WinRho SDF

WinRho SDF™

Cangene

Rho (D) Immune Globulin (Human)

Passive Immunizing Agent

Action And Clinical Pharmacology: Rho (D) Immune Globulin (Human) is a sterile freeze-dried gamma globulin (IgG) fraction of human plasma containing antibodies to Rho (D), prepared by an anion-exchange column chromatography method.

The incorporation of the Solvent Detergent step, which includes treatment with Tri-n-butyl phosphate and Triton X-100, in the WinRho SDF process is designed to increase the safety of the product by reducing the risk of transmission of lipid enveloped viruses, such as hepatitis B, hepatitis C and HIV. WinRho SDF is filtered using a Planova 35 nm Virus Filter which has been validated to be effective in the removal of nonlipid enveloped viruses. Virus models for hepatitis A and human parvovirus B-19 were all shown to be removed after Planova 35 nm virus filtration. Table I summarizes test viruses and their respective log virus reductions.

The WinRho SDF process is based on the process used to manufacture WinRho, a product that has been used for over 10 years in the prevention of Rh alloimmunization.

The product potency is expressed in international units by comparison to the World Health Organization (WHO) standard. A 1 500 International Unit (IU) (300 g) vial contains sufficient anti-Rho (D) to effectively suppress the immunizing potential of approximately 17 mL of Rho (D) positive red blood cells. (In the past, a full dose of Rho (D) Immune Globulin (Human) has traditionally been referred to as a “300 g” dose. Potency and dosing recommendations are now expressed in IU by comparison to the WHO anti-D standard. The conversion of “g” to “IU” is 1 g=5 IU).

Prevention of Rh Immunization: Rho (D) Immune Globulin (Human) is used to suppress the immune response of non-sensitized Rho (D) negative individuals who receive Rho (D) positive blood either by fetomaternal hemorrhage during delivery of an Rho (D) positive infant, abortion (either spontaneous or induced), following amniocentesis, abdominal trauma or accidental transfusion. Administration of anti-Rho (D) antibody to the Rho (D) negative mother prevents an immune response with subsequent anti-Rho (D) antibody formation. The exact mechanism of action has yet to be determined.

Rho (D) Immune Globulin (Human), when administered within 72 hours of a full-term delivery of an Rho (D) positive infant by an Rho (D) negative mother, will reduce the incidence of Rh alloimmunization from 12 to 13% to 1 to 2%. The 1 to 2% is, for the most part, due to alloimmunization during the last trimester of pregnancy. When treatment is given both antenatally at 28 weeks gestation and postpartum the Rh immunization rate drops to about 0.1%.

Treatment of Immune Thrombocytopenic Purpura (ITP): Rho (D) Immune Globulin (Human) is used to increase platelet counts in nonsplenectomized Rho (D) positive patients with ITP and to alleviate clinical signs of bleeding in this patient population. The mechanism of action is not completely understood, but is thought to be due to the production of of anti-Rho (D)-coated red blood cell complexes resulting in Fc receptor blockade, thus sparing antibody-coated platelets. In a clinical study of WinRho therapy of children with chronic ITP (duration of ITP >6 months), administration of anti-Rho (D) increased platelet counts from 36±14´10L to 263±138 x 10L; peak platelet levels were recorded at about 1 week after WinRho therapy; the effect of WinRho on platelet levels lasted a median of 29 days from the start of therapy. Comparable results were obtained in a clinical study of both adult and children with ITP of varying etiologies including ITP secondary to HIV infection. However, larger increases in platelet levels were seen in children than in adults.

When Rho (D) Immune Globulin (Human) is administered by an i.v. route, peak levels are achieved within 2 hours, while the mean time to peak is 5 to 10 days when drug is administered by an i.m. route. When 600 IU (120 g) of product was administered to nonpregnant volunteers, the peak levels of passive anti-Rho (D) antibody that were achieved were about 40 ng/mL when the drug was administered by an i.v. route and about 20 ng/mL when the drug was administered by an i.m. route. In a clinical study with Rho (D) negative volunteers, Rho (D) positive red cells were completely cleared from the circulation within 8 hours of i.v. administration of WinRho SD Rho (D) Immune Globulin (Human).

