NDC 44206-300 Rhophylac

Human Rho(d) Immune Globulin

NDC Product Code 44206-300

NDC 44206-300-01

Package Description: 1 SYRINGE, GLASS in 1 CARTON > 2 mL in 1 SYRINGE, GLASS (44206-300-90)

NDC 44206-300-10

Package Description: 10 SYRINGE, GLASS in 1 CARTON > 2 mL in 1 SYRINGE, GLASS (44206-300-90)

NDC Product Information

Rhophylac with NDC 44206-300 is a a plasma derivative product labeled by Csl Behring Ag. The generic name of Rhophylac is human rho(d) immune globulin. The product's dosage form is solution and is administered via intramuscular; intravenous form.

Labeler Name: Csl Behring Ag

Dosage Form: Solution - A clear, homogeneous liquid1 dosage form that contains one or more chemical substances dissolved in a solvent or mixture of mutually miscible solvents.

Product Type: Plasma Derivative What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Rhophylac Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • HUMAN RHO(D) IMMUNE GLOBULIN 1500 [iU]/2mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ALBUMIN HUMAN (UNII: ZIF514RVZR)
  • HUMAN IMMUNOGLOBULIN A (UNII: 741C1PWQ88)
  • GLYCINE (UNII: TE7660XO1C)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intramuscular - Administration within a muscle.
  • Intravenous - Administration within or into a vein or veins.
  • Intramuscular - Administration within a muscle.
  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Human Immunoglobulin G - [EPC] (Established Pharmacologic Class)
  • Passively Acquired Immunity - [PE] (Physiologic Effect)
  • Endogenous Antigen Neutralization - [MoA] (Mechanism of Action)
  • Immunoglobulins - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Csl Behring Ag
Labeler Code: 44206
FDA Application Number: BLA125070 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-06-2009 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Rhophylac Product Label Images

Rhophylac Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Other

RHOPHYLAC®Rh0(D) Immune Globulin Intravenous (Human)

  • Both IndicationsInform patients to immediately report the following signs and symptoms to their physician: hives, chest tightness, wheezing, hypotension, and anaphylaxis [see Warnings and Precautions (5.1.1)].Inform patients that Rhophylac is made from human blood and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Explain that the risk Rhophylac may transmit an infectious agent has been reduced by screening all plasma donors, by testing the donated plasma for certain viruses, and by inactivating and/or removing certain viruses during manufacturing. Advise patients to report any symptoms that concern them and that may be related to viral infections [see Warnings and Precautions (5.1.3)].Inform patients that Rhophylac may interfere with the response to live virus vaccines (e.g., measles, mumps, rubella, and varicella), and instruct them to notify their healthcare professional of this potential interaction when they are receiving vaccinations.

  • Suppression of Rh IsoimmunizationInform patients receiving the antepartum dose of Rhophylac for suppression of Rh isoimmunization that they will need a second dose within 72 hours of birth if the baby's blood type is Rh-positive.

  • ITPInstruct patients being treated with Rhophylac for ITP to immediately report symptoms of intravascular hemolysis, including back pain, shaking chills, fever, discolored urine, decreased urine output, sudden weight gain, edema, and/or shortness of breath [see Warnings and Precautions (5.2.1)].

1 Indications And Usage

Rhophylac is an Rh0(D) Immune Globulin Intravenous (Human) (anti-D) product that is indicated for the suppression of Rh isoimmunization in non-sensitized Rh0(D)-negative patients and for the treatment of immune thrombocytopenic purpura (ITP) in Rh0(D)-positive patients.

1.2 Itp

Rhophylac is indicated in Rh0(D)-positive, non-splenectomized adult patients with chronic ITP to raise platelet counts.

2 Dosage And Administration

As with all blood products, patients should be observed for at least 20 minutes following administration of Rhophylac.

