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ZELAPAR Orally Disintegrating Tablets contain selegiline hydrochloride, a levorotatory acetylenic derivative of phenethylamine. Selegiline hydrochloride is described chemically as: (-)-(R)-N, α- dimethyl-N-2-propynylphenethylamine hydrochloride and its structural formula is:
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Its empirical formula is C13H17N·HCl, representing a molecular weight of 223.75. Selegiline hydrochloride is a white to almost white crystalline powder that is freely soluble in water, chloroform, and methanol.
ZELAPAR Orally Disintegrating Tablets are available for oral administration (not to be swallowed) in a strength of 1.25 mg. Each lyophilized orally disintegrating tablet contains the following inactive ingredients: gelatin, mannitol, glycine, aspartame, citric acid, yellow iron oxide, and grapefruit flavor.
GAMMAGARD LIQUID is indicated as replacement therapy for primary humoral immunodeficiency (PI) in adult and pediatric patients two years of age or older. This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. 1,2
GAMMAGARD LIQUID is indicated as a maintenance therapy to improve muscle strength and disability in adult patients with Multifocal Motor Neuropathy (MMN).
Table 1 : Dosage and Administration
| Dose | Initial Infusion rate | Maintenance Infusion rate |
| Intravenous Administration | ||
| Primary Immunodeficiency | ||
| 300 to 600 milligram/kg every 3 to 4 weeks based on clinical response | 0.5 mL/kg/hr (0.8 milligram/kg/min) for 30 minutes | Increase every 30 minutes (if tolerated) up to 5 mL/kg/hr (8 milligram/kg/min) |
| Multifocal Motor Neuropathy | ||
| Dose range 0.5 to 2.4 grams/kg/month based on clinical response | 0.5 mL/kg/hr (0.8 milligram/kg/min) | Infusion rate may be increased if tolerated up to 5.4 mL/kg/hr (9 milligram/kg/min) |
| Subcutaneous Administration: | ||
| Primary Immunodeficiency | ||
| Initial Dose is 1.37 previous intravenous dose divided by # of weeks between intravenous doses. | 40 kg RW and greater: 30 mL/site at 20 mL/hr/site. | 40 kg BW and greater: 30 mL/site at 20 to 30 mL/hr/site. |
| Maintenance dose is based on clinical response and target IgG trough level | Under 40 kg BW:20 mL/site at 15 mL/hr/site. | Under 40 kg BW:20 mL/site at 15 to 20 mL/hr/site. |
Adjust dose according to IgG levels and clinical response, as the frequency and dose of immune globulin may vary from patient to patient.
No randomized controlled clinical studies are available to determine an optimum trough serum IgG level for intravenous treatment. If a patient misses a dose, administer the missed dose as soon as possible, and then resume scheduled treatments every 3 or 4 weeks, as applicable.
Prior to switching from intravenous to subcutaneous treatment, obtain the patient's serum IgG trough level to guide subsequent dose adjustments. Start the initial subcutaneous dose approximately one week after the last intravenous infusion.
The dose may need to be adjusted to achieve the desired clinical response. In the clinical study, the dose ranged between 0.5 to 2.4 grams/kg/month (See Table 1). While receiving GAMMAGARD LIQUID, 9% of subjects in the clinical study experienced neurological decompensation that required an increase in dose. In order to avoid worsening of muscle weakness in patients, dose adjustment may be necessary.
Based on the results of clinical studies, the expected increase in serum IgG trough level during weekly subcutaneous treatment at the dose adjusted to provide a comparable AUC, is approximately 281 milligram/dL higher than the last trough level during prior stable intravenous treatment. To calculate the target trough IgG level for subcutaneous treatment, add 281 milligram/dL to the IgG trough level obtained after the last intravenous treatment.
To guide dose adjustment, calculate the difference between the patient's target serum IgG trough level and the IgG trough level during subcutaneous treatment. Find this difference in the columns of Table 2 and the corresponding amount (in mL) by which to increase (or decrease) the weekly dose based on the patient's body weight. If the difference between measured and target trough levels is less than 100 milligram/dL then no adjustment is necessary. However, the patient's clinical response should be the primary consideration in dose adjustment.
Table 2 : Change in Weekly Dose of GAMMAGARD LIQUID for Intended IgG Trough Level Adjustment*
| Body Weight | Difference between Measured and Target IgG Trough Levels | |||
| 100 mg/dL | 200 mg/dL | 300 mg/dL | 400 mg/dL | |
| 10 kg | 2 mL | 4 mL | 6 mL | 8 mL |
| 20 kg | 4 mL | 8 mL | 11 mL | 15 mL |
| 30 kg | 6 mL | 11 mL | 17 mL | 23 mL |
| 40 kg | 8 mL | 15 mL | 23 mL | 30 mL |
| 50 kg | 9 mL | 19 mL | 28 mL | 38 mL |
| 60 kg | 11 mL | 23 mL | 34 mL | 45 mL |
| 70 kg | 13 mL | 26 mL | 40 mL | 53 mL |
| 80 kg | 15 mL | 30 mL | 45 mL | 60 mL |
| 90 kg | 17 mL | 34 mL | 51 mL | 68 mL |
| 100 kg | 19 mL | 38 mL | 57 mL | 75 mL |
| 110 kg | 21 mL | 42 mL | 62 mL | 83 mL |
| 120 kg | 23 mL | 45 mL | 68 mL | 91 mL |
| 130 kg | 25 mL | 49 mL | 74 mL | 98 mL |
| 140 kg | 26 mL | 53 mL | 79 mL | 106 mL |
| *Derived using a linear approximation to the nomogram method with a slope of 5.3 kg/dL. | ||||
Example 1: A patient with a body weight of 80 kg has a measured IgG trough level of 800 milligram/dL and the target trough level is 1000 milligram/dL. The desired target trough level difference is 200 milligram/dL (1000 milligram/dL minus 800 milligram/dL). The weekly dose of GAMMAGARD LIQUID should be increased by 30 mL (3.0 gm).
Example 2: A patient with a body weight of 60 kg has a measured IgG trough of 1000 milligram/dL and the target trough level is 800 milligram/dL. The desired target trough level difference is 200 milligram/dL (800 milligram/dL minus 1000 milligram/dL). The weekly dose of GAMMAGARD LIQUID should be decreased by 23 mL (2.3 gm).
If a patient has been exposed to measles, it may be prudent to administer an extra dose of GAMMAGARD LIQUID as soon as possible and within 6 days of exposure. A dose of 400 mg/kg should provide a serum level > 240 mIU/mL of measles antibodies for at least two weeks.
If a patient is at risk of future measles exposure and receives a dose of less than 530 mg/kg every 3-4 weeks, the dose should be increased to at least 530 mg/kg. This should provide a serum level of 240 mIU/mL of measles antibodies for at least 22 days after infusion.
Table 3 : Infusion Rates for Intravenous Administration
| PI | MMN | |
| Initial | 0.5 mL/kg/hr (0.8 milligram/kg/min) for 30 minutes | Increasing rates of infusion starting at 0.5mL/kg/h (0.8 milligram/kg/min) |
| Subsequent | Increase every 30 minutes (if tolerated) up to 5 mL/kg/hr (8 milligram/kg/min) | Increasing to a maximum rate of 5.4 mL/kg /hr if tolerated (9 milligram/kg/min) |
Monitor patient vital signs throughout the infusion. Certain adverse reactions such as headaches, flushing, and changes in pulse rate and blood pressure may be related to the rate of infusion. Slow or stop infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that does not result in recurrence of the symptoms.
Adverse reactions may occur more frequently in patients receiving immune globulin for the first time, upon switching brands or if there has been a long interval since the previous infusion.2 In such cases, start at lower infusion rates and gradually increase as tolerated.
Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients over 65 years of age or judged to be at risk for renal dysfunction or thrombotic events, administer GAMMAGARD LIQUID at the minimum infusion rate practicable. In such cases, the maximal rate should be less than 3.3 milligram/kg/min (<2mL/kg/hr); consider discontinuation of administration if renal function deteriorates [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Table 4 : Infusion Rates for Subcutaneous Administration
| 40 kg BW and greater | Under 40 kg BW | |
| Initial | 30 mL/site at a rate of 20 mL/hr/site | 20 mL/site at a rate of 15 mL/hr/site |
| Maintenance | 30 mL/site at a rate of 20 to 30 mL/hr/site | 20 mL/site at a rate of 15 to 20 mL/hr/site |
Suggested areas for subcutaneous infusion of GAMMAGARD LIQUID are abdomen, thighs, upper arms, or lower back. Infusion sites should be at least two inches apart, avoiding bony prominences. Rotate sites each week.