When only 600 IU (120 g) of drug is administered to pregnant women, passive anti-Rho (D) antibodies are not detectable in the circulation for more than 6 weeks and therefore a dose of 1 500 IU (300 g) should be used for antenatal administration.

WinRho SD Rho (D) Immune Globulin (Human) has been shown to increase platelets in ITP patients. Platelet counts usually rise within 1 to 2 days and peak within 7 to 14 days after initiation of therapy. The duration of response is variable; however, the average duration is approximately 30 days.

Indications And Clinical Uses: Pregnancy and Other Obstetric Conditions: For the prevention of Rh immunization of Rho (D) negative women at risk of developing Rh antibodies. Rho (D) Immune Globulin (Human) prevents the development of Rh antibodies in the Rho (D) negative and previously not sensitized mother carrying a Rho (D) positive fetus, thus preventing the occurrence of hemolytic disease in the fetus or the newborn.

For the prevention of Rh immunization in Rho (D) negative mothers who have not been previously sensitized to the Rho (D) factor.

The administration of Rho (D) Immune Globulin (Human) to women satisfying the above conditions should be done at about 28 weeks gestation when the child’s father is either Rho (D) positive or unknown.

Rho (D) Immune Globulin (Human) should be administered within 72 hours after delivery if the baby is Rho (D) positive or unknown.

Rho (D) Immune Globulin (Human) administration is also recommended in these same women within 72 hours after spontaneous or induced abortion, amniocentesis, chorion villus sampling, ruptured tubal pregnancy, abdominal trauma or transplacental hemorrhage, unless the blood type of the fetus or the father is confirmed to be Rho (D) negative. It should be administered as soon as possible in the case of maternal bleeding due to threatened abortion.

Transfusion: Rho (D) Immune Globulin (Human) is recommended to prevent alloimmunization in Rho (D) negative individuals transfused with Rho (D) positive red blood cells or blood components with red blood cells. Treatment is indicated if the individual who has received the transfusion is a female child or adult in her childbearing years. Treatment should only then be carried out (without preceding exchange transfusion), if the transfused Rho (D) positive blood represents less than 20% of the total circulating red cells.

Immune Thrombocytopenic Purpura (ITP): Rho (D) Immune Globulin (Human) is recommended in the treatment of destructive thrombocytopenia of an immune etiology in situations where platelet counts must be increased to control bleeding. Clinical studies have shown that the peak platelet counts occur about 7 days after i.v. anti-Rho (D) treatment. The effect is not curative but is transient; platelet counts are usually elevated from several days to several weeks. For individuals with chronic ITP, a maintenance dosage is recommended with the dosage schedule determined on an individual basis.

Rho (D) Immune Globulin (Human) is recommended for the treatment of nonsplenectomized Rho (D) positive 1) children with chronic or acute ITP, 2) adults with chronic ITP, or 3) children and adults with ITP secondary to HIV infection in clinical situations requiring an increase in platelet count to prevent excessive hemorrhage.

Childhood Chronic ITP: In an open-label, single arm, multicentre study, 24 nonsplenectomized, Rho (D) positive children with ITP of greater than 6 months’ duration were treated initially with 250 IU (50 g)/kg Rho (D) Immune Globulin (Human) (125 IU/kg [25 g/kg] on days 1 and 2), with subsequent doses ranging from 125 to 275 IU (25 to 55 g)/kg. Response was defined as a platelet increase to at least 50 000/mmand a doubling of the baseline. Nineteen of 24 patients responded for an overall response rate of 79%, an overall mean peak platelet count of 229 400/mm(range 43 300 to 456 000), and a mean duration of response of 36.5 days (range 6 to 84).

