RHOPHYLAC (human rho- d immune globulin solution
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Patient Information

Both Indications

• Inform patients to immediately report the following signs and symptoms to their physician: hives, chest tightness, wheezing, hypotension, and anaphylaxis[seeWarnings 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[seeWarnings 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[seeWarnings and Precautions (5.2.1)].

1. No Title 1572553831
2. Highlights Of Prescribing Information
3. See Full Prescribing Information For Complete Boxed Warning. This Warning Does Not Apply To Rh0(d)-negative Patients Treated For The Suppression Of Rh Isoimmunization.
4. Recent Major Changes
5. Indications And Usage
6. Dosage And Administration
7. Dosage Forms And Strengths
8. Contraindications
9. Warnings And Precautions
10. Adverse Reactions
11. Drug Interactions
12. Use In Specific Populations
13. 1 Indications And Usage
14. 2 Dosage And Administration
15. 3 Dosage Forms And Strengths
16. 4 Contraindications
17. 5 Warnings And Precautions
18. 6 Adverse Reactions
19. 7 Drug Interactions
20. 8 Use In Specific Populations
21. 10 Overdosage
22. 11 Description
23. 12 Clinical Pharmacology
24. 14 Clinical Studies
25. 15 References
26. 16 How Supplied/storage And Handling
27. Full Prescribing Information

No Title 1572553831 ⮝

PRINCIPAL DISPLAY PANEL - 300 mcg Syringe Carton

NDC 44206-300-01
300 mcg

Rh0(D) Immune Globulin Intravenous (Human)
Rhophylac
1500 IU

For Intravenous or Intramuscular Injection. Rx only

CSL Behring

RHOPHYLAC human rho(d) immune globulin solution

Product Information Product Type PLASMA DERIVATIVE Item Code (Source) NDC:44206-300 Route of Administration INTRAVENOUS, INTRAMUSCULAR

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HUMAN RHO(D) IMMUNE GLOBULIN (UNII: 48W7181FLP) (HUMAN RHO(D) IMMUNE GLOBULIN - UNII:48W7181FLP) HUMAN RHO(D) IMMUNE GLOBULIN 1500 [iU] in 2 mL

Inactive Ingredients Ingredient Name Strength Albumin Human (UNII: ZIF514RVZR) 20 mg in 2 mL Human Immunoglobulin A (UNII: 741C1PWQ88) Glycine (UNII: TE7660XO1C) Sodium Chloride (UNII: 451W47IQ8X)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:44206-300-01 1 in 1 CARTON 1 NDC:44206-300-90 2 mL in 1 SYRINGE, GLASS; Type 3: Prefilled Biologic Delivery Device/System (syringe, patch, etc.) 2 NDC:44206-300-10 10 in 1 CARTON 2 NDC:44206-300-90 2 mL in 1 SYRINGE, GLASS; Type 3: Prefilled Biologic Delivery Device/System (syringe, patch, etc.)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125070 01/06/2009

Labeler - CSL Behring AG (481152762)

Establishment
Name	Address	ID/FEI	Business Operations
CSL Behring AG		481152762	MANUFACTURE

Revised: 5/2016 Document Id: 81aef654-4f74-4547-a259-d558b6869c54 60683-0 Set id: c1b5d801-336f-4541-a7d9-a8d4a110a4cc Version: 9 Effective Time: 20160516 CSL Behring AG

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use RHOPHYLAC safely and effectively. See full prescribing information for RHOPHYLAC.

RHOPHYLAC
Rh0(D) Immune Globulin Intravenous (Human) 1500 IU (300 mcg)
Solution for Intravenous (IV) or Intramuscular (IM) Injection
Initial U.S. Approval: 2004

See Full Prescribing Information For Complete Boxed Warning. This Warning Does Not Apply To Rh0(d)-negative Patients Treated For The Suppression Of Rh Isoimmunization. ⮝

• Intravascular hemolysis leading to death has been reported in Rh0(D)-positive patients treated for immune thrombocytopenic purpura (ITP) with Rh0(D) Immune Globulin Intravenous (Human) products.
• Intravascular hemolysis can lead to clinically compromising anemia and multi-system organ failure including acute respiratory distress syndrome (ARDS), acute renal insufficiency, renal failure, and disseminated intravascular coagulation (DIC) have been reported.
• Monitor patients for signs and symptoms of intravascular hemolysis in a healthcare setting for at least 8 hours after administration.

