Profilnine
Factor IX ComplexProfilnine
FULL PRESCRIBING INFORMATION: CONTENTS*
- PROFILNINE DESCRIPTION
- CLINICAL PHARMACOLOGY
- PROFILNINE INDICATIONS AND USAGE
- PROFILNINE CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- PROFILNINE ADVERSE REACTIONS
- PROFILNINE DOSAGE AND ADMINISTRATION
- ADMINISTRATION
- HOW SUPPLIED
- REFERENCES
FULL PRESCRIBING INFORMATION
Solvent Detergent Treated /Nanofiltered
DESCRIPTION
Factor IX Complex, Profilnine®, is a solvent detergent treated, nanofiltered, sterile, lyophilized concentrate of coagulation factors IX, II, and X and low levels of factor VII. The factor II content is not more than (NMT) 150 units* per 100 factor IX units, the factor X content is NMT 100 units per 100 factor IX units, and the factor VII content is NMT 35 units per 100 factor IX units. Profilnine is intended for intravenous administration only. Each vial is a single dose container and is labeled with the factor IX potency expressed in international units. Profilnine does not contain heparin and contains no preservatives. Profilnine contains few, if any, activated factors based on results from the non-activated partial thromboplastin time (NAPTT) test(1 , 2 ).
Profilnine is prepared from pooled human plasma and purified by diethylaminoethyl (DEAE) cellulose adsorption. The risk of transmission of infective agents by Profilnine has been substantially reduced by donor selection procedures and virus screening of individual donations and plasma pools by serological and nucleic acid testing. In addition, specific, effective virus elimination steps such as nanofiltration(3) and solvent/detergent (tri-n-butyl phosphate/TNBP) treatment(4) have been incorporated into the Profilnine manufacturing process. Additional removal of some viruses occurs during the DEAE cellulose product purification step.
The ability of the manufacturing process to eliminate virus from Profilnine was evaluated in the laboratory by intentionally adding virus to product just prior to the elimination step and monitoring virus removal. Table 1 shows the amounts of virus that can be removed by solvent detergent treatment, nanofiltration and purification by DEAE chromatography when vesicular stomatitis virus (VSV), human immunodeficiency virus-1 and 2 (HIV-1, HIV-2), parvo virus, West Nile virus (WNV), bovine viral diarrhea virus (BVDV), hepatitis A virus (HAV) and pseudorabies virus (PRV) were evaluated in these virus spiking studies. The results indicate that the solvent detergent treatment step effectively inactivates enveloped viruses and the nanofiltration step effectively removes both enveloped and non-enveloped viruses.
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* Unit refers to International Unit in the labeling of Profilnine.
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* Porcine, NT=Not tested, Env=enveloped |
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Virus |
Virus Type |
Model For: |
Virus Reduction (log 10 ) | ||
| Process Step | |||||
| 1st DEAE Chromatography | Solvent-Detergent | Nanofiltration | |||
| Sindbis | Env | Hepatitis C | 1.4 | ≥ 5.3 | NT |
| VSV | Env | Robust enveloped viruses | NT | ≥ 4.9 | NT |
| HIV-1 | Env | HIV-1 | NT | ≥ 12.2 | ≥ 6.2 |
| HIV-2 | Env | HIV-2 | NT | ≥ 6.0 | NT |
| WNV | Env | WNV | NT | NT | ≥ 6.6 |
| BVDV | Env | Hepatitis C | NT | NT | ≥ 4.9 |
| Parvo* | Non-Env | Parvovirus B19 | NT | NT | ≥ 6.1 |
| HAV | Non-Env | HAV | NT | NT | ≥ 5.8 |
| PRV | Non-Env | Hepatitis B | NT | NT | ≥ 5.3 |
CLINICAL PHARMACOLOGY
Profilnine is a mixture of the vitamin K-dependent clotting factors IX, II, X and low levels of VII. The administration of Profilnine temporarily increases the plasma levels of factor IX, thus enabling a temporary correction of the factor deficiency.
A clinical study that evaluated twelve subjects with hemophilia B indicated that, following administration of Profilnine, the factor IX in vivo half-life was 24.68 ± 8.29 hours and recovery was 1.15 ± 0.16 units/dL per unit infused per kg body weight(5).
Administration of factor IX complex can result in higher than normal levels of factor II due to its significantly longer half-life(6).
INDICATIONS AND USAGE
Profilnine is indicated for the prevention and control of bleeding in patients with factor IX deficiency (hemophilia B).