Childhood Acute ITP: A multicentre, randomized, controlled trial comparing Rho (D) IGIV to high dose and low dose Immune Globulin (Human) and prednisone was conducted in 146 nonsplenectomized, Rho (D) positive children with acute ITP and platelet counts less than 20 000/mm Of 38 patients receiving Rho (D) IGIV (125 IU/kg [25 g/kg] on days 1 and 2), 32 patients (84%) responded (platelet count ³50 000/mm with a mean peak platelet count of 319 500/mm(range 61 000 to 892 000), with no statistically significant differences compared to other treatment arms. The mean times to achieving ³20 000/mmor ³50 000/mmplatelets for patients receiving Rho (D) IGIV were 1.9 and 2.8 days respectively. When comparing the different therapies for time to platelet count ³20 000/mmor ³50 000/mm no statistically significant differences among treatment groups were detected, with a range of 1.3 to 1.9 days and 2.0 to 3.2 days, respectively.

Adult Chronic ITP: Twenty-four nonsplenectomized, Rho (D) positive adults with ITP of greater than 6 months’ duration and platelet counts
ITP Secondary to HIV Infection: Eleven children and 52 adults who were nonsplenectomized, Rho (D) positive with all Walter Reed classes of HIV infection and ITP, with initial platelet counts of £30 000/mmor requiring therapy, were treated with 100 to 375 IU (20 to 75 g)/kg Rho (D) IGIV in an open-label trial. Rho (D) IGIV was administered for an average of 7.3 courses (range 1 to 57) over a mean period of 407 days (range 6 to 1 952). Fifty-seven of 63 patients responded (increase ³20 000/mm during the first 6 courses of therapy for an overall response rate of 90%. The overall mean change in platelet count for 6 courses was 60 900/mm(range -2 000 to 565 000), and the mean peak platelet count was 81 700/mm(range 16 000 to 593 000).

Contra-Indications: Prevention of Rh Immunization: When Rho (D) Immune Globulin (Human) is used to prevent Rh alloimmunization, it should not be administered to: 1) Rho (D) positive individuals including babies; 2) Rho (D) negative women who are Rh immunized as evidenced by standard manual Rh antibody screening tests; 3) individuals with a history of anaphylactic or other severe systemic reaction to immune globulins.

Immune Thrombocytopenic Purpura: When Rho(D) Immune Globulin (Human) is used to treat patients with ITP, it should not be administered to: 1) Rho (D) negative individuals, 2) splenectomized individuals, 3) individuals with known hypersensitivity to plasma products.

Manufacturers’ Warnings In Clinical States: Rho (D) Immune Globulin (Human) contains trace quantities of IgA. Although WinRho has been used successfully to treat selected IgA deficient individuals, the physician must weigh the potential benefit of treatment with Rho (D) Immune Globulin (Human) against the potential for hypersensitivity reactions. Individuals deficient in IgA have a potential for development of IgA antibodies and anaphylactic reactions after administration of blood components containing IgA; Burks et al. (1986) have reported that as little as 15 g IgA/mL of blood product has elicited an anaphylactic reaction in IgA deficient individuals. Individuals known to have had an anaphylactic or severe systemic reaction to human globulin should not receive Rho (D) Immune Globulin (Human) or any other Immune Glubulin (Human).

Rho (D) Immune Globulin (Human) must be administered via the i.v. route for the treatment of ITP as its efficacy has not been established by the i.m. or s.c. routes.

Rho (D) Immune Globulin (Human) should not be administered to Rho (D) negative or splenectomized individuals as its efficacy in these patients has not been demonstrated.

Precautions: General: A large fetomaternal hemorrhage late in pregnancy or following delivery may cause a weak mixed field positive Dtest result. Such an individual should be screened for a large fetomaternal hemorrhage and the Rho (D) Immune Globulin (Human) adjusted accordingly. Rho (D) Immune Globulin (Human) should be administered if there is any doubt about the mother’s blood type.

Plasma used in manufacturing has been tested in accordance with regulations and has been treated to inactivate lipid and nonlipid enveloped virus; however, the possibility of transmission of infectious disease cannot be excluded.

