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Human normal immunoglobulin for intravenous administration
Unmodified immunoglobulin G (IgG) of human origin, supplied in units of 6 g, At least 96% of the total protein is IgG (at least 90% of it as monomers or dimers). The remainder consists of IgG fragments, albumin, small amounts of IgA (maximum 40 mg/g protein), polymeric IgG and traces of IgM. The distribution of the IgG subclasses closely resembles that in normal human plasma.
Sucrose (1.64-1.69g/l per g protein) is added as a stabilizer, and the preparation also contains traces of sodium chloride (see List of excipients).
Sandoglobulin is a polyvalent human immunogloublin product possessing a broad spectrum of opsonic and neutralising antibodies against bacteria, viruses and other pathogens.
Lyophilized powder for solution for intravenous administration.
Sandoglobulin is indicated for the treatment of patients in whom substitution of naturally occurring antibodies is clinically appropriate.
Established uses include:
Sandoglobulin® is administered as an intravenous infusion.
The dose and dosage regimens to be used depend on the indication (replacement or immunomodulation), the patient's immune status, the severity of the disease, and individual tolerance. The dosage may need to be individualized for each patient. The following dosage regimens are guidelines only.
The recommended starting dose is 0.4-0.8 g/kg body weight (most commonly 0.4 g/kg body weight), given at intervals of 3 to 4 weeks.
The dose and dosage interval should be adjusted to maintain a trough plasma concentration of IgG of at least 4-6 g/L. Three to 6 months are required after the initiation of therapy to reach the desired trough level. The dose required to reach a trough level of 6 g/L is of the order of 0.2-0.8 g/kg body weight/month. The dosage interval when steady state has been reached varies from 2 to 4 weeks.
0.2-0.4 g/kg body weight at intervals of 3-4 weeks. For the prevention of infection in bone marrow allograft recipients, the recommended dose is 0.5 g/kg body weight; it may be given once, 7 days before transplantation, and be repeated at weekly intervals during the first 3 months after transplantation and at monthly intervals for the subsequent 9-month period.
For initial therapy, 0.4 g/kg body weight given on 2-5 consecutive days, or 0.8-1 g/kg body weight once or on days 1 and 3. If necessary, this should be followed by 0.4 g/kg body weight given at 1-week to 4-week intervals in order to maintain an adequate platelet count.
1.6-2.0 g/kg body weight given in divided doses over 2-5 days, or 2 g as a single dose, usually as a supplement to standard therapy with acetylsalicylic acid preparations.
Depending on the patient's requirements, the lyophilized powder can be dissolved in 0.9% sodium chloride, water for injection, or 5% dextrose. The concentration of Sandoglobulin in any of these solutions for i.v. infusion may range from 3% to 12%, depending on the volume used. It should be noted that a 3% solution of Sandoglobulin in water for injection is hypotonic (192 mOsm/kg).
Patients being treated with Sandoglobulin for the first time should be given a 3% infusion at an initial rate of 0.5 -1.0 mL/min (approximately 10-20 drops/min with a normal adult infusion set). If no adverse reactions occur within 15 minutes, the rate may be gradually increased to a maximum of 2.5 mL/min (approximately 50 drops/min with a normal adult infusion set). In small children the infusion should be given at an initial rate of 1-2 mg/kg body weight/min.
In patients receiving Sandoglobulin regularly and tolerating it well, higher concentrations (up to a maximum of 12%) may be used, but the infusion should always start at a low rate, and close monitoring of the patient is required when the rate is gradually increased.
Hypersensitivity to human immunoglobulins, especially in patients with IgA deficiency known to have antibodies to IgA.
Patients with agammaglobulinemia or severe hypogammaglobulinemia who have never received immunoglobulin replacement therapy, or whose time from last treatment is greater than 8 weeks, may be at risk of suffering from anaphylactoid reactions, occasionally leading to shock, when receiving intravenous immunoglobulin (IVIG) as a rapid infusion. In such patients, rapid infusion must therefore be avoided; vital signs should be monitored continuously, and careful surveillance of the patient is required throughout the infusion. Adrenaline and a parenteral corticosteroid preparation should be available for treatment of a possibly occurring anaphylactoid reaction (see Undesirable effects).
