MITOMYCIN-C KYOWA 2 MG POWDER FOR SOLUTION FOR INJECTION
Active substance(s): MITOMYCIN C
1-6 weekly intervals. A course ranging from 40-80 mg is often required for a satisfactory result when
used alone or in combination with other treatments. Thus, the period of treatment could last from just
a few weeks up to a number of months, depending on the condition being treated. In the treatment of
bladder cancer, the recommended dose is 20-40mg administered into the bladder, weekly or three
times a week for a total of 20 doses. The dosage may be decreased if side effects are a problem.
If during treatment you develop a dry cough, breathlessness, rapid breathing or anything else which
suggests your lungs might be affected, you may require to be monitored by X-rays of your chest
that could continue up to 4 weeks after the end of treatment.
If you are given more Mitomycin-C Kyowa than you should
If you have been accidentally given a higher dose you may experience symptoms such as fever,
nausea, vomiting and blood disorders. Your doctor may give you supportive treatment for any
symptoms that may occur.
4. POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you notice any of the following severe reactions tell your doctor immediately:
• severe breathlessness
• pneumonia – fever, chills, shortness of breath or a cough
• severe allergic reaction – you may experience a sudden itchy rash (hives), swelling of the
hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or
breathing), and you may feel you are going to faint.
If you experience any of the following tell your doctor as soon as possible:
• fever on the day of treatment
• loss of appetite and weight loss
• tiredness, weakness and headache
• feeling or being sick (this may shortly disappear during treatment)
• high blood pressure or flushing
• pain, swelling, redness or tenderness at the site of the injection
• sores mouth and mouth ulcers
• diarrhoea, abdominal discomfort or constipation
• hardening, thickening, redness, tenderness or swelling of the tips of the fingers and hair loss
• changes in urinating or pain when urinating
• ridging of nails, blisters on pressure points e.g. elbows
• easily pick up infections
• reduced blood flow to the fingers, toes and tip of the nose
• bleeding and bruising
• severe damage and potentially rupture of the wall of the bladder resulting in severe lower
abdominal pain, difficulty or inability to pass urine, and possibly blood in the urine.
• severe damage to the penis resulting in pain in the penis, abnormal colour of the penis and
potential difficulty in passing urine
• increase in blood pressure in the blood vessels of the lungs (pulmonary hypertension),
e.g. leading to shortness of breath, dizziness and fainting
• obstructive disease of the pulmonary veins or pulmonary veno-occlusive disease (PVOD).
Symptoms may include shortness of breath, fainting and coughing up blood.
• numbness, swelling and painful redness on palms of the hands and soles of feet (palmarplantar erythrodysaesthesia (PPE)/hand-foot syndrome).
Kidney or liver problems have also been reported. Your doctor will monitor your kidney (urine test)
and liver (blood test) regularly.
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in
this leaflet. You can also report side effects directly via the Yellow Card Scheme (www.mhra.gov.
By reporting side effects you can help provide more information on the safety of this medicine.
5. HOW TO STORE MITOMYCIN-C KYOWA
Keep out of the sight and reach of children.
Mitomyicin-C Kyowa should be kept in its original packaging.
Do not use this medicine after the expiry date which is stated on the label after “Exp Date”. The
expiry date refers to the last day of that month.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help to protect the environment.
6. CONTENTS OF THE PACK AND OTHER INFORMATION
What Mitomycin-C Kyowa contains
- The active substance is mitomycin-C
- The other ingredient is sodium chloride
What Mitomycin-C Kyowa looks like and contents of the pack
Mitomycin-C Kyowa is a powder which is mixed before injection. It is packaged in glass vials with a
rubber stopper and aluminium seal.
Marketing Authorisation Holder
Kyowa Kirin Ltd.
Galabank Business Park
This medicinal product is authorised in the Member States of the EEA under the following
This leaflet was last revised in 05/2016.
SUMMARY OF PRODUCT CHARACTERISTICS
TECHNICAL LEAFLET FOR THE PROFESSIONAL
Mitomycin-C Kyowa® 2mg / Mitomycin-C Kyowa® 10mg
Mitomycin-C Kyowa® 20mg / Mitomycin-C Kyowa® 40mg
1. NAME OF THE MEDICINAL PRODUCT
Mitomycin-C Kyowa, 2 mg, 10 mg, 20 mg, 40 mg powder for solution
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Mitomycin C 2, 10, 20 or 40 mg
For the full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM
Powder for solution for injection.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Antimitotic and cytotoxic
Recommended for certain types of cancer in combination with other
drugs or after primary therapy has failed. It has been successfully
used to improve subjective and objective symptoms in a wide range of
As a single agent in the treatment of superficial bladder cancer.
