hypotension (5 subjects, 7%), infusion site reactions (5 subjects, 7%) vomiting (5 subjects, 7%), myalgia (4 subjects, 5%), chills (4 subjects, 5%), tachycardia (4 subjects, 5%), chest pain/discomfort (4 subjects, 5%), pain (4 subjects, 5%), dizziness (4 subjects, 5%), malaise (4 subjects, 5%), dysuria (4 subjects, 5%), and dry skin (4 subjects, 5%).

The most common ARs observed in the chronic ITP clinical trial were headache (12 subjects, 34%), vomiting (8 subjects, 23%), nausea (5 subjects, 14%), pyrexia (5 subjects, 14%), pruritus (2 subjects, 6%) and arthralgia (2 subjects, 6%).

Clinical Trials Experience

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

In a multicenter, open-label, non-randomized clinical trial, 50 subjects with primary humoral immunodeficiency received doses of Gammaplex ranging from 279 to 799 mg/kg every 21 days (mean dose 465 mg/kg) or 28 days (mean dose 458 mg/kg), for up to 12 months [see Clinical Studies].

Twenty-four subjects (48%) had an AR at some time during the clinical trial that was considered product-related. Of these 24 subjects, three had ARs that were considered definitely related to Gammaplex including headache, pyrexia, tachycardia, chest discomfort, and hypertension. More subjects with the 21-day infusion cycle had at least one AR (14 of 22 subjects, 64%) than subjects with the 28-day infusion cycle (10 of 28 subjects, 36%). The total number of ARs during infusion or within 72 hours of infusion was 237 (a rate of 0.34 ARs per infusion), reflecting that some subjects experienced more than one AR during the observation period. The percentage of Gammaplex infusions with one or more ARs within 72 hours of infusion was 21%. The upper bound of the 1-sided 95% confidence interval for this percentage was 24%, which was below the pre-specified upper limit of 40% for this safety endpoint.

The most common ARs observed in this clinical trial were headache (18 subjects, 36%), fatigue (6 subjects, 12%), nausea (6 subjects, 12%), pyrexia (6 subjects, 12%), pain (4 subjects, 8%), hypertension (3 subjects, 6%), chills (3 subjects, 6%), myalgia (3 subjects, 6%) and vomiting (3 subjects, 6%). Two subjects experienced serious ARs (thrombosis and chest pain).

Forty-seven of the 50 subjects enrolled in this clinical trial had a negative direct antiglobulin test (DAT) at baseline. Of these 47 subjects, 4 (9%) developed a positive DAT at some time during the clinical trial. However, no subjects showed evidence of hemolytic anemia.

There was no evidence of transmission of hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or parvovirus B19 during this clinical trial.

Table 2: Adverse Reactions (ARs*) Occurring in > 5% of Subjects with PI**

Table 3: ARs* in > 5% of Pediatric Subjects with PI**

In a multicenter, open-label, non-randomized clinical trial, 25 children and adolescents with primary humoral immunodeficiency received doses of Gammaplex ranging from 300 to 800 mg/kg every 21 days (mean dose 545 mg/kg) or 28 days (mean dose 521 mg/kg), for up to 12 months [see Clinical Studies].

Fourteen subjects (56%) had an AR at some time during the clinical trial that was considered product-related. Of these 14 subjects, two had ARs that were considered definitely related to Gammaplex including headache, fatigue and myalgia. Seven subjects with the 21-day infusion cycle had at least one AR (7 of 14 subjects, 50%), as did seven subjects with the 28-day infusion cycle (7 of 11 subjects, 64%).

In a multicenter, open-label, non-randomized clinical trial, 35 subjects with chronic immune thrombocytopenic purpura were treated with a nominal dose of 1,000 mg/kg on each of two consecutive days (total dose 2,000 mg/kg). Doses of Gammaplex ranged from 482 to 1149 mg/kg on an infusion day. The median total dose per subject was 2035 mg/kg. Pre-medication with antihistamine or analgesic drugs was permitted if required, but corticosteroids were not permitted prior to infusion as pre-medication. Ten subjects received corticosteroids for ITP during the trial and one additional subject received corticosteroids as pre-medication in violation of the protocol. All 35 subjects received at least one infusion of clinical trial drug, and all but one subject completed the first course of treatment.

Twenty-four subjects (69%) reported at least one AR (103 in total); the most commonly reported being headache (12 subjects, 34%), vomiting (8 subjects, 23%), nausea (5 subjects, 14%), pyrexia (5 subjects, 14%), pruritus (2 subjects, 6%), dehydration (2 subjects, 6%) and arthralgia (2 subjects, 6%). Three subjects experienced a total of five serious ARs. Of the five serious ARs, one subject had three concurrently (vomiting, dehydration and headache) and two subjects each had one serious AR (headache). One of these latter two subjects discontinued from the clinical trial because of the severe headache. Table 4 lists the ARs in more than 5% of subjects.

