Special Warning : אזהרת שימוש

WARNINGS
Intravascular Hemolysis (IVH)

Intravascular hemolysis (IVH) leading to death has been reported in patients treated for immune thrombocytopenic purpura (ITP) with Rh0D immune Globulins.
IVH can lead to clinically compromising anemia and multi-system organ failure including acute respiratory distress symdrome (ARDS).
Serious complications including severe anemia, acute renal insufficiency, renal failure and disseminated intravascular coagulation (DIC) have also been reported.
Closely monitor patients treated with KamRho-D I.V. for ITP in a health care setting for at least eight hours after administration. Perform a dipstick urinalysis at baseline, 2 hours, 4 hours after administration 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 hematuria. 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 KamRho-D I.V. administration, post-treatment laboratory tests should be performed including plasma hemoglobin.


Recommendations Regarding Thrombosis
•   Care should be used when immune globulin products are given to individuals determined to be at increased risk of thrombosis.
•   Patients at increased risk of thrombosis include those with acquired or hereditary hypercoagulable states, prolonged immobilization, in-dwelling vascular catheters, advanced age, estrogen use, a history of venous or arterial thrombosis, cardiovascular risk factors (including history of atherosclerosis and/or impaired cardiac output), and hyperviscosity (including cryoglobulins, fasting chylomicronemia and/or high triglyceride levels, and monoclonal gammopathies).
•   As noted in product labeling, patients at risk for thrombosis should receive immune globulin products at the slowest infusion rate practicable, and these individuals should be monitored for thrombotic complications.
•   Consideration should also be given to measurement of baseline blood viscosity in individuals at risk for hyperviscosity.

For patients judged to be at risk of developing thrombotic events, administer Rh 0 D immune Globulins at a minimum rate of infusion.



Recommendations Regarding Hemolysis

•   Heightened awareness of the potential for hemolysis is recommended in individuals receiving immune globulin products, particularly those who are determined to be at increased risk.
•   Patients at increased risk for hemolysis following treatment with immune globulins include those with non-O blood group types, those who have underlying associated inflammatory conditions, and those receiving high cumulative doses of immune globulins over the course of several days.
•   As noted in product labeling, patients receiving immune globulin products should be monitored for hemolysis, particularly those at increased risk.
•   Clinical symptoms and signs of hemolysis include fever, chills and dark urine. If these occur, appropriate laboratory testing should be obtained.


Route of Administration
KamRho-D I.V. must be administered only intravenously. The solution must be withdrawn from the vial using the provided Filter Needle. See Instructions for use and handling.
For the suppression of Rh alloimmunization, administer to the mother. Do not administer to the infant.

Patients should be observed at least 20 minutes after administration.

If symptoms of an anaphylactic reaction or other allergic reactions occur, the injection should be discontinued immediately.

Transmissible Infectious Agents
KamRho-D I.V. is made of human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current viruses (see DESCRIPTION). Despite these measures, such products can still potentially transmit disease. Because this product 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.
All the infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Kamada Ltd. The physician should discuss the risks and benefits of this product with the patient.


PRECAUTIONS

General
Each plasma unit used in manufacturing KamRho-D I.V. has been tested in accordance with FDA regulations.
The process includes Solvent/Detergent and heat treatment to inactivate non-enveloped viruses. In addition, the purification process itself has been shown to reduce non-enveloped viruses by several logs.
However, the possibility of transmission of infectious disease cannot be excluded. As with all preparations administered by the I.V. route, bleeding complications may be encountered in patients with thrombocytopenia or other bleeding disorders. KamRho-D (Human) should not be administered to Rho (D) negative individuals who are Rh immunized as evidenced by standard Rh antibody screening tests.

A large fetomaternal hemorrhage late in pregnancy or following delivery may cause a weak mixed field u positive D test result. Such an individual should be assessed for a large fetomaternal hemorrhage and the dose of KamRho-D I.V. adjusted accordingly.

Hypersensitivity
Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. KamRho-D I.V. is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction (see CONTRAINDICATIONS).
True hypersensitivity reactions are rare, but allergic responses to anti-D immunoglobulin may occur.
Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, chest tightness, wheezing, hypotension and anaphylaxis. The treatment required depends on the nature and severity of the side effect. In case of shock, the standard medical treatment for shock should be implemented.