2.1 Preparation And Handling

  • Rhophylac is a clear or slightly opalescent, colorless to pale yellow solution. Inspect Rhophylac visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates. Prior to intravenous use, ensure that the needle-free intravenous administration system is compatible with the tip of the Rhophylac glass syringe. Do not freeze. Bring Rhophylac to room temperature before use. Rhophylac is for single use only. Dispose of any unused product or waste material in accordance with local requirements.

2.2 Suppression Of Rh Isoimmunization

  • Rhophylac should be administered by intravenous or intramuscular injection. If large doses (greater than 5 mL) are required and intramuscular injection is chosen, it is advisable to administer Rhophylac in divided doses at different sites.
  • Ensure the site of administration will allow the injection to reach the muscle if Rhophylac is administered intramuscularly. Consider intravenous administration if reaching the muscle is of concern [see Adverse Reactions (6.2)]. Do not administer Rhophylac subcutaneously into the fatty tissue.
  • Table 1 provides dosing guidelines based on the condition being treated.Table 1. Dosing Guidelines for Suppression of Rh IsoimmunizationIndicationTiming of AdministrationDoseA 1500 IU (300 mcg) dose of Rhophylac will suppress the immunizing potential of ≤15 mL of Rh0(D)-positive RBCs.1 (Administer by Intravenous or Intramuscular Injection)IU, international units; mcg, micrograms.Rh-incompatible pregnancy Routine antepartum prophylaxisAt Week 28-30 of gestation1500 IU (300 mcg) Postpartum prophylaxis(required only if the newborn is Rh0(D)-positive)Within 72 hours of birth1500 IU (300 mcg)The dose of Rhophylac must be increased if the patient is exposed to >15 mL of Rh0(D)-positive RBCs; in this case, follow the dosing guidelines for excessive fetomaternal hemorrhage. Obstetric complications(e.g., miscarriage, abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from antepartum hemorrhage) Within 72 hours of complication1500 IU (300 mcg) Invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy) or obstetric manipulative procedures (e.g., external version, abdominal trauma)Within 72 hours of procedure1500 IU (300 mcg) Excessive fetomaternal hemorrhage(>15 mL)Within 72 hours of complication1500 IU (300 mcg) plus:100 IU (20 mcg) per mL fetal RBCs in excess of 15 mL if excess transplacental bleeding is quantifiedorAn additional 1500 IU (300 mcg) dose if excess transplacental bleeding cannot be quantifiedIncompatible transfusionsWithin 72 hours of exposure100 IU (20 mcg) per 2 mL transfused blood or per 1 mL erythrocyte concentrate

2.3 Itp

For treatment of ITP, ADMINISTER RHOPHYLAC BY THE INTRAVENOUS ROUTE ONLY [see Dosage and Administration (2.1)]. Do not administer intramuscularly.A 250 IU (50 mcg) per kg body weight dose of Rhophylac is recommended for patients with ITP. The following formula can be used to calculate the recommended amount of Rhophylac to administer:Dose (IU) × body weight (kg) = Total IU / 1500 IU per syringe = Number of syringesRhophylac should be administered at a rate of 2 mL per 15 to 60 seconds.

3 Dosage Forms And Strengths

1500 IU (300 mcg) per 2 mL prefilled, ready-to-use, glass syringe for IV or IM use

4 Contraindications

  • Rhophylac is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.Rhophylac is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity to Rhophylac or any of its components.Do not administer Rhophylac to the newborn infant of a mother that received Rhophylac postpartum.

6 Adverse Reactions

The most serious adverse reactions in patients receiving Rh0(D) Immune Globulin Intravenous (Human) have been observed in the treatment of ITP and include intravascular hemolysis, clinically compromising anemia, acute renal insufficiency, and, very rarely, DIC and death [see Boxed Warning, and Warnings and Precautions (5.2.1)].2The most common adverse reactions observed in the use of Rhophylac for suppression of Rh isoimmunization (≥0.5% of subjects) are nausea, dizziness, headache, injection-site pain, and malaise.The most common adverse reactions observed in the treatment of ITP (>14% of subjects) are chills, pyrexia/increased body temperature, and headache. Hemolysis (manifested by an increase in bilirubin, a decrease in hemoglobin, or a decrease in haptoglobin) was also observed.

