WINRHO SDF Solution for injection Ref.[50374] Active ingredients: Human normal immunoglobulin G

5.1 Hypersensitivity

Severe hypersensitivity reactions may occur [see Contraindications (4)]. If symptoms of allergic or early signs of hypersensitivity reactions (including generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis) occur, discontinue WinRho SDF infusion immediately and institute appropriate treatment. WinRho SDF should be administered in a setting where appropriate equipment, medication such as epinephrine, and personnel trained in the management of hypersensitivity, anaphylaxis and shock are available.

WinRho SDF contains ≤40 mcg/mL IgA [see Description (11)]. Patients with antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. WinRho SDF is contraindicated in IgA-deficient patients with antibodies to IgA or a history of hypersensitivity reaction to WinRho SDF or any of its components [see Contraindications (4)].

WinRho SDF contains 10% maltose, a disaccharide sugar derived from corn. Patients with corn allergy should avoid using WinRho SDF due to risk of hypersensitivity. [see Contraindications (4)]

5.2 Intravascular Hemolysis (IVH) for ITP Treatment

IVH leading to death has been reported in patients treated for ITP with WinRho SDF.

IVH can lead to clinically compromising anemia and multi-system organ failure including acute respiratory distress syndrome (ARDS).

Serious complications including severe anemia, acute renal insufficiency, renal failure and disseminated intravascular coagulation (DIC) have also been reported. ^7,8

Closely monitor patients treated with WinRho SDF for ITP in a healthcare setting for at least 8 hours after administration. Perform a dipstick urinalysis to monitor for hematuria and hemoglobinuria at baseline and then after administration at 2 hours, 4 hours and prior to the end of the monitoring period. Alert patients and monitor for signs and symptoms of IVH including back pain, shaking chills, fever, and discolored urine or hemoglobinuria. Absence of these signs and/or symptoms of IVH within eight hours do not indicate IVH cannot occur subsequently. If signs and/or symptoms of IVH are present or if IVH is suspected after WinRho SDF administration, perform post-treatment laboratory tests including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect).

5.3 Hemolysis for ITP Treatment

Although the mechanism of action of WinRho SDF in the treatment of ITP is not completely understood it is postulated that anti-D binds to the Rh_o(D) RBC resulting in formation of antibody-coated RBC complexes. Immune-mediated clearance of the antibody-coated RBC complexes would spare the antibody-coated platelets because of the preferential destruction of antibody-coated RBC complexes by the macrophages located in the reticuloendothelial system. ^9-11 The side effect of this action is a decrease in hemoglobin levels (extravascular hemolysis). ⁷ The pooled data from ITP clinical studies demonstrated a mean decrease from baseline in hemoglobin levels of 1.2 g/dL within 7 days after administration of WinRho SDF.

In patients with pre-disposing conditions, renal and cardiovascular complications of IVH may occur more frequently. Patients of advanced age (age over 65 years) with co-morbid conditions may be at an increased risk of developing sequelae from acute hemolytic reactions. If a patient has evidence of hemolysis (reticulocytosis greater than 3%) or is at high risk for hemolysis [positive direct antiglobulin test (DAT) not attributed to previous immune globulin administration], alternate therapies must be used.

If the patient has lower than normal hemoglobin levels (less than 10 g/dL), a reduced dose of 125 to 200 IU/kg (25 to 40 mcg/kg) should be given to minimize the risk of increasing the severity of anemia in the patient. Alternative treatments should be used in patients with hemoglobin levels that are less than 8 g/dL due to the risk of increasing the severity of the anemia [see Dose (2.1)].

Significant anemia may present with pallor, hypotension, or tachycardia while acute renal insufficiency may present with oliguria or anuria, edema and dyspnea. Patients with IVH who develop DIC may exhibit signs and symptoms of increased bruising and prolongation of bleeding time and clotting time which may be difficult to detect in the ITP population. Consequently, the diagnosis of this serious complication of IVH is dependent on laboratory testing [see Warnings and Precautions (5.9)]. Previous uneventful administration of WinRho SDF does not preclude the possibility of an occurrence of IVH and its complications following any subsequent administration of WinRho SDF. Have confirmatory laboratory testing on ITP patients presenting with signs and/or symptoms of IVH and its complications after anti-D administration [see Warnings and Precautions (5.9)]

If ITP patients are to be transfused, use Rh_o(D)-negative red blood cells (PRBCs) so as not to exacerbate ongoing hemolysis.

5.4 Transmissible Infectious Agents

Because WinRho SDF is made from human plasma; it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of transmitting an infectious agent has been reduced by screening plasma donors for prior exposure to certain pathogens, testing for the presence of certain current viral infections, and including virus inactivation/removal steps in the manufacturing process [see Description (11)].

