1. NAME OF THE MEDICINAL PRODUCT

BCG-medac, powder and solvent for suspension for intravesical use

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

After reconstitution, one vial contains:

BCG (Bacillus Calmette Guérin) bacteria seed RIVM derived from seed 1173-P2

………………………………………………………………………2 x 108 to 3 x 109 viable units

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Powder and solvent for suspension for intravesical use

White powder and colourless, clear solution

4. CLINICAL PARTICULARS

4. 1    Therapeutic indications

Treatment of non-invasive urothelial bladder carcinoma:

• curative treatment of carcinoma in situ

• prophylactic treatment of recurrence of :

- urothelial carcinoma limited to mucosa :

- Ta G1-G2 if multifocal and/or recurrent tumour

- Ta G3

- urothelial carcinoma in lamina propria but not the muscular of the bladder (T1)

- carcinoma in situ

4.2 Posology and method of administration

Dosage

The content of one vial is required for one bladder instillation. Instructions for reconstitution are given under 6.6.

Duration

Carcinoma in situ

A standard treatment schedule consists of one intravesical instillation of BCG-medac per week for six consecutive weeks as induction therapy. BCG treatment must not start until 2 - 3 weeks after transurethral resection (TUR). After a treatment-free interval of 4 weeks intravesical administration should continue using maintenance therapy for at least one year. Maintenance treatment schemes are described below.

Induction therapy (Prophylactic treatment of recurrence)

BCG therapy should begin about 2 - 3 weeks after TUR) or bladder biopsy, and without traumatic catheterisation, and be repeated at weekly intervals for 6 weeks. In intermediate and high-risk tumours this should be followed by maintenance therapy.

Maintenance therapy

One schedule consists of a 12 months therapy with treatments at monthly intervals. Another maintenance scheme consists of 3 instillations at weekly intervals at month 3, 6, 12, 18, 24, 30, and 36. In this scheme a total of 27 instillations are administered during a period of three years.

The specified treatment schedules with different BCG strains have been tested in clinical studies carried out in large numbers of patients. At present it is not possible to state whether one or the other of these regimens is superior to the remaining schedule.

Administration

BCG-medac should be administered in the conditions required for intravesical endoscopy.

The patient should not drink over a period of 4 hours before the instillation until 2 hours after the instillation. The bladder must be emptied before BCG instillation. BCG-medac is introduced into the bladder by means of a catheter and at low pressure. The instilled BCG-medac suspension must remain in the bladder for a period of 2 hours if possible. During this period the suspension should have sufficient contact with the entire mucosal surface of the bladder. Therefore the patient should be mobilised as much as possible. After 2 hours the patient should void the instilled suspension by preference in a sitting position.

In case of no specific medical contra-indication, a hyperhydratation is recommended to patient

for 48 hours following each instillation.

BCG-medac should not be used in children as safety and efficacy have not been established.

There are no special instructions for the use in elderly.

4.3 Contraindications

Hypersensitivity to any of the ingredients

BCG-medac should not be used in immunosuppressed patients or persons with congenital or acquired immune deficiencies, whether due to concurrent disease (e.g., positive HIV serology, leukaemia, lymphoma), cancer therapy (e.g., cytostatic drugs, radiation) or immunosuppressive therapy (e.g. corticosteroids).

BCG-medac should not be administered to persons with active tuberculosis. The risk of active tuberculosis must be ruled out by appropriate anamnesis and if indicated by diagnostic tests according to local guidelines.

Past history of radiotherapy of the bladder

Treatment with BCG-medac is contraindicated in women during lactation (see section 4.6).

BCG-medac must not be instilled before 2 to 3 weeks after a TUR, a bladder biopsy or a traumatic catheterisation.

Perforation of the bladder (see section 4.4)

Acute urinary tract infection (see section 4.4)

4.4 Special warnings and precautions for use

BCG-medac may not be used for subcutaneous, intradermal, intramuscular or intravenous administration or vaccination.

Treatment of symptoms, signs or syndrome

See section 4.8.

Number of BCG instillations

Side effects of BCG treatment are frequent but generally mild and transient. Adverse reactions usually increase with the number of BCG instillations.

Severe systemic BCG infection/reaction

Systemic BCG infections/reactions have been rarely reported and are described as fever

> 39.5 °C during at least 12 hours, fever > 38.5 °C during at least 48 hours, miliary pneumonia, granulomatous hepatitis, liver function test abnormalities, organic dysfunction (other than genito-urinary tract) with granulomatous inflammation at biopsy, Reiter´s syndrome.

The possibility of severe systemic BCG infections has to be considered before starting the therapy.

Traumatic instillation could promote BCG septicaemic events with possible septic shock and potential fatalities.