In the treatment of ITP, if the patient has a lower than normal hemoglobin level (less than 10 g/dL), a reduced dose of 125 to 200 IU/kg (25 to 40 g/kg) body weight should be given to minimize the risk of increasing the severity of anemia in the patient. Rho (D) Immune Globulin (Human) must be used with extreme caution in patients with a hemoglobin level that is less than 8 g/dL due to the risk of increasing the severity of the anemia.

Drug Interactions: Administration of Rho (D) Immune Globulin (Human) with other drugs has not been evaluated. It is recommended that Rho (D) Immune Globulin (Human) be administered separately from other drugs. Refer to Dosage section for information on drug compatibility.

Pregnancy: Category C: Animal reproduction studies have not been conducted with Rho (D) Immune Globulin (Human). It is not known whether Rho (D) Immune Globulin (Human) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Rho (D) Immune Globulin (Human) should be given to a pregnant woman only if clearly needed.

Laboratory Tests: In addition to anti-D antibody, Rho (D) Immune Globulin (Human) contains trace amounts of anti-C, E, A and B. These antibodies may be detected by laboratory screening tests.

In the prevention of Rh immunization, the presence of passively administered Rh antibody in maternal or fetal blood can lead to a positive direct antiglobulin (Coombs’) test. In case of doubt as to the individual’s Rh group or immune status, Rho (D) Immune Globulin (Human) should be administered.

In the treatment of ITP, the presence of passively administered anti-Rho (D) can lead to positive direct antiglobulin (Coombs’) test. Interpretation of this result must be made in the context of the patient’s clinical and supporting laboratory data.

Adverse Reactions: Prevention of Rh Immunization: Reactions to Rho (D) Immune Globulin (Human) are rare in Rho (D) negative individuals. Discomfort and light swelling at the site of injection and slight elevation in temperature have been reported in a small number of cases.

In a clinical study with 5 healthy Rho (D) negative males, Rho (D) positive fetal red cells were administered to volunteers by i.v. infusion and then 1 to 2 days later the fetal red cells were cleared by i.v. administration of 600 IU (120 g) WinRho SD. At 6 to 8 hours after administration of WinRho SD to these subjects, there was an elevation in mean levels of granulocytes from 4.25 to 7.88´10L(p
Treatment of ITP: Rho (D) Immune Globulin (Human) is adminsitered to Rho (D) positive patients with ITP. Therefore, side effects related to the destruction of Rho (D) positive red cells, such as decreased hemoglobin, can be expected. At the recommended initial i.v. dose of 250 IU/kg (50 g/kg), the mean maximum decrease in hemaglobin was 1.70 g/dL (range +0.40 to -6.1 g/dL). At a reduced dose, ranging from 125 to 200 IU/kg (25 to 40 g/kg), the mean maximum decrease in hemoglobin was 0.81 g/dL (range +0.65 to -1.9 g/dL). Only 5/137 (3.7%) of patients had a maximum decrease in hemoglobin of greater than 4 g/dL (range 4.2 to 6.1 g/dL). In most cases, the red blood cell destruction is believed to occur in the spleen. However, there have been rare reports of acute onset of hemoglobinuria consistent with intravascular hemolysis and accompanied by reversible acute renal impairment. There have also been 2 cases of acute onset of hemoglobinuria without renal impairment in patients receiving red blood cell transfusion concurrent with WinRho SD.

In a clinical study of treatment of 48 Rho (D) positive individuals with autoimmune thrombocytopenic purpura of various etiologies with multiple treatments of 50 to 250 IU (10 to 50 g)/kg body weight of WinRho (Bussel et al., 1991), 5 adverse reactions occurred during or immediately after the anti-Rho (D) infusions. Two reactions were severe: 1 occurred in a patient with known hypersensitivity to plasma products; the other occurred in a patient who had received i.v. WinRho before and numerous times since without any reactions. Both reactions resulted in shaking and chills with gradual recovery within 1 hour.

