Mitomycin 1 Mg/Ml Powder For Solution For Injection/Infusion Or Intravesical Use

Document: spc-doc_PL 27904-0009 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Mitomycin 1 mg/ml powder for solution for injection/infusion or intravesical use

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of Mitomycin contains 2 mg mitomycin Each vial of Mitomycin contains 10 mg mitomycin Each vial of Mitomycin contains 20 mg mitomycin Each vial of Mitomycin contains 40 mg mitomycin

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection/infusion or intravesical use.

Grey to grey blue powder or cake.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Mitomycin is used in palliative tumour therapy.

Intravenous use of mitomycin is indicated as monochemotherapy or in combined cytostatic chemotherapy in adult patients with:

• advanced colorectal carcinoma

• advanced gastric carcinoma

• advanced and/or metastatic breast carcinoma

• advanced oesophageal carcinoma

• advanced cervical carcinoma

• non-small-cell bronchial carcinoma

advanced pancreatic carcinoma advanced tumours of the head and neck

Furthermore, mitomycin is indicated as intravesical administration for relapse prevention in adult patients with superficial urinary bladder carcinoma after transurethral resection.

4.2 Posology and method of administration

Posology

Mitomycin should only be used by doctors experienced in this therapy if there is a strict indication and with continual monitoring of the haematological parameters. It is essential that the injection is administered intravenously. If the medicinal product is injected perivasally, extensive necrosis occurs in the area concerned.

Unless otherwise prescribed, mitomycin is dosed as follows:

Intravenous administration

In cytostatic monochemotherapy, mitomycin is usually administered intravenously as a bolus injection.

The recommended dosages are 10 - 20 mg/m² body surface area every 6 - 8 weeks,

8 - 12 mg/m² body surface area every 3 - 4, weeks or 5 - 10 mg/m² of body surface every 3 - 6 weeks, depending on the therapeutic scheme used.

In combination therapy, the dosage is considerably lower. Because of the risk of additive myelotoxicity, proven treatment protocols may not be deviated from without a specific reason.

Intravesical administration

There are many intravesical mitomycin regimens, varying in dose of mitomycin used, the frequency of instillation and the duration of therapy.

Unless otherwise specified, the dosage of mitomycin is 40 mg mitomycin instilled into the bladder once weekly. Regimens with instillations every 2 weeks, every month or 3 monthly can also be used.

The specialist should decide on the optimum regime, frequency and duration of therapy on an individual patient basis.

The urine pH should be higher than pH 6.

Special populations

The dose must be reduced in patients who have undergone extensive previous cytostatic therapy, in case of myelosuppression or in elderly patients.

Insufficient data from clinical studies are available concerning the use of mitomycin in patients > 65 years of age.

The product should not be used in patients with renal impairment (see section 4.3)

The product is not recommended in patients with hepatic impairment due to lack of efficacy and safety data in this group of patients.

Paediatric population

The safety and efficacy of mitomycin in children have not been established. No data are available.

Method of administration

Mitomycin is intended for injection or infusion into a blood vessel (intravenous use) or for intravesical instillation after being dissolved. Partial use is applicable.

Precautions to be taken before handling or administering the medicinal product

• Mitomycin 20 mg must not be used in mixed injections.

• Other injection solutions or infusion solutions must be administered separately.

• It is essential that the injection is administered intravenously.

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

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Breastfeeding

In systemic therapy

Pancytopenia, isolated leukopenia or thrombopenia, haemorrhagic diathesis and acute infections are absolute contraindications.

Restrictive or obstructive disturbances to pulmonary ventilation, renal dysfunction, liver dysfunction and/or a poor general state of health are relative contraindications.

Temporal connection with radiotherapy or other cytostatic may be a further contraindication.

Intravesical therapy Bladder wall perforation Cystitis

4.4 Special warnings and precautions for use

Due to the toxic effects on the bone marrow of mitomycin, other myelotoxic therapy modalities (in particular other cytostatics, radiation) must be administered with particular caution in order to minimise the risk of additive myelosuppression.

It is essential that the injection is administered intravenously. If the medicinal product is injected perivasally, extensive necrosis occurs in the area concerned. To avoid necrosis following recommendations apply:

• Always inject into large veins in the arms.

• Do not directly inject intravenously, but rather into the tube of a good and securely running infusion.

• Before removing the cannula after central venous administration, flush it through for a few minutes using the infusion in order to release any residual mitomycin.

If extravasation occurs, immediate topical use of dimethylsulfoxide (DMSO 99 %), repeated every 4-8 hours as well as the use of dry cold compresses is recommended.