Very rarely, IVIG may cause a precipitous fall in blood pressure associated with the clinical signs of anaphylaxis even in patients in whom previous administration of immunoglobulin preparations was well tolerated.
Since serious adverse reactions, which may be of the anaphylactoid type, occur either shortly after the start of administration or, often, within the next 30-60 minutes, patients should be observed for at least 20 minutes after administration.
As with other IVIG preparations, cases of transient increase in creatinine levels have been rarely reported after Sandoglobulin administration, leading to acute renal failure in some patients, especially in elderly patients with diabetes or pre-existing impairment of renal function. Most patients presented with multiple risk factors and the majority was receiving IVIG for the first time. More than 50% of the patients who developed acute renal failure, received > 0.4 g/kg body weight per day. Although in most cases the increase was mild, transient (5-12 days) and noted 2-5 days after the infusion, supportive therapy may occasionally be required. Patients presenting with the above conditions should be adequately hydrated prior to the infusion and they or their guardian should be instructed to report noteworthy decreases in urine output.
A few cases of usually mild hemolysis have been reported after infusion of Sandoglobulin as well as with other IVIG preparations. They were attributed to transferral of blood-type antibodies and appear to be promoted by concomitant blood transfusion.
Primarily in patients presenting with idiopathic thrombocytopenic purpura and receiving high IVIG doses, aseptic meningeal irritation with transient alteration of cerebrospinal fluid has been reported after the infusion of Sandoglobulin as well as with other IVIG preparations. Discontinuation has resulted in remission within several days.
When medicinal products prepared from human blood or plasma are administered, infectious diseases due to transmission of infective agents cannot be totally excluded despite careful donor selection, screening of donations, and virus inactivation steps during manufacture. This also applies to pathogens of as yet unknown nature. (See also Safety with regard to viral infection).
The 'Instructions for use/handling' should be carefully followed. Shaking the bottle resulting in foaming must be avoided. The reconstituted product should be inspected visually for particulate matter. The solution should be used only if it is clear. Once prepared, it should be infused without delay. Partially used bottles should be discarded.
Sandoglobulin should not be mixed with any other drug and should always be given through a separate infusion line.
The effectiveness of an active immunization can be reduced by simultaneous treatment with IVIG. Immunoglobulin administration may impair the efficacy of live-attenuated virus vaccines such as measles, rubella, mumps, and varicella. Impairment can last up to 1 year. In children who receive doses of 0.4 g-1.0 g/kg body weight IVIG for repeat treatment of idiopathic thrombocytopenic purpura or for other disorders, measles vaccine should be deferred for at least 8 months.
After the administration of immunoglobulin, the transitory rise of the passively transferred antibodies into the patient's blood may lead to false positive results in serological testing.
No animal reproduction studies with Sandoglobulin have been performed, and experience in pregnant women is limited. Although no adverse effects on the foetus or on reproduction capacity have been reported, Sandoglobulin should be given to pregnant women only if clearly needed.
Being normal constituents of human plasma, the proteins contained in Sandoglobulin are likely to be excreted into breast milk without having an adverse effect on the breast-fed infant. They may contribute to the transfer of protective antibodies to the neonate.
There is no evidence that Sandoglobulin affects the patient's ability to drive or use machines.
Patients naive to IgG usually experience a higher frequency of adverse events, also of minor nature, than those well maintained on regular therapy.
If the contraindications, precautions for use, and recommendations for dosage and administration are observed (see corresponding sections), severe adverse reactions to Sandoglobulin are rare.
Less severe reactions which are commonly observed during or after the infusion include: headache, hyperthermia, nausea, vomiting, diarrhoea, fatigue, malaise, dizziness, chills, sweating, back pain, myalgia, flushing. Uncommon adverse reactions are: abdominal pain, cyanosis, dyspnea, feeling of tightness or pain in the chest, rigor, pallor, hypertension, hypotension, tachycardia. Most of these effects are related to the rate of infusion, and may be relieved by reducing the rate or temporarily stopping the infusion.
In a few patients, skin reactions including eczema have been observed several days after the administration of Sandoglobulin.
Severe hypotension, circulatory collapse and loss of consciousness are very rare events. If such reactions occur, the infusion should be discontinued until the symptoms have subsided, and therapy with adrenaline, corticosteroids, an antihistamine, and i.v. fluid may be indicated.
