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Novartis Vaccines

Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR
Telephone: +44 (0)1276 694 490
Fax: +44 (0)1276 698 460
WWW: http://www.novartis.com
Medical Information Direct Line: +44 (0)8457 451 500
Medical Information e-mail: service.uk@novartis.com
Medical Information Fax: +44 (0)1517 055 669

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Summary of Product Characteristics last updated on the eMC: 10/06/2010
SPC Rabipur


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1. Name of the medicinal product

Powder and solvent for solution for injection

Rabies vaccine, inactivated


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2. Qualitative and quantitative composition

After reconstitution, 1 dose (1 ml) contains:

Rabies virus* (Inactivated, strain Flury LEP)....................= 2.5 IU

* produced on puri?ed chick embryo cells

For a list of excipients, see section 6.1.


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3. Pharmaceutical form

Powder and solvent for solution for injection.

A clear colourless solution results after reconstitution of the white freeze-dried powder with the clear and colourless solvent.


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4. Clinical particulars

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4.1 Therapeutic indications

a) Pre-exposure prophylaxis (before possible risk of exposure to rabies)

b) Post-exposure prophylaxis (after known or possible exposure to rabies)

Consideration should be given to national and/or WHO guidance regarding the prevention of rabies.


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4.2 Posology and method of administration

Posology

The recommended single intramuscular dose is 1 ml in all age groups.

Whenever possible according to vaccine availability, it is recommended that one type of cell culture vaccine should be used throughout the course of pre- or post-exposure immunisation. However, adherence to the recommended schedules is of critical importance for post-exposure prophylaxis, even if another type of cell culture vaccine has to be used.

PRE-EXPOSURE PROPHYLAXIS

Primary immunisation

In previously unvaccinated persons, an initial course of pre-exposure prophylaxis consists of three doses (each of 1 ml) administered on days 0, 7 and 21 or 28.

Booster doses

The need of intermittent serological testing for the presence of antibody ≥ 0.5 IU/ml (as assessed by the Rapid Focus-Fluorescent inhibition Test) and the administration of booster doses should be assessed in accordance with official recommendations.

The following provides general guidance:

• Testing for neutralising antibodies at 6-month intervals is usually recommended if the risk of exposure is high (e. g. Laboratory staff working with rabies virus).

• In persons who are considered to be at continuing risk of exposure to rabies (e.g. veterinarians and their assistants, wildlife workers, hunters), a serological test should usually be performed at least every 2 years, with shorter intervals if appropriate to the perceived degree of risk.

• In above mentioned cases, a booster dose should be given should the antibody titre fall below 0.5 IU/ml.

• Alternatively, booster doses may be given at official recommended intervals without prior serological testing, according to the perceived risk. Experience shows that reinforcing doses are generally required every 2-5 years.

Rabipur may be used for booster vaccination after prior immunisation with human diploid cell rabies vaccine.

POST-EXPOSURE PROPHYLAXIS

Post-exposure immunisation should begin as soon as possible after exposure and should be accompanied by local measures to the site of inoculation so as to reduce the risk of infection. Official guidance should be sought regarding the appropriate concomitant measures that should be taken to prevent establishment of infection (see also section 4.4).

Previously fully immunised individuals

For WHO exposure categories II and III, and in category I cases where there is uncertainty regarding the correct classification of exposure (see Table l below), two doses (each of 1 ml) should be administered, one each on days 0 and 3. On a case by case basis, schedule A (see Table 2 below) may be applied if the last dose of vaccine was given more than two years previously.

Table 1: Immunisation schedules appropriate to different type of contact, exposure and recommended post-exposure prophylaxis (WHO 2004)

Category

Type of contact with a suspect or confirmed rabid domestic or wilda) animal, or animal unavailable for testing

Type of exposure

Recommended post-exposure prophylaxis

I

Touching or feeding of animals

Licks on intact skin

Touching of inoculated animal lure with intact skin

None

None, if reliable case history is available.

In case of unreliable case history, treat according to schedule A (see Table 2).

II

Nibbling of uncovered skin

Minor scratches or abrasions without bleeding

Touching of inoculated animal lure with skin damaged

Minor

Administer vaccine immediatelyb)

Stop treatment if animal remains healthy throughout an observation period of 10 daysc) or if animal is proven to be negative for rabies by reliable laboratory using appropriate diagnostic techniques

In case of uncertainty and/or exposure in a high-risk area, administer active and passive treatment as in schedule B (see Table 2).