Report all infections thought to have been transmitted by WinRho SDF to Saol Therapeutics Inc. at 1-833-644-4216. The physician should discuss the risks and benefits of this product with the patient.

5.5 Acute Renal Insufficiency/Failure

Acute renal insufficiency/failure, osmotic nephropathy, acute tubular necrosis, proximal tubular nephropathy, and death may occur upon use of Immune Globulin Intravenous (IGIV) products, including WinRho SDF. ² Ensure that patients are not volume depleted before administering WinRho SDF. For patients at risk of renal insufficiency or failure, including those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs, administer WinRho SDF at the minimum infusion rate practicable and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of WinRho SDF and at appropriate intervals thereafter.

5.6 Thromboembolic Events

Thromboembolic events may occur during or following treatment with WinRho SDF and other IGIV products. ^3,4 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, history of arterial or venous thrombosis, estrogen use, indwelling central vascular catheters, and/or known/suspected hyperviscosity. Thrombosis may occur in the absence of known risk factors.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients who are at risk of developing thromboembolic events, administer WinRho SDF at the minimum rate of infusion practicable.

5.7 Interference with Serological Testing

After administration of WinRho SDF, a transitory increase of various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, C and E) and other blood group antibodies [for example, anti Duffy, anti Kidd (anti JKa) antibodies] ⁵ may cause a positive direct or indirect (Coombs') test.

A large fetomaternal hemorrhage late in pregnancy or following delivery may cause a weak mixed field positive D ^u test result. Assess such an individual for a large fetomaternal hemorrhage and adjust the dose of WinRho SDF accordingly. The presence of passively administered anti Rh_o(D) in maternal or fetal blood can lead to a positive direct Coombs' test. If there is an uncertainty about the father’s Rh group or immune status, administer WinRho SDF to the mother.

5.8 Transfusion-Related Acute Lung Injury (TRALI)

Non-cardiogenic pulmonary edema may occur in patients following IGIV treatment, including WinRho SDF. ⁶ TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following administration of blood products.

Monitor patients for pulmonary adverse reaction. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.

5.9 Monitoring: Laboratory Tests

• For all ITP patients, blood type, blood count, reticulocyte count, DAT and dipstick urinalysis are recommended before deciding to treat patients with WinRho SDF. In patients with evidence of hemolysis (reticulocytosis greater than 3%), or patients at risk of hemolysis (positive DAT not attributed to previous immune globulin administration) use other treatments. ¹
• Closely monitor patients administered WinRho SDF for at least 8 hours post administration and perform a dipstick urinalysis to monitor for hematuria and hemoglobinuria at baseline and then after administration at 2 hours, 4 hours and prior to the end of the monitoring period.
• If signs and/or symptoms of IVH and its complications are present after anti-D administration, perform appropriate confirmatory laboratory testing including, but not limited to, CBC (i.e. hemoglobin, platelet counts), haptoglobin, plasma hemoglobin, urine dipstick, 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).
• Periodic monitoring of renal function and urine output in patients who are at increased risk of developing acute renal failure [see Warnings and Precautions (5.5)]. Assess renal function in these at-risk patients, including measurement of BUN and serum creatinine, before the initial infusion of WinRho SDF and at appropriate intervals thereafter.
• If TRALI is suspected in ITP patients, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient serum [see Warnings and Precautions (5.9)].

5.10 Interference with Blood Glucose Testing: False High Blood Glucose Levels

The liquid formulation of WinRho SDF contains maltose. Maltose in IGIV products has been shown to give falsely high blood glucose levels in certain types of blood glucose testing systems [for example, by systems based on glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods]. Due to the potential for falsely elevated glucose readings, only use testing systems that are glucose-specific to test or monitor blood glucose levels in patients receiving maltose-containing parenteral products, including WinRho SDF Liquid.

Carefully review the product information of the blood glucose testing system, including that of the test strips, to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products.

5.11 Suppression of Rh Isoimmunization

Do not administer WinRho SDF to Rh_o(D)-negative individuals who are Rh immunized as evidenced by an indirect antiglobulin (Coombs') test revealing the presence of anti-Rh_o(D) (anti-D) antibody. For postpartum use following an Rh-incompatible pregnancy administer WinRho SDF to the mother only. Do not administer to the newborn infant.

Serious adverse reactions, some of these cases resulted in fatal outcome, have been observed in patients receiving WinRho SDF for the treatment of ITP. These include: intravascular hemolysis (IVH), clinically compromising anemia, acute renal insufficiency and DIC [see Adverse Reactions, (6.2)].