Recent Major Changes ⮝

Dosage and Administration (2.2)	05/2016
Warnings and Precautions (5.1.1)	05/2016

Indications And Usage ⮝

Rhophylac is an Rh0(D) Immune Globulin Intravenous (Human) indicated for:

Suppression of Rhesus (Rh) Isoimmunization (1.1) in:

• Pregnancy and obstetric conditions in non-sensitized, Rh0(D)-negative women with an Rh-incompatible pregnancy, including:
  • Routine antepartum and postpartum Rh prophylaxis
  • Rh prophylaxis in obstetric complications or invasive procedures
• Incompatible transfusions in Rh0(D)-negative individuals transfused with blood components containing Rh0(D)-positive red blood cells (RBCs)

Immune Thrombocytopenic Purpura (ITP) (1.2)

• Raising platelet counts in Rh0(D)-positive, non-splenectomized adults with chronic ITP

Dosage And Administration ⮝

Suppression of Rh Isoimmunization (2.2) (IV or IM administration only)

Indication	Timing	Dose*(IV or IM)
IU, international units; mcg, micrograms.
* A 1500 IU (300 mcg) dose of Rhophylac will suppress the immunizing potential of 15 mL of Rh0(D)-positive RBCs.1 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.
Rh-incompatible pregnancy
Routine antepartum prophylaxis	At Week 28-30 of gestation	1500 IU (300 mcg)
Postpartum prophylaxis	Within 72 hours of birth	1500 IU (300 mcg)
Obstetric complications/ invasive procedures	Within 72 hours of complication/procedure	1500 IU (300 mcg)
Excessive fetomaternal hemorrhage (>15 mL)	Within 72 hours of complication	1500 IU (300 mcg) plus: 100 IU (20 mcg) per mL fetal RBCs in excess of 15 mL if excess transplacental bleeding is quantified, OR An additional 1500 IU (300 mcg) if excess transplacental bleeding cannot be quantified
Incompatible transfusions	Within 72 hours of exposure	100 IU (20 mcg) per 2 mL transfused blood or per 1 mL erythrocyte concentrate

ITP (2.3) (IV administration only)

Dose	Rate of administration
250 IU (50 mcg) per kg body weight	2 mL per 15 to 60 seconds

Dosage Forms And Strengths ⮝

1500 IU (300 mcg) per 2 mL prefilled, ready-to-use glass syringe (3)

Contraindications ⮝

• History of anaphylactic or severe systemic reaction to human immune globulin products (4)
• IgA deficient patients with antibodies against IgA and a history of hypersensitivity to Rhophylac or any of its components (4)
• Do not administer Rhophylac to the newborn infant of the mother that received Rhophylac postpartum (4).

Warnings And Precautions ⮝

Both Indications (5.1)

• IgA deficient patients with known antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions (5.1.1).
• Rhophylac is made from human blood; therefore it may contain infectious agents; e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (5.1.3).

ITP (5.2)

• Serious intravascular hemolysis has occurred in a clinical study; monitor patients for signs and symptoms and perform confirmatory laboratory tests (5.2.1).
• In ITP patients with pre-existing anemia, Rhophylac may increase the severity of anemia (5.2.2).

Adverse Reactions ⮝

Suppression of Rh Isoimmunization

The most common adverse reactions, reported in 0.5% of subjects, are nausea, dizziness, headache, injection-site pain, and malaise (6.1).

ITP

The most common adverse reactions, reported in > 14% of subjects, are chills, pyrexia/increased body temperature, headache, and hemolysis (increased bilirubin, decreased hemoglobin, or decreased haptoglobin) (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

Immunoglobulin administration may transiently interfere with the immune response to live virus vaccines, such as measles, mumps and rubella (7.1).

Use In Specific Populations ⮝

ITP

• Pregnancy: No human or animal data. Use only if clearly needed (8.1).

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 5/2016

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.

1.1 Suppression of Rh Isoimmunization

Pregnancy and Obstetric Conditions

Rhophylac is indicated for suppression of rhesus (Rh) isoimmunization in non-sensitized Rh0(D)-negative women with an Rh-incompatible pregnancy, including:

• Routine antepartum and postpartum Rh prophylaxis
• Rh prophylaxis in cases of:

  Obstetric complications (e.g., miscarriage, abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from antepartum hemorrhage)

  Invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy) or obstetric manipulative procedures (e.g., external version, abdominal trauma)

An Rh-incompatible pregnancy is assumed if the fetus/baby is either Rh0(D)-positive or Rh0(D)-unknown or if the father is either Rh0(D)-positive or Rh0(D)-unknown.

