A polyclonal antibody to the D antigens present on the RBCs of Rh+ patients
Administered over 5 to 30 minutes
Mode of action
Although the mode of action is not completely understood, Anti-D (WinRho) may "lead to a more specific and efficient immune blockade" than IVIG. " Saturation of the Fc Receptors with antibody coated erythrocytes would lead to immune-mediated red blood cell clearance and allow antibody-coated platelets to escape phagocytosis. Ref. Seminars in Hematology, Vol 35, No 1, Suppl 1 (January), 1998 pp 16; Anti D: Mechanisms of Action, Russel E Ware and Sherri A Zimmerman.
CONTRAINDICATIONS
When WinRho® SDF is used to treat patients with ITP, it should not be administered to:
- Rho (D) negative individuals,
- Splenectomized individuals,
- Individuals with known hypersensitivity to plasma products.
Physicians should discuss the risks and benefits of WinRho® SDF and alert patients who are being treated for ITP, about the signs and symptoms associated with the following rare serious adverse events reported through post marketing surveillance:
Among patients treated for ITP, there have been rare post marketing reports of signs and symptoms consistent with intravascular hemolysis that included back pain, and discoloured urine occurring, in most cases, within four hours of administration. Potentially serious complications of intravascular hemolysis that have also been reported include clinically compromising anemia, acute renal insufficiency or disseminated intravascular coagulation (DIC) that have, in some cases, been fatal. The extent of risk of intravascular hemolysis and its complications is not known but is reported to be rare (< 1 / 1000) , especially for DIC, which is very rare (< 1 / 10,000) . In the rare cases reported following anti-D administration, there was no discernible contribution of age, gender, pre-treatment renal function, pretreatment haemoglobin, concomitantly administered blood/blood products, co-morbid conditions or previous treatment with WinRho® SDF to the development of intravascular hemolysis and its complications.
WinRho® SDF, Rho (D) Immune Globulin (Human) contains trace quantities of IgA. Although WWinRho® SDF has been used successfully to treat selected IgA deficient individuals, the physician must weigh the potential benefit of treatment with WinRho® SDF 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 µg 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 WinRho® SDF or any other Immune Globulin (Human).
WinRho® SDF must be administered via the intravenous route for the treatment of ITP as its efficacy has not been established by the intramuscular or subcutaneous routes.
WWinRho® SDF should not be administered to Rho (D) negative or splenectomized individuals as its efficacy in these patients has not been demonstrated.
PRECAUTIONS
General
Proper care should be taken when calculating the dose of WinRho® SDF to be administered. A confusion between International Units (IU) and Micrograms (µg) of product or between Pounds (lbs) and Kilograms (kg) for the patient’s body weight could result in either an overdose that could lead to a severe hemolytic reaction (see SYMPTOMS AND TREATMENT OF OVERDOSAGE section) or a dose too low to be effective.
Plasma used in manufacturing has been tested in accordance with regulations and has been treated to inactivate lipid and non-lipid enveloped viruses, however, the possibility of transmission of infectious disease cannot be excluded.
Following administration of WinRho® SDF, Rho (D) positive ITP patients should be monitored for signs and/or symptoms of intravascular hemolysis and its complications, which include:
- Hemoglobinuria
- Pallor
- Hypotension
- Tachycardia
- Oliguria or anuria
- Edema
- Dyspnea
The diagnosis of a serious complication of an intravascular hemolysis is dependent on laboratory testing. (See PRECAUTIONS Laboratory Tests, Treatment of ITP)
If patients are to be transfused, Rho (D) negative red blood cells (PRBCs) should be used so as not to exacerbate ongoing IVH. Platelet products may contain up to 5.0 mL of RBCs, thus caution should likewise be exercised if platelets from Rho (D) positive donors are transfused.