The most common adverse reactions observed for all indications are: headache, chills, fever, asthenia, pallor, diarrhea, nausea, vomiting, arthralgia, myalgia, dizziness, hyperkinesia, abdominal or back pain, hypotension, hypertension, increased LDH, somnolence, vasodilation, pruritus, rash and sweating. All adverse reactions listed occurred in ≤2% of WinRho SDF doses administered in clinical trials.

Adverse reactions observed in the use of WinRho SDF for Suppression of Rh Isoimmunization are <0.1% in Rh_o(D)-negative individuals.

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

Treatment of ITP

The safety of WinRho SDF was evaluated in clinical trials (n=161) in children and adults with acute and chronic ITP and adults and children with ITP secondary to HIV. Overall, 417 adverse events were reported by 91 patients (57%). The most common adverse events were headache (14% of the patients), fever (11% of the patients) and asthenia (11% of the patients). A total of 117 adverse drug reactions were reported by 46 patients (29%). Headache, chills, and fever were the most common related adverse events (Table 5). With respect to safety profile per administration, 60/848 (7%) of WinRho SDF infusions had at least one adverse reaction. The most common adverse reactions were headache (19 infusions; 2%), chills (14 infusions; <2%), and fever (9 infusions; 1%).

Table 5. Adverse Drug Reactions with an Incidence ≥5% of Patients:

In four clinical trials of patients treated with the recommended initial intravenous dose of 250 IU/kg (50 mcg/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 mcg/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).

Suppression of Rh Isoimmunization

In the clinical trial of 1,186 Rh_o(D)-negative pregnant women, no adverse reactions were reported to Rh_o(D) IGIV.

The following adverse reactions listed by body system have been identified during the post-approval use of WinRho SDF. Because post-marketing 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.

Intravascular hemolysis (IVH) leading to death has been reported in patients treated with WinRho SDF for immune thrombocytopenic purpura (ITP).

Serious complications including severe anemia, acute renal insufficiency, renal failure and disseminated intravascular coagulation (DIC) have also been reported.

Blood and Lymphatic: Intravascular hemolysis, disseminated Intravascular coagulation, hemoglobinemia

Cardiac: Cardiac arrest, cardiac failure, myocardial infarction, tachycardia

Gastrointestinal: Nausea

General: Chest pain, fatigue, edema, pain

Hepatobilliary: Jaundice

Immune System: Anaphylactic reaction/shock, hypersensitivity, injection site reaction including induration, pruritus and/or swelling

Musculoskeletal: Myalgia, muscle spasm, pain in extremities

Renal: Renal failure, anuria, chromaturia, hematuria, hemoglobinuria

Respiratory: Acute respiratory distress syndrome, dyspnea, transfusion related acute lung injury

Skin: Hyperhidrosis, pruritus, rash

Healthcare professionals should report serious adverse reactions following the administration of WinRho SDF to Saol Therapeutics Inc. at 1-833-644-4216 or FDA’s MedWatch reporting system by phone (1-800-FDA-1088).

7.1 Live Virus Vaccines

Administration of WinRho SDF concomitantly with other drugs has not been evaluated. 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 [17.1]). Do not give immunization with live vaccines within 3 months after WinRho SDF administration.

Risk Summary

For the treatment of ITP, there is no human data or animal data available to establish the presence or absence of drug-associated risk.

When administered to pregnant women in a clinical trial to evaluate WinRho SDF for suppression of Rh isoimmunization [see Clinical Studies (14.2)] following dosing regimens similar to Table 2 [see Dosing and Administration (2.1)], WinRho SDF was not shown to harm the fetus or newborn.¹²

Risk Summary

There is no information regarding the presence of WinRho SDF in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WinRho SDF and any potential adverse effects on the breastfed infant from WinRho SDF or from the underlying maternal condition.

The safety and effectiveness of WinRho SDF has been evaluated for the treatment of chronic or acute ITP in children and in children (<16 years of age) with ITP secondary to HIV infection [see Adverse Reactions (6.2)]. The dosing recommendation in the treatment of children with ITP is the same as in adults [see Dosage and Administration (2.1)].

8.5 Geriatric Use

Clinical studies of WinRho SDF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post marketing clinical experience suggests that patients of advanced age (age over 65) with co-morbid conditions including but not limited to cardio-respiratory decompensation, renal failure or insufficiency or prothrombotic conditions are at increased risk of developing serious complications from acute hemolytic reactions such as IVH. Patients receiving doses in excess of 300 IU/kg of WinRho SDF may also be at an increased risk of developing increased hemolysis. Fatal outcomes associated with IVH and its complications have occurred most frequently in patients of advanced age (age over 65) with co-morbid conditions.

Given the prevalence of co-morbid conditions and concomitant drug therapy in geriatric patients, consider starting at the low end of the dosing range when using WinRho SDF in this population.