Lomustine Medac 40mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lomustine "medac" 40 mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Lomustine (CCNU) 40 mg per capsule
3 PHARMACEUTICAL FORM
Hard capsule
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
As palliative or supplementary treatment, usually in combination with radiotherapy and/or surgery as part of multiple drug regimens in:
Brain tumours (primary or metastatic)
Lung tumours (especially oat-cell carcinoma)
Hodgkin’s disease (resistant to conventional combination chemo-therapy) Malignant melanoma (metastatic)
Lomustine "medac" may also be of value as second-line treatment in Non-Hodgkin's lymphoma, myelomatosis, gastrointestinal tumours, carcinoma of the kidney, the testis, the ovary, the cervix uteri and the breast.
4.2 Posology and method of administration
Dosage
Adults:
Lomustine "medac" is given by mouth. The recommended dose in patients with normally functioning bone marrow receiving Lomustine "medac" as their only chemotherapy is 120-130 mg/m2 as a single dose every six to eight weeks (or as a divided dose over 3 days, e.g. 40 mg/m2/day).
Dosage is reduced if:
(i) Lomustine "medac" is being given as part of a drug regimen which includes other marrow-depressant drugs, and
(ii) In the presence of leucopenia below 3,000/mm3 or thrombocytopenia below 75,000/mm3.
Marrow depression after Lomustine "medac" is sustained longer than after nitrogen mustards and recovery of white cell and platelet counts may not occur for six weeks or more. Blood elements depressed below the above levels should be allowed to recover to 4,000/mm3 (WBC) and 100,000/mm3 (platelets) before repeating Lomustine "medac" dosage.
Children:
Until further data is available, administration of Lomustine "medac" to children with malignancies other than brain tumours should be restricted to specialised centres and exceptional situations. Dosage in children, like that in adults, is based on body surface area (120 - 130 mg/m2 every six to eight weeks, with the same qualifications as apply to adults).
Route of Administration:
Lomustine "medac" is given by mouth.
4.3 Contraindications
Lomustine can cause birth defects. Men and women are recommended to take contraceptive precautions during therapy with lomustine and for 6 months after treatment. Men should be informed about the risk for an irreversible infertility due to treatment with lomustine (see section 4.6).
Lomustine "medac" should not be administered to patients who are pregnant or to mothers who are breast feeding.
Other contraindications are:
(i) Previous hypersensitivity to nitrosoureas;
(ii) Previous failure of the tumour to respond to other nitrosoureas;
(ii) Severe bone-marrow depression;
(iii) Severe renal impairment;
(iv) Coeliac disease or wheat allergy;
(v) Concomitant use of yellow fever vaccine or other live vaccines is contraindicated in immunosuppressed patients (see section 4.5).
4.4 Special warnings and precautions for use
Patients receiving LOMUSTINE "MEDAC" chemotherapy should be under the care of doctors experienced in cancer treatment. Delayed bone- marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to bleeding and overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of lomustine.
Therefore, blood counts should be carried out before starting the drug and at frequent intervals (preferably weekly for at least 6 weeks after a dose; see 4.8) during treatment. Treatment and dosage is governed principally by the haemoglobin, white cell count and platelet count. Liver and kidney function should also be assessed periodically.
Patients must be strictly instructed not to use higher doses of lomustine than recommended by a physician and should be told that lomustine is taken as a single oral dose and will not be repeated for at least 6 weeks.
The bone- marrow toxicity of lomustine is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose.
Caution should be used in administering lomustine to patients with decreased circulating platelets, leukocytes, or erythrocytes.
Pulmonary toxicity from lomustine appears to be dose- related (see 4.8). Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLco) are particularly at risk.
Since lomustine may cause liver dysfunction, it is recommended that liver function tests be monitored periodically (see 4.8).
Renal function tests should also be monitored periodically (see 4.8).
Long term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies.
Care must be taken whenever handling anticancer products. Steps should be taken to avoid exposure. This includes appropriate equipment, such as, wearing gloves, and washing hands with soap and water after handling such products.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
Lomustine "medac" use in combination with theophylline or with the H2-receptor antagonist cimetidine may potentiate bone marrow toxicity. Cross resistance with other nitrosoureas is usual, but cross resistance with conventional alkylating agents is unusual.
Pre-treatment with phenobarbital can lead to a reduced antitumour effect of lomustine due to an accelerated elimination caused by induction of microsomal liver enzyms.