6.1 Clinical Studies Experience

Because clinical studies are conducted under different protocols and widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

Because postmarketing adverse 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 product exposure. The following adverse reactions have been identified during post-approval use of Rhophylac:

7.1 Live Virus Vaccines

Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as measles, mumps, rubella, and varicella [see Patient Counseling Information (17)]. Do not immunize with live vaccines within 3 months after the final dose of Rhophylac. If Rhophylac is administered within 14 days after administration of a live vaccine, the immune response to the vaccination may be inhibited.3

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Rhophylac.

8.4 Pediatric Use

Suppression of Rh Isoimmunization in Incompatible TransfusionsThe safety and effectiveness of Rhophylac have not been established in pediatric subjects being treated for an incompatible transfusion. The physician should weigh the potential risks against the benefits of Rhophylac, particularly in girls whose later pregnancies may be affected if Rh isoimmunization occurs.Chronic ITPThe safety and effectiveness of Rhophylac have not been established in pediatric subjects with chronic ITP. Dosing in the treatment of children with chronic ITP is expected to be similar to adults.

10 Overdosage

There are no reports of known overdoses in patients being treated for suppression of Rh isoimmunization or ITP. Patients with incompatible transfusion or ITP who receive an overdose of Rh0(D) immune globulin should be monitored because of the potential risk for hemolysis.

11 Description

Rhophylac is a sterile Rh0(D) Immune Globulin Intravenous (Human) (anti-D) solution in a ready-to-use prefilled glass syringe for intravenous or intramuscular injection. One syringe contains at least 1500 IU (300 mcg) of IgG antibodies to Rh0(D) in a 2 mL solution, sufficient to suppress the immune response to at least 15 mL of Rh-positive RBCs.1 The product potency is expressed in IUs by comparison to the World Health Organization (WHO) standard, which is also the US and the European Pharmacopoeia standard.Plasma is obtained from healthy Rh0(D)-negative donors who have been immunized with Rh0(D)-positive RBCs. The donors are screened carefully to reduce the risk of receiving donations containing blood-borne pathogens. Each plasma donation used in the manufacture of Rhophylac is tested for the presence of HBV surface antigen (HBsAg), HIV-1/2, and HCV antibodies. In addition, plasma used in the manufacture of Rhophylac is tested by FDA-licensed Nucleic Acid Testing (NAT) for HBV, HCV, and HIV-1 and found to be negative. The source plasma is also tested by NAT for hepatitis A virus (HAV) and B19 virus (B19V).Rhophylac is produced by an ion-exchange chromatography isolation procedure5, using pooled plasma obtained by plasmapheresis of immunized Rh0(D)-negative US donors. The manufacturing process includes a solvent/detergent treatment step (using tri-n-butyl phosphate and Triton™ X-100) that is effective in inactivating enveloped viruses such as HIV, HCV, and HBV.6,7 Rhophylac is filtered using a Planova® 15 nanometer (nm) virus filter that has been validated to be effective in removing both enveloped and non-enveloped viruses. Table 3 presents viral clearance and inactivation data from validation studies, expressed as the mean log10 reduction factor (LRF).Table 3. Virus Inactivation and Removal in RhophylacHIVPRVBVDVMVMHIV, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a model for large, enveloped DNA viruses (e.g., herpes virus); BVDV, bovine viral diarrhea virus, a model for HCV and West Nile virus; MVM, minute virus of mice, a model for B19V and other small, non-enveloped DNA viruses.Virus propertyGenomeRNADNARNADNAEnvelopeYesYesYesNoSize (nm)80-100120-20040-7018-24Manufacturing stepMean LRFSolvent/detergent treatment≥6.0≥5.6≥5.4Not testedChromatographic process steps4.5≥3.91.6≥2.6Virus filtration≥6.3≥5.6≥5.53.4Overall reduction(log10 units)≥16.8≥15.1≥12.5≥6.0Rhophylac contains a maximum of 30 mg/mL of human plasma proteins, 10 mg/mL of which is human albumin added as a stabilizer. Prior to the addition of the stabilizer, Rhophylac has a purity greater than 95% IgG. Rhophylac contains less than 5 mcg/mL of IgA, which is the limit of detection. Additional excipients are approximately 20 mg/mL of glycine and up to 0.25 M of sodium chloride. Rhophylac contains no preservative. Human albumin is manufactured from pooled plasma of US donors by cold ethanol fractionation, followed by pasteurization.