If the patient has a lower than normal haemoglobin level (less than 10 g/dL), a reduced dose of 125 to 200 IU/kg (25 to 40 µg/kg) body weight should be given to minimize the risk of increasing the severity of anaemia in the patient. WinRho® SDF, Rho (D) Immune Globulin (Human), must be used with extreme caution in patients with a hemoglobin level that is less than 8 µg/dL due to the risk of increasing the severity of the anemia.
RESPONSE RATES :
In our clinical trials, the response rates of different treatment populations to WinRho® SDF are as follows :
Childhood Acute ITP (AITP)-84%
Childhood Chronic ITP (CITP)– 92%
Adult Chronic (BITP-2) – 90%
Secondary to HIV (BITP-1) – 88%
Please see the Safety and Efficacy Section of this website for more information.
Information for the Patient
ITP
Patients should be instructed to immediately report symptoms of back pain, discolored urine, decreased urine output, sudden weight gain, fluid retention/edema and/or shortness of breath to their physicians.
Drug Interactions
Administration of WinRho® SDF, Rho (D) Immune Globulin (Human) concomitantly with other drugs has not been evaluated. It is recommended that WinRho® SDF be administered separately from other drugs. Refer to Dosage and Administration section for information on drug compatibility.
Pregnancy Category C
Animal reproduction studies have not been conducted withWinRho® SDF. It is not known whether WinRho® SDF can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. WinRho® SDF should be given to a pregnant woman only if clearly needed.
Laboratory Tests
In addition to anti-D antibody, WinRho® SDF contains trace amounts of anti-C, E, A and B. These antibodies may be detected by laboratory screening tests.
The presence of passively administered anti-Rho (D) can lead to positive direct antiglobulin and indirect antiglobulin (Coombs’) test. Interpretation of direct and indirect antiglobulin tests must be made in the context of the patient’s underlying clinical condition and supporting laboratory data.
ITP patients presenting with signs and/or symptoms of intravascular hemolysis and its complications after anti-D administration should have confirmatory laboratory testing that may include, but is not limited to, CBC (i.e. hemogloblin, platelet counts), haptoglobin, plasma haemoglobin, urine dipstick and microscopic urinalysis, assessment of renal function (i.e. BUN, serum creatinine), liver function (i.e. LDH, direct and indirect bilirubin) and DIC specific tests such as D-dimer or Fibrin Degradation products (FDP) or Fibrin Split Products (FSP).
ADVERSE REACTIONS
The most serious adverse reactions have been observed in patients receiving WinRho® SDF for treatment of ITP. These include: intravascular hemolysis, clinically compromising anemia, acute renal insufficiency and DIC, leading in some cases to death.
General Adverse Reactions
In addition to the adverse reactions described above, the following have been reported infrequently in clinical trials and/or post marketing experience, in patients treated for ITP and/or the prevention of Rh immunization, and are thought to be temporally associated with WinRho® SDF use: asthenia, abdominal or back pain, hypotension, pallor, diarrhea, increased LDH, arthralgia, myalgia, dizziness, nausea, vomiting, hypertension, hyperkinesia, somnolence, vasodilation, pruritus, rash and sweating.
As is the case with all drugs of this nature, there is a remote chance of an allergic or anaphylactoid reaction with WinRho® SDF 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, subcutaneous injection of epinephrine hydrochloride should be instituted followed by intravenous administration of hydrocortisone if necessary.
WinRho® SDF, Rho (D) Immune Globulin (Human), is administered to Rho (D) positive patients with ITP. Therefore, side effects related to the destruction of Rho (D) positive red blood cells, most notably a decreased haemoglobin, can be expected. In 4 clinical trials of patients treated with the recommended initial intravenous dose of 250 IU/kg (50 µg/kg), the mean maximum decrease in hemoglobin 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 µg/kg), the mean maximum decrease in haemoglobin was 0.81 g/dL (range +0.65 to -1.9 g/dL). Only 5 of 137 patients (3.7%) had a maximum decrease in haemoglobin of greater than 4 g/dL (range 4.2 to 6.1 g/dL). In most cases, the RBC destruction is believed to occur in the spleen. However, signs and symptoms consistent with IVH, including back pain, shaking chills, and/or hemoglobinuria, have been reported, occurring within minutes and up to a few days after WinRho® SDF administration.