In addition it has been shown that post-operative instillations of
Mitomycin-C can reduce recurrence rates in newly diagnosed
patients with superficial bladder cancer.
As a single agent and in combination with other drugs in metastatic
In combination with other agents in advanced squamous cell
carcinoma of the uterine cervix.
It shows a degree of activity as part of combination therapy in
carcinoma of the stomach, pancreas and lung (particularly nonsmall cell).
It shows a degree of activity as a single agent and in combination in
liver cancer when given by the intra-arterial route.
It has a possible role in combination with other cytotoxic drugs in
It shows a degree of activity as a single agent or part of
combination therapy in cancer of the head and neck.
It shows a degree of activity as a single agent in cancer of the
It has a possible role in skin cancer.
10. It has a degree of activity in leukaemia and non-solid tumours.
11. It has a possible role in sarcomas.
12. It has been successfully used in combination with surgery, preoperatively (oesophageal squamous cell carcinoma) and postoperatively (gastric cancer).
13. It has shown to be effective when used in combination with
4.2 Posology and method of administration
The safety and efficacy of Mitomycin C in children has not been
established. No data are available.
Intravenously, the dose should be given as slowly as possible and with
great care in order to avoid extravasation.
The usual dose is in the range of 4-10 mg (0.06-0.15 mg/kg) given at
1-6 weekly intervals depending on whether other drugs are given in
combination and on bone marrow recovery.
In a number of combination schedules, the dose is 10 mg/m2 of body
surface area, the course being repeated at intervals for as long as
required. A course ranging from 40-80 mg (0.58-1.2 mg/kg) is often
required for a satisfactory response when used alone or in combination.
A higher dosage course may be given when used alone or as part of a
particular combination schedule and total cumulative doses exceeding
2 mg/kg have been given.
For administration into specific tissues, Mitomycin-C Kyowa can be
given by the intra-arterial route directly into the tumours.
Because of cumulative myelosuppression, patients should be fully
re-evaluated after each course and the dose reduced if the patient has
experienced any toxic effects. Doses greater than 0.6 mg/kg have not
been shown to be more effective and are more toxic than lower doses.
If disease progression continues after two courses of treatment, the drug
should be stopped since the chances of response are minimal.
Use in patients with bladder tumours
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 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
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.
Patients who have demonstrated a hypersensitive or idiosyncratic
reaction to Mitomycin-C Kyowa or any of the components of the product
in the past. Thrombocytopenia, coagulation disorders and increased
4.4 Special warnings and precautions for use
Mitomycin-C Kyowa should be administered under the supervision
of a physician experienced in cytotoxic cancer chemotherapy.
Local ulceration and cellulitis may be caused by tissue extravasation
during intravenous injection and utmost care should be taken in
administration. If extravasation occurs, it is recommended that the area
is immediately infiltrated with sodium bicarbonate 8.4% solution, followed
by an injection of 4 mg dexamethasone. A systemic injection of 200 mg
of Vitamin B6 may be of some value in promoting the regrowth of tissues
that have been damaged.
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.
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. Serious
adverse reactions such as bone marrow depression may occur. If any
abnormality is observed, appropriate measures such as reduction of the
dose and suspension of administration should be taken.
Extravascular leakage may cause induration or necrosis at the injection
site. Intraarterial administration may cause skin disorders such as pain,
redness, erythema, blisters, erosion and ulceration which may lead to
skin/muscle necrosis. Since the influx of the drug solution into other sites
than the targeted site in the administration to the hepatic artery may
cause gastroduodenal ulcer, haemorrhage, perforation, etc, the location
of the end of the catheter and drug distribution area should be confirmed
photographically or by other means, paying attention to possible
deviation or shift of the catheter and infusion rate. Administration should
be discontinued and appropriate measures should be taken, if any of
such symptoms develops.
Severe renal toxicity has occasionally been reported after treatment and
renal function should be monitored before starting treatment and again
after each course.
Mitomycin-C Kyowa should be administered with care in children and
patients with the following:
Hepatic or renal dysfunction as adverse reactions may be enhanced
one marrow depression and bleeding tendency as these may be
Infections as these may be aggravated due to bone marrow
Varicella as fatal systemic disorders may occur
In case administration of this drug is required in children or patients with
reproductive possibility, potential effects on gonad should be considered.
The safety of Mitomycin-C injection in children has not been established.
Special attention should be paid to the manifestation of adverse reactions
when administered in children.
Because elderly patients often have reduced physiological function, bone
marrow depression, which may be protracted, and renal disorder are likely
to occur. Administer Mitomycin-C Kyowa with caution in this population
while closely monitoring patient’s condition and paying special attention to
the dose and dosing interval.
