MITOMYCIN-C
Treatment schedules
1. For solitary superficial tumours at first presentation:3 a single dose, 40mg in 40mls of Water for Injection as soon as possible after surgery, patient retains for at least 1 hour.
2. For multifocal and/or recurrent disease : (Treatment Regime)4 40mg in 40mls of Water for Injection, once a week for 6-8 weeks, patient retains for at least 1 hour.
3. Maintenance therapy:5 40mg in 100mls normal saline, once a month for up to 12 months, patient retains for at least 1 hour.
4. Response rates : Complete response rate reported between 37-77% 6,7,8
General InformationAn antibiotic with antitumour properties, isolated from the bacterium Streptomyces caespitosus in 1958.
An alkylating agent which interferes with the cross-linking of DNA.
A high molecular weight (334) gives rise to little systemic absorption when given intravesically.4
Generally very well tolerated with mild frequency and cystitis reported2
Safety Precautions : see Appendix 2
Cost: £77 36 + VAT per 40mg dose
References1. C.R.C. Data 1990
2. Hall RR, Parmar MKB et al. Br Med J 1994; 308: 257 - 60
3. Tolley DA, Hargreave TB et al. Br Med J 1988; 396: 1759 - 61
4. Macfarlane JR, Tolley DA et al. Br J Urol 1985; 57: 37-9
5. Hamby F, Hastie KJ et al. Br J Urol 1993; 71: 183-6
6. Harrison GSM, Green D et al Br J Urol 1983; 55: 676-9
7. Koontz WW, Honey NM et al. Urology 1985; 26 (Suppl 4): 30-1
8. Denis L, Keuppens F et al in Clinical and Biological Research 1985; 185:113-22
Summary of Product Characteristics
1. Trade Name of the Medicinal Product
Mitomycin-C Kyowa 20mg or 40 mg.2. Qualitative and Quantitative Composition
Active Constituent Quantity per vial Mitomycin-C 20 mg or 40 mg 3. Pharmaceutical Form
Sterile powder for injection.
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 neoplastic conditions.
1. 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.
2. As a single agent and in combination with other drugs in metastatic breast cancer.
3. In combination with other agents in advanced squamous cell carcinoma of the uterine cervix.
4. It shows a degree of activity as part of combination therapy in carcinoma of the stomach, pancreas and lung (particularly non-small cell).
5. It shows a degree of activity as a single agent and in combination in liver cancer when given by the intra-arterial route.
6. It has a possible role in combination with other cytotoxic drugs in colo-rectal cancer.
7. It shows a degree of activity as a single agent or part of combination therapy in cancer of the head and neck.
8. It shows a degree of activity as a single agent in cancer of the prostate.
9. 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, pre-operatively (oesophageal squamous cell carcinoma) and post-operatively (gastric cancer).
13. It has shown to be effective when used in combination with radiotherapy.
4.2 Posology and Method of AdministrationFor parenteral use
Intravenously, the dose should be given with great care in order to avoid extravasation. The usual dose is in the range of 4 - 10mg (0.06-0.15mg/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 10mg/m2 of body surface area, the course being repeated at intervals for as long as required. A course ranging from 40-80mg (0.58 -1.2mg/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 2mg/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 0.6mg/kg have not been shown to be more effective and are more toxic than lower doses.
Treatment of superficial bladder tumours : In the treatment of superficial bladder tumours the usual dose is 20-40mg dissolved in 20-40ml 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 areas.
In the prevention of recurrent superficial bladder tumours, various doses have been used. These include 20mg in 20ml of diluent every two weeks and 40mg in 40ml of diluent monthly or three monthly. The dose is instilled into the bladder through a urethral catheter.
4.3 Contra-indications
Patients who have demonstrated a hypersensitive or idiosyncratic reaction to Mitomycin-C Kyowa in the past. Thrombocytopenia, coagulation disorders and increased bleeding tendency.
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 4mg dexamethasone.
A systemic injection of 200mg of Vitamin B6 may be of some value in promoting the regrowth of tissues that have been damaged.
Mitomycin-C Kyowa should not be allowed to come into contact with the skin. If it does, it should be washed several times with 8.4% sodium bicarbonate solution, followed by soap and 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 8.4% sodium bicarbonate solution. It should then be observed for several days for evidence of corneal damage. If necessary, appropriate treatment should be instituted.
4.5 Interactions with other Medicaments and other forms of Interaction
Not Known.
4.6 Pregnancy and Lactation
Mitomycin-C Kyowa should not normally be administrated to patients who are pregnant or to mothers who are breast-feeding. Teratological changes have been noted in animal studies.
4.7 Effects 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.
4.8 Undesired Effects
Thrombocytopenia and leucopenia resulting from myelosuppression, which is delayed and cumulative. Patients should be monitored closely during each course of treatment, 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. If disease progression continues after two courses of treatment, the drug should be stopped since the chances of response are minimal. Severe renal toxicity has occasionally been reported after treatment and renal function should be monitored before starting treatment and again after each course. Nausea and vomiting are sometimes experienced immediately after treatment, but these are usually mild and of short duration. Pulmonary toxicity and fever have been reported. 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). Bleeding, rashes and mouth ulcers have been reported. General weakness and lethargy have been reported on rare occasions. Other reported effects include anorexia, diarrhoea, stomatitis, interstitial pneumonitis, pulmonary fibrosis and microangiopathic haemolytic anaemia syndrome.
4.9 Overdose
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 be instituted.
Pharmacological Properties
5.1 Pharmacodynamic Properties
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 in adults.
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.
Pharmaceutical Particulars
6.1 List of Excipients
Sodium Chloride Ph.Eur.
6.2 Incompatibilities
Not known
6.3 Shelf Life
Four years from the date of manufacture.
After reconstitution, the solution is stable for 24 hours when protected from light and stored in a cool place. Do not refrigerate.
6.4 Special Precautions for Storage
None.
6.5 Nature and Contents of Container
Mitomycin-C Kyowa consists of a blue/purple crystalline powder, contained within a colourless, type 1 glass vial with a rubber stopper and an aluminium seal.
The vials are packaged into cardboard cartons containing 1 or 5 vials.
6.6 Instruction for Use/Handling
The contents of the vial should be reconstituted with Water for Injection or saline, at least 20ml for the 20mg / at least 40ml for the 40mg vial.
Administrative Data
7. Marketing Authorisation Holder
Kyowa Hakko (UK) Ltd
258 Bath Road
Slough
Berkshire
SL1 4DX8. Marketing Authorisation Number
PL 12196/0003
9. Date of First Authorisation/Renewal of Authorisation
26th November 1992
10. Date of (Partial) Revision of the Text
May 1999