This information is intended for use by health professionals

1. Name of the medicinal product

Mitomycin-C Kyowa 40 mg, powder for intravesical solution.

2. Qualitative and quantitative composition

Each vial contains 40 mg of Mitomycin C.

Excipient(s) with known effect

Each vial also contains 378 mg of sodium (as sodium chloride).

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Powder for intravesical solution.

Blue-purple powder.

4. Clinical particulars
4.1 Therapeutic indications

As a single agent in the treatment of superficial bladder cancer. In addition it has been shown that post-operative instillations of Mitomycin-C Kyowa 40 mg can reduce recurrence rates in newly diagnosed patients with superficial bladder cancer.

4.2 Posology and method of administration

Posology

In the treatment of superficial bladder tumours the usual dose is 20-40 mg dissolved in 20-40 ml of diluent, instilled into the bladder through a urethral catheter, weekly or three times a week for a total of 20 doses. The dose should be retained by the patient for a minimum of one hour. During this one-hour period the patient should be rotated every 15 minutes to ensure that the Mitomycin-C Kyowa 40 mg comes into contact with all areas of the bladder urothelium.

When the bladder is emptied in the voiding process, care must be taken to ensure that no contamination occurs locally in the groin and genitalia areas.

In the prevention of recurrent superficial bladder tumours, various doses have been used. These include 20 mg in 20 ml of diluent every two weeks and 40 mg in 40 ml of diluent monthly or three monthly. The dose is instilled into the bladder through a urethral catheter.

In both cases, the dose should be adjusted in accordance with the age and condition of the patient.

Paediatric population

The safety and efficacy of Mitomycin-C Kyowa 40 mg in children has not been established. No data are available.

Method of administration

Mitomycin-C Kyowa 40 mg is intended for intravesical use only after being dissolved.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Thrombocytopenia, coagulation disorders and increased bleeding tendency.

4.4 Special warnings and precautions for use

Mitomycin-C Kyowa 40 mg should be administered under the supervision of a physician experienced in cytotoxic cancer chemotherapy.

Mitomycin-C Kyowa 40 mg should be administered with care in the following patients:

1) Patients with hepatic or renal dysfunction as adverse reactions may be enhanced. Severe renal toxicity has occasionally been reported after treatment and renal function should be monitored before starting treatment and again after each course.

2) Patients with bone marrow depression since administration of this product may exacerbate bone marrow depression.

3) Patients complicated with infection since administration of this product may aggravate infection due to bone marrow depression.

4) Patients with varicella since fatal systemic disorders may occur.

Important Precautions

1) Patients should be carefully monitored with frequent laboratory testing (haematological test, liver function test, renal function test, etc.) paying particular attention to peripheral blood count including platelet count because serious adverse reactions such as bone marrow depression may occur. No repeat dose should be given unless the leucocyte count is above 3.0 x 109/L or more and the platelet count is 90 x 109/L or more. The nadir is usually around four weeks after treatment and toxicity is usually cumulative, with increasing risk after each course of treatment. If any abnormality is observed, appropriate measures such as reduction of the dose or discontinuation of administration should be taken. Additionally, Mitomycin-C Kyowa 40 mg should be administered with care because long-term use of the product may cause enhanced adverse reactions, which may be protracted.

2) Special precautions are required due to the possible manifestation or aggravation of infectious disease and bleeding tendency.

3) Attention should be paid to possible occurrence of acute leukaemia or myelodysplastic syndrome (MDS) in the patients treated with Mitomycin-C Kyowa 40 mg in combination with other antineoplastic agents.

4) Mitomycin-C Kyowa 40 mg should be administered with care in children, paying special attention to the manifestation of adverse reactions.

Precautions during administration

Since calcinosis, contracted bladder and cystitis associated with dysuria, pollakiuria, bladder perforation, bladder necrosis and/or penile necrosis may occur in patients receiving intravesical Mitomycin-C Kyowa 40 mg, the drug should be carefully injected. Caution should be exercised when administering intravesical Mitomycin-C Kyowa 40 mg in patients who are at risk of bladder perforation (e.g. following bladder surgery) due to the risk of extravasation from bladder.

