Xembify
(immune globulin subcutaneous (human) - klhw)Dosage & Administration
For subcutaneous infusion only
Dose ( 2.1)
XEMBIFY can be administered at regular intervals from daily up to every two weeks (biweekly).
Administration
Infusion sites: up to 6 infusion sites simultaneously, with at least 2 inches (5 cm) between sites avoiding bony prominences, visible blood vessels, scars, and any areas of inflammation (irritation) or infection. Rotate sites for each administration.
| Patient Age | Maximum Volume (mL/infusion site) | Infusion Rate (mL/hr/infusion site) |
| Children 2 to <10 years | 25 | ≤25 |
| Adults, children ≥10 years | 25 | ≤35 |
Xembify Prescribing Information
- Thrombosis may occur with immune globulin products, including XEMBIFY. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. [see Warnings and Precautions (5.2), Patient Counseling Information (17)]
- For patients at risk of thrombosis, administer XEMBIFY at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. [see Warnings and Precautions (5.2)]
XEMBIFY® (immune globulin subcutaneous, human–klhw) is a 20% immune globulin solution for subcutaneous injection indicated for treatment of primary humoral immunodeficiency (PI) in patients 2 years of age and older. This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.1-4
For subcutaneous infusion only
Dose
XEMBIFY can be administered at regular intervals from daily up to every two weeks (biweekly).
Doses divided over the course of a week, once weekly, or biweekly achieve similar exposure when administered regularly at steady-state.
Individualize the dose based on the patient’s pharmacokinetic and clinical response.
Monitor serum IgG trough levels regularly to guide subsequent dose adjustments and dosing intervals as needed (see Dose adjustments).
If a patient is switching to XEMBIFY, obtain the patient’s serum IgG trough level to guide subsequent dose adjustments.
Switching to XEMBIFY from intravenous immune globulin (IVIG) Begin treatment with XEMBIFY one week after the patient’s last IVIG infusion.
Calculate the initial weekly dose of XEMBIFY. Divide the previous monthly (or every 3 weeks) IVIG dose in grams by the number of weeks between IVIG infusions, then multiply this dose by the dose adjustment factor of 1.37.
| Initial weekly dose (grams) = | Prior IVIG dose (in grams) | x 1.37 |
| Number of weeks between IVIG doses |
To convert the XEMBIFY dose (in grams) to milliliters (mL), multiply the calculated Initial SC dose (in grams) by 5.
To determine the dose for alternative regular dosing intervals:
-Frequent dosing (2-7 times per week): Divide the calculated weekly dose by the desired number of times per week.
-Biweekly dosing: Multiply the calculated weekly dose by 2.
To guide dose adjustments, see section Dose adjustments .
Switching to XEMBIFY from subcutaneous immune globulin (IGSC)
Administer the same weekly dose of XEMBIFY (in grams) as the weekly dose of prior IGSC treatment (in grams).
To convert the XEMBIFY dose (in grams) to milliliters (mL), multiply the calculated Initial SC dose (in grams) by 5.
To determine the dose for alternative regular dosing intervals:
-Frequent dosing (2-7 times per week): Divide the calculated weekly dose by the desired number of times per week.
-Biweekly dosing: Multiply the calculated weekly dose by 2.
To guide dose adjustments, see section Dose adjustments .
Treatment-naïve patients
The recommended dosage for treatment naïve patients with Primary Immunodeficiency is shown in Table 1.
| Loading Dose | Maintenance Dose | IgG Trough Monitoring |
| 150 mg/kg/day for 5 consecutive days | 150 mg/kg/week - weekly administrations starts at Day 8 | Monitor IgG trough levels every 2 weeks for the first 8 weeks of XEMBIFY dosing |
To guide dose adjustments, see section Dose adjustments .
Dose adjustments
For dose adjustments, calculate the difference (in mg/dL) of the patient’s serum IgG trough level from the target IgG trough level, then find this difference in Table 2 (below). Locate the corresponding amount (in mL) by which to increase or decrease the weekly dose based on the patient’s body weight. For example, if a patient with a body weight of 70 kg has an actual IgG trough level of 900 mg/dL and the target level is 1,000 mg/dL, this results in a difference of 100 mg/dL. Therefore, increase the weekly dose of subcutaneous dose by 5 mL.
The patient’s clinical response should be the primary consideration in dose adjustment. If a patient on XEMBIFY does not maintain an adequate clinical response or a serum IgG trough level equivalent to that of a previous treatment, adjust the dose accordingly.
