İHALE DÜNYASI
İHALE DÜNYASI
Berinert is a human plasma-derived, purified, pasteurized, lyophilized concentrate of C1 esterase inhibitor to be reconstituted for intravenous administration. Berinert is prepared from large pools of human plasma from US donors. One standard unit of C1 esterase inhibitor concentrate is equal to the amount of C1 esterase inhibitor in 1 mL of fresh citrated human plasma, which is equivalent to 270 mg/L or 2.5 µM/L. No international laboratory standard for quantifying C1 esterase inhibitor. An in-house standard is used to assure lot-to-lot consistency in product potency. C1 esterase inhibitor is a soluble, single-chain glycoprotein containing 478 amino acid residues organized into three beta-sheets and eight or nine alpha-helices. 3 The heavily glycosylated molecule has an apparent molecular weight of 105 kD, of which the carbohydrate chains comprise 26% to 35%. 4 Each vial of Berinert contains 500 units C1 esterase inhibitor, 50 to 80 mg total protein, 85 to 115 mg glycine, 70 to 100 mg sodium chloride, and 25 to 35 mg sodium citrate. All plasma used in the manufacture of Berinert is obtained from US donors and is tested using serological assays for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV. Additionally, the plasma is tested with Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be non-reactive (negative). In addition, the plasma is tested by NAT for HAV and Human Parvovirus B19. Only plasma that has passed virus screening is used for production, and the limit for Parvovirus B19 in the fractionation pool is set not to exceed 10 4 IU of Parvovirus B19 DNA per mL. The manufacturing process for Berinert includes multiple steps that reduce the risk of virus transmission. The virus inactivation/reduction capacity of three steps (pasteurization in aqueous solution at 60°C for 10 hours, hydrophobic interaction chromatography, and the combination of ion exchange chromatographies and ammonium sulphate precipitation) was evaluated in a series of in vitro spiking experiments. The total mean cumulative virus inactivation/reduction is shown in Table 5. Table 5: Mean Virus Inactivation/Reductions in Berinert Virus Studied Pasteurization [log 10 ] Hydrophobic Interaction Chromatography [log 10 ] DEAE-Sephadex A50 Chromatography QAE-Sephadex Chromatography and Ammonium Sulphate Precipitation [log10] Total Cumulative [log 10 ] HIV-1, Human immunodeficiency virus type 1, a model for HIV-1 and HIV-2 BVDV, Bovine viral diarrhea virus, a model for HCV PRV, Pseudorabies virus, a model for large enveloped DNA viruses (eg, herpes virus) WNV, West Nile virus HAV, Hepatitis A virus CPV, Canine parvovirus B19V, Human Parvovirus B19 ND, Not determined NA, Not applicable Enveloped Viruses HIV-1 ?6.6 ?4.5 4.3 ?15.4 BVDV ?9.2 ?4.6 NA ?13.8 PRV 6.3 ?6.5 ?7.7 ?20.5 WNV ?7.0 ND NA NA Non-Enveloped Viruses HAV ?6.4 4.5 NA ?10.9 CPV 1.4 6.1 NA 7.5 B19V 3.9 ND NA NA
Berinert is a plasma-derived concentrate of C1 Esterase Inhibitor (Human) indicated for the treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) in adult and adolescent patients. The safety and efficacy of Berinert for prophylactic therapy have not been established. Berinert is a plasma-derived C1 Esterase Inhibitor (Human) indicated for the treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) in adult and adolescent patients ( 1 ). The safety and efficacy of Berinert for prophylactic therapy have not been established ( 1 ).