Occurrence of acute leukaemia (in some cases following preleukaemic
phase) and myelodysplastic syndrome has been reported in the patients
treated with Mitomycin-C Kyowa concomitantly with other antineoplastic
4.5 Interaction with other medicinal products and other forms of
Mitomycin-C Kyowa should be administered with care when it is
coadministered with other antineoplastic agents or irradiation. The adverse
reactions of each drug may be enhanced, for example bone marrow
depression. With vinca alkaloids adverse reactions of shortness of breath
and bronchospasm may be enhanced.
Immune system disorders
Respiratory and mediastinal disorders
Respiratory disorders such as interstitial lung disease,
Diarrhoea, constipation, abdominal discomfort, stomatitis
Parenchymatous liver disorder, cholecystitis, jaundice
Skin and subcutaneous tissue disorders
Renal and urinary disorders
4.6 Fertility, pregnancy and lactation
Mitomycin-C Kyowa should not normally be administered to patients who
are pregnant, who may possibly be pregnant or to mothers who are breastfeeding. Teratological changes have been noted in animal studies.
Acute renal failure, renal disorder, cystitis, haemturia, proteinuria, serious nephropathy, albuminuria
Pyrexia, chills, malaise, injection site phlebitis, oedema,
generalised weakness and lethargy
ffects on ability to drive and use machines
Generalised weakness and lethargy have been reported on rare occasions.
If affected, patients should be advised not to drive or operate machinery.
The main adverse reactions collected from literature were leucopenia
in 130 (40.2%) of 323 patients, thrombocytopenia in 75 (24.7%) of 304
patients, anorexia in 58 (21.8%) of 266 patients, nausea/vomiting in 41
(15.4%) of 266 patients, malaise in 15 (5.6%) of 266 patients, weight loss in
18 (5.5%) of 329 patients, bleeding tendency in 12 (3.6%) of 329 patients
and anaemia in 10 (3.0%) of 329 patients.
Nausea and vomiting are sometimes experienced immediately after
treatment, but these are usually mild and of short duration. Pulmonary
toxicities such as pulmonary oedema, interstitial pneumonia and pulmonary
fibrosis (accompanied by fever, coughing, dyspnoea, abnormal x-ray
findings and eosinophilia), pulmonary hypertension and pulmonary venoocclusive disease (PVOD) have been reported. If signs of these conditions
are observed, discontinue treatment and take appropriate measures.
Skin toxicity may occur in a small proportion of patients, with side effects
such as alopecia (although this is less frequent and less severe than with
certain other cytotoxic agents). Palmar plantar erythrodysaesthesia (PPE),
bleeding, rashes and mouth ulcers have been reported.
Shock or anaphylactoid reaction may occur, patients should be carefully
observed. If symptoms such as itching, rash, hot flush, sweating, dyspnoea
and decreased blood pressure occur, treatment should be immediately
discontinued and appropriate measures should be taken.
Administration related Undesirable Effects
Cystitis, atrophy of the bladder, contracted bladder (pollakiuria, dysuria),
calcinosis, bladder necrosis, bladder perforation and penile necrosis have
been reported when given by intravesical instillation.
Administration to the hepatic artery may cause liver and biliary tract disorders
such as cholecystitis, cholangitis (also sclerosing), biloma, bile duct necrosis
and parenchymatous liver disorder. Drug distribution area should be confirmed
photographically or by other means, and treatment should be discontinued and
appropriate measures taken if any abnormal signs are noted.
The following administration related adverse reactions have also been
reported: vascular pain, phlebitis, thrombus, induration or necrosis at the
injection site, pain, redness erythema, blisters, erosion and ulceration which
may lead to skin/muscle necrosis.
Other reported effects, not already described in the text above, include
Infections and Infestations
Bacterial, viral or fungal infections, sepsis and septic shock
Neoplasms benign and malignant
Myelodysplastic syndrome, acute myeloid leukaemia, acute
Blood and lymphatic system disorders
Bone marrow depression, pancytopenia, neutropenia,
granulocytopenia, febrile neutropenia, erythropenia,
microangiopathic haemolytic anaemia, haemolytic
uraemic syndrome, thrombotic thrombocytopenic purpura,
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 Yellow Card Scheme
In the unlikely event of accidental overdosage then an increase in the
more common side effects should be expected, such as fever, nausea,
vomiting and myelosuppression. Appropriate supportive measures should
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: L01D
Pharmacotherapeutic group: Other cytotoxic antibiotics
Mitomycin-C Kyowa 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 is rapidly cleared from the serum after
intravenous administration. The time required to reduce the serum
concentration by 50% after a 30mg bolus injection is 17 minutes.
