Mitomycin

Mitomycin is used in palliative tumour therapy. Mitomycin is administered intravenously as monochemotherapy or in combined cytostatic chemotherapy in adults with: • advanced metastatic gastric carcinoma • advanced and/or metastatic breast cancer Furthermore mitomycin is administered intravenously in combined chemotherapy in adults with: • non-small cell bronchial carcinoma • advanced pancreatic carcinoma Intravesical administration for relapse prevention in adults with superficial urinary bladder carcinoma after transurethral resection.

Posology Mitomycin should only be used by doctors experienced in this therapy if there is a strict indication and, in case of intravenous use, with continual monitoring of the haematological parameters. Intravenous administration It is essential that the injection is administered intravenous.

If the medicinal product is injected perivasally, extensive necrosis occurs in the concerned area.

Unless otherwise prescribed, mitomycin is dosed as follows:

In cytostatic monochemotherapy, mitomycin is usually administered intravenously as a bolus injection. The recommended dosage is 10 - 20 mg/m2 of body surface area every 6 - 8 weeks, 8 - 12 mg/m2 of body surface area every 3 - 4 weeks or 5-10 mg/m2 of body surface area every 1-6 weeks, depending on the therapeutic scheme used.

Mitomycin 20 mg, powder for solution for injection/infusion may not be reconstituted in water. A dose greater than 20 mg/m2 gives more toxic manifestations without therapeutic benefits. The maximum cumulative dose of mitomycin is 60 mg/m2.

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. 9%) solution or Water for Injection (WFI), is instilled weekly into the bladder.

The treatment period is 8 to 12 weeks. In the case of intravesical administration the urine pH should be higher than pH 6. 15 mg/kg of body weight) instilled into the bladder though a urethral catheter 1 or 3 times per week. The solution should be retained in the bladder for 1-2 hours.

Special populations The dose must be reduced in patients who have undergone extensive previous cytostatic therapy, in case of myelosuppression or in elderly patients (only valid for intravenous use of mitomycin). Older patients Insufficient data from clinical studies are available concerning the use of mitomycin in patients ≥ 65 years of age.

3). Paediatric population The safety and efficacy of mitomycin in children aged from 0 to 17 years have not been established. No data are available. Method of administration Mitomycin is only intended for intravenous injection or infusion into a blood vessel (intravenous use) or for intravesical instillation after being dissolved.

Partial use is applicable (only valid for intravenous use of mitomycin). Intravenous administration Precautions to be taken before handling or administering the medicinal product • Mitomycin 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 intravenous. Intravesical administration It is advised to use this medicinal product at its optimal pH (urinary pH > 6) and to maintain the concentration of mitomycin by reducing fluid intake before, during and after instillation.

The bladder must be emptied before instillation. Mitomycin is introduced into the bladder by means of a catheter and at low pressure. The length of individual instillation should be 1 – 2 hours. During this period the solution 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 solution, preferably in a sitting position. 6.

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) Possible side-effects under systemic therapy The most common side effects of mitomycin administered systemically are gastrointestinal symptoms like nausea and vomiting and bone marrow suppression with leukopenia and mostly dominant thrombocytopenia.

This 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 the lymphatic system disorders Very common Bone marrow suppression, leucopenia thrombocytopenia Rare Haemolytic anaemia, thrombotic microangiopathy (TMA), incl. thrombotic thrombocytopenic purpura (TTP) Not known Anaemia Infections and infestations Rare Life-threatening infection, sepsis Not known Infection Immune system disorders Very rare Severe allergic reaction Cardiac disorders Rare Heart failure after previous therapy with anthracyclines Respiratory, thoracic and mediastinal disorders Common 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 Hepato-biliary disorders Rare Liver dysfunction, increased transaminases, jaundice, veno-occlusive disease (VOD) of the liver Skin and subcutaneous tissue disorders Common Exanthema, allergic skin rash, contact dermatitis, Palmar plantar erythrodysaesthesia (PPE) Uncommon Alopecia Rare Generalised exanthema Renal and urinary disorders Common Renal dysfunction, increase in serum creatinine, glomerulopathy, Nephrotoxicity Rare Haemolytic uraemic syndrome(HUS) (commonly fatal), microangiopathic- haemolytic anaemia (MAHA syndrome) General disorders and administration site conditions Common Following Extravasation: Cellulitis, tissue necrosis Uncommon Fever Possible side-effects under intravesical therapy Adverse reactions may result either from the solution for intravesical instillation or after deep resection.