14.1 Suppression Of Rh Isoimmunization

  • In two clinical studies, 447 Rh0(D)-negative pregnant women received a 1500 IU (300 mcg) dose of Rhophylac during Week 28 of gestation. The women who gave birth to an Rh0(D)-positive baby received a second 1500 IU (300 mcg) dose within 72 hours of birth.Study 1 (Pharmacokinetic Study) – Eight of the women who participated in the pharmacokinetic study [see Clinical Pharmacology (12.3)] gave birth to an Rh0(D)-positive baby and received the postpartum dose of 1500 IU (300 mcg) of Rhophylac.9 Antibody tests performed 6 to 8 months later were negative for all women. This suggests that no Rh0(D) immunization occurred.Study 2 (Pivotal Study) – In an open-label, single-arm clinical study at 22 centers in the US and United Kingdom, 432 pregnant women received the antepartum dose of 1500 IU (300 mcg) of Rhophylac either as an intravenous or intramuscular injection (two randomized groups of 216 women each).11 Subjects received an additional 1500 IU (300 mcg) dose if an obstetric complication occurred between the routine antepartum dose and birth or if extensive fetomaternal hemorrhage was measured after birth. Of the 270 women who gave birth to an Rh0(D)-positive baby, 248 women were evaluated for Rh0(D) immunization 6 to 11.5 months postpartum. None of these women developed antibodies against the Rh0(D) antigen.

14.2 Itp

In an open-label, single-arm, multicenter study, 98 Rh0(D)-positive adult subjects with chronic ITP and a platelet count of 30 × 109/L or less were treated with Rhophylac. Subjects received a single intravenous dose of 250 IU (50 mcg) per kg body weight.The primary efficacy endpoint was the response rate defined as achieving a platelet count of ≥30 × 109/L as well as an increase of >20 × 109/L within 15 days after treatment with Rhophylac. Secondary efficacy endpoints included the response rate defined as an increase in platelet counts to ≥50 × 109/L within 15 days after treatment and, in subjects who had bleeding at baseline, the regression of hemorrhage defined as any decrease from baseline in the severity of overall bleeding status.Table 4 presents the primary response rates for the intent-to-treat (ITT) and per-protocol (PP) populations.Table 4. Primary Response Rates (ITT and PP Populations)Analysis PopulationNo. SubjectsNo. RespondersPrimary Response Rate at Day 15% Responders95% Confidence Interval (CI)ITT986566.3%56.5%, 74.9%PP926267.4%57.3%, 76.1%The primary efficacy response rate (ITT population) demonstrated a clinically relevant response to treatment, i.e., the lower bound of the 95% confidence interval (CI) was greater than the predefined response rate of 50%. The median time to platelet response was 3 days, and the median duration of platelet response was 22 days.Table 5 presents the response rates by baseline platelet count for subjects in the ITT population.Table 5. Response Rates By Baseline Platelet Count (ITT Population)Response Rates at Day 15Baseline Platelet count (× 109/L)Total No. SubjectsNo. (%) Subjects Achieving a Platelet Count of ≥30 × 109/L and an Increase of >20 × 109/LNo. (%) Subjects With an Increase in Platelet Counts to ≥50 × 109/L≤103815 (39.5)10 (26.3)>10 to 202822 (78.6)17 (60.7)>20 to 302724 (88.9)22 (81.5)>30Reflects subjects with a platelet count of ≤30 × 109/L at screening but >30 × 109/L immediately before treatment.54 (80.0)5 (100.0)Overall (all subjects)9865 (66.3)54 (55.1)During the study, an overall regression of hemorrhage was seen in 44 (88%, 95% CI: 76% to 94%) of the 50 subjects with bleeding at baseline. The percentage of subjects showing a regression of hemorrhage increased from 20% at Day 2 to 64% at Day 15. There was no evidence of an association between the overall hemorrhage regression rate and baseline platelet count.Approximately half of the 98 subjects in the ITT population had evidence of bleeding at baseline. Post-baseline, the percentage of subjects without bleeding increased to a maximum of 70.4% at Day 8.