After injection of 30mg, 20mg or 10mg intravenously, the maximal
serum concentrations were 2.4 mcg/ml, 1.7 mcg/ml and 0.52mcg/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 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 is similar to that
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber which are
additional to that already included elsewhere in the SPC.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium Chloride Ph.Eur.
6.3 Shelf life
Mitomycin-C 2 mg and 10 mg: 4 years
Mitomycin-C 20 mg: 3 years
Mitomycin-C 40 mg: 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
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 is contained within a colourless, type I or III
glass vial with a rubber stopper and an aluminium seal.
The 10, 20 and 40 mg vials are packaged into cardboard
cartons containing 1 or 5 vials. The 2 mg vials are packaged
into cardboard trays with an overwrap containing 10 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 5 ml for the 2 mg, at least 10 ml
for the 10 mg, at least 20 ml for the 20 mg and at least 40 ml
for the 40 mg vial. If possible, avoid mixing with other low pH
Mitomycin-C Kyowa 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
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE
Date of first authorisation: 26th November 1992
Date of latest renewal: 29 June 2006
10. DATE OF REVISION OF THE TEXT
PACKAGE LEAFLET: INFORMATION FOR THE USER
2, 10, 20 or 40 mg Powder for solution for injection
Read all of this leaflet carefully before you start using this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
- If you get any of the side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
In this leaflet:
1. What Mitomycin-C Kyowa is and what it is used for
2. What you need to know before you use Mitomycin-C Kyowa
3. How to use Mitomycin-C Kyowa
4. Possible side effects
5. How to store Mitomycin-C Kyowa
6. Contents of the pack and other information
1. WHAT MITOMYCIN-C KYOWA IS AND WHAT IT IS USED FOR
As a single medicine or in a combination with other medicines, Mitomycin-C Kyowa can be used
to treat different types of cancers in many different parts of the body as described below:• In bladder cancer Mitomycin-C Kyowa can be given by injection or, alternatively introduced
directly into the bladder after surgery to reduce the chances of a recurrence of the condition
• Breast cancer and cancer of the neck of the womb (the cervix).
• It shows some activity in cancers of the stomach, pancreas, lung, liver, head and neck, prostate,
leukaemia (a disease of the blood) and certain other types of tumours.
• It has a possible role with other anti-cancer medicines in cancer of the lower bowel, skin cancer
and sarcomas (cancers of a particular kind of body tissue called connective tissue).
• It has been successfully used in combination with surgery, before operations (in cases of cancer
of the upper digestive tract) and after operations (in cases of cancer of the stomach).
• It has been shown to be effective when used in combination with radiotherapy.
2. WHAT YOU NEED TO KNOW BEFORE YOU USE MITOMYCIN-C KYOWA
Do not use Mitomycin-C Kyowa if you:
• are allergic (hypersensitive) to mitomycin or any of the other ingredients of Mitomycin-C Kyowa
(listed in section 6).
• have certain types of blood disorders (ask your doctor for advice).
Take special care with Mitomycin-C Kyowa if you:
• have liver or kidney problems; side effects of mitomycin may be more noticeable
• are capable of child-bearing as mitomycin may affect your ability to have children in the future
• have been told that you have bone marrow depression (your bone marrow is not able to make
the blood cells that you need); it may be made worse (especially in the elderly); infection
(including chickenpox) may be aggravated due to bone marrow depression and may lead to
Special attention will be paid if this product is given to the elderly or to children due to the possible
side effects in these age groups.
You will be given the treatment under the supervision of a healthcare professional who is
experienced in this particular branch of medicine to minimise any unwanted side effects in the
Other medicines and Mitomycin-C Kyowa
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription, or been given other treatments (e.g. radiotherapy).
When given together with certain other cancer treatment there have been some reports of problems
related to bone marrow and the occurrence of cancer involving various types of blood cells.
Pregnancy and breast-feeding
You should not be given Mitomycin-C Kyowa if you are pregnant, may be pregnant or if you are
breast-feeding. Ask your doctor for advice before taking any medicine.
Driving and using machines
A few people have reported that they feel tired or weak after the treatment. Do not drive or use
any tools or machines if you are affected.
3. HOW TO USE MITOMYCIN-C KYOWA
Always use the medicine as your doctor or pharmacist has told you. Check with your doctor or
pharmacist if you are not sure.
Mitomycin-C Kyowa is usually given by injection or as an infusion (with a drip). However in the treatment or the prevention of the recurrence of bladder cancer, a solution of Mitomycin-C Kyowa will be
given directly into the bladder through a type of tube called a catheter.
The precise dosage, frequency of dosing and duration of treatment with Mitomycin-C Kyowa will
depend on your age, weight, medical condition and whether Mitomycin-C Kyowa is being given in
combination with other drug treatment.
Source: Medicines and Healthcare Products Regulatory Agency
Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.