g. contact dermatitis, also in the form of palmar and plantar erythema), and cystitis. After intravesical administration, only minor amounts of mitomycin reach the systemic circulation. Nevertheless, in very rare cases the following systemic adverse reactions have been reported: Possible systemic adverse reactions occurring very rarely following intravesical administration: Blood and lymphatic system disorders Leukocytopenia, thrombocytopenia Respiratory, thoracic and mediastinal disorders Interstitial lung disease Gastrointestinal disorders Nausea, vomiting, diarrhoea Hepatobiliary disorders Transaminases increased Skin and subcutaneous tissue disorders Alopecia Renal and urinary disorders Renal dysfunction General disorders and administration site conditions Fever 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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

1. 6) Systemic therapy Pancytopenia, isolated leucopoenia/thrombocytopenia, haemorrhagic diathesis and acute infections are absolute contraindications. Restrictive or obstructive disturbances to pulmonary ventilation, renal dysfunction, hepatic dysfunction and/or a poor general state of health are relative contraindications.

Temporal connection with radiotherapy or other cytostatics may be a further contraindication. Intravesical therapy Perforation of the bladder wall is an absolute contraindication. Cystitis is a relative contraindication.

AND CLINICAL USE

Mitomycin for Injection is indicated in the palliative treatment as an adjunct to surgery, radiation or chemotherapy for adenocarcinoma of the stomach and colon. Mitomycin for Injection as a single agent is indicated as topical therapy for superficial (no invasion beyond the lamina propria) transitional cell carcinoma of the urinary bladder.

Efficacy has been demonstrated both in patients who have had no prior intravesical chemotherapy and in those who have failed such therapy with Thiotepa or other antineoplastic agents. CONTRAINDICATIONS Mitomycin for Injection is contraindicated in patients who have demonstrated a hypersensitivity to it in the past.

Mitomycin for Injection is contraindicated in patients with thrombocytopenia, leukopenia, coagulation disorder, or an increased bleeding tendency due to other causes. Mitomycin for Injection is contraindicated for intravesical administration in patients who have demonstrated a hypersensitive or idiosyncratic reaction to it in the past.

WARNINGS It is recommended that Mitomycin for Injection be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Since facilities for necessary laboratory studies must be available, hospitalization of patients is recommended.

Mitomycin for Injection should not be administered to any patient with a white blood cell count below 4000 mm3 and a platelet count below 150 000 mm3, or to those with potentially serious infections. Bone marrow depression, notably thrombocytopenia and leukopenia, is the most severe toxicity (see ADVERSE REACTIONS).

Thrombocytopenia may contribute to hemorrhage and leukopenia to overwhelming infection in an already compromised, poor risk patient and may result in death. Mitomycin for Injection is cytotoxic. In the treatment of each patient, the physician must weigh carefully the possibility of achieving therapeutic benefit versus the risk of toxicity.

Studies have shown that mitomycin is carcinogenic in animals. Use in Obstetrics Safe use of mitomycin in pregnant women has not been established. Mitomycin has known teratogenic properties in animals, therefore, the benefits derived from the use of Mitomycin for Injection in pregnancy must be weighed against the hazards involved.

Page 4 of 15 Nursing Women It is not known if mitomycin is excreted in human milk. It is recommended that women receiving mitomycin not breast feed because of the potential for serious adverse reactions from mitomycin in nursing infants.

PRECAUTIONS Mitomycin for Injection should be administered, preferably, to patients who are hospitalized and who can be observed carefully and frequently during and after therapy. It should be used with extreme caution in patients with significant impairment of renal function.

Since mitomycin has a high incidence of bone marrow depression, particularly thrombocytopenia and leukopenia, the following studies should be obtained frequently during therapy and for at least seven weeks following therapy: platelet count, prothrombin time, bleeding time, white blood count and differential.