15 References

  • Pollack W, Ascari WQ, Kochesky RJ, O'Connor RR, Ho TY, Tripodi D. Studies on Rh prophylaxis. 1. relationship between doses of anti-Rh and size of antigenic stimulus. Transfusion. 1971;11:333-339.Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh0(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood. 2005;106:1532-1537.Centers for Disease Control and Prevention. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices and the American Academy of Family Physicians. MMWR 2002;51 (No. RR-2):6-7.Thornton JG, Page C, Foote G, Arthur GR, Tovey LAD, Scott JS. Efficacy and long term effects of antenatal prophylaxis with anti-D immunoglobulin. Br Med J. 1989;298:1671-1673.Stucki M, Moudry R, Kempf C, Omar A, Schlegel A, Lerch PG. Characterisation of a chromatographically produced anti-D immunoglobulin product. J Chromatogr B. 1997;700:241-248.Horowitz B, Chin S, Prince AM, Brotman B, Pascual D, Williams B. Preparation and characterization of S/D-FFP, a virus sterilized "fresh frozen plasma". J Thromb Haemost. 1991;65:1163.Horowitz B, Bonomo R, Prince AM, Chin S, Brotman B, Shulman RW. Solvent/detergent-treated plasma: a virus-inactivated substitute for fresh frozen plasma. Blood. 1992;79:826-831. Lazarus AH, Crow AR. Mechanism of action of IVIG and anti-D in ITP. Transfus Apher Sci. 2003;28:249-255.Bichler J, Schöndorfer G, Pabst G, Andresen I. Pharmacokinetics of anti-D IgG in pregnant RhD-negative women. BJOG. 2003;110:39-45.Ware RE, Zimmerman SA. Anti-D: mechanisms of action. Semin Hematol. 1998;35:14-22. MacKenzie IZ, Bichler J, Mason GC, et al. Efficacy and safety of a new, chromatographically purified rhesus (D) immunoglobulin. Eur J Obstetr Gynecol Reprod Biol. 2004;117:154-161.

16.1 How Supplied

  • Rhophylac 1500 IU (300 mcg) is supplied in packages of one or ten (10) prefilled, ready-to-use, glass syringe(s), each containing 2 mL liquid for injection. Each syringe is accompanied by a SafetyGlide™ needle for intravenous or intramuscular use.Each product presentation includes a package insert and the following components:PresentationCarton NDC NumberComponents1500 IU(300 mcg)44206-300-01Single-use, prefilled 2 mL syringe [NDC 44206-300-90]SafetyGlide needle1500 IU(300 mcg)Multipack44206-300-10Ten single-use, prefilled 2 mL syringes [NDC 44206-300-90]Ten SafetyGlide needles

16.2 Storage And Handling

  • DO NOT FREEZE.Rhophylac contains no preservatives; do not store at room temperature.Store at 2 to 8°C (36 to 46°F) for a shelf life of 36 months from the date of manufacture, as indicated by the expiration date printed on the outer carton and syringe label.Keep Rhophylac in its original carton to protect it from light.The prefilled Rhophylac syringe is not made with natural rubber latex.

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