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| Difference From Target IgG Trough Level (mg/dL) | Body Weight (kg) | ||||||||||||
| 10 | 15 | 20 | 30 | 40 | 50 | 60 | 70 | 80 | 90 | 100 | 110 | 120 | |
| Dose Adjustment (mL per Week) * | |||||||||||||
| 50 | 0 | 1 | 1 | 1 | 2 | 2 | 2 | 3 | 3 | 3 | 4 | 4 | 5 |
| 100 | 1 | 1 | 2 | 2 | 3 | 4 | 5 | 5 | 6 | 7 | 8 | 8 | 9 |
| 150 | 1 | 2 | 2 | 3 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 13 | 14 |
| 200 | 2 | 2 | 3 | 5 | 6 | 8 | 9 | 11 | 12 | 14 | 15 | 17 | 18 |
| 250 | 2 | 3 | 4 | 6 | 8 | 9 | 11 | 13 | 15 | 17 | 19 | 21 | 23 |
| 300 | 2 | 3 | 5 | 7 | 9 | 11 | 14 | 16 | 18 | 20 | 23 | 25 | 27 |
| 350 | 3 | 4 | 5 | 8 | 11 | 13 | 16 | 19 | 21 | 24 | 27 | 29 | 32 |
| 400 | 3 | 5 | 6 | 9 | 12 | 15 | 18 | 21 | 24 | 27 | 30 | 33 | 36 |
| 450 | 3 | 5 | 7 | 10 | 14 | 17 | 20 | 24 | 27 | 31 | 34 | 38 | 41 |
| 500 | 4 | 6 | 8 | 11 | 15 | 19 | 23 | 27 | 30 | 34 | 38 | 42 | 45 |
Preparation and Handling
XEMBIFY is a clear to slightly opalescent, and colorless or pale yellow solution.
Visually inspect XEMBIFY for particulate matter and discoloration prior to administration, whenever solution and container permit.
Do not use if the solution is cloudy or turbid.
Do not shake.
Do not dilute.
The XEMBIFY vial is for single use only.
Do not store any vial that has been entered by a needle during preparation for infusion, punctured, partially used, or opened.
Administer within 8 hours after beginning infusion preparation (i.e., once XEMBIFY is transferred from the vial into a syringe).
Administer XEMBIFY separately from other drugs or medications that the patient may be receiving.
Do not mix XEMBIFY with other medications including immune globulins from other manufacturers.
Do not use after expiration date.
Discard unused portion.
Administration
Prior to use, allow the solution to reach ambient room temperature.
Do not shake.
Follow the steps below and use aseptic technique to administer XEMBIFY.
1. Inspect the vials: inspect for clarity, color, and expiration date (s).
2. Prepare for infusion:
Gather supplies: XEMBIFY vial(s), ancillary supplies, sharps container, patient’s
treatment diary/logbook, and the infusion pump.
Prepare a clean work area.
Wash hands.
3. Remove the protective cap from the vial to expose the central portion of the stopper.
If the packaging shows any sign of tampering, do not use the product and notify
Grifols Therapeutics LLC immediately [1-800-520-2807].
4. Wipe the stopper with alcohol and allow to dry.
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12. Repeat priming and needle insertion steps using a new needle, administration tubing
and a new infusion site. Secure the needle in place by applying sterile gauze or
transparent dressing over the site.
13. Infuse XEMBIFY at a maximum rate as per Table 3 using up to 6 infusion sites. Ensure
that the infusion sites are at least 2 inches (5 cm) apart for patients of all ages. The
number of infusion sites is at healthcare provider discretion. Children will require less
total volume for a specific XEMBIFY dose (mg/kg body weight) than adults. The
healthcare provider may choose a smaller volume/site for children and/or fewer infusion
sites to achieve the target total dose, depending on the needs of the child. The total dose
volume of XEMBIFY is divided by the desired volume (mL/site) to obtain number
of infusion sites to be used.
| Patient Age | Maximum Volume to Be Infused SC | Rate | Number of Infusion Sites | Site Distance Apart |
| Children 2 to <10 years of age | 25 mL per site | ≤25 mL/hr/infusion site | ≤6 | ≥2 inches (5 cm) |
| Adults and children 10 years and older | 25 mL per site | ≤35 mL/hr/infusion site | ≤6 | ≥2 inches (5 cm) |
Record information about the infusion (e.g., lot number, expiration date, dose, date,
time, infusion site location(s), side effects) in a patient treatment record or infusion
log.
14. Discard the needle(s) and infusion line(s) in an appropriate container. Follow the
manufacturer’s instructions for storage of the infusion pump.
15. Discard partially used vial(s).
XEMBIFY is a protein solution containing 20% IgG (200 mg/mL; 0.2 g/mL) for subcutaneous infusion.
Pregnancy
Risk Summary
No human data are available to indicate the presence or absence of drug associated risk. Animal reproduction studies have not been conducted with XEMBIFY. It is not known whether XEMBIFY can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. XEMBIFY should be given to a pregnant woman only if clearly indicated. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Lactation
Risk Summary
No human data are available to indicate the presence or absence of drug associated risk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XEMBIFY and any potential adverse effects on the breastfed infant from XEMBIFY or from the underlying maternal condition.
Pediatric Use
XEMBIFY was evaluated in 14 pediatric patients (2-16 years of age) with PI in a multi-center clinical trial (Study 1) and in 29 pediatric patients in Study 2 [see Clinical Studies (14)]. The safety and efficacy profiles were similar to adult patients. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.
The safety and effectiveness of XEMBIFY in pediatric patients below 2 years of age have not been established.
Geriatric Use
Clinical studies of XEMBIFY did not include sufficient numbers of patients over age 65 years to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
XEMBIFY is contraindicated in:
Patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.
IgA deficient patients with antibodies against IgA and history of hypersensitivity to human immune globulin treatment.
Aseptic Meningitis Syndrome
Aseptic meningitis syndrome (AMS) has been reported with the use of human immune globulin administered intravenously and subcutaneously, including XEMBIFY. AMS usually begins within several hours to 2 days following immune globulin treatment. AMS may occur more frequently in females than in males.
AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. Cerebrospinal fluid (CSF) studies frequently show pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. To rule out other causes of meningitis, conduct a thorough neurological examination on patients exhibiting such symptoms and signs, including CSF studies. AMS may occur more frequently in association with high doses (>2 g/kg) and/or rapid infusion of immune globulin products. Discontinuation of immune globulin treatment has resulted in remission of AMS within several days without sequelae.
Thrombosis
Thrombosis may occur following treatment with immune globulin products, including XEMBIFY.5-7 Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.
Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer XEMBIFY at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. [see Boxed Warning, Dosage and Administration (2.3), Patient Counseling Information (17)]
Hypersensitivity
Severe hypersensitivity reactions may occur with human immune globulin products, including XEMBIFY. If a hypersensitivity reaction occurs, discontinue the XEMBIFY infusion immediately and institute appropriate treatment.
XEMBIFY contains IgA. Patients with known anti-IgA antibodies have a greater risk of developing potentially severe hypersensitivity reactions, including anaphylaxis. XEMBIFY is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity to human immune globulin treatment. [see Contraindications (4)]
Renal Dysfunction/Failure
Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death may occur upon use of human immune globulin products, especially those containing sucrose.8,9 XEMBIFY does not contain sucrose. Ensure that patients are not volume depleted prior to administration of XEMBIFY.
In patients with any degree of preexisting renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65 years, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs), monitor renal function and consider lower, more frequent dosing. [see Dosage and Administration (2.3)]
Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, prior to the initial infusion of XEMBIFY and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of XEMBIFY. [see Patient Counseling Information (17)]
Hemolysis
IgG products, including XEMBIFY can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin (Coombs’) test result and hemolysis.10-13 Delayed hemolytic anemia can develop subsequent to human immune globulin therapy due to enhanced RBC sequestration, and acute hemolysis consistent with intravascular hemolysis has been reported. [see Adverse Reactions (6)]
Monitor XEMBIFY recipients for clinical signs and symptoms of hemolysis, particularly patients with risk factors such as non-O blood group, or patients receiving high IgG doses (≥ 2 grams/kg).14 Underlying inflammatory state in an individual patient may increase the risk of hemolysis, but its role is uncertain.15
If signs and/or symptoms of hemolysis are present after XEMBIFY infusion, perform appropriate confirmatory laboratory testing.
Transfusion-Related Acute Lung Injury
Noncardiogenic pulmonary edema (transfusion-related acute lung injury [TRALI]) may occur in patients following treatment with human immune globulin products.16 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment.
Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.
Transmissible Infectious Agents
Because XEMBIFY is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or CJD have been associated with the use of XEMBIFY. ALL infections suspected by a physician to have possibly been transmitted by XEMBIFY should be reported by the physician or other healthcare provider to Grifols Therapeutics LLC [1-800-520-2807].
Interference with Laboratory Tests
After infusion with XEMBIFY, the transitory rise of various passively transferred antibodies in the patient’s blood may yield false-positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in other clinical trials of another drug and may not reflect the rates observed in clinical practice.
Study 1
The safety of XEMBIFY was evaluated in an open-label, single-arm prospective multi-center study in North America in patients with PI who received subcutaneous XEMBIFY for at least 6 months [see Clinical Studies (14)].
A total of 49 patients (including 14 patients between 2 to 16 years of age) received 1053 XEMBIFY infusions during the clinical trial. The average number of infusions per patient was 21.5 infusions, median 24 infusions (range 1-26 infusions).
A total of 390 local infusion site reactions occurred at a rate per infusion of 0.370 (approximately 1 in 2.7 infusions). Of these, the most common was infusion site erythema which had a median duration of 24.9 hours. Infusion site swelling, and infusion site pain had median durations of 24.5 and 22.8 hours, respectively. Local infusion site reactions of all kinds by site of infusion (where site of infusion was recorded) occurred in 50.0% and 52.6% of patients during infusions in the abdomen versus thigh, respectively, and across 773 abdominal infusions and 279 thigh infusions rates were 0.184 and 0.735 per infusion, respectively; this corresponds to 1 in 5.4 infusions (for abdomen) and 1 in 1.4 infusions (for thigh). No local infusion site reactions were considered severe or serious.
The adverse reactions occurring in ≥ 5% of patients on XEMBIFY in the clinical trial for the duration of the subcutaneous (SC) phase are shown in Table 4 below which includes all treatment-emergent adverse reactions except infections.
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| Adverse Reaction † | By Patient n (%) ‡ (N=49 patients) | By Infusion n (rate) § (N=1053 infusions) |
| Infusion site erythema | 19 (39%) | 123 (<1) |
| Infusion site pain | 9 (18%) | 32 (<1) |
| Infusion site swelling | 8 (16%) | 124 (<1) |
| Infusion site bruising | 8 (16%) | 26 (<1) |
| Infusion site nodule | 8 (16%) | 13 (<1) |
| Infusion site pruritus | 5 (10%) | 28 (<1) |
| Infusion site induration | 4 (8%) | 6 (<1) |
| Infusion site scab | 3 (6%) | 6 (<1) |
| Infusion site edema | 3 (6%) | 5 (<1) |
| Cough | 3 (6%) | 4 (<1) |
| Diarrhea | 3 (6%) | 3 (<1) |
Four patients discontinued XEMBIFY due to adverse reactions which were infusion site nodules, infusion site discomfort, skin papules/plaques, and arthralgia/myalgia.
