Tetanus Immunoglobulin-VF (For Intravenous Use)

MIMS Revision Date: 01 July 2021

Notes

Distributed by Australian Red Cross Lifeblood

1 Name of Medicine

Human tetanus immunoglobulin.

2 Qualitative and Quantitative Composition

Tetanus Immunoglobulin-VF (For Intravenous Use) is a sterile, preservative free solution containing 50-70 mg/mL human plasma protein of which at least 98% is immunoglobulin (mainly IgG), with a tetanus antitoxin activity of 4,000 IU per vial.
The distribution of the IgG subclasses closely resembles that found in normal human plasma (approximate mean ranges: 52.5-64.9% IgG₁, 29.0-42.2% IgG₂, 3.1-6.8% IgG₃, 0.4-1.2% IgG₄).
Tetanus Immunoglobulin-VF (For Intravenous Use) contains less than 0.5 mg/mL immunoglobulin A (IgA).
The pH value of the ready-to-use solution is 4.25.
Tetanus Immunoglobulin-VF (For Intravenous Use) is manufactured from human plasma collected by Australian Red Cross Lifeblood.
Isotonicity is achieved by the addition of 292 mmol/L maltose.

3 Pharmaceutical Form

Solution for intravenous infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Tetanus Immunoglobulin-VF (For Intravenous Use) is used in the management of clinical tetanus.

4.2 Dose and Method of Administration

Dosage. The recommended dose of Tetanus Immunoglobulin-VF (For Intravenous Use) for the treatment of tetanus is 4000 IU. After administration of this dose (4000 IU), it has been shown that circulating antibody levels are maintained above the minimum protective titre for at least 6 weeks. The dose, therefore, need not be repeated.
Administration. If the product appears to be turbid by transmitted light or contains any sediment it must not be used, and the vial should be returned to Australian Red Cross Lifeblood. The product does not contain an antimicrobial preservative. It must, therefore, be used immediately after opening the vial. Any unused portion must be discarded appropriately. Use in one patient on one occasion only. Do not use if the solution has been frozen.
Tetanus Immunoglobulin-VF (For Intravenous Use) should be administered by slow intravenous infusion.
It is usual to gradually increase the infusion rate to the desired rate over the first 30 minutes, provided the patient's vital signs are satisfactory at the lower rate. The infusion may be commenced at the rate of 1 mL per minute. After 15 minutes, the rate may be gradually increased to a maximum of 3 to 4 mL per minute over a further 15 minutes.
Tetanus Immunoglobulin-VF (For Intravenous Use) may be infused undiluted. Allow the preparation to reach room temperature before infusing into the patient. Remove the dust cover from the top of the vial. Apply a suitable antiseptic such as povidone-iodine or 70% ethanol to the exposed part of the rubber stopper and allow to dry.
Compatibility with other medicines. Tetanus Immunoglobulin-VF (For Intravenous Use) may be diluted with up to four times its volume of 0.9% saline or 5% glucose. No other medicine compatibilities have been evaluated. Tetanus Immunoglobulin-VF (For Intravenous Use) should be administered separately from other intravenous fluids or medications the patient is receiving.