Urinary tract infection should be excluded before each bladder instillation of BCG (bladder mucous membrane inflammation may increase the risk of haematologic dissemination of BCG). If a urinary tract infection is diagnosed during BCG therapy, the therapy should be interrupted until the urinalysis is normalised and treatment with antibiotics is completed.

Infection of implants and grafts has been reported in patients with e.g. aneurysm or prosthesis.

Persistence of BCG

There have been single case reports in which BCG bacteria persisted in the urinary tract for more than 16 months.

Fever or gross haematuria

Treatment should be postponed until resolution of concurrent fever or gross haematuria.

Low bladder capacity

The risk of bladder contracture may increase in patients with low bladder capacity.

HLA-B27

Patients with positive HLA-B27 could have an increase of the occurrence of reactional arthritis or Reiter’s syndrome.

Handling precautions

BCG-medac should not be handled either in the same room or by the same personnel preparing

cytotoxic drugs for intravenous administration. BCG-medac should not be handled by a person

who presents well-known immunodeficiency. A contact of BCG-medac with skin and mucosa

should be avoided. Contamination can lead to hypersensitivity reaction or infection of the concerned area.

Patients with immunodeficiency

Patients with well-known immunodeficiency must avoid contact with patients under treatment with BCG.

Tuberculin cutaneous tests

The intravesical treatment to BCG-medac could induce sensitivity to tuberculin and complicate subsequent interpretation to tuberculin cutaneous tests for mycobacterial infection diagnosis. Therefore, reactivity to tuberculin could be performed before administration of BCG-medac.

Pregnancy

BCG-medac is not recommended during pregnancy (see section 4.6).

Sexual transmission

Sexual transmission of BCG has not been reported yet, but it is recommended to use a condom during coitus for one week after BCG therapy.

General hygiene

It is recommended to wash hands and genital area after micturition. This applies especially to the first micturitions following BCG instillation. If skin lesions are contaminated, we recommend the use of an appropriate disinfectant.

Spillage of BCG-medac

Spillage of BCG-medac solution should be treated with a disinfectant with proven activity against mycobacteria. Spillage on the skin should be treated with an appropriate disinfectant.

4.5 Interaction with other medicinal products and other forms of interactions

BCG bacteria are sensitive to antituberculous drugs (e.g. ethambutol, streptomycin, p-aminosalicylic acid (PAS), isoniazid (INH) and rifampicin), antibiotics, antiseptics and lubricants. A resistance against pyrazinamide and cycloserine has been described.

During intravesical BCG instillation therapy, simultaneous administration of antituberculous agents and antibiotics like fluoroquinolones, doxycycline or gentamicin should be avoided due to sensitivity of BCG to those drugs.

4.6 Pregnancy and lactation

Pregnancy (see section 4.4):

There are no adequate data from the use of BCG-medac in pregnant women. Reproductive animal studies are not performed. BCG-medac is not recommended during pregnancy.

Lactation:

There are no adequate data from the excretion of these bacteria in breast milk. This treatment is contra-indicated in nursing women (see section 4.3).

4.7 Effects on ability to drive and use machines

Local or systemic symptoms during therapy with BCG-medac could affect the ability to drive or operate machines.

4.8 Undesirable effects

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Side effects of BCG treatment are frequent but generally mild and transient. Adverse reactions usually increase with the number of BCG instillations.

In uncommon cases, arthritis/arthralgias, skin rash, may occur. In most cases of arthritis, arthralgias and skin rash, these can be attributed to hypersensitivity reactions of the patient to BCG. It may be necessary in some cases to discontinue the administration of BCG-medac.

Local adverse reactions:

Discomfort and pain when urinating and frequent urination occur in up to 90 % of the patients. The cystitis and inflammatory reaction (granulomata) may be an essential part of the antitumour activity. Further local side effects which are uncommonly observed: macroscopic haematuria, urinary tract infection, bladder retraction, urinary obstruction, bladder contracture, symptomatic granulomatous prostatitis, orchitis and epididymitis. Renal abscess is rarely observed. Furthermore genital disorders (e. g. vaginal pain, dyspareunia) may occur with an unknown frequency.

Transient systemic BCG reaction:

Low grade fever, flu-like symptoms and general discomfort may occur. These symptoms usually subside within 24 - 48 hours and should be managed by standard symptomatic treatment. These reactions are signs of a starting immune reaction. All patients receiving the product should be carefully monitored and advised to report all incidences of fever and other events outside the urinary tract.

Severe systemic adverse reactions/infections:

Systemic adverse reactions/infections are defined as: Fever > 39.5 °C during at least 12 hours, fever > 38.5 °C during at least 48 hours, miliary pneumonia due to BCG, granulomatous hepatitis, liver function test abnormalities, organic dysfunction (other than genito-urinary tract) with granulomatous inflammation at biopsy, Reiter’s syndrome. Severe systemic BCG reaction/infection can lead to BCG sepsis which is a life-threatening situation.