Study 2
The safety of XEMBIFY during 12 months of treatment was evaluated in 61 patients (including 29 pediatric patients aged 2 to ≤16 years) in a clinical trial in Europe [see Clinical Studies (14)]. Adverse reactions in pediatric and adult patients were similar to those observed in Study 1. Among early withdrawals from the study, one patient discontinued XEMBIFY due to a related infusion site fibroma that resolved.
Study 3
The safety of XEMBIFY was compared between weekly and biweekly dosing during a single-sequence weekly-to-biweekly crossover study of 27 treatment-experienced adult patients with PI [see Clinical Studies (14)]. The incidence of adverse reactions was similar between dosing regimens and similar to those observed in Study 1.
The safety of XEMBIFY administered to 6 treatment-naïve adults with PI was assessed during a loading dose phase of 5 daily treatments with XEMBIFY followed by a weekly maintenance phase [see Clinical Studies (14)]. Adverse reactions occurring in more than one patient included infusion site swelling in 2 (33%) patients during or after 13 infusions and infusion site bruising in 2 (33%) patients during or after 2 infusions.
Postmarketing Experience
The following adverse events have been identified during post approval use of XEMBIFY. Because these events are reported voluntarily and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these events or establish a causal relationship to product exposure.
Immune system disorders: Anaphylactic reaction and hypersensitivity
Nervous system disorders: Aseptic meningitis, dizziness, and paresthesia
Cardiovascular disorders: Tachycardia and hypotension
Respiratory, thoracic and mediastinal disorders: Dyspnea and chest discomfort
General disorders and administration site conditions: Injection site reactions (such as
induration and warmth), chills, fatigue, and pain
The following adverse events have been identified and reported during the postmarketing use of immune globulin products administered subcutaneously:
Nervous system disorders: Tremor
Respiratory, thoracic and mediastinal disorders: Laryngospasm
Serological Testing
Various passively transferred antibodies in immunoglobulin preparations, including XEMBIFY, can confound the results of serological testing.
Live Attenuated Virus Vaccines
Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, rubella and varicella. Inform the immunizing healthcare provider of recent therapy with XEMBIFY so that appropriate measures may be taken.
XEMBIFY, immune globulin subcutaneous, human-klhw, is a 20% ready-to-use sterile, non-pyrogenic solution of human immune globulin protein for subcutaneous administration. The purity is ≥ 98% IgG with a sub-class distribution similar to that found in normal serum.
XEMBIFY consists of 18% to 22% protein in 0.16 M to 0.26 M glycine and 10 to 40 mcg/ mL polysorbate 80 at a pH of 4.1 to 4.8. The solution is clear to slightly opalescent, and colorless or pale yellow. The osmolality range is 280 to 404 mOsmol/kg. XEMBIFY contains no preservative and is not made with natural rubber latex.
XEMBIFY is made from large pools of human plasma by a combination of cold ethanol fractionation, caprylate precipitation and filtration, and anion-exchange chromatography. Isotonicity is achieved by the addition of glycine. XEMBIFY is incubated in the final container (at the low pH of 4.1 to 4.8).
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, using the following enveloped and non-enveloped viruses: human immunodeficiency virus, type I (HIV-1) as the relevant virus for HIV-1 and HIV-2; bovine viral diarrhea virus (BVDV) as a model for hepatitis C virus; pseudorabies virus (PRV) as a model for large enveloped DNA viruses (e.g. herpes viruses); West Nile Virus (WNV) as a relevant virus; Reovirus type 3 (Reo) as a model for non-enveloped viruses and for its resistance to physical and chemical inactivation; hepatitis A virus (HAV) as relevant non-enveloped virus, and porcine parvovirus (PPV) as a model for human parvovirus B19.
Overall virus clearance capacity was calculated only from steps that were mechanistically independent from each other and truly additive. In addition, each step was verified to provide robust virus reduction across the production range for key parameters.
| Process Step | Enveloped Virus | Non-Enveloped Virus | |||||
| HIV-1 | BVDV | PRV | WNV | Reo3 | HAV | PPV | |
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| Caprylate Precipitation/Depth Filtration | C/I * | 2.7 | C/I * | C/I * | ≥3.5 | ≥3.6 | 4.0 |
| Caprylate Incubation † | ≥4.5 | ≥4.5 | ≥4.6 | ≥5.1 | NA ‡ | NA ‡ | NA ‡ |
| Column Chromatography | ≥3.0 | 4.0 | ≥3.3 | ND § | ≥4.0 | ≥1.4 | 4.2 |
| Nanofiltration | ≥3.7 | ≥4.1 | ND § | ND § | ≥1.8 | ND § | 0.5 |
| Low pH Final Container Incubation | ≥5.3 | 4.9 | ≥5.1 | ≥5.3 | NA ‡ | NA ‡ | NA ‡ |
| Overall Clearance Capacity | ≥16.5 | ≥20.2 | ≥13.0 | ≥10.4 | ≥9.3 | ≥5.0 | 8.2 |
Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the variant Creutzfeldt-Jakob disease (vCJD), and Creutzfeldt-Jakob disease (CJD) agents.
Several of the individual production steps of the manufacturing process have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include depth filtrations (a total of ≥ 6.6 log10). These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed.