The persistence of thrombocytopenia below 150 000 mm3, or a significant prolongation of prothrombin time or bleeding time, or a white blood cell count below 4000 mm3 is an indication for the termination of therapy. Hemolytic Uremic Syndrome (HUS), a serious complication of chemotherapy, consisting primarily of microangiopathic hemolytic anemia, thrombocytopenia and irreversible renal failure has been reported in patients receiving mitomycin.

The syndrome may occur at any time during systemic therapy with mitomycin as a single agent or in combination with other cytotoxic drugs; however, most cases occur at doses 60 mg of mitomycin. Blood product transfusion may exacerbate the symptoms associated with this syndrome.

The incidence of the syndrome has not been defined. (See ADVERSE REACTIONS) Patients should be advised of the potential toxicity of this drug, particularly bone marrow depression. A low incidence of septicemic deaths, as a result of leukopenia attributable to the drug, have been reported.

Patients receiving Mitomycin for Injection should be observed for evidence of renal toxicity. 7 mg percent. Mitomycin-associated pulmonary toxicity has been reported. Cases have been reported with both single-agent therapy and combination chemotherapy.

Dyspnea and nonproductive cough are the usual presenting symptoms. Radiographic evidence of interstitial infiltrates may or may not be present. If other etiologies have been eliminated, a diagnosis of mitomycin-related pulmonary toxicity may be made.

Signs and symptoms of pneumonitis associated with mitomycin may be reversed if appropriate therapy is instituted early and mitomycin is discontinued. Corticosteroids have been reported by several authors to expedite symptomatic relief.

Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids in patients who had previously or simultaneously received mitomycin. The onset of this acute respiratory distress occurred within minutes to hours after the Page 5 of 15 vinca alkaloid injection.

The total number of doses for each drug has varied considerably. Bronchodilators, steroids and / or oxygen have produced symptomatic relief. A few cases of adult respiratory distress syndrome have been reported in patients receiving mitomycin, in combination with other chemotherapy, and maintained at FiO2 concentrations greater than 50% perioperatively.

Therefore, caution should be exercised using only enough oxygen to provide adequate arterial saturation, since oxygen itself is toxic to the lungs. Careful attention should be paid to fluid balance and overhydration should be avoided.

ADVERSE REACTIONS Bone Marrow Toxicity The most serious and most common toxicity of mitomycin is thrombocytopenia and […]

Mitomycin for Injection should be given with care to avoid extravasation of the compound into the tissue. If extravasation occurs, cellulitis, ulceration and slough may result. 5 Shake well until dissolved. If the product does not dissolve immediately, shake under warm tap water for approximately two minutes until a solution is obtained.

All steps of dilution and administration must be conducted using non-PVC materials and containers. Intravenous Use After full hematological recovery from any previous chemotherapy, either of the following Dosage Schedules may be used at 6 to 8 week intervals.

Because of cumulative myelosuppression, patients should be re-evaluated after each course of Mitomycin for Injection and the dose reduced if the patient has experienced any toxicities (see Guide to Dosage Adjustment). Doses greater than 20 mg / m2 do not demonstrate increased effectiveness and are more toxic than lower doses.

(1) 20 mg / m2 intravenously as a single dose via a functioning intravenous catheter. (2) 2 mg / m2 / day intravenously for 5 days. After a drug free interval of 2 days, 2 mg / m2 / day for 5 days, thus making the total initial dose of 20 mg / m2 given over 10 days.

Intravesical Use A dose of 20 to 40 mg intravesically once per week for 8 weeks. Patients are advised to abstain from liquids for 12 hours prior to therapy. The patient is catheterized, the bladder is drained and Mitomycin for Injection is instilled.

The solution should be retained for 2 hours. If desired, the patient may rotate positions every 15 minutes, for maximum area-contact.

The following schedule is suggested as a Guide to Dosage Adjustment:

Guide to Dosage Adjustment Nadir After Prior Dose Leukocytes Platelets Percentage of Prior Dose to be Given > 4000 >100 000 100% Page 8 of 15 3000 - 3999 75 000 – 99 999 100% 2000 - 2999 25 000 – 74 999 70% <2000 <25000 50% No repeat dosage should be given until leukocyte count has returned to 3000 and platelet count to 75 000.