A (plastic) surgeon should be consulted at an early stage (within 72 hours). A systemic injection of 200 mg of Vitamin B6 may be of some value in promoting the regrowth of tissues that have been damaged.

Long-term therapy may result in cumulative bone marrow toxicity. Bone marrow suppression may only manifest itself after a delay, being expressed most strongly after 4-6 weeks, accumulating after prolonged use and therefore often requiring an individual dose adjustment.

Elderly patients often have reduced physiological function, bone marrow depression, which may be protracted, so administer mitomycin with special caution in this population while closely monitoring patient's condition.

Mitomycin is a mutagenic and potentially carcinogenic substance in humans. Contact with the skin and mucous membranes is to be avoided.

In the case of pulmonary symptoms, which cannot be attributed to the underlying disease, therapy should be stopped immediately. Pulmonary toxicity can be well treated with steroids.

Therapy should be stopped immediately also if there are symptoms of haemolysis or indications of renal dysfunction (nephrotoxicity). The occurrence of a haemolytic-uraemic syndrome (HUS: irreversible renal failure, microangiopathic haemolytic anaemia [MAHA syndrome] and thrombocytopenia) is commonly fatal.

At doses of > 30 mg of mitomycin/m² of body surface microangiopathic-haemolytic anaemia has been observed. Close monitoring of renal function is recommended.

New findings suggest a therapeutic trial may be appropriate for the removal of immune complexes that seem to play a significant role in the onset of symptoms by means of staphylococcal protein A.

Occurrence of acute leukaemia (in some cases following preleukaemic phase) and myelodysplastic syndrome has been reported in the patients treated concomitantly with other antineoplastic agents.

Recommended check-ups and safety measures in the case of intravenous administration:

Before the start of treatment

• Complete blood count

• Pulmonary function test if pre-existing lung dysfunction is suspected

• Renal function test in order to exclude renal insufficiency

• Liver function test in order to exclude liver insufficiency

During the treatment

• Regular monitoring of the blood count

• Close monitoring of renal function

4.5 Interaction with other medicinal products and other forms of interaction

Myelotoxic interactions with other bone marrow-toxic treatment modalities (especially other cytotoxic medicinal products, radiation) are possible.

Combination with vinca alkaloids or bleomycin may reinforce pulmonary toxicity.

An increased risk of haemolytic-uraemic syndrome has been reported in patients receiving a concomitant administration of mitomycin and 5-fluorouracil or tamoxifen.

In animal experiments, pyridoxine hydrochloride (vitamin B6) resulted in the loss of effect of mitomycin.

No injections with live vaccines should be carried out in connection with mitomycin treatment as this may result in an increased risk of infection by the live vaccine.

The cardiotoxicity of Adriamycin (doxorubicin) may be reinforced by mitomycin.

4.6 Fertility, pregnancy and lactation

Pregnancy

Mitomycin is genotoxic and can adversely affect the development of an embryo. Mitomycin should not be used during pregnancy. If treatment of a pregnant patient is vitally indicated, medical counselling should be provided regarding the risk of harmful effects on the child associated with the treatment.

Lactation

Mitomycin is excreted in human milk. Breast-feeding must be discontinued during treatment (see section 4.3).

Fertility

Women must not become pregnant during treatment with mitomycin. In the event of pregnancy during treatment, genetic counselling must be provided. Sexually mature female patients should take contraceptive measures or practise sexual abstinence during chemotherapy and for 6 months afterwards.

Mitomycin is genotoxic. Men treated with mitomycin are therefore advised not to father a child during treatment and for 6 months afterwards and to seek advice on sperm conservation before starting the therapy due to the possibility of irreversible infertility caused by mitomycin therapy.

4.7 Effects on ability to drive and use machines

Even when used in accordance with instructions these medicinal products may cause nausea and vomiting and thereby reduce reaction times to such an extent that the ability to drive a motor vehicle or operate machinery is impaired. This applies even more in connection with alcohol.

4.8 Undesirable effects

Undesirable effects are listed below by system organ class and frequency. Frequencies below are defined as:

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 or not known (cannot be estimated from the available data))

The most common undesirable effects of systemically administered mitomycin are gastrointestinal symptoms, such as nausea and vomiting, and bone marrow suppression with leukopenia and generally dominant thrombopenia. Bone marrow suppression occurs in up to 65 % of patients. As the effect in prolonged use is cumulative, bone marrow suppression is often dose-limiting.

In up to 10 % of patients serious organ toxicity in the form of interstitial pneumonia or nephrotoxicity must be expected.