Profilnine contains non-therapeutic levels of factor VII, and is not indicated for use in the treatment of factor VII deficiency.
CONTRAINDICATIONS
None known.
WARNINGS
Because Profilnine is made from pooled human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. Stringent procedures designed to reduce the risk of adventitious agent transmission have been employed in the manufacture of this product, from the screening of plasma donors and the collection and testing of plasma to the application of viral elimination/reduction steps such as DEAE chromatography, solvent detergent treatment and nanofiltration in the manufacturing process (3, 4). Despite these measures, such products can potentially transmit disease: therefore the risk of infectious agents cannot be totally eliminated. The physician must weigh the risks and benefits of using this product and discuss these issues with the patient. Appropriate vaccination (hepatitis A and B) for patients in receipt of plasma derived factor IX complex concentrates is recommended.
The use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications and the use of such products may be potentially hazardous in patients undergoing surgery, in patients post surgery, in patients with known liver disease, and in patients with signs of fibrinolysis, thrombosis or disseminated intravascular coagulation (DIC)(6). For these patients, clinical surveillance for early signs of consumptive coagulopathy should be initiated with appropriate biological testing when administering this product. Profilnine should only be administered to patients when the beneficial effects of use outweigh the serious risk of potential hypercoagulation.
PRECAUTIONS
General
Exercise caution when handling Profilnine due to the limited risk of exposure to viral infection.
Discard any unused Profilnine vial contents. Discard administration equipment after single use. Do not resterilize components. Do not reuse components.
Information for Patients
After repeated treatment with Profilnine, patients should be monitored for the development of neutralizing antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing.
Hypersensitivity and allergic type hypersensitivity reactions, including anaphylaxis, have been reported for all factor IX complex concentrate products. Patients must be informed of the early symptoms and signs of hypersensitivity reaction, including hives, generalized urticaria, angioedema, chest tightness, dyspnea, wheezing, faintness, hypotension, tachycardia and anaphylaxis. Patients must be advised to discontinue use of the product and contact their physician and/or seek immediate emergency care if these symptoms occur.
Pregnancy Category C
Animal reproduction studies have not been conducted with Profilnine. It is also not known whether Profilnine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Profilnine should be given to a pregnant woman only if clearly indicated.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 16 have not been established. However, across a well controlled half-life and recovery clinical trial in patients previously treated with factor IX concentrates for Hemophilia B, the two pediatric patients receiving Profilnine responded similarly when compared with the adult patients.
ADVERSE REACTIONS
As with other intravenous administration of other plasma-derived products, the following reactions may be observed following administration: headache, fever, chills, flushing, nausea, vomiting, tingling lethargy, hives, or manifestation of allergic reactions.
In addition, during post-approval use of Profilnine, cases of allergic/hypersensitivity reactions (including urticaria, shortness of breath, hypotension, and pruritus) and adverse reactions characterized by either thrombosis or disseminated intravascular coagulation (DIC) have been reported. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
To report SUSPECTED ADVERSE REACTIONS, contact Grifols at 1-888-GRIFOLS (1-888-474-3657) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DOSAGE AND ADMINISTRATION
DOSE
For adult usage:
Each vial of Profilnine is labeled with total units expressed as international units (IU) according to the WHO International Standard. One unit approximates the activity in one mL of normal plasma.
A 1% increase in factor IX (0.01 units)/units administered/kg can be expected(1,5). The amount of Profilnine required to establish hemostasis will vary with each patient and depends on the circumstances. The following formula may be used as a guide in determining the number of units to be administered:
In normal clinical practice there is variability among patients and their clinical condition. Therefore, the factor IX level of each patient should be monitored frequently during replacement therapy.
| Type of Hemorrhage or Surgical Procedure | Treatment Guidelines | |
| Mild to moderate Hemorrhages | Mild to moderate hemorrhage usually can be effectively treated with a single dose of product sufficient to raise plasma factor IX levels to 20 to 30 percent of normal. Daily infusions are generally required. |
|
| Major Hemorrhages | For more severe hemorrhage, plasma factor IX levels should be raised to 30 to 50 percent of normal. Daily infusions are generally required. |
|
| Surgery | Surgery associated with bleeding in factor IX deficient patients requires factor IX levels of 30 to 50 percent for at least one week postoperatively. For dental extractions, the factor IX level should be raised to 50 percent immediately prior to procedure; additional factor IX complex may be given if bleeding recurs. |
For pediatric usage: See PRECAUTIONS
RECONSTITUTION
Use Aseptic Technique
- Ensure that concentrate (Profilnine) and diluent (Sterile Water for Injection, USP) are at room temperature (but not above 37° C) before reconstitution.