The weekly dose (mL) should be divided by 30 or 20, based on patient weight above, to determine the number of sites required. Simultaneous subcutaneous infusion at multiple sites can be facilitated by use of a multi-needle administration set.
If multiple sites are used, the rate set on the pump should be the rate per site multiplied by the number of sites (e.g., 30 mL x 4 sites = 120 mL/hr). The number of simultaneous sites should be limited to 8, or maximum infusion rate of 240 mL/hr.
If multiple sites are used, the rate set on the pump should be the rate per site multiplied by the number of sites (e.g., 20 mL x 3 sites = 60 mL/hr). The number of simultaneous sites should be limited to 8, or maximum infusion rate of 160 mL/hr.
Instruct patients to observe the following procedures:
1. Aseptic technique - Use aseptic technique when preparing and infusing GAMMAGARD LIQUID.
2. Assemble supplies - Set up a clean work area and gather all supplies necessary for the subcutaneous infusion: vial(s) of GAMMAGARD LIQUID, ancillary supplies, sharps container and pump. If GAMMAGARD LIQUID has already been pooled into a bag or a syringe, skip to Step 5.
3. Product preparation - Remove the protective cap from the vial to expose the center of the vial. Wipe the stopper with an alcohol pad and allow to dry.
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4. Withdraw GAMMAGARD LIQUID from the vials - Attach a sterile syringe to a needle and draw air into the syringe barrel equal to the amount of product to be withdrawn. Inject the air into the vial and withdraw the desired volume of GAMMAGARD LIQUID. If multiple vials are required to achieve the desired dose, repeat this step.
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5. Prepare the infusion pump and tubing - Follow the manufacturer's instructions for preparing the pump and administration tubing, if needed. Be sure to prime the pump tubing to ensure that no air is left in the tubing and needle.
6. Select the infusion sites - Select the number of infusion sites depending on the volume of the total dose. [See DOSAGE AND ADMINISTRATION] for recommended maximum volumes and rates. Potential sites for infusion include the back of arms, abdomen, thighs, and lower back (see Figure below). Ensure sites are at least 2 inches apart; avoid bony prominences.
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7. Cleanse the infusion site(s) - Cleanse the infusion site(s) with an antiseptic skin preparation (e.g., alcohol pad) using a circular motion working from the center of the site and moving to the outside. Allow to dry.
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8. Insert the needle - Choose the correct needle length to assure that GAMMAGARD LIQUID is delivered into the subcutaneous space. Grasp the skin and pinch at least one inch of skin between two fingers. Insert needle at a 90-degree angle with a darting motion into the subcutaneous tissue. Secure the needle.
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9. Check for proper needle placement - Prior to the start of infusion, check each needle for correct placement to make sure that a blood vessel has not been punctured. Gently pull back on the attached syringe plunger and monitor for any blood return in the needle set. If you see any blood, remove and discard the needle set. Repeat priming and needle insertion steps in a different infusion site with a new needle set.
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10. Secure the needle to the skin - Secure the needle(s) in place by applying a sterile protective dressing over the site.
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11. Start infusion of GAMMAGARD LIQUID - Follow the manufacturer's instructions to turn pump on.
12. Document the infusion - Remove the peel-off label with product lot number and expiration date from the GAMMAGARD LIQUID vial and place in treatment diary/log book to keep track of the product lots used. Keep the treatment diary/log book current by recording the time, date, dose, product label and any reactions after each infusion.
13. Remove needle set - After the infusion is complete, remove the needle set and gently press a small piece of gauze over the needle insertion site and cover with a protective dressing. Discard any unused solution and disposable supplies in accordance with local requirements,
GAMMAGARD LIQUID is an aqueous solution containing 10% IgG (100 milligram/mL).
GAMMAGARD LIQUID is supplied in single use bottles containing the labeled amount of functionally active IgG. The packaging of this product is not made with natural rubber latex.
The following presentations of GAMMAGARD LIQUID are available:
| NDC Number | Volume | Grams Protein |
| 0944-2700-02 | 10 mL | 1.0 |
| 0944-2700-03 | 25 mL | 2.5 |
| 0944-2700-04 | 50 mL | 5.0 |
| 0944-2700-05 | 100 mL | 10.0 |
| 0944-2700-06 | 200 mL | 20.0 |
| 0944-2700-07 | 300 mL | 30.0 |
REFERENCES
1. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, Buckley R, Chinen J, El-Gamal Y, Mazer BD, Nelson Jr. RP, Patel DD, Secord E, Sorenson RU, Wasserman RL, Cunningham-Rundles C, Use of Intravenous Immunoglobulin in Human Disease: A Review of Evidence by Members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma, and Immunology. J Allergy Clin Immunol 2006; 117:S525-53.
2. Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94(suppl 1):S1-63.
Baxalta US Inc., Lexington, MA 02421 USA, U.S. License No. 2020, GLQ352. Revised: Mar 2021
PI: Intravenous: The serious adverse reaction seen during intravenous treatment in the clinical studies for PI was aseptic meningitis. The most common adverse reactions for PI (observed in ≥5% of subjects) were headache, fatigue, pyrexia, nausea, chills, rigors, pain in extremity, diarrhea, migraine, dizziness, vomiting, cough, urticaria, asthma, pharyngolaryngeal pain, rash, arthralgia, myalgia, oedema peripheral, pruritus, and cardiac murmur.
Subcutaneous: No serious adverse reactions were observed during the clinical study of subcutaneous treatment. The most common adverse reactions during subcutaneous treatment (observed in ≥5% of PI subjects) were infusion site (local) event, headache, fatigue, heart rate increased, pyrexia, abdominal pain upper, nausea, vomiting, asthma, blood pressure systolic increased, diarrhea, ear pain, aphthous stomatitis, migraine, oropharyngeal pain, and pain in extremity.
MMN: The serious adverse reactions in the clinical study for MMN were pulmonary embolism and blurred vision. The most common adverse reactions for MMN (observed in ≥5% of subjects) were headache, chest discomfort, muscle spasms, muscular weakness, nausea, oropharyngeal pain, and pain in extremity.
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.
The safety of GAMMAGARD LIQUID intravenous infusion was evaluated in 61 subjects.
Fifteen adverse reactions in 8 subjects were serious. Of these, two episodes of aseptic meningitis in one subject were deemed possibly related to infusion of GAMMAGARD LIQUID.
There were 400 non-serious adverse reactions. Of these, 217 were rated as mild (transient discomfort that resolves spontaneously or with minimal intervention), 164 were rated as moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 19 were rated as severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae). All of the severe non-serious adverse experiences were transient, did not lead to hospitalization, and resolved without complication. One subject withdrew from the study due to a non-serious adverse experience (papular rash).
Adverse reactions with a frequency of ≥5% (defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period) are shown in Table 5.
Table 5 : Adverse Reactions Occurring in ≥5% of Subjects
| Events | By Infusion N (%) (N=1812 Infusions) |
By Subject N (%) (N=61 Subjects) |
| Headache | 94 (5.2%) | 29 (47.5%) |
| Fatigue | 33 (1.8%) | 14 (23.0%) |
| Pyrexia | 28(1.5%) | 17 (27.9%) |
| Nausea | 17 (0.9%) | 11 (18.0%) |
| Chills | 14 (0.8%) | 8(13.1%) |
| Rigors | 14 (0.8%) | 8(13.1%) |
| Pain in extremity | 13 (0.7%) | 7 (11.5%) |
| Diarrhea | 12 (0.7%) | 9(14.8%) |
| Migraine | 12 (0.7%) | 4 (6.6%) |
| Dizziness | 11 (0.6%) | 8(13.1%) |
| Vomiting | 11 (0.6%) | 9(14.8%) |
| Cough | 9 (0.5%) | 8(13.1%) |
| Urticaria | 9 (0.5%) | 5 (8.2%) |
| Asthma | 7 (0.4%) | 6 (9.8%) |
| Pharyngolaryngeal pain | 7 (0.4%) | 5 (8.2%) |
| Rash | 6 (0.3%) | 4 (6.6%) |
| Arthralgia | 5 (0.3%) | 4 (6.6%) |
| Myalgia | 5 (0.3%) | 5 (8.2%) |
| Oedema peripheral | 5 (0.3%) | 5 (8.2%) |
| Pruritus | 5 (0.3%) | 4 (6.6%) |
| Cardiac murmur | 4 (0.2%) | 4 (6.6%) |
Pooled analysis of 4 short term clinical studies with 106 subjects (total of 854 infusions) showed no differences in the safety profile of GAMMAGARD LIQUID. These short term studies were designed to stabilize the immune globulin treatment or as a safety follow-up study. They were not designed to study the safety, efficacy and tolerability of GAMMAGARD LIQUID. No additional adverse reactions were reported during the study periods.
