FDA Label for Rhophylac

Other

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

Both Indications

• Inform 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 Isoimmunization

• Inform 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.

ITP

• Instruct 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.

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 syringes

Rhophylac 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)].²

The 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 Transfusions

The 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 ITP

The 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).

Rhophylac 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.

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.

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:

Presentation	Carton NDC Number	Components
1500 IU (300 mcg)	44206-300-01	Single-use, prefilled 2 mL syringe [NDC 44206-300-90] SafetyGlide needle
1500 IU (300 mcg) Multipack	44206-300-10	Ten 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.

Package Label.Principal Display Panel

PRINCIPAL DISPLAY PANEL - 300 mcg Syringe Label

NDC 44206-300-90

300 mcg

Rh₀(D)
Immune Globulin
Intravenous (Human)
Rhophylac^®

1500 IU per 2 mL

For IV or IM Injection.
Rx only

CSL Behring AG
Bern, Switzerland
US License No. 1766

EXP     MM.YYYY
LOT     0000000000

Principal Display Panel - 300 mcg Syringe Label - rhophylac 01