For Intravenous Use Only. Administer Berinert at a dose of 20 units per kg body weight by intravenous injection. Berinert is provided as a freeze-dried powder for reconstitution with the diluent (sterile water) provided. Store the vial in the original carton in order to protect from light. Do not freeze. For intravenous use only. Store the vial in the original carton in order to protect from light. Store at 2-25°C (36-77°F). Do not freeze ( 2 ). Administer 20 units per kg body weight ( 2 ). Reconstitute Berinert prior to use using the diluent (sterile water) provided ( 2.1 ). Administer at room temperature within 8 hours of reconstitution ( 2.1 ). Inject at a rate of approximately 4 mL per minute ( 2.2 ). Do not mix Berinert with other medicinal products or solutions ( 2.2 ). 2.1 Preparation and Handling Check the expiration date on the product vial label. Do not use beyond the expiration date. Use aseptic technique when preparing and administering Berinert (see Reconstitution and Administration [2.2] ). After reconstitution and prior to administration, inspect Berinert visually for particulate matter and discoloration. The reconstituted solution should be colorless, clear, and free from visible particles. Do not use if the solution is cloudy, discolored, or contains particulates. The Berinert vial is for single use only. Berinert contains no preservative. Any product that has been reconstituted should be used promptly. The reconstituted solution must be used within 8 hours. Discard partially used vials. Do not freeze the reconstituted solution. 2.2 Reconstitution and Administration Each Berinert kit consists of one carton containing one single-use vial of Berinert, one 10 mL vial of diluent (sterile water), one Mix2Vial TM transfer set, and one alcohol swab. Use either the Mix2Vial transfer set provided with Berinert ( see How Supplied [16.1] ) or a commercially available double-ended needle and vented filter spike. Reconstitution The procedures below are provided as general guidelines for the reconstitution and administration of Berinert. 1. Ensure that the Berinert vial and diluent vial are at room temperature. Use aseptic technique during the reconstitution procedure. 2. Place the Berinert vial, diluent vial and Mix2Vial transfer set on a flat surface. 3. Remove the flip caps from the Berinert and diluent vials. Treat the vial stoppers with the alcohol swab provided and allow to dry prior to opening the Mix2Vial transfer set package. 4. Open the Mix2Vial transfer set package by peeling away the lid (Fig. 1). Leave the Mix2Vial transfer set in the clear package. Fig. 1 5. Place the diluent vial on a flat surface and hold the vial tightly. Grip the Mix2Vial transfer set together with the clear package and snap the blue end of the Mix2Vial transfer set onto the diluent vial stopper at a 90° angle (Fig. 2). Fig. 2 6. Carefully remove the clear package from the Mix2Vial transfer set. Make sure that you pull up only the clear package, and not the Mix2Vial transfer set (Fig. 3). Fig. 3 7. With the Berinert vial placed firmly on a flat surface, invert the diluent vial with the Mix2Vial transfer set attached and snap the transparent adapter onto the Berinert vial stopper at a 90° angle (Fig. 4). The diluent will automatically transfer into the Berinert vial. Fig. 4 8. With the diluent and Berinert vial still attached to the Mix2Vial transfer set, gently swirl the Berinert vial to ensure that the Berinert is fully dissolved (Fig. 5). Do not shake the vial. Fig. 5 9. With one hand, grasp the Berinert-side of the Mix2Vial transfer set and with the other hand grasp the blue diluent-side of the Mix2Vial transfer set and unscrew the set into two pieces. (Fig. 6). Fig. 6 10. Draw air into an empty, sterile syringe. While the Berinert vial is upright, screw the syringe to the Mix2Vial transfer set. Inject air into the Berinert vial. While keeping the syringe plunger pressed, invert the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly. (Fig. 7). Fig. 7 11. Now that the concentrate has been transferred into the syringe, firmly grasp the barrel of the syringe (keeping the plunger facing down) and unscrew the syringe from the Mix2Vial transfer set (Fig. 8). Attach the syringe to a suitable intravenous (IV) administration set. Fig. 8 12. If the same patient is to receive more than one vial, the contents of multiple vials may be pooled in a single administration device (eg, syringe). A new unused Mix2Vial transfer set should be used for each Berinert vial. 13. Do not refrigerate after reconstitution. When reconstitution is carried out using aseptic technique, administration may begin within 8 hours, provided the solution has been stored at up to 25°C (77°F). Do not refrigerate or freeze the reconstituted solution. Figure Figure Figure Figure Figure Figure Figure Figure Administration Do not mix Berinert with other medicinal products and administer by a separate infusion line. Use aseptic technique when administering Berinert. Administer Berinert by slow intravenous injection at a rate of approximately 4 mL per minute.
Berinert is contraindicated in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations. Do not use in patients with a history of life-threatening immediate hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations ( 4 ).