Renal failure
In general, acute renal failure (ARF) is reported to be associated with the administration of Intravenous Immunoglobulin (IGIV) products. KamRho-D I.V. does not contain sucrose or any other sugar as a stabilizer. Nevertheless, it is recommended that renal function be assessed prior to and following IV administration of KamRho-D I.V., especially in patient at risk of developing ARF. In these patients, the IVIG product should be administrated at the minimum practical dosage and rate of infusion.

It is recommended that, whenever possible, each time KamRho-D I.V. is administrated, the name and batch number of the product is recorded in the patient file.

Criteria for KamRho-D I.V. Administration to Prevent Alloimmunization The criteria for an Rh-incompatible pregnancy requiring administration of Rho (D) immune globulin at 28 weeks gestation and within 72 hours after delivery are: The mother is Rho (D) antigen-negative; the mother is bearing a child whose father is either Rho (D) antigen-positive or Rho (D) unknown; the infant is either Rho (D) antigen-positive or Rho (D) unknown; the mother was not previously sensitized to the Rho (D) antigen (and thus does not carry anti-Rho (D) antibodies).

For Treatment of ITP:
For the treatment of ITP do not administer to Rho (D) antigen-negative individuals. Its efficacy in splenectomized patients has not been clearly demonstrated.

Post marketing surveillance of different Rh0 (D) immune globulin intravenous (Anti-D IGIV) products indicates some rare but serious adverse events associated with the use of Anti-D IGIV for treatment of ITP (See ADVERSE REACTIONS). Physicians should discuss the risks and benefits of KamRho-D I.V.
and alert patients who are being treated for ITP, about the signs and symptoms associated with these rare serious adverse events

Following administration of KamRho-D I.V., Rho(D) positive ITP patients should be monitored for signs and/or symptoms of acute hemoglobinemia or hemoglobinuria or IVH and its complications, compromising anemia, and renal insufficiency as well as signs and symptoms of disseminated intravascular coagulation (DIC), which include:

•   hemoglobinuria
•   pallor
•   hypotension
•   tachycardia
•   oliguria or anuria
•   edema
•   chest pain
•   dyspnea
•   increased bruising and prolongation of bleeding time and clotting time which may be difficult to detect in the ITP population.

The diagnosis of a serious complication of an acute hemoglobinemia or hemoglobinuria is dependent on laboratory testing.

Previous, uneventful administration of anti-D IGIV provides no assurance that a subsequent [4] administration will be uneventful

Patients being treated for ITP should be instructed to immediately report symptoms of back pain, shaking chills, fever, discolored urine, decreased urine output, sudden weight gain, fluid retention/edema, chest pain and/or shortness of breath, to their physicians.

If transfusion is indicated, Rho(D) negative packed red blood cells (PRBC) should be used so as not to exacerbate ongoing acute hemoglobinemia or hemoglobinuria. Platelet products may contain up to 5.0 mL of red blood cells; thus caution should likewise be exercised if platelets from Rh o (D) positive donors are transfused.

If the patient’s hemoglobin level is lower than 10 g/dL, a reduced dose should be administered )See ADMINISTRATION and DOSAGE). In patients with hemoglobin levels that are less than 8 g/dL, alternative treatments should be sought due to the risk of increasing the severity of anemia.

ITP patients should be carefully monitored for any symptoms throughout the infusion period. In particular, patients naïve to human immunoglobulin, patients switched from an alternative product or when there has been a long interval since the previous infusion. Patients should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs.

In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the side effect.


Thrombotic Events
Thrombotic events may occur following treatment with Rh0D immune Globulins (see Warnings). For patients judged to be a risk of developing thrombotic events, administer Rh0D immune Globulins at a minimum rate of infusion.

Hemolysis
Although the mechanism of action of Rh0 D immune Globulins in the treatment of ITP is not completely understood, it is postulated that anti-D binds to the Rh0(D) RBC resulting in formation of antibody-coated RBC complexes. Immune-medicated 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. The side effects of this reaction is a decrease in hemoglobin levels (extravascular hemolysis). The pooled data from ITP clinical studies demonstrated a maximum decrease from baseline in hemoglobin levels of 1.2 g/dL within 7 days after administration of Rh0D immune Globulins.

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 µg/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 ADMINISTRATION and DOSAGE) 
Transfusion-related Acute Lung Injury (TRALI)
Noncardiogenic pulmonary edema may occur in patients following IGIV treatment. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function. Symptoms typically appear within 1 to 6 hours following treatment.

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

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