The safety of GAMMAGARD LIQUID in subcutaneous infusion was evaluated in 47 subjects.
Adverse reactions with a frequency of ≥5% (defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period) are shown in Table 6.
Table 6 : Adverse Reactions Occurring in ≥5% of Subjects
| Events | By Infusion N (%) (N=2294 infusions) |
By Subject N (%) (N=47 Subjects) |
|
| Infusion site (local) event | 55 (2.4%) | 21 (44.7%) | |
| Headache | 31 (1.4%) | 19 (40.4%) | |
| Fatigue | 11 (0.5%) | 7(14.9%) | |
| Heart rate increased | 11 (0.5%) | 3 (6.4%) | |
| Pyrexia | 11 (0.5%) | 9(19.1%) | |
| Abdominal pain upper | 9 (0.4%) | 5 (10.6%) | |
| Nausea | 7 (0.3%) | 3 (6.4%) | |
| Vomiting | 7 (0.3%) | 5 (10.6%) | |
| Asthma | 6 (0.3%) | 4 (8.5%) | |
| Blood pressure systolic increased | 6 (0.3%) | 3 (6.4%) | |
| Diarrhea | 5 (0.2%) | 3 (6.4%) | |
| Ear pain | 4 (0.2%) | 3 (6.4%) | |
| Aphthous stomatitis | 3 (0.1%) | 3 (6.4%) | |
| Migraine | 3 (0.1%) | 3 (6.4%) | |
| Oropharyngeal pain | 3 (0.1%) | 3 (6.4%) | |
| Pain in extremity | 3 (0.1%) | 3 (6.4%) | |
Of the 348 non-serious adverse reactions, 228 were rated as mild (transient discomfort that resolves spontaneously or with minimal intervention), 112 were rated as moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 8 were rated as severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae). Neither of the severe adverse reactions required hospitalization or resulted in sequelae.
Local Adverse Reactions
Local adverse reactions reported as mild (transient discomfort that resolves spontaneously or with minimal intervention) were rash, erythema, edema, hemorrhage, and irritation. Local adverse reactions reported as mild or moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae) were pain, hematoma, pruritus, and swelling.
One subject withdrew from the study after 10 treatments with GAMMAGARD LIQUID subcutaneous infusion (2.5 months) due to increased fatigue and malaise.
The overall rate of local adverse reactions (excluding infections) during subcutaneous treatment was 2.4% per infusion. In subcutaneous naive subjects, the incidence of local adverse reactions (N=1757 infusions) was 2.8% (2.2% mild and 0.6% moderate with no severe adverse reactions). In the subjects who were subcutaneous experienced (N=537 infusions), the incidence of local adverse reactions was 1.1% (1.1% mild, and no moderate or severe adverse reactions).
After all subcutaneous doses were adjusted, only one subject did not reach the maximum rate allowed in the protocol for one or more infusions, 20 mL/site/hour if weight was below 40 kg and 30/mL/hour for weight 40 kg and greater. Overall, 70% (31 of 44) of subjects opted for the highest rate for all infusions. No subject limited the infusion rate due to an adverse reaction. Median duration of each weekly infusion was 1.2 hours (range: 0.8-2.3 hours). The rate set on the pump was the rate per site multiplied by the number of sites, with no maximum.
During subcutaneous treatment, 99.8% of infusions were completed without a reduction, interruption, or discontinuation for tolerability reasons. The proportion of subjects who experienced local adverse reactions (excluding infections) was highest immediately following the switch from intravenous to subcutaneous treatment in all age groups. The rate of local adverse reactions per infusion immediately after switching from intravenous to subcutaneous treatment was 4.9% (29/595), decreasing to 1.5% (8/538) by the end of the study and to 1.1% (10/893) in the Study Extension. There was a decrease of local adverse reactions over subsequent subcutaneous infusions.
Eight (17%) subjects experienced a local adverse reaction during the first infusion, but that decreased to 1 (2.2%) for subsequent infusions, ranging from 0 to 4 (8.7%) during the first year of subcutaneous treatment. No subject reported a local adverse reaction from week 53 to end of study at week 68.
Analysis of a short term follow-up safety study of 10 subjects who were treated with subcutaneous administration of GAMMAGARD LIQUID (total of 218 infusions) showed no differences in the safety profile. The follow-up safety study was not designed to study the safety, efficacy and tolerability of GAMMAGARD LIQUID and no additional adverse reactions were reported during the study period.
The safety of GAMMAGARD LIQUID was evaluated in 44 subjects with MMN who received a total of 983 infusions. Two serious adverse reactions, pulmonary embolism and blurred vision, occurred.
In the study, among the 317 non-serious adverse reactions, 176 were considered ARs. Of these, 126 were mild (transient discomfort that resolves spontaneously or with minimal intervention), 37 were moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae) and 13 were severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae).
Adverse reactions with a frequency ≥5% (defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period) are shown in Table 7.
Table 7 : Adverse Reactions Occurring in ≥5% of MMN Subjects
| Events | GAMMAGARD LIQUID | Placebo | ||
| By Infusion N (%) (N=983 Infusions) |
By Subject N (%) (N=44 Subjects) |
By Infusion N (%) (N=129 Infusions) |
By Subject N (%) (N=43 Subjects) |
|
| Headache | 28 (2.85%) | 14 (31.82%) | 3 (2.33%) | 2 (4.65%) |
| Chest Discomfort | 3 (0.31%) | 3 (6.82%) | 0 (0.00%) | 0 (0.00%) |
| Muscle Spasms | 3 (0.31%) | 3 (6.82%) | 0 (0.00%) | 0 (0.00%) |
| Muscular weakness | 4(0.41%) | 3 (6.82%) | 1 (0.78%) | 1 (2.33%) |
| Nausea | 28 (2.85%) | 3 (6.82%) | 2(1.55%) | 1 (2.33%) |
| Oropharyngeal pain | 4(0.41%) | 3 (6.82%) | 0 (0.00%) | 0 (0.00%) |
| Pain in extremity | 4(0.41%) | 3 (6.82%) | 1 (0.78%) | 1 (2.33%) |
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.
Blood and Lymphatic System Disorders : Hemolysis
Immune System Disorders : Anaphylactic shock
Nervous System Disorders : Cerebral vascular accident, transient ischemic attack, tremor
Cardiac Disorders : Myocardial infarction
Vascular Disorders : Deep vein thrombosis, hypotension
Respiratory, Thoracic and Mediastinal Disorders : Pulmonary embolism, pulmonary edema
Skin and Subcutaneous Tissue Disorders : Hyperhidrosis
General Disorders and Administration-Site Conditions : Chest pain
Investigations : Coombs direct test positive, oxygen saturation decreased
Injury, Poisoning and Procedural Complications : Transfusion-related acute lung injury
Immune System Disorders : Hypersensitive
Musculoskeletal and Connective Tissue Disorders : Myalgia
General Disorders and Administration-Site Conditions : Chills
In addition to the adverse reactions listed above, the following reactions have been identified for immune globulin products administered intravenously:
Renal and Urinary Disorders : Osmotic nephropathy
Respiratory, Thoracic and Mediastinal Disorders : Cyanosis, hypoxemia, bronchospasm, apnea, Acute Respiratory Distress Syndrome (ARDS)
Integumentary : Bullous dermatitis, epidermolysis, erythema multiforme, Stevens-Johnson Syndrome
Vascular Disorders : Cardiac arrest, vascular collapse
Nervous System Disorders : Coma, seizures, loss of consciousness
Blood and Lymphatic System Disorders : Pancytopenia
Gastrointestinal : Hepatic dysfunction
The adverse reactions listed below have been identified and reported with the use of another immune globlin products administered subcutaneously:
Immune System Disorders : Anaphylactic reaction
Nervous System Disorders : Paresthesia, tremor
Cardiac Disorders : Tachycardia
Vascular Disorders : Hypotension
Respiratory, Thoracic and Mediastinal Disorders : Dyspnea, laryngospasm
General Disorders and Administration-Site Conditions : Chest discomfort, injection site reaction (including induration, warmth)
Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as mumps, rubella and varicella for up to 6 months, and for a year or more to measles (rubeola). Inform the immunizing physician of recent therapy with GAMMAGARD LIQUID so that appropriate precautions can be taken [see Patient Counseling Information].
