Mitokebir

Mitokebir is used in palliative tumour therapy.

Mitokebir is administered intravenously as monochemotherapy or in combined cytostatic chemotherapy in the case of:

- advanced metastatic gastric carcinoma

- advanced and/or metastatic breast cancer

Furthermore Mitokebir is administered intravenously in combined chemotherapy in the case of:

- non-small cell bronchial carcinoma

- advanced pancreatic carcinoma

Intravesical administration for relapse prevention in superficial urinary bladder carcinoma after transurethral resection.

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.

Posology

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

Unless otherwise prescribed, Mitokebir is dosed as follows:

Intravenous administration

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

A dose greater than 20 mg/m² gives more toxic manifestations without therapeutic benefits. The maximum cumulative dose of Mitokebir 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.

Intravesical administration

In intravesical therapy, 20 - 40 mg of Mitokebir in 20 - 40 ml of phosphate buffer pH 7.4 or sodium chloride (0.9%) solution, 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.

Alternative dose recommendation in the prevention of recurrent superficial bladder tumours is 4-10 mg (0.06-0.15 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 population

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

Older patients

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

The product should not be used in patients with renal impairment

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

Paediatric population

The safety and efficacy of Mitokebir in children aged from 0 to 17 years have not been established.

Method of administration

Mitokebir is intended for intravenous injection or infusion or for intravesical instillation after being dissolved. Partial use is applicable.

Mitokebir 10 mg, powder for solution for injection/infusion or intravesical use may not be reconstituted in water, regardless the method of administration (i.e. intravenous or intravesical)

Notes

- Mitokebir 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.

Paediatric population

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

Intravenous administration

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.

Intra-arterial administration

For administration into specific tissues, Mitokebir can be given by the intra-arterial route directly into the tumours.

Dose reductions

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.

Disease progression

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 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.

-

- Breastfeeding

Systemic therapy

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

Restrictive or obstructive disturbances to pulmonary ventilation, renal function, liver function 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

Perforation of the bladder wall is an absolute contraindication.

Cystitis is a relative contraindication.

Patients who have demonstrated a hypersensitive or idiosyncratic reaction to Mitokebir or any of the components of the product in the past. Thrombocytopenia, coagulation disorders and increased bleeding tendency.

Due to the toxic effects on the bone marrow of Mitokebir, 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 intravenous. 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 Mitokebir.

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.

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 Mitokebir with special caution in this population while closely monitoring patient's condition.

Particular caution is required when possible occurrence or aggravation of infectious disease and bleeding tendency.

Mitokebir 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).

At doses of > 30 mg of Mitokebir/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.

Immunisation with live virus vaccines (e.g. yellow fever vaccination) increases the risk of infection and other adverse reactions such as vaccinia gangrenosa and generalized vaccinia, in patients with reduced immunocompetence, such as during treatment with Mitokebir. Therefore, live virus vaccines should not be administered during therapy. It is advised to use live virus vaccines with caution after stopping chemotherapy, and vaccinate not sooner than 3 months after the last dose of chemotherapy.

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 therapy

- Regular checks of the blood count

- Close monitoring of renal function

Mitokebir 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.

Mitokebir should be administered with care in children and patients with the following:

- Hepatic or renal dysfunction as adverse reactions may be enhanced

- Bone marrow depression and bleeding tendency as these may be exacerbated

- Infections as these may be aggravated due to bone marrow depression

- 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 Mitokebir 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 Mitokebir concomitantly with other antineoplastic agents.

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.

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

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 Mitokebir 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.

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

Mitokebir is potentially hepatotoxic.

Possible side-effects under intravesical 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

Website: www.mhra.gov.uk/yellowcard

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 veno-occlusive 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 the following:

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 (www.mhra.gov.uk/yellowcard).

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.

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.

Pharmacotherapeutic group: Antineoplastic agent, Other cytotoxic antibiotics

ATC Code: L01DC03

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

Mitokebir is an antibiotic isolated from Streptomyces caespitosus with anti-neoplastic effect. It is present in an inactive form. Activation to a trifunctional alkylating agent is rapid, 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 Mitokebir. The 3 alkylating radicals all stem from a quinone, an aziridine and a urethane group. The mechanism of action is based predominantly on the alkylation of DNA (RNA to a lesser extent) 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 ones. As with other alkylating agents, proliferating cells are damaged to a greater extent than those that are in the resting phase (GO) 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.

ATC Code: L01D

Pharmacotherapeutic group: Other cytotoxic antibiotics

Mitokebir 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.

After the intravenous administration of 10 - 20 mg/m² of Mitokebir, maximum plasma levels of 0.4 - 3.2 µg/ml have been measured. The biological half-life is short and is between 40 and 50 minutes. The serum level falls biexponentially, steeply at first within the first 45 minutes, and then more slowly.

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 Mitokebir have been found in the gall bladder. Renal excretion plays only a minor role with respect to the elimination.

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

In vivo, Mitokebir 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 Mitokebir 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 Mitokebir is similar to that in adults.

In animals, Mitokebir is toxic to all proliferating tissues, particularly the cells of the bone marrow and the mucous membrane of the gastrointestinal tract, resulting in the inhibition of spermiogenesis.

Mitokebir has mutagenic, carcinogenic and teratogenic effects which can be demonstrated in corresponding experimental systems.

Local tolerance

Mitokebir causes severe necrosis in the case of paravenous injection or leakage from the blood vessel into surrounding tissue.

There are no preclinical data of relevance to the prescriber which are additional to that already included elsewhere in the SPC.

Not known

Intravenous use:

Mitokebir 10 mg, powder for solution for injection/infusion or intravesical use may not be reconstituted in water.

The contents of the vial should be reconstituted with saline or 20% glucose solution in a ration of:

10 ml for the 10 mg of Mitokebir.

Intravesical use:

Mitokebir 10 mg, powder for solution for injection/infusion or intravesical use may not be reconstituted in water.

The contents of the vial should be reconstituted with saline or phosphate buffer 7.4 in a ration of:

10 ml for the 10 mg of Mitokebir.

Pregnant healthcare personnel should not handle and/or administer drug product. Mitokebir 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 saline solution. It should then be observed for several days for evidence of corneal damage. If necessary, appropriate treatment should be instituted.

The reconstituted solution is clear blue-violet colour free from visible particulate matter.

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

Waste material should be destroyed according to hospital standard procedures applicable to cytotoxic agents with due regard to current laws related to the disposal of hazardous waste.

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 injectable solutions.

Mitokebir 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.