Adverse reactions : תופעות לוואי

ADVERSE REACTIONS

The most serious adverse reactions have been observed in patients receiving KamRho-D I.V. for treatment of ITP. These include: intravascular hemolysis (IVH), clinically compromising anemia, acute renal insufficiency, DIC, and death. [See WARNINGS.]

Intravascular hemolysis (IVH) leading to death has been reported in patients treated for immune thrombocytopenic purpura (ITP) with Rh0D immune Globulins.

Occasionally fever, malaise, headache, cutaneous reaction and chills occur. In rare cases: nausea, vomiting, hypotension, tachycardia, and allergic or anaphylactic type reaction, including dyspnea and shock, are reported, even when the patient has shown no hypersensitivity to previous administration.

Rh Alloimmunization Suppression
Adverse reactions to Rho (D) immune globulin are infrequent in Rho (D) antigen-negative individuals.
Discomfort and swelling at the site of the injection and slight elevation in temperature might occur in a small number of cases. As is the case with all drugs of this nature, there is a remote chance of an anaphylactic reaction 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 0.3 ml 1:1000 aqueous solution should be immediately instituted, followed by intravenous administration of hydrocortisone, 50 to 100 mg, if necessary. Elevated bilirubin levels have been reported in some individuals receiving multiple doses of Rho (D) Immune Globulin (Human), following mismatched transfusions. This is believed to be due to a relatively rapid rate of foreign red cell destruction.

ITP
Side effects related to the destruction of Rho (D) antigen-positive red cells, such as decreased hemoglobin, can be expected. The most common adverse events are: headache, chills and fever. Such symptoms are commonly associated with infusions of immunoglobulins.
Among patients treated for ITP with anti-D IGIV, there have been rare postmarketing reports of signs and [5] symptoms consistent with acute hemoglobinemia or hemoglobinuria that included back pain, shaking chills, fever and discolored urine occurring, in most cases, within four hours of administration. Potentially serious complications of acute hemoglobinemia or hemoglobinuria that have also been reported include clinically compromising anemia, acute renal insufficiency or disseminated intravascular coagulation (DIC) that have, in some cases, been fatal. One case of acute respiratory distress syndrome (ARDS) was [4]                                                                         [4,5] reported . For further information please refer to the literature referenced below          .
Instruct patients being treated with KamRho-D I.V. for ITP to immediately report symptoms of intravascular hemolysis including back pain, shaking chills, fever, discolored urine, decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath to their physicians.
Prior to discharge, instruct patients to continue self-monitor for the signs and symptoms of IVH over 72 hours, especially for discoloration of urine, and to seek medical attention immediately in the event that signs/symptoms of IVH occur following KamRho-D I.V. administration.
If signs and/or symptoms of IVH and its complications are present after anti-D administration, appropriate confirmatory laboratory testing should be done that may include, but is 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).

ITP and suppression of RH Isoimmunization
Inform patient of the early signs of hypersensitivity reactions to KamRho-D I.V., including hives, generalized urticaria, chest tightness, wheezing, hypotension and anaphylaxis and advise them to notify their physician if they experience these symptoms.

The most common adverse reactions observed for all indications are: Headaches, chills, fever, asthenia, pallor, diarrhea, nausea, vomiting, myalgia, dizziness, hyperkinesia , abdominal or back pain, hypotension, hypertension, increased LDH, somnolence, vasodilatation, pruritus, rash and sweating. All adverse reactions listed occurred in≤2% of Rh0D immune Globulins doses administered in clinical trials.


Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il Additionally, you should also report to Kamada LTD to email address: pharmacovigilance@kamada.com

ADMINISTRATION and DOSAGE

KamRho-D I.V. must be administered only intravenously.

Pregnancy
A 300 g (1500 IU) dose of KamRho-D I.V. should be administered at 28 weeks gestation. If KamRho-D I.V. is administered early in the pregnancy, it is recommended that KamRho-D I.V. be administered at 
12-week intervals in order to maintain an adequate level of passively acquired anti-Rh immunity. A 120 g (600 IU) dose should be administered as soon as possible after delivery of a confirmed Rh o (D) positive baby and normally no later than 72 hours after delivery. In the event that the Rh status of the baby is not known at 72 hours, KamRho-D I.V. should be administered to the mother within 72 hours after delivery. If more than 72 hours have elapsed, KamRho-D I.V. should not be withheld, but administered as soon as possible up to 28 days after delivery.

Other Obstetric Conditions
A 120 g (600 IU) dose of KamRho-D I.V. should be administered immediately after abortion, amniocentesis (after 34 weeks gestation) or any other manipulation late in pregnancy (after 34 weeks gestation) associated with increased risk of Rh alloimmunization. Administration should take place within 72 hours after the event. A 300 g (1500 IU) dose of KamRho-D I.V. should be administered immediately after amniocentesis before 34 weeks gestation or after chorionic villus sampling. This dose should be repeated every 12 weeks while the woman is pregnant. In case of threatened abortion, KamRho-D I.V. should be administered as soon as possible.

Idiopathic Thrombocytopenic Purpura (ITP):
To raise the platelet count in appropriately selected patients with ITP, an initial dose of 50 g/kg (250 IU/kg) body weight of KamRho-D I.V. should be administered. If the patient’s hemoglobin level is < 10 g/dL, the dose should be reduced to 25-40 g/kg (125-200 IU/kg) body weight. Additional doses of between 25-60 g/kg body weight may be administered depending on the patient’s clinical response.
Treatment should be monitored by measuring the patient’s hemoglobin level, reticulocyte count, and platelet count. Patients who develop anemia after treatment may require lower doses, or discontinuation of the drug depending on the severity of the anemia.
In patients with hemoglobin levels that are less than 8g/dL, alternative treatments should be sought due to the risk of increasing the severity of anemia.


Injection
Parenteral products such as KamRho-D I.V. should be inspected for foreign particulate and discoloration prior to administration. The color may vary from colorless to pale yellow. Do not use solutions that are cloudy.


Intravenous Administration
The recommended dose may be injected into a suitable vein at a rate of 2 ml per 60 seconds. KamRho-D I.V. should be administered separately from other drugs.
In patients at risk for acute renal failure or thromboembolic adverse reactions, intravenous immunoglobulin products should be administered at the minimum infusion-rate practicable.


Laboratory Tests
The intrapartum administration of KamRho-D I.V. may result in a positive direct antiglobulin test in the baby after delivery. In rare cases, this may also put into question the true status of the infant’s Rh blood type. Appropriate laboratory tests should be performed to resolve such problems. The presence of administered KamRho-D I.V. in the maternal circulation may cause a positive indirect antiglobulin test. If there is uncertainty about mother’s Rh group or immune status, KamRho-D I.V. should be administered to the mother. The occurrence of a large feto-maternal hemorrhage late in pregnancy or at delivery may cause spurious mixed field agglutination reactions in an Rho (D) negative mother, and may result in her u being mistyped as Rho (D) positive or D . Such instances may indicate the need for a larger than normal dose of KamRho-D.

ITP patients presenting with signs and/or symptoms of acute hemoglobinemia or hemoglobinuria and its complications after anti-D IGIV administration should have confirmatory laboratory testing that may include, but are not limited to, CBC (i.e. hemoglobin, platelet counts), haptoglobin, plasma hemoglobin, PT and PTT, 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).