This medicinal product contains 378 mg sodium per vial, equivalent to 19 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Paediatric population

The safety of Mitomycin-C Kyowa 40 mg in low birth weight infants, neonates, infants and children has not been established (see Important precaution 4) and section 4.6).

Use in the elderly

Because elderly patients often have reduced physiological function, bone marrow depression, which may be protracted, and renal disorder are likely to occur. Mitomycin-C Kyowa 40 mg should therefore be administered cautiously in elderly patients while closely monitoring patient's condition and paying special attention to the dose and dosing interval.

4.5 Interaction with other medicinal products and other forms of interaction

Mitomycin-C Kyowa 40 mg should be administered with care when co-administered with the following:

• Other antineoplastic agents and irradiation as adverse reactions such as bone marrow depression may be enhanced.

• Vinca alkaloid antineoplastic agents, such as vindesine sulfate, as shortness of breath and bronchospasm may occur.

4.6 Fertility, pregnancy and lactation

Pregnancy

Studies in animals have shown reproductive toxicity (see section 5.3).

Mitomycin-C Kyowa 40 mg is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breastfeeding

Breastfeeding should be discontinued during treatment with Mitomycin-C Kyowa 40 mg.

It is unknown whether Mitomycin C/metabolites are excreted in human milk.

A risk to the newborns/infants cannot be excluded.

Fertility

In case that administration of Mitomycin-C Kyowa 40 mg is required in children or patients with reproductive possibility, potential effects on gonad function should be considered.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

Generalised weakness and lethargy have been reported on rare occasions. If affected, patients should be advised not to drive or operate machinery.

4.8 Undesirable effects

MedDRA (Medical Dictionary of Regulatory Activities) terminology was used to describe System Organ Classes and adverse drug reactions (represented by Preferred Terms). The adverse drug reactions are presented by System Organ Class, and are ranked by frequency, using the following convention:

Very common

≥1/10

Common

≥1/100 to <1/10

Uncommon

≥1/1,000 to <1/100

Rare

≥1/10,000 to <1/1,000

Very rare

<1/10,000

Not known

cannot be estimated from the available data

The most commonly reported undesirable effects following intravesical administration of Mitomycin-C Kyowa 40 mg are bladder irritation, haematuria, malaise, cystitis, dysuria, pruritus, and rash.

SOC

PTs

Infections and infestations

Frequency: Not known

Infection bacterial, viral or fungal infections, sepsis and septic shock

Blood and lymphatic system disorders

Frequency: Very rare

Thrombocytopenia and leukopenia

Frequency: Not known

Bone marrow suppression, anaemia, neutropenia, pancytopenia, granulocytopenia, erythropenia, eosinophilia

Immune system disorders

Frequency: Common

Hypersensitivity

Frequency: Very rare

Anaphylactic reaction, anaphylactic shock

Metabolism and nutrition disorders

Frequency: Not known

Anorexia, weight loss

Vascular disorders

Frequency: Not known

Flushing, hypertension, haemorrhage

Respiratory, thoracic and mediastinal disorders

Frequency: Very rare

Interstitial lung disease

Frequency: Not known

Respiratory disorders, pulmonary fibrosis, bronchospasm, coughing, pulmonary oedema

Gastrointestinal disorders

Frequency: Very rare

Nausea and vomiting, diarrhoea

Frequency: Not known

Constipation

Hepatobiliary disorders

Frequency: Not known

Liver disorder, jaundice

Skin and subcutaneous tissue disorders

Frequency: Common

Rash, pruritus, palmar-plantar erythrodysaesthesia syndrome

Frequency: Very rare

Alopecia

Frequency: Not known

Erythema, blisters, ulceration, skin necrosis

Renal and urinary disorder

Frequency: Very common

Haematuria, bladder irritation

Frequency: Common

Cystitis, bladder pain, bladder spasm, dysuria, pollakiuria

Frequency: Very rare

Acute renal failure, renal disorder (including abnormal changes in blood urea nitrogen (BUN), creatinine, creatinine clearance), bladder perforation, bladder necrosis

Frequency: Not known

Contracted bladder, micturition urgency, proteinuria

Reproductive system and breast disorders

Frequency: Not known

Penile necrosis

General disorders and administration site conditions

Frequency: Very common

Malaise

Frequency: Not known

Pyrexia (chills), oedema, calcinosis, pain, generalised weakness, lethargy

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Some cases of overdose have been reported.