Included as part of the "PRECAUTIONS" Section
ZELAPAR should not be used at daily doses exceeding those recommended (2.5 mg/day) because of the risks associated with non-selective inhibition of MAO [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
The selectivity of ZELAPAR for MAO-B may not be absolute even at the recommended daily dose of 2.5 mg daily. The selectivity of MAO-B inhibitors typically decreases, and it is ultimately lost as the dose is increased beyond recommended doses. Hypertensive reactions associated with ingestion of tyramine-containing foods have been reported even in patients taking the recommended daily dose of swallowed selegiline, a dose which is generally believed to be selective for MAOB.
Selectivity for MAO-B inhibition is gradually lost with increasing daily doses. An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg ZELAPAR daily [see DRUG INTERACTIONS]. However, the precise dose at which ZELAPAR becomes a non-selective inhibitor of all MAO enzymes in individual patients is unknown.
Reports of hypertensive reactions have occurred in patients who ingested tyramine-containing consumables (i.e., food or drink) while receiving swallowed selegiline at the recommended dose (a dose believed to be relatively selective for MAOB).
The safe use of ZELAPAR at doses above 2.5 mg daily without dietary tyramine restrictions has not been established.
A pharmacodynamic study showed increased tyramine sensitivity for increasing blood pressure and decreased selectivity for MAO-B with dosing above the recommended level (2.5 mg daily) [see CLINICAL PHARMACOLOGY].
Uncontrolled hypertension has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).
After starting ZELAPAR, monitor patients for new onset hypertension or exacerbation of hypertension that is not adequately controlled.
Serotonin syndrome and hyperpyrexia have been reported with the combined treatment of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (ELDEPRYL), rasagiline (AZILECT), and Zydis selegiline (ZELAPAR).
Serotonin syndrome is a potentially serious condition, which can result in death. Typical clinical signs and symptoms include behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, hypotension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor).
In the post-marketing period, fatal and non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with ZELAPAR [see CONTRAINDICATIONS and DRUG INTERACTIONS].
Clinical studies of ZELAPAR did not allow concomitant use of any selective serotonin re-uptake inhibitor (e.g., fluoxetine-Prozac, fluvoxamine-Luvox, paroxetine-Paxil, sertraline, venlafaxine-Effexor, or nefazodone-Serzone) or any non-selective serotonin reuptake inhibiting antidepressant drug (except when taken at a low dose and only at night for the purpose of effective sleep) with ZELAPAR.
Because the mechanisms responsible for these reactions are not fully understood, avoid the combination of ZELAPAR with any antidepressant. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. In patients taking antidepressants with a long half-life (e.g., fluoxetine and its active metabolite), allow at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) to elapse between discontinuation of fluoxetine and initiation of ZELAPAR [see DRUG INTERACTIONS].
Patients with Parkinson’s disease treated with ZELAPAR or other drugs increasing dopaminergic tone have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment.
It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment.
Somnolence may occur in patients receiving ZELAPAR. There was an increased risk for somnolence in geriatric patients (≥65 years) vs. non-geriatric patients treated with ZELAPAR. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with ZELAPAR. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with ZELAPAR.
Before initiating treatment with ZELAPAR, advise patients about the potential to develop drowsiness and specifically ask about factors that may increase this risk, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), ZELAPAR should ordinarily be discontinued. If a decision is made to continue ZELAPAR, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
Assessments of orthostatic (supine and standing) blood pressures at different times throughout the 12 week study period in two controlled trials showed that the frequency of orthostatic hypotension (>20 mm Hg decrease in systolic blood pressure and/or >10 mm Hg decrease in diastolic blood pressure) was greater with ZELAPAR treatment than with placebo treatment. Patients taking ZELAPAR were most likely to experience a decline in systolic and diastolic blood pressure at 8 weeks (2 weeks after initiating 2.5 mg ZELAPAR). At that time, the incidence of systolic orthostatic hypotension was about 21% in ZELAPAR-treated patients and 9% in placebo-treated patients. The incidence of diastolic orthostatic hypotension was about 12% in ZELAPAR-treated patients and about 4% in placebo-treated patients. Thus, it appears that there may be an increased risk for orthostatic hypotension in the period after increasing the daily dose of ZELAPAR from 1.25 to 2.5 mg.
The incidence of orthostatic hypotension was higher in geriatric patients (≥65 years) than in non-geriatric patients. In the geriatric patients, orthostatic hypotension occurred in about 3% of ZELAPAR-treated patients compared to 0% of placebo-treated patients.
ZELAPAR may potentiate dopaminergic side effects of levodopa and may cause dyskinesia or exacerbate preexisting dyskinesia. In controlled trials, the incidence of dyskinesia was 6% in ZELAPAR-treated patients and 3% in placebo-treated patients. Decreasing the dose of levodopa may lessen dyskinesia. The incidence of dyskinesia causing study discontinuation was greater on ZELAPAR than on placebo.
In controlled trials, hallucination was reported by 4% of ZELAPAR-treated patients and 2% in placebo-treated patients. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of ZELAPAR-treated patients, compared to no patient on placebo.
Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during ZELAPAR treatment or after starting or increasing the dose of ZELAPAR. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Patients with a major psychotic disorder should ordinarily not be treated with ZELAPAR because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of ZELAPAR [see DRUG INTERACTIONS].
Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ZELAPAR, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge eating, or other urges while being treated with ZELAPAR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ZELAPAR.
Although not reported with ZELAPAR in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.
In the controlled clinical trials, periodic examinations of the tongue and oral mucosa were performed. At the end of the study, the frequency of mild oropharyngeal abnormality (e.g., swallowing pain, mouth pain, discrete areas of focal reddening, multiple foci of reddening, edema, and/or ulceration) in patients without similar abnormality at baseline was 10% in ZELAPAR-treated patients compared to 3% in placebo-treated patients.
Phenylalanine can be harmful to patients with phenylketonuria (PKU). ZELAPAR contains phenylalanine, a component of aspartame. Each ZELAPAR 1.25 mg tablet contains 1.25 mg phenylalanine. Patients taking the 2.5 mg dose of ZELAPAR will receive 2.5 mg phenylalanine. Before prescribing ZELAPAR to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including ZELAPAR.
Carcinogenicity studies of orally administered selegiline are not available for ZELAPAR.
Carcinogenicity studies of selegiline have not been conducted using the buccal route.
Selegiline was negative in the in vitro bacterial reverse mutation (Ames) assay in and the in vivo micronucleus assay. In the in vitro chromosomal aberration assay in mammalian cells, selegiline was negative in the absence of metabolic activation but was clastogenic in the presence of metabolic activation.
When selegiline was administered orally to male (5, 10, and 40 mg/kg/day) and female (1, 5, and 25 mg/kg/day) rats prior to and during mating and continuing in females to gestation day 7, a decreased number of implantations was observed at the highest doses tested. In males, a reduction in sperm count and density was observed at the highest dose tested. The no-effect doses for reproductive impairment in rats (10 mg/kg/day in males and 5 mg/kg/day in females) are approximately 40 (males) and 20 (females) times the maximum recommended human dose of 2.5 mg/day on a mg/m2 basis.
No fertility studies have been conducted with selegiline using the buccal route.