- Remove the plastic flip off cap from the diluent vial.
- Gently swab the exposed stopper surface with a cleansing agent such as alcohol trying to avoid leaving any excess cleansing agent on the stopper.
- Open the Mix2Vial® package by peeling away the lid (Figure 1). Leave the Mix2Vial in the clear outer packaging.
- Place the diluent vial upright on an even surface and hold the vial tight and pick up the Mix2Vial in its clear outer packaging. Holding the diluent vial securely, push the blue end of the Mix2Vial vertically down through the diluent vial stopper (Figure 2).
- While holding onto the diluent vial, carefully remove the clear outer packaging from the Mix2Vial set, ensuring the Mix2Vial remains attached to the diluent vial (Figure 3).
- Place the product vial upright on an even surface, invert the diluent vial with the Mix2Vial attached.
- While holding the product vial securely on a flat surface, push the clear end of the Mix2Vial set vertically down through the product vial stopper (Figure 4). The diluent will automatically transfer out of its vial into the product vial. (NOTE: If the Mix2Vial is connected at an angle, the vacuum may be released from the product vial and the diluent will not transfer into the product vial.)
- With the diluent and product vials still attached to the Mix2Vial, gently swirl the product vial to ensure the product is fully dissolved (Figure 5). Reconstitution requires less than 10 minutes. Do not shake the vial.
- Disconnect the Mix2Vial into two separate pieces (Figure 6) by holding each vial adapter and twisting counterclockwise. After separating, discard the diluent vial with the blue end of the Mix2Vial.
- Draw air into an empty, sterile syringe. Keeping the product vial upright with the clear end of the Mix2Vial attached, screw the disposable syringe onto the luer lock portion of the Mix2Vial device by pressing and twisting clockwise. Inject air into the product vial.
- While keeping the syringe plunger depressed, invert the system upside down and draw the reconstituted product into the syringe by pulling the plunger back slowly (Figure 7).
- When the reconstituted product has been transferred into the syringe, firmly hold the barrel of the syringe and the clear vial adapter (keeping the syringe plunger facing down) and unscrew the syringe from the Mix2Vial (Figure 8). Hold the syringe upright and push the plunger until no air is left in the syringe. Attach the syringe to a venipuncture set. [NOTE: If the same patient is to receive more than one vial of concentrate, the contents of two vials may be drawn into the same syringe through a separate unused Mix2Vial set before attaching to the venipuncture set.]
- Use the prepared drug as soon as possible within three hours after reconstitution.
- After reconstitution, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstitution procedure is strictly followed, a few small particles may occasionally remain. The Mix2Vial set will remove particles and the labeled potency will not be reduced.
- Discard all administration equipment after use into the appropriate safety container. Do not reuse.
ADMINISTRATION
Intravenous administration of Profilnine should be initiated promptly following reconstitution with the supplied diluent. Although Profilnine is stable for at least three hours at room temperature after reconstitution, prompt administration is recommended to avoid ill effects of any inadvertent bacterial contamination occurring during reconstitution. Profilnine may be administered by injection (plastic disposable syringe only) or infusion. Administer at room temperature, do not refrigerate after reconstitution and discard any unused contents. Do not administer Profilnine at a rate exceeding 10 mL/minute. Rapid administration may result in vasomotor reactions.
HOW SUPPLIED
Profilnine is supplied in sterile lyophilized form in single dose vials accompanied by a suitable volume of diluent (Sterile Water for Injection, USP), according to factor IX potency. Each vial is labeled with the factor IX potency expressed in International Units which is referenced to the WHO International Standard. Profilnine is packaged with a Mix2Vial filter transfer set for use in administration.
It is available in the following potencies, and the product is also color coded based upon assay on the carton and vial label as follows:
| Potency | Carton NDC | Assay Color Code |
| 500 units FIX/5 mL | 68516-3201-1 | 500 units FIX Range - blue |
| 1000 units FIX/10 mL | 68516-3202-2 | 1000 units FIX Range - red |
| 1500 units FIX/10 mL | 68516-3203-2 | 1500 units FIX Range - black |
STORAGE
Profilnine is stable for three years, up to the expiration date printed on its label, provided that the storage temperature does not exceed 25 °C (77 °F). Do not freeze.