In trials in subjects (n=161) with childhood acute ITP, adults and children with chronic ITP, and adults and children with ITP secondary to HIV, 60/848 (7%) of infusions were associated with at least 1 adverse event that was considered to be related to the study medication. The most common adverse events were headache (19 infusions; 2%), chills (14 infusions;
General Adverse Reactions: In addition to the adverse reactions described above, the following have been reported infrequently in clinical trials and/or postmarketing experience, in patients treated for ITP and/or the prevention of Rh immunization, and are thought to be temporally associated with Rho (D) Immune Globulin (Human) use: asthenia, abdominal or back pain, hypotension, pallor, diarrhea, increased LDH, arthralgia, myalgia, dizziness, hyperkinesia, somnolence, vasodilation, pruritus, rash and sweating.

As is the case with all drugs of this nature, there is a remote chance of an idiosyncratic or anaphylactoid reaction with Rho (D) Immune Globulin (Human) in individuals with hypersensitivity to blood products. In the event of an immediate reaction (anaphylaxis) characterized by collapse, rapid pulse, shallow respiration, pallor, cyanosis, edema or generalized urticaria, s.c. injection of epinephrine HCl 0.3 mL 1:1 000 aqueous solution should be instituted, followed by i.v. administration of hydrocortisone 50 to 100 mg if necessary.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: If an Rho (D) positive individual is treated with large doses of Rho (D) Immune Globulin (Human), a mild anemia may develop. However, this is normally compensated for by elevated red cell production. Normally, medical intervention other than discontinuation of Rho (D) Immune Globulin (Human) treatment would not be required.

There are no reports of known overdoses in patients being treated for Rh isoimmunization or ITP. In clinical studies with nonpregnant Rho (D) positive patients with ITP (n=141) treated with 600 to 32 500 IU (120 to 6 500 g) of Rho (D) IGIV, there were no signs or symptoms that warranted medical intervention. However, these same doses were associated with a mild, transient hemolytic anemia.

Dosage And Administration: Pregnancy and Other Obstetric Conditions: A 1 500 IU (300 g) dose of Rho (D) Immune Globulin (Human) should be given by i.v. or i.m. administration at 28 weeks gestation. A 600 IU (120 g) dose of Rho (D) Immune Globulin (Human) should be given by i.v. or i.m. administration as soon after delivery of a confirmed Rho (D) positive baby as possible and no later than 72 hours after delivery. In the event that the Rh status of the baby is not known at 72 hours, Rho (D) Immune Globulin (Human) should be administered to the mother at 72 hours after delivery.

If more than 72 hours have elapsed, Rho (D) Immune Globulin (Human) should not be withheld but should be administered as soon as possible up to 28 days after delivery.

A 600 IU (120 g) dose of Rho (D) Immune Globulin (Human) should be given by i.v. or i.m. administration immediately after therapeutic abortion, amniocentesis (after 34 weeks gestation) or other manipulation late in pregnancy (34 weeks gestation) associated with increased risk of Rho (D) immunization and, in any event, no later than 72 hours after the event.

A 1 500 IU (300 g) dose of Rho (D) Immune Globulin (Human) should be given by i.v. or i.m. administration immediately after amniocentesis before 34 weeks gestation or after chorion villus sampling, and this dosage should be repeated every 12 weeks while the woman is pregnant. In the case of threatened abortion, Rho (D) Immune Globulin (Human) should be administered as soon as possible.

Administer 3 000 IU (600 g) every 8 hours via the i.v. route until the total dose, calculated from the above table, is administered.

Administer 6 000 IU (1 200 g) every 12 hours via the i.m. route until the total dose, calculated from Table III, is administered.

Immune Thrombocytopenic Purpura: Rho (D) Immune Globulin (Human) must be given by i.v. administration for the treatment of ITP. An i.v. dose of from 125 to 250 IU/kg (25 to 50 g/kg) body weight is recommended for individuals with ITP.