There are no adequate data on the developmental risk associated with the use of ZELAPAR in pregnant women. In animal studies, administration of selegiline during pregnancy was associated with developmental toxicity (decreased embryofetal and postnatal offspring growth and survival) at doses greater than those used clinically.
In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown.
Animal Data
In rats administered selegiline orally (5, 10, and 40 mg/kg/day) throughout the period of organogenesis, a decrease in fetal body weight was observed at the mid and high doses. The no-effect dose for embryofetal developmental toxicity in rats (5 mg/kg/day) is approximately 20 times the maximum recommended human dose (MRHD) of 2.5 mg/day on a mg/m2 basis.
In rabbits administered selegiline orally (5, 30, and 60 mg/kg/day) throughout the period of organogenesis, embryolethality was observed at the highest dose tested and reduced fetal body weight was observed at the mid and high doses. The no-effect dose for embryofetal developmental toxicity in rabbits (5 mg/kg/day) is approximately 40 times the MRHD on a mg/m2 basis.
In rats administered selegiline orally (0.3, 1, and 10 mg/kg/day) during gestation and lactation, decreases in offspring survival and body weights were observed at the highest dose tested. The no-effect dose for pre-and postnatal developmental toxicity (1 mg/kg/day) is approximately 4 times the MRHD on a mg/m2 basis.
There are no data on the presence of selegiline or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Selegiline and metabolites were detected in rat milk at levels higher than those in maternal plasma.
Because of the potential for serious adverse reactions in breastfed infants from ZELAPAR, including the potential for hypertensive reactions, advise a woman that breastfeeding is not recommended during treatment with ZELAPAR and for 7 days after the final dose.
Safety and effectiveness in pediatric patients have not been established.
The overall incidence of adverse reactions was increased in geriatric patients (≥65 years) compared to non-geriatric patients (<65 years). Clinical studies did not include a sufficient number of geriatric subjects older than 75 years to determine whether they respond differently to ZELAPAR.
Analysis of adverse reaction incidence in each group was conducted to calculate and compare relative risk (ZELAPAR % / Placebo %) for each treatment. The relative risk was ≥2 fold higher for ZELAPAR treatment in the geriatric patients compared to the non-geriatric patients for hypertension, orthostatic/postural hypotension [see WARNINGS AND PRECAUTIONS]. The incidence of orthostatic hypotension by measurement of blood pressure was also higher in geriatric patients than in non-geriatric patients. In the geriatric patients, the treatment difference for incidence of orthostatic hypotension determined by supine and standing blood measurements was 3%.
Patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9) may require a dose reduction of ZELAPAR (from 2.5 to 1.25 mg daily) depending on the clinical response. ZELAPAR is not recommended in patients with severe hepatic impairment (Child-Pugh score >9) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
No dose adjustment of ZELAPAR is required in patients with mild to moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min). ZELAPAR is not recommended in patients with severe renal impairment and patients with end-stage renal disease [ESRD] (CLcr <30 mL/min) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
With intravenous administration, overdose of GAMMAGARD LIQUID may lead to fluid overload and hyperviscosity. Patients at risk of complications of fluid overload and hyperviscosity include elderly patients and those with cardiac or renal impairment.
GAMMAGARD LIQUID is contraindicated in patients who have a history of anaphylactic or severe systemic hypersensitivity reactions to administration of human immune globulin.
GAMMAGARD LIQUID is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity. Anaphylaxis has been reported with intravenous use of GAMMAGARD LIQUID and is theoretically possible following subcutaneous administration [see WARNINGS AND PRECAUTIONS].
GAMMAGARD LIQUID supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. GAMMAGARD LIQUID also contains a spectrum of antibodies capable of interacting with and altering the activity of cells of the immune system as well as antibodies capable of reacting with cells such as erythrocytes. The role of these antibodies and the mechanism of action of IgG in GAMMAGARD LIQUID have not been fully elucidated.
Following intravenous infusion, IGIV products show a biphasic decay curve. The initial (α) phase is characterized by an immediate post-infusion peak in serum IgG and is followed by rapid decay due to equilibration between the plasma and extravascular fluid compartments. The second (β) phase is characterized by a slower and constant rate of decay. The commonly cited “normal” half-life of 18 to 25 days is based on studies in which tiny quantities of radiolabeled IgG are injected into healthy individuals. When radiolabeled IgG was injected into patients with hypogammaglobulinemia or agammaglobulinemia, highly variable half-lives ranging from 12 to 40 days were observed. In other radiolabeled studies, high serum concentrations of IgG, and hypermetabolism associated with fever and infection, have been seen to coincide with a shortened IgG half-life.
In contrast, pharmacokinetic studies in immunodeficient patients are based on the decline of IgG concentrations following infusion of large quantities of immune globulin. In such studies, investigators have reported uniformly prolonged half-lives of 26 to 35 days. Pharmacokinetic parameters for GAMMAGARD LIQUID were determined from total IgG levels following the fourth infusion in subjects with primary humoral immunodeficiency (N=61) treated intravenously with the product every 3 or 4 weeks according to the regimen used prior to entering the study. Of these, 57 had sufficient pharmacokinetic data to be included in the dataset. The median weight-adjusted dose per subject was 455 milligram/kg/4 weeks with a range of 262 to 710.
Pharmacokinetic parameters are presented in Table 9.
Table 9 : Summary of Intravenous Pharmacokinetic Parameters in 57 Subjects
| Parameter | Median | 95% Confidence Interval |
| Dose of IgG (milligram/kg/4 weeks) | 455 | Range: 262-710 |
| Elimination Half-Life (T ½ days) | 35 | (31.42) |
| AUC0-21d (milligram-days/dL) | 29139 | (27494. 30490) |
| Cmax (Peak, milligram/dL) | 2050 | (1980.2200) |
| Cmin (Trough, milligram/dL) | 1030 | (939.1110) |
| Incremental recovery (milligram/dL)/(milligram/kg) | 2.3 | (2.2. 2.6) |
| Abbreviations: AUC=area under the curve Cmax =maximum concentration Cmin =minimum concentration |
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Median IgG trough levels were maintained between 960 to 1120 milligram/dL. These dosing regimens maintained serum trough IgG levels generally considered adequate to prevent bacterial infections. The elimination half-life of GAMMAGARD LIQUID (35 days) was similar to that reported for other IGIV products.
Pharmacokinetic (PK) parameters of subcutaneously administered GAMMAGARD LIQUID were evaluated in subjects with primary immunodeficiency (PI) who were 12 years and older during a clinical study [see Clinical Studies].
Subjects were treated intravenously for 12 weeks with GAMMAGARD LIQUID and then switched to weekly subcutaneous GAMMAGARD LIQUID infusions. Initially, all subjects were treated for a minimum of 12 weeks at a subcutaneous dose that was 130% of the intravenous dose. A comparison of the area under the curve (AUC) for intravenous and subcutaneous infusions done on the first 15 adult subjects determined that the subcutaneous dose required to provide an exposure from subcutaneous administration that was not inferior to the exposure from intravenous administration was 137% of the intravenous dose. Subsequently, all subjects were treated with this dose for 6 weeks after which the dose was individualized for all subjects using IgG trough levels, as described below. After a minimum of 8 weeks at this subcutaneous dose, a PK evaluation was conducted on subjects 12 years of age or older (N=32).
The mean adjusted dose at the end of the study was 137.3% (125.7 to 150.8) of the intravenous dose for subjects 12 years and older, and 141.0% (100.5 to 160.0) for subjects under the age of 12. Thus, a significant dosing difference was not required for children. At this dose adjustment, the geometric mean ratio of the AUC for subcutaneous vs. intravenous GAMMAGARD LIQUID administration was 95.2% (90% confidence limit: 92.3 to 98.2). The peak IgG level occurred 2.9 (1.2 to 3.2) days after subcutaneous administration.
Pharmacokinetic parameters of GAMMAGARD LIQUID administered intravenously versus subcutaneously in the clinical study are shown in Table 10. The mean peak IgG level was lower (1393 ± 289 milligram/dL) during subcutaneous treatment than with intravenous treatment (2240 ± 536 milligram/dL), consistent with lower weekly doses compared with doses administered every 3 or 4 weeks intravenously. In contrast, the mean trough level was higher when GAMMAGARD LIQUID was given subcutaneously (1202 ± 282 milligram/dL) than when it was given intravenously (1050 ± 260 milligram/dL), a result of both higher monthly dose and more frequent dosing. The median IgG trough level during intravenous treatment in this clinical study, 1010 milligram/dL (95% CI: 940 to 1240), was similar to the median IgG trough level of 1030 milligram/dL (95% CI: 939 to 1110) during intravenous treatment as shown in Table 9. By contrast, the median IgG trough level during subcutaneous treatment was higher, at 1260 milligram/dL (95% CI: 1060 to 1400).