Mitomycin is potentially hepatotoxic.

Blood and lymphatic system disorders	Very common
	Bone marrow suppression,leucopenia thrombocytopenia Rare Life-threatening infection, sepsis, haemolytic anaemia
Immune system disorders	Very rare Severe allergic reaction
Cardiac disorders	Rare Heart failure after previous therapy with anthracyclines
Respiratory, thoracic and mediastinal disorders	Common (> 1/100 to < 1/10) Interstitial pneumonia, dyspnoe,cough, shortness of breath Rare Pulmonary hypertension, pulmonary veno- occlusive disease (PVOD)
Gastrointestinal disorders	Very common Nausea, vomiting Uncommon Mucositis, stomatitis, diarrhoea, anorexia
Hepatobiliary disorders	Rare Hepatic dysfunction, transaminases increased, icterus,

	veno-occlusive liver disease (VOD)
Skin and subcutaneous tissue disorders	Common Exanthema, allergic skin rash, contact dermatitis, palmar-plantar erythema Uncommon Alopecia Rare Exanthema, generalised
Renal and urinary disorders	Common Renal dysfunction, serum creatinine increased, glomerulopathy, nephrotoxicity Rare Haemolytic uraemic syndrome (HUS) (commonly fatal), microangiopathic haemolytic anaemia (MAHA syndrome)
General disorders and administration site conditions	Common In the event of extravasation: Cellulitis, tissue necrosis Uncommon Fever

Possible side-effects under intravesical therapy

Skin and subcutaneous tissue disorders

Common

Pruritus, allergic skin rash, contact dermatitis, palmar-plantar erythema

Rare

Generalised exanthema

Renal and urinary disorders

Common

Cystitis (possibly haemorrhagic), dysuria, nocturia, pollakisuria, haematuria, local irritation of the bladder wall

Very rare

Necrotising cystitis, allergic (eosinophilic) cystitis, stenosis of the efferent urinary tract, reduction in bladder capacity, bladder wall calcification and bladder wall fibrosis, bladder perforation.

If cystitis does occur, symptomatic treatment with local anti-inflammatories and analgesics should be given. In most cases the mitomycin therapy can be continued, if necessary at a reduced dose. Isolated cases of allergic (eosinophilic) cystitis have been reported which necessitated discontinuation of therapy.

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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In case of overdose severe myelotoxicity or even myelophthisis must be expected, with the full-blown clinical effect only appearing after approximately 2 weeks.

The period until which the number of leucocytes falls to the lowest value may be 4 weeks. Prolonged close haematological monitoring therefore also has to be carried out if an overdose is suspected.

As there are no effective antidotes available, the greatest level of caution is required during each application.

However, up till now, no cases of overdose of intravesical administration of mitomycin have been reported.

As no effective antidote is available, the utmost caution should be exercised at each administration.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, cytotoxic antibiotics and related substances, other cytotoxic antibiotics, ATC code: L01DC03

The antibiotic mitomycin is a cytostatic medicinal product from the group of alkylating agents.

Mitomycin is an antibiotic with an antineoplastic effect which is isolated from Streptomyces caespitosus. It is present in an inactive form. Activation to a trifunctional alkylating agent takes place rapidly, either at physiological pH in the presence of NADPH in serum or intracellularly in virtually all cells of the body with the exception of the cerebrum, as the blood-brain barrier is not overcome by mitomycin. The three alkylating radicals all stem from a quinone, an aziridine and a urethane group. The mechanism of action is based predominantly on DNA (to a lesser extent RNA) alkylation, with the corresponding inhibition of DNA synthesis. The degree of DNA damage correlates with the clinical effect and is lower in resistant cells than in sensitive cells. As with other alkylating agents, proliferating cells are damaged to a greater extent than those in the resting phase (G0) of the cell cycle. Additionally, free peroxide radicals are released, particularly in the case of higher doses, which result in DNA breaks. The release of peroxide radicals is associated with the organ-specific pattern of side effects.

5.2 Pharmacokinetic properties

Following intravenous administration of 10 - 20 mg/m² mitomycin, peak plasma levels of 0.4 - 3.2 pg/ml have been measured. The biological half life is short, between 40 and 50 minutes. The serum level falls biexponentially, steeply within the first 45 minutes and more slowly thereafter.

After approximately 3 hours the serum levels are usually below the detection limit. The main location for metabolism and elimination is the liver. Accordingly, high concentrations of mitomycin have been found in the gall bladder. Renal excretion plays only a minor role with respect to the elimination.