Incompatible Transfusions

Rhophylac is indicated for the suppression of Rh isoimmunization in Rh0(D)-negative individuals transfused with Rh0(D)-positive red blood cells (RBCs) or blood components containing Rh0(D)-positive RBCs.

Treatment can be given without a preceding exchange transfusion when the transfused blood represents less than 20% of the total circulating RBCs. If the volume exceeds 20%, an exchange transfusion should be considered prior to administering Rhophylac.

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 Isoimmunization

Indication	Timing of Administration	Dose* (Administer by Intravenous or Intramuscular Injection)
IU, international units; mcg, micrograms.
* A 1500 IU (300 mcg) dose of Rhophylac will suppress the immunizing potential of 15 mL of Rh0(D)-positive RBCs.1 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.
Rh-incompatible pregnancy
Routine antepartum prophylaxis	At Week 28-30 of gestation	1500 IU (300 mcg)
Postpartum prophylaxis (required only if the newborn is Rh0(D)-positive)	Within 72 hours of birth	1500 IU (300 mcg)
Obstetric complications (e.g., miscarriage, abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from antepartum hemorrhage)	Within 72 hours of complication	1500 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 procedure	1500 IU (300 mcg)
Excessive fetomaternal hemorrhage (>15 mL)	Within 72 hours of complication	1500 IU (300 mcg) plus: 100 IU (20 mcg) per mL fetal RBCs in excess of 15 mL if excess transplacental bleeding is quantified or An additional 1500 IU (300 mcg) dose if excess transplacental bleeding cannot be quantified
Incompatible transfusions	Within 72 hours of exposure	100 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 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.

5 Warnings And Precautions ⮝

5.1 Both Indications

5.1.1 Hypersensitivity

Severe hypersensitivity reactions may occur even in patients who have tolerated previous administrations. If symptoms of allergic or early signs of hypersensitivity reactions (including generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis) occur, discontinue Rhophylac administration immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

Rhophylac contains trace amounts of IgA (less than 5 mcg/mL) [see Description (11)]. Patients with known antibodies to IgA have a risk of developing potentially severe hypersensitivity and anaphylactic reactions. Rhophylac is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reactions to Rhophylac or any of its components [see Contraindications (4)].

5.1.2 Interference with Laboratory Tests

The administration of Rh0(D) immune globulin may affect the results of blood typing, the antibody screening test, and the direct antiglobulin (Coombs') test. Antepartum administration of Rh0(D) immune globulin to the mother can also affect these tests in the newborn infant.

Rhophylac can contain antibodies to other Rh antigens (e.g., anti-C antibodies), which might be detected by sensitive serological tests following administration.

5.1.3 Transmissible Infectious Agents

Because Rhophylac is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for Rhophylac.

Report any infections thought to be possibly transmitted by Rhophylac to CSL Behring Pharmacovigilance at 1-866-915-6958.

5.2 ITP

5.2.1 Intravascular Hemolysis

Serious intravascular hemolysis has occurred in a clinical study with Rhophylac. All cases resolved completely. However, as reported in the literature, some Rh0(D)-positive patients treated with Rh0(D) Immune Globulin Intravenous (Human) for ITP developed clinically compromising anemia, acute renal insufficiency, and, very rarely, disseminated intravascular coagulation (DIC) and death.2 Note: This warning does not apply to Rh0(D)-negative patients treated for the suppression of Rh isoimmunization.

Monitor patients in a healthcare setting for at least 8 hours after administration of Rhophylac. Perform a dipstick urinalysis at baseline, 2 hours and 4 hours after administration, and prior to the end of the monitoring period.

Alert patients to, and monitor them for, the signs and symptoms of intravascular hemolysis, including back pain, shaking chills, fever, and discolored urine or hematuria. Absence of these signs and/or symptoms of intravascular hemolysis within 8 hours do not indicate intravascular hemolysis cannot occur subsequently.

If signs and/or symptoms of intravascular hemolysis are present or suspected after Rhophylac administration, perform post-treatment laboratory tests, including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect). DIC may be difficult to detect in the ITP population; the diagnosis is dependent mainly on laboratory testing.

If patients who develop hemolysis with clinically compromising anemia after receiving Rhophylac are to be transfused, Rh0(D)-negative packed RBCs should be used to avoid exacerbating ongoing hemolysis.