4.3 Contraindications

None known (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Tetanus Immunoglobulin-VF (For Intravenous Use) should be given to the following patients only if the benefits outweigh the possible risks:
patients who have had a true anaphylactic reaction to the active substance or to any of the components of the product;
patients with IgA deficiency, unless they have been tested and shown not to have circulating anti-IgA antibodies, since these patients may experience severe reactions to the IgA which is present in trace amounts.
Route of administration. Tetanus Immunoglobulin-VF (For Intravenous Use) must not be administered intramuscularly. Other routes of administration have not been evaluated.
Hypersensitivity. Tetanus Immunoglobulin-VF (For Intravenous Use) contains trace amounts of IgA which may provoke anaphylaxis in patients with anti-IgA antibodies, such as those with IgA deficiency.
Rarely human tetanus immunoglobulin can induce a precipitous fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human tetanus immunoglobulin. These reactions may be related to the rate of infusion. Accordingly, the infusion rate given (see Section 4.2 Dose and Method of Administration) should be closely followed at least until the physician has had sufficient experience with a given patient. In case of anaphylactic reaction, the infusion should be stopped immediately. The patient's vital signs should be monitored regularly, and careful observation made for any symptoms throughout the entire infusion and for at least 20 minutes after administration. In the case of shock, treatment should follow the guidelines of shock therapy. Adrenaline (epinephrine), oxygen, antihistamine and steroids should be available for the treatment of acute anaphylactic reactions.
Aseptic meningitis syndrome. Aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with human intravenous immunoglobulin (IVIg) treatment. The syndrome usually begins within several hours to two days following IVIg treatment. It is characterised by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis, predominantly from the granulocytic series, and elevated protein levels. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IVIg treatment. Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae.
Acute renal failure. There have been occasional reports of renal dysfunction and acute renal failure in patients receiving IVIg products. Patients at increased risk are those with pre-existing renal insufficiency, diabetes mellitus, age greater than 65 years, volume depletion, sepsis and monoclonal gammopathy, and those taking concomitant nephrotoxic medicines. The majority of such incidents have been associated with sucrose-containing products. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser accounted for a disproportionate higher share of the total number. Tetanus Immunoglobulin-VF (For Intravenous Use) contains maltose, but it does not contain sucrose. The following precautions should be followed: patients should be adequately hydrated prior to the initiation of the IVIg infusion and the recommended dose should not be exceeded. Renal function should be monitored in patients at increased risk of developing acute renal failure. If renal function deteriorates, discontinuation of IVIg should be considered. In patients at risk of acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose possible based on clinical judgement.
Pathogen safety. This product is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses and, theoretically, Creutzfeldt-Jakob disease (CJD) agents, 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 infectious agents and by testing for the presence of certain viral markers.
In addition, the manufacturing process for Tetanus Immunoglobulin-VF (For Intravenous Use) contains specific steps to reduce the possibility of viral transmission including low pH incubation for viral inactivation and nanofiltration for virus removal. The current procedures applied in the manufacture of this product are effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and the non-enveloped viruses, such as hepatitis A virus (HAV) and human parvovirus B19.
There is reassuring clinical experience regarding the lack of parvovirus B19 transmission with immunoglobulins and the nanofiltration step of the manufacturing process has been shown to remove such viruses (or viruses of similar size). The product is known to contain antibodies to the virus.
Immunoglobulins for intravenous infusion, prepared by this process have not been implicated in the transmission of human immunodeficiency virus (HIV). Studies using plasma spiked with HIV have shown that the Cohn cold-ethanol fractionation process produces a very large reduction in virus titre with undetectable levels in the immunoglobulin fraction. Studies have shown that incubation at 27°C and pH 4.25, as performed in the manufacture of this product, also produces a very large reduction in HIV titre. Epidemiological studies have not recognised any cluster of AIDS patients or HIV seroconversion in immunoglobulin recipients.
Despite these measures, such products may still potentially transmit disease. There is also the possibility that other known or unknown infectious agents may be present in such products. Vaccination should be considered where appropriate for patients in receipt of medicinal products manufactured from human plasma.
It is strongly recommended that every time that Tetanus Immunoglobulin-VF (For Intravenous Use) is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.
Use in the elderly. The use of this product in the elderly population has not been established in appropriate studies. To date, this population is not over-represented in spontaneous reports of adverse events associated with the use of CSL's IVIg therapeutic medicines.
Paediatric use. The use of this product in the paediatric population has not been established in appropriate studies. To date, this population is not over-represented in spontaneous reports of adverse events associated with the use of CSL's IVIg therapeutic medicines.
Effects on laboratory tests. After infusion of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing. Passive transmission of antibodies to erythrocyte antigens (e.g. anti-A, anti-B, antiD) may interfere with some serological tests for red cell allo-antibodies (e.g. Coombs' test).
Interference with glucose estimations. The maltose present in Tetanus Immunoglobulin-VF (For Intravenous Use) may interfere with some blood glucose measurements, resulting in the overestimation of blood glucose results. If this glucose measurement is used to guide treatment, hypoglycaemia may occur. Only certain glucose tests using glucose dehydrogenase have been implicated, so when monitoring glucose levels in patients receiving Tetanus Immunoglobulin-VF (For Intravenous Use), information from the manufacturer of the glucose meter and/or test strips should be reviewed to ensure that maltose does not interfere with the blood glucose reading.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Live attenuated virus vaccines. Passively acquired antibody can interfere with the response to live attenuated virus vaccines. Therefore, administration of such vaccines, e.g. poliomyelitis or measles, should be deferred until approximately three months after passive immunisation. In the case of measles, the decrease in efficacy may persist for up to one year. Therefore, patients receiving measles vaccine should have their antibody status checked.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. No reproductive toxicity studies have been conducted with Tetanus Immunoglobulin-VF (For Intravenous Use). There have been no reports of such effects associated with the use of CSL's plasma-derived therapeutic medicines.
Use in pregnancy. The safety of Tetanus Immunoglobulin-VF (For Intravenous Use) for use in human pregnancy has not been established in controlled clinical trials and therefore it should be given to pregnant women only if clearly needed. However, clinical experience with other immunoglobulin preparations given during pregnancy suggests that there are no adverse effects on the foetus.
Use in lactation. Immunoglobulins are excreted in breast milk and may contribute to the transfer of protective antibodies to the neonate. It is not known, however, whether this applies to passively administered Tetanus Immunoglobulin-VF (For Intravenous Use). Clinical experience with immunoglobulins suggests that no harmful effects on the neonate are to be expected.