During intravesical therapy mitomycin is only absorbed in insignificant doses. Nevertheless, a systemic effect cannot be excluded completely.

5.3 Preclinical safety data

In animal studies mitomycin has a toxic effect on all proliferating tissues, in particular on the cells of the bone marrow and the gastrointestinal mucosa, and spermatogenesis is inhibited.

Mitomycin has mutagenic, carcinogenic and teratogenic properties, which can be demonstrated in appropriate experimental models.

If injected outside a vein, or in the event of extravasation into surrounding tissue, mitomycin causes severe necrosis.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Urea

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Mitomycin , vials with 2 mg (10 mg, 20 mg, 40 mg) mitomycin 18 months

From a chemical and physical point of view the reconstituted product should be used within 24 hours.

From a microbiological point of view, this product should be unsed immmediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless reconstitution / dilution (etc) has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store the vial in the outer carton in order to protect the contents from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Mitomycin 2 mg:

Packs of 1, 5 and 10 6 ml clear glass vials (type I) with fluoropolymer coated bromobutyl rubber stopper and a flip off aluminium seal

Mitomycin 10 mg:

Packs of 1, 5 and 10 10 ml clear glass vials (type I) with fluoropolymer coated bromobutyl rubber stopper and a flip off aluminium seal

Mitomycin 20 mg:

Packs of 1, 5 and 10 20 ml clear glass vials (type I) with fluoropolymer coated bromobutyl rubber stopper and a flip off aluminium seal

Mitomycin 40 mg:

Packs of 1, 5 and 10 50 ml clear glass vials (type I) with fluoropolymer coated bromobutyl rubber stopper and a flip off aluminium seal

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Reconstitution of solution for injection or infusion ready for use

Mitomycin 2 mg:

Dissolve the contents of one 2 mg vial of Mitomycin in 2 ml water for injections by inverting the vial.

If the powder does not dissolve immediately, leave to stand at room temperature until fully dissolved. The contents of the vial must dissolve to form a blue-purple clear solution within 2 minutes.

Mitomycin 10 mg:

Dissolve the contents of one 10 mg vial of Mitomycin in 10 ml water for injections by inverting the vial.

If the powder does not dissolve immediately, leave to stand at room temperature until fully dissolved. The contents of the vial must dissolve to form a blue-purple clear solution within 2 minutes.

Mitomycin 20 mg:

Dissolve the contents of one 20 mg vial of Mitomycin in 20 ml water for injections by inverting the vial.

If the powder does not dissolve immediately, leave to stand at room temperature until fully dissolved. The contents of the vial must dissolve to form a blue-purple clear solution within 2 minutes.

Reconstitution of solution for intravesical use ready for use

Mitomycin 2 mg:

Dissolve the contents of 10 - 20 vials of Mitomycin 2 mg (equivalent to 20 - 40 mg mitomycin) in 20 - 40 ml sterile 0.9 % sodium chloride solution. The contents of the vial must dissolve to form a blue-purple clear solution within 2 minutes.

Mitomycin 10 mg:

Dissolve the contents of 2 - 4 vials of Mitomycin 10 mg (equivalent to 20 - 40 mg mitomycin) in 20 - 40 ml sterile 0.9 % sodium chloride solution. The contents of the vial must dissolve to form a blue-purple clear solution within 2 minutes.

Mitomycin 20 mg:

Dissolve the contents of 1 - 2 vials of Mitomycin 20 mg (equivalent to 20 - 40 mg mitomycin) in 20 - 40 ml sterile 0.9 % sodium chloride solution. The contents of the vial must dissolve to form a blue-purple clear solution within 2 minutes.

Mitomycin 40 mg:

Dissolve the content of one vial of Mitomycin 40 mg (equivalent to 40 mg mitomycin) in 40 ml sterile 0.9 % sodium chloride solution. The contents of the vial must dissolve to form a blue-purple clear solution within 2 minutes.

Only clear solutions may be used.

The content of the vials is intended for single use/single entry only.

Unused solution must be discarded.

Protect the reconstituted solution from light.

Mitomycin must not be used in mixed injections. Other solutions for injection or infusion must be administered separately.

Where relevant, intravascular injection, avoiding extravasation, is essential.

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

7 MARKETING AUTHORISATION HOLDER

PHARMALEX GMBH

JOSEPH-MAYER-STRASSE 13-15

MANNHEIM

D-68167

GERMANY

8 MARKETING AUTHORISATION NUMBER(S)

PL 27904/0009

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 16/12/2015

DATE OF REVISION OF THE TEXT

16/12/2015