Treatment recommendations see table below.

corticosteroids.

Seek the opinion of a specialist for infectious diseases.

* Caution: BCG bacteria are sensitive to all antituberculous drugs currently used, except for pyrazinamide. If a triple antituberculosis therapy is necessary, the combination usually recommended is isoniazid (INH), rifampicin and ethambutol.

4.9 Overdose

Overdosage is unlikely to occur as one vial of BCG-medac corresponds to one dose.

There are no data indicating that an overdosage may lead to any other symptoms than the described undesirable effects.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulating agent

ATC Code: L03AX03

BCG-medac is a lyophilised suspension of live Bacillus Calmette-Guérin bacteria derived from Mycobacterium bovis, strain RIVM.

BCG-medac stimulates the immune system and has anti-tumour activity.

Study data suggest that BCG acts as a non-specific immunopotentiator, not by a single mechanism but by a variety of actions involving cells of the immune system. BCG has a stimulating effect on the spleen, enhances macrophage function in the spleen and activates natural killer cells. BCG instillation stimulates the increase of granulocytes, monocytes/macrophages and T-lymphocytes, indicating local activation of the immune system. Cytokines IL1, IL2, IL6 and TNFα are also increased.

5.2 Pharmacokinetic properties

Most of the bacilli are excreted in the urine in the first hours after the instillation. Whether mycobacteria might be able to pass the intact urothelial wall is still unknown. There have been single case reports in which BCG bacteria persisted in the urinary tract for more than 16 months (see section 4.4).

5.3 Preclinical safety data

BCG strain RIVM was tested for toxicity, immunostimulative properties and antitumour activity in a variety of animals. High doses of BCG caused weight retardation in mice and also liver disturbance was observed. Intravenous injection in rabbits appeared to be pyrogenic. Repeated instillations in guinea pigs induced inflammatory reactions in the bladder wall. As unwanted side effects granulomatous lesions in the liver and lung were present in high doses. Intravesical

application in dogs showed minimal mechanical lesions of the urothelium whereas no signs of active inflammation were observed in the suburothelial stroma.

No mutagenicity, carcinogenicity and reproduction studies have been performed.

6. PHARMACEUTICAL PARTICULARS

6. 1    List of excipients

Powder: polygeline, glucose anhydrous and polysorbate 80.

Solvent: sodium chloride and water for injections.

6.2 Incompatibilities

BCG-medac is incompatible with hypotonic and hypertonic solutions.

6.3 Shelf life

2 years or 3 years when the amount of viable units at release is greater than 5 x 108 cfu/vial, in any case not longer than 4 years from the date of harvest.

After reconstitution the product should be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions of the reconstituted product, see section 6.3.

6.5 Nature and contents of container

Powder in a vial (type I glass) with a rubber stopper + 50 ml of solvent in a bag (PVC) with a connecting piece and a catheter adapter (conical or Luer-Lock adapter) with or without catheter – pack size of 1, 3, 5 or 6.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Instructions for use/handling

Before use the product has to be resuspended under aseptic conditions with sterile 0.9 % sodium chloride solution (see below). Remix the suspension before use by rotating gently. Avoid skin contact with BCG-medac. The use of gloves is recommended.

Visible macroscopic particles do not affect the efficacy and safety of the product.

The following handling instructions are used for the system with conical or Luer-Lock adapter.

1. Tear open the protective bag but do not remove it completely! This will protect the tip of the instillation system from contamination up to the last minute.

2. Remove the caps of the vial and instillation system. Lay out a disposal bag.

3. Press the BCG-medac vial upright and firmly onto the adapter of the instillation system. Turn the vial 3 – 4 times in both directions.

4. Break open the mechanism in the tube of the adapter by repeated bidirectional bending. This establishes the connection. Please hold the tube – and not the vial – during this process!

5. Pump the liquid into the vial. Please ensure that the vial is not completely filled!

6. Invert the combined system; pump in air with the vial at the top. Draw the reconstituted BCG into the instillation system. Do not remove the vial.

7. Keep the instillation system upright. Now remove the protective bag completely. Connect the catheter adapter to the catheter. Now break open the closure mechanism in the tube by bidirectional bending and instil the drug. At the end of instillation free the catheter by pressing air through. Keep the solvent bag squeezed and place it together with the catheter into the disposal bag.

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

7. MARKETING AUTHORISATION HOLDER

medac

Gesellschaft für klinische

Spezialpräparate mbH

Fehlandtstraße 3

D-20354 Hamburg

8. MARKETING AUTHORISATION NUMBER

national

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

national

10. DATE OF REVISION OF THE TEXT