1. Name Of The Medicinal Product
Human Rabies Immunoglobulin
2. Qualitative And Quantitative Composition
Human Rabies Immunoglobulin Ph.Eur.*
Human Rabies Immunoglobulin is presented as a vial size of 500 iu. Each millilitre contains: 40-180 mg/ml human protein of which at least 95% are gammaglobulins. This product is prepared from plasma from screened donors. Donors are selected from the USA.
* One millilitre contains not less than 150 iu of rabies antibody.
3. Pharmaceutical Form
Solution for injection.
4. Clinical Particulars
4.1 Therapeutic Indications
The use of Human Rabies Immunoglobulin is specified in the World Health Organisation (WHO) guidelines for specific systemic treatment. These guidelines are outlined in the table below:
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a This observation period applies only to dogs and cats. Other domestic and wild animals suspected as rabid should be killed and examined using the fluorescent antibody techniques.
b All unprovoked bites in endemic areas should be considered suspect unless proved negative by laboratory examination of the animal's brain.
c During the usual period of 10 days, begin treatment with vaccine at first sign of rabies in a dog or cat that has bitten someone. The symptomatic animal should be killed immediately and examined using the fluorescent antibody technique.
d Or if the animal's brain is found to be negative by fluorescent antibody examination.
e In general, exposure to rodents, rabbits and hares seldom, if ever, requires specific anti-rabies treatment.
4.2 Posology And Method Of Administration
4.2.1 Posology
The recommended dose for both children and adults is 20 iu/kg body weight. Up to half of the dose should be injected into and around the wound after thorough cleansing and the remainder given by intramuscular injection.
DO NOT EXCEED THE RECOMMENDED DOSE, because this may affect the response to the rabies vaccine.
4.2.2 Method of administration
Human Rabies Immunoglobulin should be administered by slow injection via the intramuscular route only. Human Rabies Immunoglobulin and rabies vaccine should be administered with separate syringes and into different injection sites with separate lymphatic drainage.
Up to half of the calculated amount should be infiltrated around the wound. This should be administered intramuscularly, as far as possible in the region affected.
The remainder must be injected intramuscularly at a different site, preferably intra-gluteally.
If large total doses (
In the case of clotting disorders where intramuscular injections are contra-indicated, Human Rabies Immunoglobulin may be administered subcutaneously. Careful manual pressure with a compress should be applied to the site after the injection.
Human Rabies Immunoglobulin is for single injection only; any used materials and unused solution should be discarded by approved means.
4.3 Contraindications
The lethal risk associated with rabies outweighs any potential contra-indication - see the special warnings section, below.
4.4 Special Warnings And Precautions For Use
Human Rabies Immunoglobulin must not be administered intravenously, because the preparation may cause severe reactions if given by this route.
Injections should be made intramuscularly and care should be taken to draw back the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel.
It is imperative that the stated dose is not exceeded, as this could affect the immune response to the vaccine, administered at the same time.
True allergic reactions to Human Rabies Immunoglobulin are rare, when administered by the prescribed intramuscular route. In the case of shock, treatment should follow the guidelines for therapy of shock.
Suspicion of allergic or anaphylactic type reaction requires the injection be discontinued immediately.
Patients should be observed for at least twenty minutes after administration.
In the case of clotting disorders where intramuscular injections are normally contra-indicated, the patient should receive the appropriate medication for the disorder or the injection given subcutaneously. Careful manual pressure with a compress should be applied to the site after the injection.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
4.5.1 Rabies vaccine
Human Rabies Immunoglobulin may reduce the immune response to rabies vaccine, if the recommended dosage is exceeded. Human Rabies Immunoglobulin and rabies vaccine should be administered with separate syringes and into different injection sites with separate lymphatic drainage.
4.5.2 Live attenuated virus vaccines
Human Rabies Immunoglobulin administration may interfere with response to live virus vaccines, such as measles, rubella, mumps and varicella, for a period of at least six weeks and up to three months. Such vaccinations should only be given after an interval of three months after administration of Human Rabies Immunoglobulin.
4.5.3 Interference with serological testing
After injection of immunoglobulin, the transitory rise of the passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.
4.6 Pregnancy And Lactation
There is inadequate evidence of safety in human pregnancy, but intramuscular immunoglobulins, especially Anti-D Immunoglobulin, have been widely used during pregnancy for many years without apparent ill consequence. No animal studies have been carried out. Human Rabies Immunoglobulin should be given to a pregnant woman or breast-feeding mother only if clearly needed. The transplacental passage of Human Rabies Immunoglobulin may be assumed. The transfer of immunoglobulin G into the newborn during breast-feeding may be assumed.
The risk/benefit of Human Rabies Immunoglobulin administration should be assessed for each individual case.
4.7 Effects On Ability To Drive And Use Machines
There are no indications that Human Rabies Immunoglobulin may impair the ability to drive or use machines.