Rho (D) Immune Globulin (Human) should be reconstituted only with the accompanying vial of 0.9% Sodium Chloride Injection. It should not be administered with other products. After confirming that the patient is Rho (D) positive, an initial dose of 250 IU (50 g)/kg body weight is recommended for the treatment of ITP. If the patient has a hemoglobin level that is less than 10 g/dL, a reduced dose of 125 to 200 IU/kg (25 to 40 g/kg) should be given to minimize the risk of increasing the severity of anemia in the patient. The initial dose may be administered in 2 divided doses given on separate days, if desired.

If subsequent therapy is required to elevate platelet counts, an i.v. dose of 125 to 300 IU/kg (25 to 60 g/kg) body weight of Rho (D) Immune Globulin (Human) is recommended. The frequency and dose used should be administered by the patient’s clinical response by assessing platelet counts, red cells counts, hemoglobin and reticulocyte levels.

Administration: Reconstitution: Rho (D) Immune Globulin (Human) should be reconstituted only with the accompanying vial of 0.9% Sodium Chloride Injection. Use aseptic technique throughout. 1) Reconstitute shortly before use. 2) Remove caps from the diluent and product vials. 3) Wipe exposed central portion of the rubber stopper with suitable disinfectant. 4) Withdraw diluent using a suitable syringe and needle. Use 1.25 to 2.5 mL of Sodium Chloride Injection for i.v. injection or 1.25 mL for i.m. injection for 600 IU (120 g) and 1 500 IU (300 g). Use 8.5 mL of Saline for Injection for i.v. and i.m. injection for 5 000 IU (1 000 g). 5) Inject diluent slowly at an angle so that the liquid is directed onto the inside glass wall of the vial containing the freeze-dried pellet. 6) Wet pellet by gently tilting and inverting the vial. Avoid frothing. Gently swirl upright vial until dissolved (less than 10 minutes).

Injection: Parenteral products such as Rho (D) Immune Globulin (Human) should be inspected for particulate matter and discoloration prior to administration.

Use product within 4 hours of reconstitution. Aseptically administer the product i.v. in a suitable vein with a rate of injection of 1 500 IU (300 g)/5 to 15 seconds. I.M. injections are made into the deltoid muscle of the upper arm or the anterolateral aspect of the upper thigh. Due to the risk of sciatic nerve injury, the gluteal region should not be used as a routine injection site. If the gluteal region is used, use only the upper, outer quadrant.

Stability and Storage Recommendations: Stable at 2 to 8°C until the expiry date indicated on the label. Store at 2 to 8°C. Do not freeze. Do not use after expiration date. Discard any unused portion.

Availability And Storage: 600 IU (120 g) and 1 500 IU (300 g): Each 3 mL type 1 glass tubing vial fitted with a 13 mm lyophilization stopper of rubber formulation and a 13 mm flip-off seal of freeze-dried contains: approximately 600 IU (120 g) or 1 500 IU (300 g) of freeze-dried anti-Rho (D). One vial of 2.5 mL saline 0.9% Sodium Chloride Injection, USP, sterile nonpyrogenic for reconstitution of WinRho SDF. Final product formulation includes the addition of sodium chloride to yield 0.04 M, glycine to yield O.1 M and polysorbate 80 to yield 0.01%.

5 000 IU (1 000 g): Each 6 mL type 1 glass tubing vial fitted with a 20 mm lyophilization stopper of rubber formulation and a 20 mm flip-off seal of freeze-dried contains: approximately 5 000 IU (1 000 g) of anti-Rho(D). One vial of 8.5 mL saline 0.9% Sodium Chloride Injection, USP, sterile nonpyrogenic for reconstitution of WinRho SDF. Final product formulation includes the addition of sodium chloride to yield 0.04 M, glycine to yield 0.1 M and polysorbate 80 to yield 0.01%.

WinRho SDF™ Cangene Rho (D) Immune Globulin (Human) Passive Immunizing Agent

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