Strict monitoring of the patient and appropriate treatment should be performed.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC Code: L01D

Pharmacotherapeutic group: Other cytotoxic antibiotics

Mitomycin-C Kyowa 40 mg is an antitumour antibiotic that is activated in the tissues to an alkylating agent which disrupts deoxyribonucleic acid (DNA) in cancer cells by forming a complex with DNA and also acts by inhibiting division of cancer cells by interfering with the biosynthesis of DNA.

5.2 Pharmacokinetic properties

In vivo, Mitomycin-C Kyowa 40 mg is rapidly cleared from the serum after intravenous administration. The time required to reduce the serum concentration by 50% after a 30 mg bolus injection is 17 minutes. After injection of 30 mg, 20 mg or 10 mg intravenously, the maximal serum concentrations were 2.4 mcg/ml, 1.7 mcg/ml and 0.52 mcg/ml respectively. Clearance is effected primarily by metabolism in the liver, but metabolism occurs in other tissues as well. The rate of clearance is inversely proportional to the maximal serum concentration because, it is thought, of saturation of the degradative pathways. Approximately 10% of a dose of Mitomycin-C Kyowa 40 mg is excreted unchanged in the urine. Since metabolic pathways are saturated at relatively low doses, the percentage dose excreted in the urine increases with increasing dose. In children, the excretion of intravenously administered Mitomycin-C Kyowa 40 mg is similar to that in adults.

5.3 Preclinical safety data

Animal studies with mice have shown teratogenicity of Mitomycin-C Kyowa 40 mg manifested as developmental inhibition, cleft palate, hypoplastic tail, hypoplastic jaws, ectrodactyly, etc.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium Chloride Ph.Eur.

6.2 Incompatibilities

Not known

6.3 Shelf life

2 years

After reconstitution, the solution is chemically and physically stable for 24 hours when protected from light and stored in a cool place. Do not refrigerate.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Store in the original package.

The reconstituted solution should be protected from light and stored in a cool place (See Section 6.3).

6.5 Nature and contents of container

Mitomycin-C Kyowa 40 mg is contained within a colourless, type I glass vial with a rubber stopper and an aluminium cap with coloured lid.

The following colours of lid are used to distinguish between the different strengths of the product.

Strength

Size of vial

Colour of lid

2 mg

10 ml

Purple

10 mg

30 ml

Purple

20 mg

30 ml

Violet

40 mg

50 ml

Lavender

The vials are packaged into cardboard cartons containing 1 or 5 vials.

6.6 Special precautions for disposal and other handling

The contents of the vial should be reconstituted with Water for Injection or saline, at least 40 ml for the 40 mg vial. If possible, avoid mixing with injectable solutions which have a low pH.

Mitomycin-C Kyowa 40 mg should not be allowed to come into contact with the skin. If it does, it should be washed thoroughly with soap and plenty of water. Hand creams and emollients should not be used as they may assist the penetration of the drug into the epidermal tissue.

In the event of contact with the eye, it should be rinsed several times with saline solution. It should then be observed for several days for evidence of corneal damage. If necessary, appropriate treatment should be instituted.

7. Marketing authorisation holder

Kyowa Kirin Ltd

Galabank Business Park

Galashiels

TD1 1QH

8. Marketing authorisation number(s)

PL16508/0045

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 26 November 1992

Date of latest renewal: 29 June 2006

10. Date of revision of the text

May 2019