4.8 Undesirable Effects
As with all intramuscular injections, some short term discomfort can be expected at the injection site. In rare instances local induration can occur. Deep intramuscular injection can reduce the risk. Human Rabies Immunoglobulin is well tolerated, although very rarely, anaphylactic reactions may occur in patients, usually with primary antibody deficiency, who have antibodies to IgA, or in patients who have had an atypical reaction to blood transfusions or treatment with plasma derivatives.
Other side effects which have been reported with intramuscular immunoglobulin are chest pain, dyspnoea, tremor, dizziness, facial oedema, glossitis, buccal ulceration and arthralgia.
To reduce the risk of transmission of infective agents, stringent controls are applied to the selection of blood donors and donations. In addition, virus removal and / or inactivation procedures are included in the production process.
All donations have been tested by validated procedures, and found to be non-reactive for recognised markers of virus infection (hepatitis B surface antigen, antibodies to HIV-1, HIV-2 and HCV). Plasma pools are also tested negative for these markers and additionally for HCV-RNA.
The organic solvent (Tri-n-butyl Phosphate, TnBP) and detergent (Polysorbate 80) treatment in BPL's Human Rabies Immunoglobulin manufacturing process is used for the inactivation of lipid enveloped viruses such as hepatitis B, hepatitis C and HIV. Viral inactivation combined with donor and product screening for hepatitis and human immunodeficiency viruses greatly reduces the likelihood of viral contamination of this product. In virus inactivation studies using a model lipid enveloped virus, the solvent detergent treatment stage of BPL's Human Rabies Immunoglobulin manufacturing process reduces virus infectivity to undetectable levels, i.e. a minimum 6 log reduction.
When medicinal products prepared from human blood or plasma are administered, the transmission of disease by infective agents of known, and as of yet unknown origin, cannot be totally excluded.
The current procedures applied in the manufacture of medicinal products derived from human blood or plasma are effective against enveloped viruses such as HIV, hepatitis B and hepatitis C viruses, but are of limited value against non-enveloped viruses such as hepatitis A virus.
4.9 Overdose
Human Rabies Immunoglobulin is a concentrate of the gammaglobulin fraction of human immune plasma. Overdosage is unlikely to lead to more frequent or more severe adverse reactions than the recommended dose.
Overdose of Human Rabies Immunoglobulin may reduce the immune response to rabies vaccine, administered at the same time.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: immune sera and immunoglobulins: Rabies Immunoglobulin. ATC code: J06B B05.
The pharmacodynamic effects in vivo of the specific neutralising antibodies against rabies virus is not fully documented, but Rabies Immunoglobulin has been proven to be effective in preventing the rabid infection.
5.2 Pharmacokinetic Properties
Measurable levels of antibodies to rabies are found in serum approximately twenty minutes after intramuscular injection. Peak serum levels are achieved two to three days later.
The biological half-life is 21-22 days, i.e. that time taken for a 50% reduction of peak concentration in the plasma.
5.3 Preclinical Safety Data
Human Rabies Immunoglobulin is a preparation of human plasma proteins, so safety testing in animals is not particularly relevant to the safety of use in man. Acute toxicity studies in rat and mouse showed species specific reactions which bear no relevance to administration in humans. Repeated dose toxicity testing and embryo-fetal toxicity studies are impracticable due to the induction of, and interference with, antibodies to human protein. Clinical experience provides no sign of tumourigenic and mutagenic effects of immunoglobulins.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride
Glycine
Sodium acetate trihydrate
Sodium hydroxide
6.2 Incompatibilities
Pharmaceutical agents should not normally be added to Human Rabies Immunoglobulin as their effects on the product have not been established.
6.3 Shelf Life
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6.4 Special Precautions For Storage
Human Rabies Immunoglobulin should be stored in its carton between 2°C and 8°C. Storage for up to one week at ambient temperatures (25°C) in the original container is not detrimental. DO NOT FREEZE.
6.5 Nature And Contents Of Container
Neutral borosilicate glass vial (type I Ph.Eur.) with overseal consisting of a halobutyl rubber wad (type I Ph.Eur.), clear lacquered aluminium skirt and flip-off polypropylene cap.
6.6 Special Precautions For Disposal And Other Handling
Human Rabies Immunoglobulin is for single use only; any used materials and unused solution should be discarded by approved means.
The condition of date-expired, or incorrectly stored product cannot be guaranteed. Such product may be unsafe, and should not be used.
Solutions which are cloudy or have deposits should not be used.
7. Marketing Authorisation Holder
Bio Products Laboratory
Dagger Lane
Elstree
Hertfordshire
WD6 3BX
United Kingdom.
8. Marketing Authorisation Number(S)
PL 08801/0014
9. Date Of First Authorisation/Renewal Of The Authorisation
February 1992
10. Date Of Revision Of The Text
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