Based on a review of clinical and laboratory data, 4/35 subjects (11%) with drops in hemoglobin exceeding 2 g/dL following administration of Gammaplex were considered to have experienced suspected treatment-emergent hemolysis. Milder treatment-emergent hemolysis could not be excluded for an additional 7 subjects, giving a total of 11 of 35 subjects (31%) for whom hemolysis could not be excluded (not including an additional two subjects who lacked follow-up testing for hemolysis, so their hemolysis status was considered unassessable). Data for two subjects were consistent with possible intravascular hemolysis, including one subject who may also have had an element of extravascular hemolysis. Nine of the possible hemolysis cases were mild and appeared consistent with possible extravascular hemolysis.

There was no evidence of transmission of HBV, HCV, HIV and parvovirus B19 during this clinical trial.

Table 4: Adverse Reactions (ARs*) Occurring in > 5% of Subjects with ITP

Postmarketing Experience

Because adverse reactions are voluntarily reported post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

In addition to the adverse reactions identified in clinical studies [see ADVERSE REACTIONS], the following adverse reactions have been identified during postmarketing use of Gammaplex:

• Infusion reactions: Dizziness,
• Respiratory: Pulmonary embolism, dyspnea, respiratory distress
• Cardiovascular: Myocardial infarction, other thromboembolic event
• Neurological: Migraine, aseptic meningitis
• Integumentary: Rash, urticaria
• Musculoskeletal: Musculoskeletal pain

The following adverse reactions have been identified during post-marketing use of intravenous immune globulins9:

• Infusion reactions: Hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure
• Renal: Acute renal dysfunction/failure, osmotic nephropathy
• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
• Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
• Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome
• Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
• Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test
• Gastrointestinal: Hepatic dysfunction, abdominal pain
• General/Body as a Whole: Pyrexia, rigors

Read the entire FDA prescribing information for Gammaplex (Immune Globulin Intravenous (Human), 5% Liquid )

• Octagam

© Gammaplex Patient Information is supplied by Cerner Multum, Inc. and Gammaplex Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Immune globulin injection is used to prevent or treat diseases that occur when your body has a weak immune system. Immune globulin contains antibodies that make your immune system stronger. It is used for patients who have primary humoral immunodeficiency (PI), idiopathic thrombocytopenic purpura (ITP), chronic immune thrombocytopenic purpura, or chronic inflammatory demyelinating polyneuropathy (CIDP). It is also used to improve muscle strength and disability in patients with multifocal motor neuropathy (MMN). Immune globulin injection belongs to a group of medicines known as immunizing agents.

This medicine is to be given only by or under the supervision of your doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Gammaplex (immune globulin injection (IV)), please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Gammaplex. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Gammaplex.

Review Date: October 4, 2017

Two serious adverse reactions, thrombosis and chest pain, were observed in a clinical study subject receiving Gammaplex.

The most common adverse reactions to Gammaplex (reported in >5% of clinical trial subjects) were headache, fatigue, nausea, pyrexia, hypertension, myalgia, pain, and vomiting.

Clinical Studies Experience

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

In a multicenter, open-label, non-randomized clinical study, 50 subjects with primary humoral immunodeficiency received doses of Gammaplex ranging from 279 to 799 mg/kg every 21days (mean dose 465 mg/kg) or 28 days (mean dose 458 mg/kg), for up to 12 months (see Clinical Studies [14.1]). Routine premedication was not allowed. Of the 703 infusions administered, 2 (4%) subjects received premedication (antipyretic, antihistamine, or antiemetic agent) prior to 2 courses of treatment, because of experience with consecutive infusion-related adverse reactions.

All 50 subjects had an adverse event at some time during the study. Twenty-four subjects (48.0%) had an adverse reaction at some time during the study that was considered product-related. More subjects with the 21-day infusion cycle had at least one adverse reaction (14 of 22 subjects, 63.6%) than subjects with the 28-day infusion cycle (10 of 28 subjects, 35.7%). Of these 24 subjects who showed adverse reactions, only 3 subjects had adverse reactions that were considered definitely related to Gammaplex: headache, pyrexia, tachycardia, chest discomfort, and hypertension.

The most common adverse reactions observed in this clinical trial were headache (18 subjects, 36.0%), fatigue (6 subjects, 12.0%), nausea (6 subjects, 12.0%), pyrexia (6 subjects, 12.0%), hypertension (3 subjects, 6.0%), myalgia (3 subjects, 6.0%), pain (3 subjects, 6.0%), and vomiting (3 subjects, 6.0%).

Temporally associated adverse events (AEs) are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. In this study, the upper bound of the 1-sided 97.5% confidence interval for the proportion of Gammaplex infusions temporally associated with one or more AEs was 24.2% (actual proportion: 21.2%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 237 (a rate of 0.34 AEs per infusion), reflecting that some subjects experienced more than one AE during the observation period.

Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Gammaplex infusion or within 72 hours after the end of an infusion, irrespective of causality.

Of the 237 temporally associated AEs reported for the 50 subjects, the investigators judged 115 to be related to the infusion of Gammaplex. The most common temporally associated AEs judged to be related to Gammaplex infusion were headache (32% of subjects), pyrexia (8% of subjects), and nausea (8% of subjects).

Five subjects (10%) experienced seven serious AEs. Two of these serious AEs were considered related to Gammaplex treatment (thrombosis and chest pain). Three other subjects withdrew from the study due to the following AEs: paresthesia, bronchospasm, and pregnancy.