Mechanism of Action
XEMBIFY supplies a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against bacterial, viral, parasitic, and mycoplasmal agents and their toxins. XEMBIFY also contains a spectrum of antibodies capable of interacting with and altering the activity of cells of the immune system. The role of these antibodies and the mechanism of action of XEMBIFY are not fully understood.
Pharmacodynamics
Human normal immunoglobulin contains mainly (IgG) with a broad spectrum of antibodies against infectious agents. Human normal immunoglobulin contains the IgG antibodies present in the normal population. XEMBIFY has a distribution of IgG subclasses closely proportional to that in native human plasma. Adequate doses of XEMBIFY may restore abnormally low IgG levels to the normal range.
Pharmacokinetics
Pharmacokinetic (PK) parameters of subcutaneously administered XEMBIFY were evaluated in patients with primary immunodeficiency (PI) during a clinical trial in North America. [see Clinical Studies (14)] Patients were treated intravenously with a comparator product [GAMUNEX®-C, immune globulin injection (human), 10% caprylate/chromatography purified] during a 3-4 months run-in period prior to IV PK profiling in 50 patients, and then 49 patients switched to weekly subcutaneous infusions of XEMBIFY for 24 weeks at 137% of the intravenous dose with PK profiling at SC Week #13-14. A comparison of the area under the curve (AUC) for subcutaneous versus intravenous infusion was performed.
At the 137% dose adjustment, the geometric least-squares means ratio of the AUC for subcutaneous XEMBIFY versus IV administration of GAMUNEX-C was 104% (90% CI: 100%-107%). The peak IgG level occurred at a mean of 76 hours after subcutaneous XEMBIFY administration. The average mean IgG trough level at steady state was higher with XEMBIFY (1245 mg/dL) compared with IV GAMUNEX-C (957 mg/dL) (average mean trough ratio SC/IV of 1.3). PK parameters of XEMBIFY compared to IV GAMUNEX-C are summarized in Table 6. PK parameters did not significantly differ between age groups .
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| Phase | Statistics | AUC(0-7 days) (h*mg/dL) * | Cmax (mg/dL) | tmax (hour) |
| IV | N | 49 | 49 | 49 |
| Mean±SD | 212151±41832 | 2154±437 | 5.8±8.0 | |
| CV% | 20 | 20 | 137.9 | |
| Min, Max | 106091, 308405 | 1430, 3170 | 0.8, 48.9 | |
| SC | N | 39 | 41 | 41 |
| Mean±SD | 218316±48121 | 1395±312 | 76.1±35.7 | |
| CV% | 22 | 22 | 46.9 | |
| Min, Max | 102650, 367496 | 636, 2320 | 0.0, 167.7 † | |
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| Age Group (years) Statistics | AUC(0-7 days) (h*mg/dL) | Cmax (mg/dL) | Mean Trough (mg/dL) | tmax (hour) |
| 2 -5 (n) | 1 | 1 | 1 | 1 |
| Mean±SD | 183864±NC * | 1130±NC * | 1078±NC * | 72±NC * |
| >5 -12 (n) | 5 | 5 | 6 | 5 |
| Mean±SD | 215558±27604 | 1372±183 | 1194±183 | 71±26 |
| CV% | 13 | 13 | 15 | 37 |
| Min, Max | 187838, 245614 | 1200, 1580 | 993, 1510 | 28, 101 |
| >12 -16 (n) | 4 | 5 | 5 | 5 |
| Mean±SD | 240009±40578 | 1548±281 | 1379±209 | 73±50 |
| CV% | 17 | 18 | 15 | 68 |
| Min, Max | 205646, 298678 | 1290, 2000 | 1095, 1665 | 24, 143 |
| >16 (n) | 29 | 30 | 32 | 30 |
| Mean±SD | 216987±52389 | 1383±335 | 1239±296 | 78±36 |
| CV% | 24 | 24 | 24 | 47 |
| Min, Max | 102650, 367496 | 636, 2320 | 652, 2048 | 0, 168 |
A study evaluating serial PK parameters between weekly and biweekly (every 2 weeks) dosing regimens for treatment-experienced adults with PI included 25 evaluable patients, including 23 who were evaluable for both dosing regimens. The geometric least-squares means ratio of the AUC(0-7 days) for XEMBIFY administration biweekly compared to weekly is 104% (90% CI: 100%-107%). PK parameters at steady state comparing weekly to biweekly dosing of XEMBIFY are summarized in Table 8. For biweekly dosing, population PK modeling demonstrates simulated steady state Cmax, Cmin, and AUCtau values of pediatric patients are within the 5th to 95th percentile of adult values.