Rx only
REFERENCES
- Menache, D., Roberts, H.R. Summary report and recommendations of the task force members and consultants. Thromb Diath Haemorrh 33:645-647, 1975.
- Kingdon, H.S., Lundblad, R.L., Veltkamp, J.J., Aronson, D.L. Potentially thrombogenic materials in Factor IX Concentrates. Thromb Diath Haemorrh 33:617- 631, 1975.
- Burnouf T, Radosevich M. Nanofiltration of plasma-derived biopharmaceutical products. Haemophilia : the official journal of the World Federation of Hemophilia. 2003;9:24-37.
- Dichtelmüller HO, Biesert L, Fabbrizzi F, Gajardo R, Gröner A, von Hoegen I, Jorquera JI, Kempf C, Kreil TR, Pifat D, Osheroff W, Poelsler G. Robustness of solvent/detergent treatment of plasma derivatives: a data collection from Plasma Protein Therapeutics Association member companies. Transfusion 49:1931-1943, 2009.
- Data on file at Grifols Biologicals Inc.
- Sorensen, B., Spahn, D.R., Innerhofer, P., Spannagl, M., Rossaint, R. Clinical review: prothrombin complex concentrates-evaluation of safety and thrombogenicity. Critical Care 15: 201-209, 2011.
Manufactured by:
Grifols Biologicals Inc.
5555 Valley Boulevard
Los Angeles, CA 90032, U.S.A.
U.S. License No. 1694
DATE OF REVISION: November 2013
3039440
Principal Display Panel – 5 mL Vial Label
GRIFOLS
NDC 68516-3204-1
Factor IX Complex
Profilnine®
500 IU FIX Range
Solvent Detergent Treated/Nanofiltered
5 mL
Storage: Store at temperature not exceeding 25° C (77° F).
Rx Only. Single dose container for intravenous
administration only.
Grifols Biologicals Inc.
5555 Valley Boulevard, Los Angeles, CA 90032, U.S.A.
U.S. License No. 1694
Principal Display Panel – 5 mL Carton Label
GRIFOLS
NDC 68516-3201-1
Factor IX Complex
Profilnine®
Solvent Detergent Treated/Nanofiltered
5 mL
500 IU FIX Range
For Intravenous Administration
Principal Display Panel – 10 mL Vial Label
GRIFOLS
NDC 68516-3205-2
Factor IX Complex
Profilnine®
1000 IU FIX Range
Solvent Detergent Treated/Nanofiltered
10 mL
Storage: Store at temperature not exceeding 25° C (77° F).
Rx Only. Single dose container for intravenous
administration only.
Grifols Biologicals Inc.
5555 Valley Boulevard, Los Angeles, CA 90032, U.S.A.
U.S. License No. 1694
Principal Display Panel – 10 mL Carton Label
GRIFOLS
NDC 68516-3202-2
Factor IX Complex
Profilnine®
Solvent Detergent Treated/Nanofiltered
10 mL
1000 IU FIX Range
For Intravenous Administration
Principal Display Panel – 10 mL Vial Label
GRIFOLS
NDC 68516-3206-2
Factor IX Complex
Profilnine®
1500 IU FIX Range
Solvent Detergent Treated/Nanofiltered
10 mL
Storage: Store at temperature not exceeding 25° C (77° F).
Rx Only. Single dose container for intravenous
administration only.
Grifols Biologicals Inc.
5555 Valley Boulevard, Los Angeles, CA 90032, U.S.A.
U.S. License No. 1694
Principal Display Panel – 10 mL Carton Label
GRIFOLS
NDC 68516-3203-2
Factor IX Complex
Profilnine®
Solvent Detergent Treated/Nanofiltered
10 mL
1500 IU FIX Range
For Intravenous Administration
Principal Display Panel – 5 mL Vial Label
NDC 63323-185-05 18505
STERILE
WATER
FOR INJECTION, USP
FOR DRUG DILUENT USE ONLY
Rx only
5 mL Single Dose Vial
Principal Display Panel – 10 mL Vial Label
NDC 63323-185-10 918510
STERILE WATER
FOR INJECTION, USP
FOR DRUG DILUENT USE ONLY
Rx only
10 mL Single Dose Vial
Profilninefactor ix complex KIT
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