Forty-seven of the 50 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 47 subjects, 4 (8.5%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia.

During this study, no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V).

Postmarketing Experience

Because adverse reactions are voluntarily reported post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse reactions have been identified during post-approval use of intravenous immune globulins10:

• Infusion reactions: hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure
• Renal: Acute renal dysfunction/failure, osmotic nephropathy
• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
• Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
• Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome
• Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
• Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test
• Gastrointestinal: Hepatic dysfunction, abdominal pain
• General/Body as a Whole: pyrexia, rigors

Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, rubella and varicella.11,12 Inform the immunizing physician of recent therapy with Gammaplex so that appropriate measures may be taken (see Patient Counseling Information [17]).

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Gammaplex. It is also not known whether Gammaplex can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Gammaplex should be given to a pregnant woman only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation13, 14

Nursing Mothers

Use of Gammaplex has not been evaluated in nursing mothers.

Pediatric Use

Six (6) pediatric patients with primary humoral immunodeficiency (2 between ages of 9 and 10, and 4 between ages 12 and 16) were included within the clinical evaluation of Gammaplex. This number of pediatric patients was too small for separate evaluation from the adult patients for safety or efficacy (see Clinical Studies [14]).

Geriatric Use

Use caution when administering Gammaplex to patients age 65 and over who are judged to be at increased risk of developing renal insufficiency or thrombotic events (see Boxed Warning, Warnings and Precautions [5.2, 5.4]). Do not exceed recommended doses, and administer Gammaplex at the minimum infusion rate practicable.

Eight (8) patients with primary humoral immunodeficiency at or over the age of 65 were included within the clinical evaluation of Gammaplex. This number of geriatric patients was too small for separate evaluation from the younger patients for safety or efficacy (see Clinical Studies [14]).

Gammaplex is a ready to use sterile solution of polyclonal human Immunoglobulin G for IV administration that contains sorbitol, glycine and polysorbate 80 as stabilizers. Specifically, Gammaplex contains approximately 5 g normal human immunoglobulin and 5 g D-sorbitol in 100 mL of buffer solution containing: 0.6 g glycine, 0.2 g sodium acetate, 0.3 g sodium chloride, and ~5 mg polysorbate 80. Immunoglobulin G purity is > 95%, the pH is in the range of 4.8 to 5.1, and osmolality is not less than 240 mOsmol/kg (typically 420 to 500 mOsmol/kg). The distribution of the four IgG subclasses is approximately 64% IgG1, 30% IgG2, 5% IgG3, and 1% IgG4. The content of IgA is lower than 10 µg/mL. The anti-D and anti-A/anti-B hemagglutinin content of the drug product is strictly controlled to specification. Gammaplex contains no reducing carbohydrate stabilizers (e.g. sucrose, maltose) and no preservative.

Gammaplex is prepared from large pools of human plasma by a combination of cold ethanol fractionation and ion exchange chromatography. Fab functions tested include antigen binding activity, and Fc functions tested include complement activation and rubella antibody-mediated hemolysis.

Gammaplex is manufactured from plasma, obtained from healthy US donors, that have passed viral screening tests. All donors are subjected to medical examinations, laboratory tests, and a review of their medical history before being allowed to donate blood or plasma. There are several stages within this manufacturing process that contribute to viral reduction, including management of donors, screening of donations and specific virus removal steps during manufacturing.

All plasma donations are screened for antibody to HIV-1/2 and HCV, and hepatitis B surface antigen (HBsAg). Furthermore, plasma mini-pools (512 donations per pool) undergo nucleic acid amplification testing (NAT) for HIV, hepatitis B virus (HBV), HCV, hepatitis A virus (HAV) and Parvovirus B19. Further testing is carried out on the manufacturing pools for HBsAg, and antibody to HIV-1/2; HCV and Parvovirus B19 are also tested by NAT, with the limit for B19 set to not exceed 104 IU B19 DNA per mL plasma.

There are three processing steps specifically designed to remove or inactivate viruses:

1) Solvent/Detergent treatment is targeted to enveloped viruses;

2) A virus filtration step using Pall Ultipor DV20 is designed to remove small viruses including non-enveloped viruses, on a size exclusion basis; and

3) The terminal low pH incubation step is identified as contributing to the overall viral clearance capacity for enveloped and non-enveloped viruses.

The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model. Overall virus reduction was calculated only from steps that were mechanistically independent from each other. In addition, each step was validated to provide robust virus reduction. The table below presents the contribution of each process step to virus reduction and the overall process reduction.

Gammaplex is supplied in a single use, clear Type II glass bottle, closed with a stopper (13% natural rubber) and oversealed with a tamper-evident cap.

The following presentations of Gammaplex are available:

Each vial has a label with a peel-off strip showing the product name and batch number.

When stored between 2 °C [35.6 °F] and 25 °C [77 °F]), Gammaplex has a shelf life of 24 months, as indicated by the expiration date printed on the outer carton and vial label.

Keep Gammaplex in its original carton to protect it from light.

DO NOT FREEZE.