The most serious adverse reaction reported in subjects enrolled in clinical studies who received Berinert was an increase in the severity of pain associated with HAE. The most common adverse reactions that have been reported in greater than 4% of the subjects who received Berinert in clinical studies were subsequent HAE attack, headache, abdominal pain, nausea, muscle spasm, pain, diarrhea and vomiting. The most serious adverse reaction reported in subjects who received Berinert was an increase in the severity of pain associated with HAE ( 6.1 ). The most common adverse reactions observed by ?4% of subjects after Berinert treatment were subsequent HAE attack, headache, abdominal pain, nausea, muscle spasm, pain, diarrhea and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies 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 practice. Placebo-controlled Clinical Study In the placebo-controlled clinical study, referred to as the randomized clinical trial (RCT) ( see Clinical Studies [14] ), 124 subjects experiencing an acute moderate to severe abdominal or facial HAE attack were treated with Berinert (either a 10 unit per kg body weight or a 20 unit per kg body weight dose), or placebo (physiological saline solution). The treatment-emergent serious adverse reactions/events that occurred in 5 subjects in the RCT were laryngeal edema, facial attack with laryngeal edema, swelling (shoulder and chest), exacerbation of hereditary angioedema, and laryngospasm. Table 1: Adverse Reactions The study protocol specified that adverse events that began within 72 hours of blinded study medication administration were to be classified as at least possibly related to study medication (ie, adverse reactions). Occurring up to 4 hours After Initial Infusion in More Than 4% of Subjects, Irrespective of Causality The following abdominal symptoms were identified in the protocol as associated with HAE abdominal attacks: abdominal pain, bloating, cramps, nausea, vomiting, and diarrhea. Adverse Reactions Number (%) of Subjects Reporting Adverse Reactions Berinert 20 units/kg (n = 43) Number (%) of Subjects Reporting Adverse Reactions Placebo Group (n = 42) Nausea 3 (7%) 5 (11.9%) Dysgeusia 2 (4.7%) 0 (0) Abdominal Pain 2 (4.7%) 3 (7.1%) Vomiting 1 (2.3%) 3 (7.1%) Diarrhea 0 (0) 4 (9.5%) Headache 0 (0) 2 (4.8%) Table 2: Adverse Reactions The study protocol specified that adverse events that began within 72 hours of blinded study medication administration were to be classified as at least possibly related to study medication (ie, adverse reactions). Occurring in More Than 4% of Subjects up to 72 hours After Infusion of Initial or Rescue Medication If a subject experienced no relief or insufficient relief of symptoms within 4 hours after infusion, investigators had the option to administer a blinded second infusion ("rescue" treatment) of Berinert (20 units/kg for the placebo group or 10 units/kg for the 10 units/kg group), or placebo (for the 20 units/kg group). by Intent-to-Treat, Irrespective of Causality Adverse Reactions Number (%) of Subjects Reporting Adverse Reactions Adverse reactions following either initial treatment and/or blinded "rescue" treatment. Because more subjects in the placebo randomization group than in the Berinert randomization group received rescue treatment, the median observation period in this analysis for subjects randomized to placebo was slightly longer than for subjects randomized to receive Berinert. Berinert 20 units/kg (n = 43) Number (%) of Subjects Reporting Adverse Reactions Placebo Group (n = 42) Nausea 3 (7%) 11 (26.2%) Headache 3 (7%) 5 (11.9%) Abdominal Pain 3 (7%) 5 (11.9%) Dysgeusia 2 (4.7%) 1 (2.4%) Vomiting 1 (2.3%) 7 (16.7%) Pain 1 (2.3%) 4 (9.5%) Muscle spasms 1 (2.3%) 4 (9.5%) Diarrhea 0 (0) 8 (19%) Back pain 0 (0) 2 (4.8%) Facial pain 0 (0) 2 (4.8%) Table 3 lists the adverse events that occurred in more than 4% of the subjects 7 to 9 days after the end of a Berinert infusion, irrespective of causality. Table 3: Adverse Events Occurring in More Than 4% of Subjects Includes subjects in the placebo group who received Berinert 20 units/kg as rescue study medication. Receiving Berinert at Either 10 Units/kg or 20 units/kg 7 to 9 Days after Infusion, Irrespective of Causality Adverse Events Number (%) of Subjects Reporting Adverse Events (n=108) Hereditary angioedema 12 (11.1%) Headache 12 (11.1%) Abdominal pain These symptoms were identified in the protocol as related to the underlying disease. Any increase in intensity or new occurrence of these symptoms after study medication administration was considered to be an adverse event. 