When Mitomycin for Injection is used in combination with other myelosuppressive agents, the doses should be adjusted accordingly. If the disease continues to progress after two courses of mitomycin, the drug should be stopped since chances of response are minimal.

Page 9 of 15 PHARMACEUTICAL INFORMATION Drug Substance Common Name: mitomycin Chemical Name: [(1aS,8S,8aR,8bS)-6-Amino-8a-methoxy-5- methyl-4,7-dioxo-1,1a,2,4,7,8,8a,8 b-octahydroazirino[2’,3’:3,4]pyrrolo[1,2-a]-indol- 8-yl]methyl carbamate (Mitomycin C).

3 g / mol Description: Mitomycin is blue-violet crystals or crystalline powder. It has a melting point of 360°C and is slightly soluble in water, freely soluble in dimethylacetamide, sparingly soluble in methanol, slightly soluble in acetone.

Composition Each vial contains mitomycin 20 mg and mannitol 40 mg. Stability and Storage Recommendations Store at controlled room temperature (15° - 30°C) protected from light. 5 Page 10 of 15 Shake well until dissolved. If the product does not dissolve immediately, shake under warm tap water for approximately two minutes until a solution is obtained.

All steps of dilution and administration must be conducted using non-PVC materials and containers. 5 mg / mL, Mitomycin for Injection is stable for 72 hours refrigerated or 6 hours at controlled room temperature (15° - 30°C), protected from light.

9% Sodium Chloride Injection is stable for 12 hours at room temperature. The reconstituted and diluted solutions should be inspected for discolouration, haziness, particulate matter and leakage prior to administration. Discard unused portion.

Handling and Disposal 1. Preparation of Mitomycin for Injection should be done in a vertical laminar flow hood (Biological Safety Cabinet - Class II). 2. Personnel preparing mitomycin should wear PVC gloves, safety glasses, disposal gowns and masks.

3. All needles, syringes, vials and other materials, which have come in contact with mitomycin should be segregated and incinerated at 1000°C or more. Sealed containers may explode. Intact vials should be returned to the manufacturer for destruction.

Proper precautions should be taken in packaging these materials for transport. Personnel regularly involved in the preparation and handling of Mitomycin for Injection should have bi-annual blood examinations. AVAILABILITY OF DOSAGE FORMS Mitomycin for Injection is supplied as a sterile lyophilized powder, preservative-free with mannitol in single use vials containing 20 mg of mitomycin, packaged individually and it is essentially free from visible particles.

The vial stopper is not made with natural rubber latex. PHARMACOLOGY Page 11 of 15 Mitomycin disappears rapidly from the plasma and there is no evidence of specific tissue localization. After intravenous injection in dogs, mitomycin appeared in the urine within 5 to 6 minutes.

Eighteen to twenty-nine percent is recovered within one hour. Simultaneous creatinine clearance studies indicate that […]

INDICATIONS AND USAGE

Mitomycin for Injection is not recommended as single-agent, primary therapy. It has been shown to be useful in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and as palliative treatment when other modalities have failed.

Mitomycin is not recommended to replace appropriate surgery and/or radiotherapy.

DOSAGE AND ADMINISTRATION

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Mitomycin should be given intravenously only, using care to avoid extravasation of the compound.

If extravasation occurs, cellulitis, ulceration, and slough may result. Each Single-Dose vial contains mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 80 mL. Shake to dissolve. If product does not dissolve immediately, allow to stand at room temperature until solution is obtained.

After full hematological recovery (see guide to dosage adjustment) from any previous chemotherapy, the following dosage schedule may be used at 6 to 8 week intervals: 20 mg/m 2 intravenously as a single dose via a functioning intravenous catheter.

Because of cumulative myelosuppression, patients should be fully re-evaluated after each course of mitomycin, and the dose reduced if the patient has experienced any toxicities. Doses greater than 20 mg/m 2 have not been shown to be more effective, and are more toxic than lower doses.

The following schedule is suggested as a guide to dosage adjustment:

Nadir After Prior Dose Leukocytes /mm 3 Platelets / mm 3 Percentage of Prior Dose to be given >4000 >100,000 100% 3000 - 3999 75,000 - 99,999 100% 2000 - 2999 25,000 - 74,999 70% <2000 <25,000 50% No repeat dosage should be given until leukocyte count has returned to 4000/mm 3 and a platelet count to 100,000/mm 3 .