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| Period | Statistics | AUC(0-7 days) (h*mg/dL) * | Cmax (mg/dL) | tmax (hour) |
| Weekly | n | 23 | 25 | 25 |
| Mean±SD | 170386 ± 35949 | 1076 ± 228 | 79 ± 40 | |
| Biweekly | n | 23 | 23 | 23 |
| Mean±SD | 174561 ± 36974 | 1151 ± 243 | 103 ± 44 | |
A study in treatment-naïve adults with PI (n=6) evaluated the trough IgG levels following initiation of a XEMBIFY loading dose regimen (150 mg/kg/day for 5 consecutive days) and after weekly maintenance XEMBIFY dosing regimen (150 mg/kg/week for 32 weeks). Following the initial loading dose and prior to initiating maintenance dosing, five (83%) patients attained an IgG trough level >700 mg/dL at Week 1 (Day 8). Three (50%) patients required dose adjustments. All 6 patients attained IgG trough levels >700 mg/dL by Week 8 and were maintained through the end of the study at Week 32. During the weekly maintenance phase patients received 150 mg/kg/week - 180 mg/kg/week of XEMBIFY and had mean trough IgG levels of at least 901 mg/dL at all timepoints from Week 8 through the end of study Week 32. Simulated population PK analysis (including data from previously treated pediatric and adult patients with PI) showed similar IgG exposure to treatment naïve patients following a loading dose and maintenance dose regimen of XEMBIFY. The IgG exposure following a loading dose plus maintenance dose regimen is expected to be similar between treatment-naïve pediatric and adult patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No nonclinical studies were conducted to evaluate the carcinogenic or mutagenic effects of XEMBIFY or its effects on fertility.
Animal Toxicology and/or Pharmacology
Single and repeated dose toxicology studies were conducted in male New Zealand White rabbits. In a single-dose toxicity study, no adverse effects were observed with subcutaneous dose levels of 500, 1000 and 1500 mg/kg. In a repeated-dose toxicity study, the systemic safety and toxicity profiles of XEMBIFY and comparator GAMUNEX-C were similar following 5 consecutive daily subcutaneous doses at levels of 500, 1000 and 1500 mg/kg/day. Transient local injection site swelling was observed in XEMBIFY but not in the GAMUNEX-C groups.
In improper delivery route studies, XEMBIFY administered as a single intravenous, intra-arterial or perivascular dose of 100 mg/kg caused injection site irritation in New Zealand White rabbits. The findings were of higher incidence following perivascular administration of either XEMBIFY or GAMUNEX-C and were within the norms of this route of administration in this species.
Study 1
Study 1 was a prospective, open-label single-arm, multi-center clinical trial designed to evaluate safety, efficacy, and pharmacokinetics of XEMBIFY in patients with PI conducted in North America. Safety and pharmacokinetics were assessed as compared to GAMUNEX-C. The GAMUNEX-C run-in phase prior to XEMBIFY (subcutaneous phase) lasted 3 or 4 months to achieve steady state prior to pharmacokinetic profiling. Efficacy was based on annualized serious bacterial infection (SBI) rate during the 6 months on XEMBIFY. The following were considered SBIs: bacteremia/sepsis, bacterial meningitis, bacterial pneumonia, osteomyelitis/septic arthritis, or visceral abscess.
A total of 53 adult and pediatric patients with PI enrolled (9% Hispanic or Latino; 91% White, 4% Black or African American, 6% American Indian or Alaskan Native). During the run-in and IV GAMUNEX-C phases, 4 patients discontinued. XEMBIFY was administered to a total of 49 patients (including 14 children aged 2 to ≤ 16 years and 35 adults) with a mean ± SD dose of 179 ± 45 mg/kg/week for a median treatment duration of 24 weeks and mean ± SD of 22 ± 7 weeks. The median dose was 171 mg/kg/week and the range of doses was 71 mg/kg/week to 276 mg/kg/week. The total exposure of XEMBIFY was 20 patient-years and 1053 infusions.
The rate of SBIs was 0.05 events per patient-year (1 event in 20 patient-years) (upper 99% confidence limit: 0.11) during XEMBIFY treatment. This annual rate was lower than 1.0 SBI/patient-year, the threshold specified as effective.
The summary of infections and associated events for patients during subcutaneous treatment with XEMBIFY in Study 1 is summarized in Table 9.
| |
| Parameters | Results |
| Number of patients (efficacy period) | 49 |
| Total number of patient days on treatment | 7,407 |
| Total number of patient-years on treatment | 20.28 |
| Infections Annual rate of SBIs *(per patient-year) | 0.05 (95% CI: 0.02 - 0.10) |
| Annual rate of infections of any kind (per patient-year) | 2.4 (95% CI: 1.6 - 3.3) |
| Days on antibiotics (prophylactic) (rate per patient-year) | 27.7 (95% CI: 13.6 - 49.0) |
| Days on antibiotics (therapeutic) (rate per patient-year) | 28.9 (95% CI: 17.3 - 44.8) |
| Days missed work/school/unable to perform normal daily activities due to infections (rate per patient-year) | 2.3 (95% CI: 1.1 - 4.2) |
| Hospitalizations due to infections (rate per patient-year) | 0.05 (95% CI: 0.02 - 0.10) |
Study 2
Study 2 was a prospective, open-label, single-arm, multi-center clinical trial designed to evaluate efficacy and safety of XEMBIFY conducted in the European Union and Australia in patients with PI. Efficacy was based on annualized SBI rate during 12 months on XEMBIFY using a 1:1 dose adjustment factor with the patient’s previous subcutaneous or IV IgG replacement regimen and a minimum XEMBIFY dose of 100 mg/kg/week. If the XEMBIFY infusion was well tolerated during 2 infusions with an initial target rate of less than or equal to 25 mL/hour/site, the infusion rate could be increased in a stepwise manner at the investigator’s discretion up to a maximum of 60 mL/hr/site, and if well tolerated, subsequent infusions could begin at that rate; the investigator could also decrease the infusion rate at any time based on the patient’s tolerability. The definition of SBI was the same as for Study 1.