7 (6.5%) Nausea 7 (6.5%) Muscle spasms 6 (5.6%) Pain 6 (5.6%) Diarrhea 5 (4.6%) Vomiting 5 (4.6%) Subjects were tested at baseline and after 3 months for possible exposure to Parvovirus B19, hepatitis B, hepatitis C, and HIV-1 and HIV-2. No subject who underwent testing evidenced seroconversion or treatment-emergent positive polymerase chain reaction testing for these pathogens. Extension Study In an interim safety analysis, of the ongoing open-label extension study, 56 subjects with 559 acute moderate to severe abdominal, facial, peripheral, and/or laryngeal attacks received a 20 unit/kg body weight dose of Berinert ( see Clinical Studies [14] ). This study provides additional safety data in subjects who received multiple infusions of the product for sequential HAE attacks (one infusion per attack). Table 4 lists the adverse events that occurred in this interim safety analysis of the ongoing open-label extension study in more than 4% of subjects up to 72 hours or 9 days after the end of a Berinert infusion, irrespective of causality. Table 4: Incidence of Adverse Events by Descending Frequency Occurring in More Than 4% of Subjects Receiving Berinert up to 72 Hours or 9 Days After Infusion, Irrespective of Causality Adverse Events Number (%) of Subjects Reporting Adverse Events up to 72 hours (n=56) Number (%) of Subjects Reporting Adverse Events up to 9 Days (n=56) Headache 3 (5.4%) 4 (7.1%) Abdominal pain 3 (5.4%) 3 (5.4%) Hereditary angioedema 2 (3.6%) 4 (7.1%) Nasopharyngitis 2 (3.6%) 3 (5.4%) 6.2 Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. Adverse reactions reported in Europe since 1979 in patients receiving Berinert for treatment of HAE include hypersensitivity/anaphylactic reactions, a few suspected cases of viral transmission, including cases of acute hepatitis C, injection-site pain, injection-site redness, chills, and fever. The following adverse reactions, identified by system organ class, have been attributed to Berinert during post-approval use outside the US. Immune System Disorder: Hypersensitivity/anaphylactic reactions, and shock General/Body as a Whole: Pain on injection, redness at injection site, chills, and fever
Hypersensitivity reactions may occur. Epinephrine should be immediately available to treat any acute severe hypersensitivity reactions following discontinuation of administration ( 5.1 ). Thrombotic events have occurred in patients receiving off-label high doses of Berinert. Monitor patients with known risk factors for thrombotic events ( 5.2 ). Berinert is made from human plasma and may contain infectious agents, eg, viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent ( 5.3 ). 5.1 Hypersensitivity Severe hypersensitivity reactions may occur. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction (see Patient Counseling Information [17] ). The signs and symptoms of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and/or anaphylaxis during or after injection of Berinert. Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment methods should be carefully considered. In case of suspected hypersensitivity, immediately discontinue administration of Berinert and institute appropriate treatment. 5.2 Thrombotic Events Thrombotic events have been reported in association with Berinert when used off-label and at higher than labeled doses. 1 Animal studies have confirmed the risk of thrombosis from intravenous administration of C1 esterase inhibitor products 2 ( see Overdosage [10] and Animal Toxicology and/or Pharmacology [13.2] ). 5.3 Transmission of Infectious Agents Because Berinert is made from human blood, it may contain infectious agents (eg, viruses and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent) that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by processes demonstrated to inactivate and/or remove certain viruses during manufacturing ( see Description [11] and Patient Counseling Information [17] ). Despite these measures, such products may still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Since 1979, a few suspected cases of viral transmission have been reported with the use of Berinert outside the US, including cases of acute hepatitis C. From the incomplete information available from these cases, it was not possible to determine with certainty if the infections were or were not related to prior administration of Berinert. The physician should discuss the risks and benefits of this product with the patient before prescribing or administering it to the patient. (See Patient Counseling Information [17.1] ). All infections thought by a physician possibly to have been transmitted by Berinert should be reported by lot number, by the physician, or other healthcare provider to the CSL Behring Pharmacovigilance Department at 1-866-915-6958.
No drug interaction studies have been conducted. No drug interaction studies have been conducted ( 7 ).