Table 10 : Pharmacokinetic Parameters of Subcutaneously Administered GAMMAGARD LIQUID Compared With GAMMAGARD LIQUID Administered Intravenously
| Subcutaneous Administration | Intravenous Administration | |
| Number of Subjects | 32 | 32 |
| Dose* (milligram/kg) | ||
| Mean ±SD | 182.6 ±48.4 | 133.2 ±36.9 |
| Range (min to max) | 94.2 to 293.8 | 62.7 to 195.4 |
| IgG Peak Levels (milligram/dL) | ||
| Mean ± SD | 1393 ±289 | 2240 ± 536 |
| Range (min to max) | 734 to 1900 | 1130 to 3610 |
| IgG Trough Levels (milligram/dL) | ||
| Mean ± SD | 1202 ±282 | 1050 ±260 |
| Range (min to max) | 621 to 1700 | 532 to 1460 |
| AUC†(days*milligram/dL) | ||
| Mean ± SD | 9176±1928 | 9958 ± 2274 |
| Range (min to max) | 4695 to 12468 | 5097 to 13831 |
| Clearance [mL/kg/day] | ||
| Mean ± SD | 2.023 ±0.528 | 1.355 ±0.316 |
| Range (min to max) | 1.225 to 3.747 | 0.880 to 2.340 |
| *Weekly equivalent dose †Standardized to a 7 day interval |
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No full pharmacokinetic study was conducted in subjects with MMN. However, trough levels of IgG were measured in this population (n = 44; five 12 week study parts). The median serum trough level of total IgG over all study parts regardless of dosing intervals and length of infusion cycles, was 16.40 g/L (95% confidence interval: 15.7 to 17.1). During placebo administration, the median trough level was 12.35 g/L (95% CI: 10.6 to 13.6). The relationship between serum IgG concentration and efficacy was not assessed.
Intravenous use of GAMMAGARD LIQUID is supported by a study in subjects (N=61) who were treated with 300 to 600 milligram/kg every 21 to 28 days for 12 months. The age range of subjects was 6 to 72 years, with 54% female and 46% male, and 93% Caucasian, 5% African-American, and 2% Asian. Three subjects were excluded from the per-protocol analysis due to non-study product related reasons. The annualized rate of prespecified acute serious bacterial infections, i.e., the mean number of prespecified acute serious bacterial infections per subject per year, was studied (see Table 11).
Table 11 : Summary of Validated Acute Serious Bacterial Infections for the Per-Protocol Analysis
| Number of Events | |
| Validated Infections* | |
| Bacteremia / Sepsis | 0 |
| Bacterial Meningitis | 0 |
| Osteomyelitis / Septic Arthritis | 0 |
| Bacterial Pneumonia | 0 |
| Visceral Abscess | 0 |
| Total | 0 |
| Hospitalizations Secondary to Infection | 0 |
| Mean Number of Validated Infections per Subject per Year | 0 |
| p-value† | p< 0.0001 |
| 95% Confidence Interval† | (0.000. 0.064) |
| *Serious acute bacterial infections were defined by FDA and met specific diagnostic requirements †The rate of validated infections was compared with a rate of 1 per subject per year, in accordance with recommendations by the FDA Blood Products Advisory Committee |
|
The annualized rate of other prespecified validated bacterial infections (see Table 12), and the number of hospitalizations secondary to all validated infectious complications also were studied (see Table 11 and Table 12).
Table 12 : Summary of Validated Other Bacterial Infections
| Number of Events | |
| Validated Infections * | |
| Urinary Tract Infection | 1 |
| Gastroenteritis | 1 |
| Lower Respiratory Tract Infection: Tracheobronchitis, Bronchiolitis | 0 |
| (Without Evidence of Pneumonia) | |
| Lower Respiratory Tract Infection: | 0 |
| Other Infections (e.g., Lung Abscess, Empyema) | |
| Otitis Media | 2 |
| Total | 4 |
| Hospitalizations Secondary to Infection | 0 |
| Mean Number of Validated Infections per Subject per Year | 0.07 |
| 95% Confidence Interval | (0.018.0.168) |
| *Other bacterial infections that met specific diagnostic requirements | |
None of the 61 treated subjects was positive for HCV, HIV-1, and HIV-2 and HBV prior to study entry and none converted from negative to positive during the 12-month period.
A prospective, open-label, non-controlled, multi-center study was conducted in the U.S. to determine the efficacy, tolerability and PK of GAMMAGARD LIQUID subcutaneous infusion in adult and pediatric subjects (N=49) with PI. All subjects were treated for 12 weeks with GAMMAGARD LIQUID intravenous infusion every 3 or 4 weeks. Subjects who were on intravenous treatment prior to entering the study were switched to GAMMAGARD LIQUID at the same dose and frequency. Subjects who were receiving subcutaneous immune globulin were switched to GAMMAGARD LIQUID at the intravenous dose they had received prior to switching to subcutaneous treatment. A PK analysis was performed at the end of the intravenous period in all subjects aged 12 years and older.
One week after the last intravenous infusion, each subject began subcutaneous treatment with GAMMAGARD LIQUID at 130% of the weekly equivalent of the intravenous dose for a minimum of 12 weeks. PK data from the first 15 adult subjects were used to determine the dose required to ensure that the IgG exposure with subcutaneous treatment was not inferior to that with intravenous treatment. The median dose determined from these subjects was 137% of the intravenous dose, and subsequently all subjects were treated for a minimum of 6 weeks at this dose. After 6 subcutaneous infusions, a trough IgG level was obtained and used to individually adapt the subcutaneous dose of GAMMAGARD LIQUID to compensate for individual variation from the mean value of 137% [see Pharmacokinetics and DOSAGE AND ADMINISTRATION].
All subjects received a minimum of 12 infusions at this individually adapted dose and continued to receive subcutaneous treatment with GAMMAGARD LIQUID until the last subject completed the study. Subjects (N=47) were treated with 2,294 subcutaneous infusions of GAMMAGARD LIQUID: 4 subjects treated for up to 29 weeks, 17 subjects for 30 to 52 weeks, and 26 subjects for 53 weeks or longer. Two subjects that completed the intravenous treatment part of the study did not continue to the subcutaneous treatment part of the study. The median duration of subcutaneous treatment was 379 days (range: 57 to 477 days).
Efficacy was determined throughout the entire subcutaneous phase. There were 31 adults aged 16 years or older, 4 adolescents aged 12 to <16 years, and 14 children aged 2 to <12 years. The volume of GAMMAGARD LIQUID infused was 30 mL per site for subjects weighing 40 kg and greater, and 20 mL per site for those weighing less than 40 kg. The total weekly dose was divided by those values to determine the number of sites.
Mean weekly subcutaneous doses ranged from 181.9 milligram/kg to 190.7 milligram/kg (at 130% to 137% of the intravenous dose). In the study, the number of infusion sites per infusion was dependent on the dose of IgG and ranged from 2 to 10. In 75% of infusions, the number of infusion sites was 5 or fewer.
There were 3 serious validated bacterial infections, all bacterial pneumonia. None of these subjects required hospitalization to treat their infection. The annual rate of acute serious bacterial infections while on GAMMAGARD LIQUID subcutaneous treatment was 0.067, with an upper 99% confidence limit of 0.133, which is lower than the minimal goal of achieving a rate of <1 bacterial infection per patient-year.
Table 13 presents a summary of infections and associated events for subjects during subcutaneous treatment with GAMMAGARD LIQUID. The annual rate of any infection in this study during subcutaneous treatment, including viral and fungal infections, was 4.1 infections per subject per year.