As with other IVIG preparations, transient renal dysfunction, hemolysis and meningeal irritation have been reported in a few patients (see Special warnings and special precautions for use).
No case of overdosage of Sandoglobulin has ever been reported; should it occur, no serious effects would be expected.
Pharmacotherapeutic group: Normal human immunoglobulin.
Sandoglobulin is a polyvalent human immunoglobulin product for i.v. infusion, possessing a broad spectrum of opsonic and neutralizing antibodies against bacteria, viruses, and other pathogens. In patients with primary or secondary immunodeficiency syndromes, Sandoglobulin replaces missing IgG antibodies, thereby reducing the risk of infection. In some other disorders of immune function, e.g. idiopathic (immune) thrombocytopenic purpura (ITP) and Kawasaki syndrome, the mechanism of action responsible for the beneficial effects of Sandoglobulin is not fully understood.
Being administered by i.v. infusion, 100% of the Sandoglobulin dose is immediately available in the patient's circulation. Thereafter, distribution between plasma and the extravascular compartment takes place and reaches equilibrium within approximately 7 days.
The antibodies present in Sandoglobulin possess the same pharmacokinetic characteristics as those of endogenous IgG. The biological half-life of IVIG is 21 days on average in subjects with normal IgG serum levels, whereas in patients with primary hypogammaglobulinemia or agammaglobulinemia treated with Sandoglobulin, the average half-life of total IgG was found to be 32 days. There are, however, considerable interindividual variations, which may be important in determining the individual dosage regimen.
Sandoglobulin is prepared from plasma obtained from non-remunerated healthy donors, who must as far as can be ascertained from their medical history, after clinical examination, and laboratory tests on their blood - be free from detectable agents of infection transmissible by transfusion of blood or blood derivatives. In particular, tests for hepatitis B surface antigen (HBsAg), antibodies directed to human immunodeficiency virus type 1 and type 2 (HIV-1/HIV-2), and hepatitis C virus (HCV), and elevated ALAT are carried out by accredited methods and must give negative results. In addition, the testing for HBsAg, HIV-1/2 and HCV antibodies is repeated on the plasma pools.
The cold ethanol fractionation is carried out according to the Kistler-Nitschmann process.
Virus removal and inactivation steps are included in the Sandoglobulin manufacturing process. The fractionation procedure by which Sandoglobulin is prepared from plasma includes several steps validated for elimination of enveloped and non-enveloped viruses. Overall viral clearance by elimination and inactivation has been documented for a variety of model viruses. The safety of the manufacturing method of Sandoglobulin was established by a virus inactivation study, which showed that the pepsin/pH 4 step used in the manufacturing process possesses inactivation capacity on the following test viruses: HIV-1 (enveloped retrovirus), pseudorabies virus (enveloped DNA virus), bovine viral diarrhoea virus (enveloped RNA virus, model for HCV), and bovine parvovirus (non-enveloped DNA virus, model for non-enveloped viruses, e.g. human parvovirus B 19).
Sandoglobulin given by i.v. infusion to laboratory animals in doses several times the therapeutic doses in man did not exert any toxic effects. However, toxicological testing in animals is of little predictive value for human use since
Being normal constituents of the human body, the proteins contained in IVIG preparations can be considered to be nontoxic in man. The broad clinical use of Sandoglobulin and other immunoglobulin preparations over more than 10 years has not revealed any toxic, mutagenic, or tumorigenic potential.
Sucrose
NaCl
Sandoglobulin contains no preservatives.
Sandoglobulin should not be mixed with any other pharmaceutical product.
4 years.
Keep in the original package (protect from light), do not store above 25° C, do not freeze.
Do not use after the expiry date.
Sandoglobulin is filled in infusion bottles (glass type II, surface treated).
Sandoglobulin 6 g: 250 mL bottle
Each pack contains a detailed instruction leaflet describing dissolution of the lyophilized powder. Reconstituted products should be inspected visually for particulate matter and discoloration prior to administration. Products which are not clear or have a sediment shall not be used.
Prescription Medicine (Blood Product)
CSL New Zealand Limited
666 Great South Road
Central Park
Penrose
AUCKLAND
Telephone: 0800 502757
15 October, 2002
(Ref: BPI 20/10/98)