III

Single or multiple transdermal bites or scratches, licks on broken skin

Contamination of mucous membrane with saliva (i.e. licks)

Exposure to batsd)

Touching of inoculated animal lure with mucous membrane or fresh skin wound

Severe

Administer rabies immunoglobulin and vaccine immediatelyb) as in schedule B (see Table 2).

Stop treatment if animal remains healthy throughout an observation period of 10 daysc) or if animal is proven to be negative for rabies by reliable laboratory using appropriate diagnostic techniques

a) Exposure to rodents, rabbits and hares seldom, if ever, requires specific anti-rabies post-exposure prophylaxis.

b) If an apparently healthy dog or cat in or from a low-risk area is placed under observation, the situation may warrant delaying initiation of treatment.

c) This observation period applies only to dogs and cats. Except in the case of threatened or endangered species, other domestic and wild animals suspected as rabid should be humanely killed and their tissues examined for the presence of rabies antigen using appropriate laboratory techniques.

d) Post-exposure prophylaxis should be considered when contact between a human and a bat has occurred unless the exposed person can rule out a bite or scratch, or exposure to a mucous membrane.

Individuals unimmunised or with uncertain immune status

Depending on the WHO category as in Table l, treatment according to schedules A or B (see Table 2 below) may be required for previously unimmunised persons and for those who have received fewer than 3 doses of vaccine or who have received a vaccine of doubtful potency.

Table 2: Post-exposure prophylaxis of subjects with no or uncertain immune status

Schedule A

Active immunisation after exposure is required

Schedule B

Active and passive immunisation after exposure are required

One injection of Rabipur i.m. on days: 0, 3, 7, 14, 28 (5-doses schedule)

Or One dose of Rabipur is given into the right deltoid muscle and one dose into the left deltoid muscle on day 0, and one dose is applied into the deltoid muscle on days 7 and 21 (2-1-1 regimen). In small children the vaccine is to be given into the thighs.

Give Rabipur as in schedule A + l × 20 IU/kg body weight human rabies immunoglobulin* concomitantly with the first dose of Rabipur. If HRIG is not available at the time of the first vaccination it must be administered not later than 7 days after the first vaccination

* Observe manufacturer's instructions regarding administration

Immunocompromised patients and patients with a particularly high risk of contracting rabies

For immunocompromised patients, those with multiple wounds and/or wounds on the head or other highly innervated areas, and those for whom there is a delay before initiation of treatment, it is recommended that:

- The days 0, 3, 7, 14 and 28 immunisation regimen should be used for these cases

-Two doses of vaccine may be given on day 0. That is, a single dose of 1 ml vaccine should be injected into the right deltoid and another single dose into the left deltoid muscle. In small children, one dose should be given into the anterolateral region of each thigh.

Severely immunosuppressed patients may not develop an immunologic response after rabies vaccination. Therefore, prompt and appropriate wound care after an exposure is an essential step in preventing death. In addition, rabies immune globulin should be administered in all immunosuppressed patients experiencing Category II and Category III wounds.

In immunocompromised patients, the neutralising antibody titre should be measured 14 days after the first injection. Patients with a titre that is less than 0.5 IU/ml should be given another two doses of vaccine simultaneously and as soon as possible. Further checks on the antibody titre should be made and further doses of vaccine should be administered as necessary.

In all cases, the immunisation schedule must be followed exactly as recommended, even if the patient does not present for treatment until a considerable time has elapsed since exposure.

Method of Administration

The vaccine should be given by intramuscular injection into the deltoid muscle, or into the anterolateral region of the thigh in small children.

It must not be given by intra-gluteal injection.

Do not administer by intravascular injection (see Section 4.4).


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4.3 Contraindications

Post-exposure prophylaxis

There are no contraindications to vaccination when post-exposure prophylaxis is indicated. However, subjects considered to be at risk of a severe hypersensitivity reaction should receive an alternative rabies vaccine if a suitable product is available (see also section 4.4 regarding previous hypersensitivity reactions).

Pre-exposure prophylaxis

Rabipur should not be administered to subjects with a history of a severe hypersensitivity reaction to any of the ingredients in the vaccine. Note that the vaccine contains polygeline and residues of chicken proteins, and may contain traces of neomycin, chlortetracycline and amphotericin B (see also section 4.4).

Vaccination should be delayed in subjects suffering from an acute febrile illness. Minor infections are not a contraindication to vaccination.


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4.4 Special warnings and precautions for use

As with all vaccines, appropriate medical treatment should be immediately available for use in the rare event of an anaphylactic reaction to the vaccine.