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/kg (10 to 50 µg/kg) body weight of WinRho® (Bussel et al., 1991), five adverse reactions occurred during or immediately after the anti-Rho (D) infusions. Two reactions were severe; one occurred in a patient with known hypersensitivity to plasma products; the other occurred in a patient who had received IV WinRho® before and numerous times since without any reactions. Both reactions resulted in shaking and chills with gradual recovery within one hour.
In clinical 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 of 848 (7%) of infusions were associated with at least one 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; < 2%), and fever (nine infusions; 1%). All are expected adverse events associated with immunoglobulin infusion.
IVH-related complications that have been reported include death (four cases reported between January 1996 and November 2000), acute onset or exacerbation of anemia, and acute onset or exacerbation of renal insufficiency. One patient died from complications secondary to IVH-induced exacerbation of anemia after administration of WinRho® SDF for treatment of ITP. Although the primary cause of death in the other three ITP patients treated with WinRho® SDF was related to underlying disease, the extent to which IVH-related clinical complications exacerbated their conditions and contributed to their deaths is unknown.
The mean maximum decrease in hemoglobin in patients who were not transfused with PRBCs was 3.7 g/dL (range: 0.1-7 g/dL). Transfusions for treatment-associated anemia were administered within hours to days of the onset of IVH and consisted of between 1 - 6 units of RBCs. Acute renal insufficiency was noted within 2 to 48 hours of the onset of IVH. The mean maximum increase in serum creatinine was 2.9 mg/dL (range: 0.1 - 10.3 mg/dL) and occurred within 2 - 9 days. The renal insufficiency in all surviving patients resolved with medical management, including dialysis, within 4 - 32 days.
The etiology of IVH following WinRho® SDF administration is unknown. No known risk factors associated with this adverse event have yet been identified from among those examined, which included age, gender, pre-treatment renal function, pre-treatment hemoglobin, concomitantly administered PRBCs, orWinRho® SDF dose. However, it is noted that about half of the reported cases occurred in children and most of these cases had a diagnosis of acute ITP. The number of reported cases appears to indicate that the IVH event, while still an uncommon occurrence, may not be as rare as initially believed.
Post Marketing Adverse Reactions
Respiratory Distress
Post marketing surveillance has noted reports of respiratory distress, possibly leading to death in elderly patients, following the administration of WinRho® SDF. Seven cases of respiratory distress or Acute Respiratory Distress Syndrome (ARDS), six of which resulted in death, have been reported post-marketing between 1995 and 2004. These patients all had underlying disease that may have been the cause or contributed to the death of these individuals. The role of WinRho® SDF in these deaths is unknown.
ITP
The following post marketing adverse events are reported voluntarily from a population of uncertain size; hence, it is not possible to estimate their frequency.
The following additional adverse reactions were reported following the use of WinRho® SDF for treatment of patients with ITP: intravascular hemolysis, clinically compromising anemia, acute renal insufficiency and DIC, leading in some cases to death.
Evaluation and interpretation of these post marketing events is confounded by underlying diagnosis, concomitant medications, pre-existing conditions and inherent limitations of passive surveillance.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
If an Rho (D) positive individual is treated with large doses of WinRho® SDF, a mild anemia may develop. However, this is normally compensated for by elevated red cell production. Normally, medical intervention other than discontinuation of WinRho® SDF treatment would not be required.
In clinical studies with non-pregnant Rho (D) positive patients with ITP (n = 141) treated with 600 to 32,500 IU (120 to 6,500 µg) 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.
In the post marketing surveillance, a case of accidental overdose due to an error in calculating the dose, resulted in a severe hemolytic reaction and ultimately death in a patient with ITP.