Study 2 enrolled 61 patients with PI, including 32 adults and 29 children aged 2 to ≤ 16 years. The majority (93%) were White, and16% were Hispanic or Latino. During the study, 6 patients discontinued (including 4 due to adverse events). XEMBIFY was administered with a median dose of 113 mg/kg/week ranging 67 to 212 mg/kg/week. The median treatment duration was 52 weeks.
There was one SBI in a 10 year old patient for an annualized SBI rate of 0.017 events per patient-year (upper 99% confidence limit: 0.036) during XEMBIFY treatment. There were a total of 14 patients who were administered XEMBIFY SC infusions at rates greater than 25 mL/hr/site. Seven patients (6 male; 1 female) received at least 3 consecutive XEMBIFY SC infusions at rates of ≥35 mL/hr/site (4 children [ages 10-15 years] and 3 adults) and maximum infusion rates ranged from 38 mL/hr/site to 80 mL/hr/site. One patient discontinued from the study early while at a sustained infusion rate of 50 mL/hr/site due to an adverse reaction of subcutaneous fibroma (mild) that was initially reported while the patient was receiving XEMBIFY at a rate of 15 mL/hr/site. One patient (maximum infusion rate 38 mL/hr/site) experienced an adverse reaction of infusion site necrosis (mild) that resulted in a decrease in XEMBIFY infusion rate to 25 mL/hr/site. All infusion site reactions at higher infusion rates were considered mild in severity.
Study 3
Study 3 was an open-label, multicenter, Phase 4 study conducted in the United States, which included two study arms. The treatment-experienced arm consisted of a single-sequence crossover of weekly-to-biweekly XEMBIFY dosing designed to evaluate the pharmacokinetic non-inferiority and safety of XEMBIFY administered every 2 weeks in treatment-experienced patients with PI. The treatment-naïve arm consisted of a loading regimen followed by weekly maintenance infusions of XEMBIFY to evaluate pharmacokinetics and safety for treatment-naïve patients initiating IgG replacement therapy for the first time.
Patients in the treatment-experienced arm received weekly XEMBIFY dosing initially and transitioned to biweekly dosing at Week 16 through Week 32. A dose adjustment factor of 1.37 was employed for patients entering this study on commercial IVIG. Patients in the treatment-naïve arm initiated IgG replacement therapy for the first time with XEMBIFY (5-day loading regimen 150 mg/kg/day followed by weekly 150 mg/kg/week); dose adjustment in the maintenance phase was allowed to achieve a target IgG trough of 700 mg/dL. Pharmacokinetic assessments were to assess XEMBIFY exposure for both treatment-experienced and treatment-naïve patients.
Thirty-three adults with PI were treated with XEMBIFY in Study 3, including 27 treatment-experienced patients and 6 treatment-naïve patients, all of whom were White and non-Hispanic/Latino. During the study 4 patients discontinued, including 3 treatment-experienced patients (2 for adverse events), and 1 treatment-naïve patient. Two treatment-experienced patients discontinued during the weekly phase and did not receive biweekly XEMBIFY.
For treatment-experienced patients during the weekly dosing period, the median XEMBIFY dose was 138 mg/kg/week ranging from 99 to 247 mg/kg/week, with a median treatment duration of 16 weeks. During the biweekly (every 2 weeks) dosing period, the median dose was 273 mg/kg/2 weeks ranging from 134 to 494 mg/kg/2 weeks, with a median treatment duration of 18 weeks.
For treatment-naïve patients the median XEMBIFY dose was 153 mg/kg per infusion ranging from 150 to 180 mg/kg per infusion with a median treatment duration of 32 weeks.
XEMBIFY exposure was similar between weekly and biweekly dosing in the treatment-experienced patients [see Clinical Pharmacology (12.3)].
Target IgG trough levels were achieved following the loading dose and maintenance dose regimen in treatment-naïve patients [see Clinical Pharmacology (12.3)].
XEMBIFY is supplied in 1, 2, 4, and 10 grams of protein in single use vials.
| Package NDC Number | Container NDC Number | Size | Grams of Protein |
| 13533-810-05 | 13533-810-06 | 5 mL | 1 |
| 13533-810-10 | 13533-810-11 | 10 mL | 2 |
| 13533-810-20 | 13533-810-21 | 20 mL | 4 |
| 13533-810-50 | 13533-810-51 | 50 mL | 10 |
Components used in the packaging are not made with natural rubber latex and contain no preservative.
Store XEMBIFY at 2–8°C (36–46°F).
Note: XEMBIFY may be stored at temperatures not to exceed 25°C (77°F) for up to 6
months any time prior to the expiration date. Following 25°C (77°F) storage, use the
product immediately or discard.
Do not freeze.
Do not use solutions that have been frozen.
Do not use after expiration date.
Discard unused portion.
Infuse XEMBIFY only after you have been trained by your healthcare provider. Below are step-by-step instructions to help you remember how to use XEMBIFY. Ask your healthcare provider about any instructions you do not understand.
Before Using XEMBIFY
Prior to use, allow the solution to come to room temperature (68-77°F or 20-25°C). This can take 60 minutes or longer.
Do not apply heat or place in the microwave.