Table 13 : Summary of Infections and Associated Events
| Number of subjects (efficacy phase) | 47 |
| Total number of subject years | 44 |
| Annual rate of any infections | 4.1 (95% Cl 3.2 to 5.1) infections/subject year |
| Antibiotic use* (prophylaxis or treatment) | 40(85.1%) |
| Number of subjects (%) | 50.2 (95% Cl 33.4 to 71.9) |
| Annual rate | days/subject year |
| Days out of work/school/day care or unable to perform normal activities | 25 (53.2%) |
| Number of subjects (%) | 4.0 (95% Cl 2.5 to 6.1) |
| Annual rate | days/subject year |
| Hospitalizations due to infections | 0 (0.0%) |
| Number of subjects (%) | 0.0 (95% Cl 0.0 to 0.1) |
| Annual rate | days/subject year |
| *Included systemic and topical antibacterial, anti-fungal, anti-viral, and anti-protozoal antimicrobials | |
A randomized, double-blind, placebo controlled, cross-over withdrawal study was conducted to evaluate the efficacy and safety/tolerability of GAMMAGARD LIQUID in adult subjects (N=44) with MMN.12 The study examined grip strength in the more affected hand11 (measured with dynamometer), and Guy's Neurological Disability Scale (GNDS) [upper limb part 6 subsection].13 Study subjects were on a regimen of licensed immunoglobulin (existing maintenance dose ranging from 0.5 to 2.0 grams/kg/month) prior to enrollment and thus, the results cannot be generalized to naïve patients.
The study comprised of five study periods, each lasting 12 weeks: 3 stabilization phases, one randomized withdrawal phase and one cross-over phase. Open-label GAMMAGARD LIQUID was administered at the beginning (study period 1) and at the end of the study (study period 5) for clinical stabilization, and between the double-blinded periods to prevent carry-over effect (study period 3). If, during either of the double-blinded treatment periods, the subject's upper limb function involving the affected muscles deteriorated such that the subject had difficulty completing daily activities or experienced a decline in grip strength of ≥50% in the more affected hand, the subject was switched directly to the next stabilization phase of open-label GAMMAGARD LIQUID (“accelerated switch”) without breaking the blind.
All subjects were treated for 12 weeks with open-label GAMMAGARD LIQUID during initial stabilization (study period 1). Each subject was then randomized in a double-blind manner to continuation of GAMMAGARD LIQUID or withdrawal of GAMMAGARD LIQUID and replacement by placebo for 12 weeks (study period 2); subjects who did not tolerate treatment were immediately transitioned to open label GAMMAGARD LIQUID. After infusion of open-label GAMMAGARD LIQUID for 12 weeks (study period 3), subjects crossed-over to receive placebo or GAMMAGARD LIQUID for 12 weeks (study period 4). No subject was allowed to experience placebo more than one time during the study. At study end, subjects were treated with open-label GAMMAGARD LIQUID for 12 weeks (study period 5).
Overall, 69% (n=29) of subjects required an accelerated switch to open-label treatment with GAMMAGARD LIQUID during the placebo period due to functional deterioration, but did not switch when receiving GAMMAGARD LIQUID. The median number of treatment days using GAMMAGARD LIQUID was 84 and the median number of days using placebo was 28. One subject (2.4%) switched to open-label treatment during blinded GAMMAGARD LIQUID cross-over period 1, but did not switch during placebo administration (p <0.001).
Forty-four subjects were evaluated to demonstrate effectiveness of GAMMAGARD LIQUID to improve or maintain muscle strength and functional ability in patients with MMN.
Statistical significance (p<0.001) favoring GAMMAGARD LIQUID over placebo was demonstrated by a substantially lower decline from baseline (22.30%; 95% CI: 9.92% to 34.67%) in mean grip strength in the more affected hand following treatment (see Table 14). The difference in relative change for GAMMAGARD LIQUID and placebo of 22.94% (95% CI: 10.69 to 35.19).
Table 14 : Relative Change in Grip Strength in the More Affected Hand during Cross-over Period (ANOVA) (mIntent-to-Treat Dataset) No. of subjects (N=41)
| Statistics | Sequence 1 | Sequence 2 | Difference | ||
| GAMMAGARD LIQUID | Placebo | Placebo | GAMMAGARD LIQUID | (GAMMAGARD LIQUID -Placebo) | |
| N | 22 | 22 | 19 | 20* | 41 |
| Mean (SD) | -16.36 (32.84) | -30.52 (29.68) | -29.19 (39.95) | 1.46 (10.72) | 22.30 (39.21) |
| Median | -3.90 | -27.00 | -25.03 | -0.11 | 26.6 |
| *A single subject in sequence 2, who was considered an outlier, was excluded from analysis | |||||
Guy's Neurological Disability Scores (GNDS) for the upper limbs, reflecting both fine motor skills and proximal strength, showed a significant difference in efficacy between GAMMAGARD LIQUID and placebo at the 2.5% level in favor of GAMMAGARD LIQUID. GNDS is a patient orientated clinical disability scale designed for multiple sclerosis and is considered appropriate for other neurological disorders.
As determined by GNDS scores for the upper limbs, 35.7% of subjects deteriorated while receiving placebo but not during treatment with GAMMAGARD LIQUID, whereas 11.9% of subjects deteriorated during GAMMAGARD LIQUID but not during the placebo period. This difference was statistically significant (p=0.021) (see Table 15). Overall, 4.8% of subjects showed deterioration with both placebo and GAMMAGARD LIQUID, while 47.6% showed no deterioration using either.
Table 15 : McNemar's Test for Subjects with Deterioration in Guy's Neurological Disability Score (Intent-to-Treat Dataset) No. of subjects (N=42)
| Deterioration on Placebo | 15 (35.7%) |
| Deterioration on GAMMAGARD LIQUID | 5 (11.9%) |
| Deterioration on both | 2 (4.8%) |
| No deterioration | 20 (47.6%) |
When data from both treatment sequences were combined, a relative decline of ≥30% in grip strength in the more affected hand occurred in 42.9% of subjects during the placebo period, but not during treatment with GAMMAGARD LIQUID, whereas 4.8% of subjects experienced a ≥30% decline during treatment with GAMMAGARD LIQUID, but not during placebo. A relative decline of ≥30% in grip strength in the less affected hand occurred in 31.0% of subjects during the placebo period, but not during treatment with GAMMAGARD LIQUID. No subject experienced a ≥30% decline during treatment with GAMMAGARD LIQUID.
The Overall Disability Sum Score (ODSS) changed by -7.14% during placebo (indicating worsening of disability) and by -1.11% (indicating minimal change in disability) during treatment with GAMMAGARD LIQUID. For this specific analysis of ODSS, lower scores represented more disability.
With the dominant hand, subjects required 17% longer to complete the 9-hole peg test (a measure of dexterity) at the end of the placebo period, compared with baseline. By contrast, at the end of the GAMMAGARD LIQUID treatment period, subjects required 1.2% longer to complete the 9-hole peg test for the dominant hand compared with baseline. With the non-dominant hand, subjects required 33% longer to complete the 9-hole peg test at the end of the placebo period and 6.7% longer at the end of the GAMMAGARD LIQUID treatment period, compared with baseline.
Compared with baseline, assessment by subjects of physical functioning, as measured by visual analog scale (VAS) showed a mean change of 290% during placebo compared with baseline. Assessment by subjects of physical functioning showed a mean change of 73% during GAMMAGARD LIQUID treatment. Higher visual analog scale scores represent more severe disability.
REFERENCES
11. Shechtman O, Gestewitz L, Kimble C. Reliability and validity of the DynEx dynamometer. J. Hand Ther. 2005;18:339-347.
12. Hahn A., et al.; A controlled trial of intravenous immunoglobulin in multifocal motor neurophathy. Journal of the Peripheral Nervous System 2013; 18:321-330
13. Sharrack B, Hughes RA. The Guy's Neurological Disability Scale (GNDS): a new disability measure for multiple sclerosis. Mult. Scler. 1999;5:223- 233.
GAMMAGARD LIQUID
Immune Globulin Infusion (Human) 10%
For Intravenous and Subcutaneous Administration
Information for Patients
The following summarizes important information about GAMMAGARD LIQUID. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about GAMMAGARD LIQUID. If you have any questions after reading this, ask your healthcare provider.
What is the most important information I need to know about GAMMAGARD LIQUID?
GAMMAGARD LIQUID can cause the following serious reactions:
What is GAMMAGARD LIQUID?