A history of allergy to eggs or a positive skin test to ovalbumin does not necessarily indicate that a subject will be allergic to Rabipur. However, subjects who have a history of a severe hypersensitivity reaction to eggs or egg products should not receive the vaccine for pre-exposure prophylaxis. Such subjects should not receive the vaccine for post-exposure prophylaxis unless a suitable alternative vaccine is not available, in which case all injections should be administered with close monitoring and with facilities for emergency treatment.

Similarly, subjects with a history of a severe hypersensitivity reaction to any of the other ingredients in Rabipur such as polygeline (stabilizer), or to amphotericin B, chlortetracycline or neomycin (which may be present as trace residues) should not receive the vaccine for pre-exposure prophylaxis. The vaccine should not be given to such persons for post-exposure prophylaxis unless a suitable alternative vaccine is not available, in which case precautions should be taken as above.

Do not administer by intravascular injection

If the vaccine is inadvertently administered into a blood vessel there is a risk of severe adverse reactions, including shock.

After contact with animals which are suspected carriers of rabies, it is essential to observe the following procedures (according to WHO 1997):

Immediate wound treatment

In order to remove rabies virus, immediately cleanse wound with soap and flush thoroughly with water. Then treat with alcohol (70%) or iodine solution. Where possible, bite injuries should not be closed with a suture, or only sutured to secure apposition.

Tetanus vaccination and rabies immunoglobulin administration

Prophylaxis against tetanus should be implemented when necessary.

In cases of indicated passive immunisation, as much of the recommended dose of human rabies immunoglobulin (HRIG) as anatomically feasible should be applied as deeply as possible in and around the wound. Any remaining HRIG should be injected intramuscularly at a site distant from the vaccination site, preferably intragluteally. For detailed information please refer to the SmPC and/or package insert of HRIG.


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4.5 Interaction with other medicinal products and other forms of interaction

Patients who are immunocompromised, including those receiving immunosuppressive therapy, may not mount an adequate response to rabies vaccine. Therefore, it is recommended that serological responses should be monitored in such patients and additional doses given as necessary (see section 4.2 for details).

Administration of rabies immunoglobulin may be necessary for management but may attenuate the effects of concomitantly administered rabies vaccine. Therefore, it is important that rabies immunoglobulin should be administered once only for treating each at-risk exposure and with adherence to the recommended dose.

Other essential inactivated vaccines may be given at the same time as Rabipur. Different injectable inactivated vaccines should be administered into separate injection sites.


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4.6 Pregnancy and lactation

No cases of harm attributable to use of Rabipur during pregnancy have been observed. While it is not known whether Rabipur enters breast milk, no risk to the breast-feeding infant has been identified. Rabipur may be administered to pregnant and breastfeeding women when post-exposure prophylaxis is required.

The vaccine may also be used for pre-exposure prophylaxis during pregnancy and in breastfeeding women if it is considered that the potential benefit outweighs any possible risk to the fetus/infant.


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4.7 Effects on ability to drive and use machines

The vaccine is unlikely to produce an effect on ability to drive and use machines.


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4.8 Undesirable effects

In clinical studies the most commonly reported solicited adverse reactions were injection site pain (30 - 85%, mainly pain due to injection) or injection site induration (15 - 35 %). Most injection site reactions were not severe and resolved within 24 to 48 hours after injection. Furthermore, the following undesirable effects were observed in clinical trials and/or during the post-marketing period:

Standard system organ class

Frequency

Adverse reactions

General disorders and administration site condition

Very common> 1/10

Injection site pain, injection site reaction, injection site induration, injection site swelling

Common> 1/100, < 1/10

Asthenia, malaise, fever, chills, fatigue, influenza like illness, injection site erythema

 

Uncommon >1/1.000, <1/100

Dizziness

Cardiac disorders

Rare> 1/10.000, < 1/1.000

Circulatory reactions (such as palpitations or hot flush)

Blood and lymphatic system disorders

Common> 1/100, < 1/10

Lymphadenopathy

Ear and labyrinth disorders

Very rare < 1/10.000

Vertigo

Eye disorders

Rare> 1/10.000, < 1/1.000

Visual disturbance

 

Common> 1/100, < 1/10

Headache

Nervous system disorders*

Rare> 1/10.000, < 1/1.000

Paraesthesia

Very rare < 1/10.000

Nervous system disorders (such as paresis or Guillain-Barré-Syndrome)

Skin disorders

Common> 1/100, < 1/10

Rash

Immune system disorders

Very rare < 1/10.000

Allergic reactions (such as anaphylaxis, bronchospasm, oedema, urticaria or pruritus), Serum-sickness like symptoms

Musculosceletal and connective tissue disorders

Common> 1/100, < 1/10

Myalgia, arthralgia

Gastrointestinal disorders

Common> 1/100, < 1/10

Gastrointestinal disorder (such as nausea or abdominal pain)

* Statistically there is no indication of increasing frequencies of primary manifestations or triggered attacks of autoimmune diseases (e.g. multiple sclerosis) after vaccination. However, in individual cases it cannot be absolutely excluded that a vaccination may trigger an episode in patients with corresponding genetic disposition. According to the current state of scientific knowledge vaccinations are not the cause of autoimmune diseases.