5.2.2 Pre-existing Anemia

The safety of Rhophylac in the treatment of ITP has not been established in patients with pre-existing anemia. Rhophylac may increase the severity of anemia.

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.

Suppression of Rh Isoimmunization

In two clinical studies, 447 Rh0(D)-negative pregnant women received either an intravenous or intramuscular injection of Rhophylac 1500 IU (300 mcg) at Week 28 of gestation. A second 1500 IU (300 mcg) dose was administered to 267 (9 in Study 1 and 258 in Study 2) of these women within 72 hours of the birth of an Rh0(D)-positive baby. In addition, 30 women in Study 2 received at least one extra antepartum 1500 IU (300 mcg) dose due to obstetric complications [see Clinical Studies (14.1)].

The most common adverse reactions in study subjects were nausea (0.7%), dizziness (0.5%), headache (0.5%), injection-site pain (0.5%), and malaise (0.5%). A laboratory finding of a transient positive anti-C antibody test was observed in 0.9% of subjects.

ITP

In a clinical study, 98 Rh0(D)-positive adult subjects with chronic ITP received an intravenous dose of Rhophylac 250 IU (50 mcg) per kg body weight [see Clinical Studies (14.2)]. Premedication to alleviate infusion-related side effects was not used except in a single subject who received acetaminophen and diphenhydramine.

Sixty-nine (70.4%) subjects had 186adverse events. Within 24 hours of dosing, 73 (74.5%) subjects experienced 183 Treatment Emergent Adverse Events, and 66 (67%) subjects experienced 156adverse reactions.

Hemolysis (manifested as an increase in bilirubin, a decrease in hemoglobin, or a decrease in haptoglobin) was observed. An increase in blood bilirubin was seen in 21% of subjects. The median decrease in hemoglobin was greatest (0.8 g/dL) at Day 6 and Day 8 following administration of Rhophylac.

Table 2 shows the most common adverse reactions observed in the clinical study.

Table 2. Most Common Treatment-Emergent Adverse Reactions in Subjects with ITP (Occurring in 10% of Subjects)

TEAR		Number of Subjects (%) With a TEAR n=98
Chills		34 (34.7%)
Pyrexia/ Increased body temperature		30 (30.6%)
Increased blood bilirubin		21 (21.4%)
Headache		11 (11.2%)

Serious adverse reactions (SARs) were reported in 4 (4.1%) subjects. SARs were intravascular hemolytic reaction (hypotension, nausea, chills and headache, and a decrease in haptoglobin and hemoglobin) in two subjects; headache, dizziness, nausea, pallor, shivering, and weakness requiring hospitalization in one subject; and an increase in blood pressure and severe headache in one subject. All four subjects recovered completely.

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:

Suppression of Rh Isoimmunization

Hypersensitivity reactions, including rare cases of anaphylactic shock or anaphylactoid reactions, headache, dizziness, vertigo, hypotension, tachycardia, dyspnea, nausea, vomiting, rash, erythema, pruritus, chills, pyrexia, malaise, diarrhea and back pain have been reported. Transient injection-site irritation and pain have been observed following intramuscular administration.

There have been reports of lack of effect in patients with a body mass index 30 when administration via the intramuscular route was attempted [see Dosing and Administration (2.2)].

ITP

Transient hemoglobinuria has been reported in a patient being treated with Rhophylac for ITP.

7 Drug Interactions ⮝

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 Use In Specific Populations ⮝

8.1 Pregnancy

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

Suppression of Rh Isoimmunization

Rhophylac is used in pregnant women for the suppression of Rh isoimmunization. The available evidence suggests that Rhophylac does not harm the fetus or affect future pregnancies or reproduction capacity when given to pregnant Rh0(D)-negative women for suppression of Rh isoimmunization.4

ITP

Rhophylac has not been evaluated in pregnant women with ITP.

8.3 Nursing Mothers

Suppression of Rh Isoimmunization

Rhophylac is used in nursing mothers for the suppression of Rh isoimmunization. No undesirable effects on a nursing infant are expected during breastfeeding.

ITP

Rhophylac has not been evaluated in nursing mothers with ITP.

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.

8.5 Geriatric Use

Suppression of Rh Isoimmunization in Incompatible Transfusions

Rhophylac has not been evaluated for treating incompatible transfusions in subjects 65 years of age and older.