Step 1: Assemble supplies
Gather the XEMBIFY vial(s), ancillary supplies, sharps container, patient’s treatment diary/logbook, and the infusion pump.
Step 2: Clean surface
Set up your infusion area on a clean, flat, non-porous surface, such as a kitchen counter.
Avoid using porous surfaces such as wood. Clean the surface with an alcohol wipe using a circular motion from the center outward.
Step 3: Wash hands
Wash and dry your hands thoroughly before using XEMBIFY.
Your healthcare provider may recommend that you use antibacterial soap or that you wear gloves.
Step 4: Check vials
The liquid in the vial should be clear to slightly opalescent, and colorless or pale yellow.
Do not use the vial if:
- the solution is cloudy or discolored. The solution should be clear to slightly opalescent, and colorless or pale yellow.
- the protective cap is missing, or there is any evidence of tampering. Tell your healthcare provider immediately.
- the expiration date has passed.
Step 5: Remove the protective cap
Remove the protective cap from the vial to expose the middle of the stopper.
Wipe the stopper with alcohol and allow to dry.
Step 6: Transfer XEMBIFY from vial(s) to syringe
Do not allow your fingers or other objects to touch the inner stem of the plunger, the syringe tip, or other areas that can touch the XEMBIFY solution. Make sure needles are capped until used and that needles and syringes stay on the clean area created in Step 2. This is called “aseptic technique” to prevent germs from getting into the XEMBIFY.
Using aseptic technique, attach each needle to the syringe tip.
Step 7: Prepare the syringe and draw XEMBIFY solution into syringe
Remove cap from needle.
Pull the syringe plunger back to the level matching the amount of XEMBIFY to be withdrawn from the vial.
Place the XEMBIFY vial on a clean flat surface and insert the needle into the center of the vial stopper.
Inject air into the vial. The amount of air should match the amount of XEMBIFY to be withdrawn.
Turn the vial upside down and withdraw the correct amount of XEMBIFY. If multiple vials are required to get the correct dose, repeat Steps 4-7.
Step 8: Fill the pump reservoir and prepare the infusion pump
Follow the pump manufacturer’s instructions for filling the pump reservoir and preparing the infusion pump, administration tubing and Y-site connection tubing, if needed.
Prime the administration tubing with XEMBIFY to take out any air left in the tubing or needle. To prime, hold the syringe in one hand and the administration tubing’s capped needle in the other. Gently squeeze on the plunger until you see a drop of XEMBIFY come out of the needle.
Step 9: Select the number and location of infusion sites
Select one or more infusion sites as directed by your healthcare provider. The number and location of injection sites depends on the volume of the total dose.
Avoid: bony areas, visible blood vessels, scars, and any areas of inflammation (irritation) or infection.
Rotate sites between future infusions.
Step 10: Prepare the infusion site
Wipe the infusion site(s) with a sterile alcohol wipe beginning at the center of each infusion site and moving outward in circular motion. Allow the infusion site(s) to dry (at least 30 seconds).
Before infusion, sites should be clean, dry, and at least 2 inches (5 cm) apart.
Step 11: Insert the needle
Grasp the skin between two fingers (pinch at least 1 inch (2.5 cm) of skin) and insert the needle at a 90-degree angle into the tissue underneath the skin or subcutaneous tissue.
Step 12: Make sure the needle is not in a blood vessel
After inserting each needle into tissue (and before your infusion), make sure that a blood vessel has not been accidentally entered. To do this, attach a sterile syringe to the end of the primed administration tubing. Pull back on the syringe plunger and watch for any blood flowing back into administration tubing.
If you see any blood, remove and discard the needle and administration tubing.
Repeat priming and needle insertion steps using a new needle, administration tubing and a new infusion site.
Secure the needle in place by applying sterile gauze or transparent dressing over the site.
Step 13: Repeat for other sites, as needed
Step 14: Infuse XEMBIFY
Infuse XEMBIFY as soon as possible after it is prepared.
Follow the pump manufacturer’s instructions for filling the tubing and using the infusion pump.
Step 15: After infusion
Follow manufacturer’s instructions to turn off pump.
Undo and discard any dressing or tape.
Gently remove the inserted needle(s) or catheter(s).
Discard any unused solution in an appropriate waste container as instructed.
Discard any used administration equipment in an appropriate waste container.
Store your supplies in a safe place.
Follow manufacturer’s instructions to care for the infusion pump.
Step 16: Record each infusion
Remove the peel-off label with the product lot number from the XEMBIFY vial and use this to complete the patient record. Include information about each infusion such as: the time, date, dose, lot number(s), infusion sites, and any reactions.
Remember to bring your journal with you when you visit your healthcare provider. Your healthcare provider may ask to see your treatment diary/logbook.
Tell your healthcare provider about any problems you have during your infusions. Call your healthcare provider for medical advice about side effects. You can also report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Manufactured by:
Grifols Therapeutics LLC
Research Triangle Park, NC 27709 USA
U.S. License No. 1871 Revised 7/2024
3067886
Mechanism of Action
XEMBIFY supplies a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against bacterial, viral, parasitic, and mycoplasmal agents and their toxins. XEMBIFY also contains a spectrum of antibodies capable of interacting with and altering the activity of cells of the immune system. The role of these antibodies and the mechanism of action of XEMBIFY are not fully understood.