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4.9 Overdose

No symptoms of overdose are known.


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5. Pharmacological properties

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5.1 Pharmacodynamic properties

ATC-Code: J07B G01

Pre-exposure Prophylaxis

In clinical trials with previously unimmunised subjects, almost all subjects achieve a protective antibody titre (≥ 0.5 IU/ml) by day 28 of a primary series of three injections of Rabipur when given according to the recommended schedule by the intramuscular route.

As antibody titres slowly decrease, booster doses are required to maintain antibody levels above 0.5 IU/ ml. However, persistence of protective antibody titres for 2 years after immunisation with Rabipur without additional booster has been found to be 100 % in clinical trials.

In clinical trials, a booster dose of Rabipur elicited a 10-fold or higher increase in Geometric Mean Titres (GMTs) by day 30. It has also been demonstrated that individuals who had previously been immunised with Human Diploid Cell Vaccine (HDCV) developed a rapid anamnestic response when boosted with Rabipur.

Persistence of antibody titres has been shown for 14 years in a limited number (n = 28) of subjects tested.

Nevertheless, the need for and timing of boosting should be assessed on a case by case basis, taking into account official guidance (see also section 4.2).

Post-exposure Prophylaxis

In clinical studies, Rabipur elicited neutralising antibodies (≥ 0.5 IU/ml) in 98% of patients within 14 days and in 99-100% of patients by day 28 – 38, when administered according to the WHO-recommended schedule of five intramuscular injections of 1 ml, one each on days 0, 3, 7, 14 and 28.

Concomitant administration of either Human Rabies Immunoglobulin (HRIG) or Equine Rabies Immunoglobulin (ERIG) with the first dose of rabies vaccine caused a slight decrease in GMTs. However, this was not considered to be clinically relevant.


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5.2 Pharmacokinetic properties

Not applicable.


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5.3 Preclinical safety data

Preclinical data including single-dose, repeated dose and local tolerance studies revealed no unexpected findings and no target organ toxicity. No genotoxicity and reproductive toxicity studies have been performed.


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6. Pharmaceutical particulars

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6.1 List of excipients

Powder:

Solvent:

Trometamol

Water for injections

Sodium chloride

 

Disodium edetate

 

Potassium-L-glutamate

 

Polygeline

 

Sucrose

 


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6.2 Incompatibilities

In the absence of compatibility studies, Rabipur must not be mixed in the same syringe with other medicinal products. No interactions with concomitant administration of other vaccines have been reported.


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6.3 Shelf life

4 years


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6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C). Do not freeze.


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6.5 Nature and contents of container

Pack containing:

Powder in a vial (type I glass) with stopper (chlorobutyl)

1 ml solvent for solution in an ampoule (type I glass)

with or without injection syringe (polypropylen with polyethylen plunger)

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

The vaccine should be visually inspected both before and after reconstitution for any foreign particulate matter and or change in physical appearance. The vaccine must not be used if any change in the appearance of the vaccine has taken place.

A clear colourless solution results after reconstitution of the white freeze-dried powder with the clear and colourless solvent.

The powder for solution should be reconstituted using the solvent for solution supplied and carefully agitated prior to injection. The reconstituted vaccine should be used immediately.

During manufacturing, the vial is sealed under vacuum. Therefore to prevent problems in withdrawing the reconstituted vaccine from the vial after reconstitution of the vaccine, it is recommended to unscrew the syringe from the needle to eliminate the negative pressure. After that, the vaccine can be easily withdrawn from the vial. It is not recommended to induce excess pressure, since overpressurization will create the problems in withdrawing the proper amount of the vaccine.

Any unused vaccine or waste material should be disposed of in accordance with local requirements.


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7. Marketing authorisation holder

Novartis Vaccines and Diagnostics GmbH

P.O. Box 16 30

35006 Marburg

Germany


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8. Marketing authorisation number(s)

PL 16033/0008


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9. Date of first authorisation/renewal of the authorisation

12/05/2003 // 12/05/2008


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10. Date of revision of the text

December 2009

RA10TJA008 April 2010



More information about this product

Link to this document from your website: http://www.medicines.org.uk/emc/medicine/14933/SPC/


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