4.7 Effects on Ability to Drive and Use Machines

No effects on ability to drive and use machines have been observed.

4.8 Adverse Effects (Undesirable Effects)

Reactions to IVIg tend to be related to the infusion rate and are most likely to occur during the first hour of the infusion. It is recommended that the patient's vital signs and general status be monitored regularly throughout the infusion.
The types of reactions that may occur include: abdominal pain, headache, chest-tightness, facial flushing or pallor, feeling hot, dyspnoea, non-urticarial skin rash, itching, hypotension, nausea or vomiting. Should any of these reactions develop during infusion of Tetanus Immunoglobulin-VF (For Intravenous Use), the infusion should be temporarily stopped until the patient improves clinically (5 to 10 minutes) and then cautiously recommenced at a slower rate.
Some patients may develop delayed adverse reactions to Tetanus Immunoglobulin-VF (For Intravenous Use) such as nausea, vomiting, chest pain, rigors or aching legs. These adverse reactions occur after the infusion has stopped but usually within 24 hours.
True anaphylactic reactions to IVIg such as urticaria, angioedema, bronchospasm or hypotension occur very rarely. Should an anaphylactic reaction to Tetanus Immunoglobulin-VF (For Intravenous Use) develop, the infusion should be stopped, and treatment instituted with adrenaline (epinephrine), oxygen, antihistamine and steroids.
There have been reports that IVIg can affect renal function. This should be monitored in patients with pre-existing renal failure who are given Tetanus Immunoglobulin-VF (For Intravenous Use).
Rarely, renal dysfunction and acute renal failure have been reported.
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdosage may lead to fluid overload and hyperviscosity, particularly in the elderly and in patients with cardiac or renal impairment.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action. Donations are selected on the basis that they contain high levels of specific antibodies against the toxin of Clostridium tetani. The protein has not been chemically or enzymatically modified.
Clinical trials. No data available.

5.2 Pharmacokinetic Properties

The antibody has a serum half-life of approximately three weeks.

5.3 Preclinical Safety Data

Genotoxicity. No genotoxicity studies have been conducted with Tetanus Immunoglobulin-VF (For Intravenous Use). There have been no reports of such effects associated with the use of CSL's plasma-derived therapeutic medicines.
Carcinogenicity. No carcinogenicity studies have been conducted with Tetanus Immunoglobulin-VF (For Intravenous Use). There have been no reports of such effects associated with the use of CSL's plasma-derived therapeutic medicines.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. (Refrigerate. Do not freeze). Protect from light.
Do not use after the expiry date.

6.5 Nature and Contents of Container

Tetanus Immunoglobulin-VF (For Intravenous Use) is available in single vials containing 4000 IU Human Tetanus Antitoxin.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure. Not applicable.
CAS number. None assigned.

7 Medicine Schedule (Poisons Standard)

S4.

Date of First Approval

04 November 1991

Date of Revision

07 June 2021

Summary Table of Changes