When mitomycin is used in combination with other myelosuppressive agents, the doses should be adjusted accordingly. If the disease continues to progress after two courses of mitomycin, the drug should be stopped since chances of response are minimal.

ADVERSE REACTIONS

4%). Thrombocytopenia and/or leukopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of the leukopenic or thrombocytopenic episodes did not recover.

Mitomycin produces cumulative myelosuppression. Integument and Mucous Membrane Toxicity This has occurred in approximately 4% of patients treated with mitomycin. Cellulitis at the injection site has been reported and is occasionally severe.

Stomatitis and alopecia also occur frequently. Rashes are rarely reported. The most important dermatological problem with this drug, however, is the necrosis and consequent sloughing of tissue which results if the drug is extravasated during injection.

Extravasation may occur with or without an accompanying stinging or burning sensation and even if there is adequate blood return when the injection needle is aspirated. There have been reports of delayed erythema and/or ulceration occurring either at or distant from the injection site, weeks to months after mitomycin, even when no obvious evidence of extravasation was observed during administration.

Skin grafting has been required in some of the cases. Elderly patients may be more susceptible than younger patients to injection site reactions (see PRECAUTIONS: Geriatric Use ). Renal Toxicity 2% of 1,281 patients demonstrated a statistically significant rise in creatinine.

There appeared to be no correlation between total dose administered or duration of therapy and the degree of renal impairment. Pulmonary Toxicity This has occurred infrequently but can be severe and may be life-threatening. Dyspnea with a non-productive cough and radiographic evidence of pulmonary infiltrates may be indicative of mitomycin-induced pulmonary toxicity.

If other etiologies are eliminated, mitomycin therapy should be discontinued. Steroids have been employed as treatment of this toxicity, but the therapeutic value has not been determined. A few cases of adult respiratory distress syndrome have been reported in patients receiving mitomycin in combination with other chemotherapy and maintained at FIO 2 concentrations greater than 50% perioperatively.

6 mg/dL) has been reported in patients receiving systemic mitomycin. Microangiopathic hemolysis with fragmented red blood cells on peripheral blood smears has occurred in 98% of patients with the syndrome. Other less frequent complications of the syndrome may include pulmonary edema (65%), neurologic abnormalities (16%), and hypertension.

Exacerbation of the symptoms associated with HUS has been reported in some patients receiving blood product transfusions. A high mortality rate (52%) has been associated with this syndrome. The syndrome may occur at any time during systemic therapy with mitomycin as a single agent or in combination with other cytotoxic drugs.

Less frequently, HUS has also been reported in patients receiving combinations of cytotoxic drugs not including mitomycin. Of 83 patients studied, 72 developed the syndrome at total doses exceeding 60 mg of mitomycin. Consequently, patients receiving ≥60 mg of mitomycin should be monitored closely for unexplained anemia with fragmented cells on peripheral blood smear, thrombocytopenia, and decreased renal function.

The incidence of the syndrome has not been defined. Therapy for the syndrome is investigational. Cardiac Toxicity Congestive heart failure, often treated effectively with diuretics and cardiac glycosides, has rarely been reported. Almost all patients who experienced this side effect had received prior doxorubicin therapy.

Acute Side Effects Due to Mitomycin were fever, anorexia, nausea, and vomiting. They occurred in about 14% of 1,281 patients. Other Headache, blurring of vision, confusion, drowsiness, syncope, fatigue, edema, thrombophlebitis, hematemesis, diarrhea, and pain.

These did not appear to be dose related and were not unequivocally drug related. They may have been due to the primary or metastatic disease processes. Malaise and asthenia have been reported as part of post-marketing surveillance. Bladder fibrosis/contraction has been reported with intravesical administration (see PRECAUTIONS ).

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CONTRAINDICATIONS

Mitomycin is contraindicated in patients who have demonstrated a hypersensitive or idiosyncratic reaction to it in the past. Mitomycin is contraindicated in patients with thrombocytopenia, coagulation disorder, or an increase in bleeding tendency due to other causes.