GAMMAGARD LIQUID is a ready-to-use, liquid medicine that contains immunoglobulin G (IgG) antibodies, which protect the body against infection.
GAMMAGARD LIQUID is used to treat patients with primary immunodeficiency diseases (PI) and patients with multifocal motor neuropathy (MMN).
There are many forms of PI. The most common types of PI result in an inability to make a very important type of protein called antibodies, which help the body fight off infections from bacteria or viruses. GAMMAGARD LIQUID is made from human plasma that is donated by healthy people. GAMMAGARD LIQUID contains antibodies collected from these healthy people that replace the missing antibodies in PI patients.
MMN is a rare disease that causes muscle weakness that worsens over time. It affects the strength of the lower parts of arms and hands more than the legs, usually without affecting the touch sensation.
Who should not use GAMMAGARD LIQUID?
Do not use GAMMAGARD LIQUID if you have a known history of a severe allergic reaction to immune globulin or other blood products. If you have such a history, discuss this with your healthcare provider to determine if GAMMAGARD LIQUID can be given to you. Tell your healthcare provider if you have a condition called selective (or severe) immunoglobulin A (IgA) deficiency.
How should I use GAMMAGARD LIQUID?
GAMMAGARD LIQUID is given into a vein (intravenously) or under the skin (subcutaneously). For patients with PI, infusions into the vein are usually given every 3 or 4 weeks whereas infusions under the skin are given every week. For patients with MMN, infusions are given into a vein every 2 to 4 weeks as ordered by your physician. You and your healthcare provider will decide which way is best for you. Most of the time infusions under the skin are given at home by patients or caregivers. Although it is possible to give yourself infusions into the vein at home they are more often given in a hospital or infusion center by a nurse.
Instructions for giving GAMMAGARD LIQUID under the skin (subcutaneously) are provided in the Instructions for Use brochure. Only use GAMMAGARD LIQUID by yourself after you have been instructed by your healthcare provider.
What should I avoid while taking GAMMAGARD LIQUID?
GAMMAGARD LIQUID can make vaccines (like measles/mumps/rubella or chickenpox vaccines) not work as well for you. Before you get any vaccines, tell your healthcare provider that you take GAMMAGARD LIQUID.
Tell your healthcare provider if you are pregnant, or plan to become pregnant, or if you are nursing.
What are the possible or reasonably likely side effects of GAMMAGARD LIQUID?
The following one or more possible reactions may occur at the site of infusion. These generally go away within a few hours, and are less likely after the first few infusions.
During the infusion of GAMMAGARD LIQUID, look out for the first signs of the following common side effects:
If any of the following problems occur after starting treatment with GAMMAGARD LIQUID, stop the infusion immediately and contact your healthcare provider or call emergency services. These could be signs of a serious problem.
These are not all of the possible side effects with GAMMAGARD LIQUID. You can ask your healthcare provider for physician's information leaflet. Tell your healthcare provider about any side effect that bothers you or that does not go away.
Whenever giving yourself treatments at home, you should have another responsible person present to help treat side effects or get help if you have a serious adverse reaction occur. Ask your healthcare provider whether you should have rescue medications, such as antihistamines or epinephrine.
How do I store GAMMAGARD LIQUID?
Store vials in their original boxes to protect from light. Do not freeze GAMMAGARD LIQUID.
You can store GAMMAGARD LIQUID in the refrigerator or at room temperature. The maximum storage time for GAMMAGARD LIQUID depends on the storage temperature you choose.
In the Refrigerator: at 2° to 8°C (36° to 46°F) for up to 36 months.
Room Temperature: up to 25°C (77°F) for up to 24 months.
The refrigerator and room temperature expiration dates are printed on the vial labels and the box. Always check the expiration date. You should not use the product after the expiration date.
Note: If you remove GAMMAGARD LIQUID from the refrigerator and store it at room temperature, do not refrigerate again.
Resources at Baxalta Available to the Patients:
For more information on patient resources, education, or insurance assistance please visit www.immunedisease.com.
Detailed Instructions for Subcutaneous Administration for Patients with PI ONLY
Do not begin subcutaneous treatment with GAMMAGARD LIQUID until you have received instructions as detailed above and are comfortable that you can perform all the steps on your own.
1. If refrigerated, remove GAMMAGARD LIQUID from refrigerator- remove the product box from the refrigerator and take the vial out of the box.
Allow vials to reach room temperature. This may take up to 60 minutes.
Do not heat up the product or shake the product.
If stored at room temperature, take the vial out of the box. Check:
Repeat this step with as many boxes of GAMMAGARD LIQUID as necessary.
2. Gather all supplies – Collect all the items you will need for the infusion: vial(s) of GAMMAGARD LIQUID, infusion supplies (needle sets, transfer needles, alcohol swabs, syringes, gauze, and tape), sharps container, infusion pump, and treatment logbook.
3. Prepare a clean work area- Clean a work area with an antibacterial cleaner and place all gathered items on the clean surface. Find a quiet work area with as few distractions as possible.
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4. Wash hands- Wash your hands thoroughly. Put on clean gloves if your health care provider has instructed you to wear them.
5. GAMMAGARD LIQUID preparation- If GAMMAGARD LIQUID is received in a bag or syringe, skip to step 7.
Remove the cap from the vial. Wipe the vial stopper with an alcohol swab and allow to air dry (at least 30 seconds).
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6. Fill syringe from GAMMAGARD LIQUID vial(s) – Remove sterile syringe from package and attach to a sterile needle. Pull back on plunger of the syringe to fill it with air, which should equal the amount of liquid you will be taking from the vial. Insert needle into the center of the vial stopper. Inject air into the vial and withdraw GAMMAGARD LIQUID into the syringe. (Example: If withdrawing 50 mL of GAMMAGARD LIQUID, inject 50 mL of air into the vial).
If multiple vials are required to achieve the desired dose, repeat this step.
If using a vented spike, it is not necessary to inject air into the vial with the syringe.
Attach a sterile syringe to the spike, insert the spike into the center of the stopper, and pull back on the plunger to withdraw the desired volume.
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7. Prepare the infusion pump and tubing – If using a syringe driver pump, attach the syringe filled with GAMMAGARD LIQUID to the needle set. On a hard surface, gently push down on the plunger to fill (prime) the pump tubing up to the needle hub. This will ensure that no air is left in the tubing and needle (see picture).
If using a portable pump with GAMMAGARD LIQUID in a bag, follow manufacturer's instructions for preparing the pump and administration tubing, if needed.
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8. Select the infusion sites - Select the number of infusion sites based on the volume of the total dose. It is recommended that you not inject more than 20 mL for children and 30 mL for adults into each infusion site.
See figure for potential locations of infusion sites (e.g., upper arms, abdomen, thighs, and lower back). Make sure sites are at least 2 inches apart. Avoid bony areas, visible blood vessels, scars and areas of inflammation (irritation) or infection.
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9. Clean the infusion site(s)- Clean the infusion site(s) with an alcohol swab. Allow to dry (at least 30 seconds).
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10. Insert the needle – Remove the needle cover. Firmly grasp skin and pinch at least one inch of skin between two fingers. Insert needle with a rapid motion straight into the skin at a 90 degree angle. Tape the needle in place. Repeat this step for each infusion site.
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11. Check for proper needle placement – Before starting the infusion, check each needle for correct placement by gently pulling back on the attached syringe plunger and looking for any blood in the needle tubing. If you see any blood, remove and throw away the needle into the sharps container. Repeat filling (priming) and needle insertion steps in a different infusion site with a new needle.
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12. Secure the needle to the skin and start infusion - Secure the needle(s) in place by putting a sterile clear bandage over the needle.
Follow the manufacturer's instructions to turn pump on. Check infusion sites occasionally throughout the infusion.
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13. Remove needle set – After the infusion is complete, remove the needle set by pulling it straight out. Gently press a small piece of gauze over the needle site and cover with a protective dressing.
Throw away any unused product in the vial and the disposable supplies into the sharps container. Dispose of the sharps container using instructions provided with the container, or contact your healthcare provider.
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14. Record the infusion - Remove the peel-off label from GAMMAGARD LIQUID vial, which has the product lot number and expiration date, and place the label in your treatment diary/log book. Write down the date, time, dose, and any reactions after each infusion.