ITP

Of the 98 subjects evaluated in the clinical study of Rhophylac for treatment of ITP [see Clinical Studies (14.2)], 19% were 65 years of age and older. No overall differences in effectiveness or safety were observed between these subjects and younger subjects.

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 Rhophylac

	HIV	PRV	BVDV	MVM
HIV, 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 property
Genome	RNA	DNA	RNA	DNA
Envelope	Yes	Yes	Yes	No
Size (nm)	80-100	120-200	40-70	18-24
Manufacturing step	Mean LRF
Solvent/detergent treatment	6.0	5.6	5.4	Not tested
Chromatographic process steps	4.5	3.9	1.6	2.6
Virus filtration	6.3	5.6	5.5	3.4
Overall reduction (log10 units)	16.8	15.1	12.5	6.0

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.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Suppression of Rh Isoimmunization

The mechanism by which Rh0(D) immune globulin suppresses immunization to Rh0(D)-positive RBCs is not completely known.

In a clinical study of Rh0(D)-negative healthy male volunteers, both the intravenous and intramuscular administration of a 1500 IU (300 mcg) dose of Rhophylac 24 hours after injection of 15 mL of Rh0(D)-positive RBCs resulted in an effective clearance of Rh0(D)-positive RBCs. On average, 99% of injected RBCs were cleared within 12 hours following intravenous administration and within 144 hours following intramuscular administration.

ITP

Rhophylac has been shown to increase platelet counts and to reduce bleeding in non-splenectomized Rh0(D)-positive subjects with chronic ITP. The mechanism of action is thought to involve the formation of Rh0(D) immune globulin RBC complexes, which are preferentially removed by the reticuloendothelial system, particularly the spleen. This results in Fc receptor blockade, thus sparing antibody-coated platelets. 8

12.3 Pharmacokinetics

Suppression of Rh Isoimmunization

In a clinical study comparing the pharmacokinetics of intravenous versus intramuscular administration, 15 Rh0(D)-negative pregnant women received a single 1500 IU (300 mcg) dose of Rhophylac at Week 28 of gestation.9

Following intravenous administration, peak serum levels of Rh0(D) immune globulin ranged from 62 to 84 ng/mL after 1 day (i.e., the time the first blood sample was taken following the antepartum dose). Mean systemic clearance was 0.20 0.03 mL/min, and half-life was 16 4 days.

Following intramuscular administration, peak serum levels ranged from 7 to 46 ng/mL and were achieved between 2 and 7 days. Mean apparent clearance was 0.29 0.12 mL/min, and half-life was 18 5 days. The absolute bioavailability of Rhophylac was 69%.

Regardless of the route of administration, Rh0(D) immune globulin titers were detected in all women up to at least 9 weeks following administration of Rhophylac.

ITP

Pharmacokinetic studies with Rhophylac were not performed in Rh0(D)-positive subjects with ITP. Rh0(D) immune globulin binds rapidly to Rh0(D)-positive erythrocytes.10

14 Clinical Studies ⮝

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 Population	No. Subjects	No. Responders	Primary Response Rate at Day 15
			% Responders	95% Confidence Interval (CI)
ITT	98	65	66.3%	56.5%, 74.9%
PP	92	62	67.4%	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 15
Baseline Platelet count ( 109/L)	Total No. Subjects	No. (%) Subjects Achieving a Platelet Count of 30 109/L and an Increase of >20 109/L	No. (%) Subjects With an Increase in Platelet Counts to 50 109/L
* Reflects subjects with a platelet count of 30 109/L at screening but >30 109/L immediately before treatment.
10	38	15 (39.5)	10 (26.3)
>10 to 20	28	22 (78.6)	17 (60.7)
>20 to 30	27	24 (88.9)	22 (81.5)
>30*	5	4 (80.0)	5 (100.0)
Overall (all subjects)	98	65 (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 ⮝

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Lazarus AH, Crow AR. Mechanism of action of IVIG and anti-D in ITP. Transfus Apher Sci. 2003;28:249-255.
9. Bichler J, Sch ndorfer G, Pabst G, Andresen I. Pharmacokinetics of anti-D IgG in pregnant RhD-negative women. BJOG. 2003;110:39-45.
10. Ware RE, Zimmerman SA. Anti-D: mechanisms of action. Semin Hematol. 1998;35:14-22.
11. 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 How Supplied/storage And Handling ⮝

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.

Full Prescribing Information ⮝

RHOPHYLAC
Rh0(D) Immune Globulin Intravenous (Human)