There is increased risk of fatal systemic vaccinal disease with the use of yellow fever vaccine. Live vaccines are contraindicated in immunosuppressed patients (see section 4.3)
Co-administration of antiepileptic drugs and chemotherapeutic drugs including lomustine can lead to complications secondary to pharmacokinetic interactions between the drugs.
4.6 Fertility, pregnancy and lactation
Lomustine is contraindicated in women who are pregnant and mothers who are breast feeding.
Pregnancy
Safe use in pregnancy has not been established. Lomustine is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Lactation
Due to the lipophilic nature of lomustine, it is likely to be excreted in breast milk. As a risk to the nursing child potentially exists, a decision should be made whether to discontinue breast-feeding or to discontinue lomustine therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.
Fertility
Lomustine can have a mutagenic effect. Men treated with lomustine are therefore advised not to father children during treatment and for up to 6 months afterwards, and to seek advice regarding sperm conservation before the start of treatment given the possibility of irreversible infertility caused by lomustine therapy.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
Lomustine "medac" capsules can impair the ability to drive and use machines, e.g. because of nausea and vomiting.
4.8 Undesirable effects
|
System Organ Class |
Frequency |
MedDRA Term |
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
Not known |
Acute leukaemia, myelodysplastic syndrome |
|
Blood and lymphatic system disorders |
Very common |
Leukopenia |
|
Not known |
Bone marrow failure, thrombocytopenia, anaemia | |
|
Nervous system disorders |
Not known |
Coordination abnormal, disorientation, lethargy, dysarthria |
|
Respiratory, thoracic and mediastinal disorders |
Not known |
Pulmonary fibrosis, lung infiltration |
|
Gastrointestinal disorders |
Not known |
Nausea, vomiting, stomatitis |
|
Hepatobiliary disorders |
Not known |
Transaminases increased, blood bilirubin increased |
|
Skin and subcutaneous tissue disorders |
Not known |
Alopecia |
|
Renal and urinary disorders |
Not known |
Renal failure, azotaemia, renal atrophy, renal injury |
|
Investigations |
Not known |
Blood alkaline phosphatase increased |
Haematological
The principal adverse effect is marrow toxicity of a delayed or prolonged nature. It usually occurs four to six weeks after drug administration and is dose- related. Thrombocytopenia appears about four weeks after a dose of Lomustine "medac" and lasts one or two weeks at a level around 80-100,000/mm3. Leucopenia appears after five to six weeks and persists for one or two weeks at about 4-5,000/mm3.
The haematological toxicity may be cumulative, leading to successively lower white cell and platelet counts with successive doses of the drug. Approximately 65% of patients receiving 130 mg/m2 develop white blood counts below 5,000 WBC/mm3. Thirty six percent developed white blood cell counts below 3,000/mm3. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose- limiting toxicities.
The occurrence of acute leukemia and bone marrow dysplasia have been reported in patients following long- term nitrosourea therapy.
Anaemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia.
Gastrointestinal
Nausea and vomiting usually occur four to six hours after a full single dose of Lomustine "medac" and last for 24-48 hours, followed by anorexia for two or three days. The effects are less troublesome if the 6 weekly dose is divided into three doses given on each of the first three days of the six week period. Gastrointestinal tolerance is usually good, however, if prophylactic antiemetics are given (e. g. metoclopramide
or chlorpromazine). Disorders of liver function have been reported commonly. They are mild in most cases. In rare cases a cholestatic jaundice occurs. Transient elevation of liver enzymes (SGOT, SGPT, LDH or alkaline phosphatase) are occasionally observed.
More rarely patients are troubled by stomatitis and diarrhoea.
Neurologic system
Mild neurologic symptoms, like e.g. apathy, disorientation, confusion and stuttering can occur uncommonly in combination therapy with other antineoplastic drugs or radiation.
Pulmonary system
Interstitial pneunomia or lung fibrosis have been reported rarely.
Renal system
Renal failure, decrease in kidney size, and progressive azotemia have been reported in single cases after prolonged treatment with lomustine and related nitrosoureas reaching a high cumulative total dose. Therefore it is recommended not to exceed a maximum cumulative total lomustine dose of 1000 mg/m2.
Kidney damage has also been reported occasionally in patients receiving lower total doses.
Other Side Effects
Loss of scalp hair has been reported rarely.
In single cases an irreversible vision loss has been reported after a combined therapy of lomustine with radiation.
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
Symptoms
Accidental overdose with lomustine has been reported, including fatal cases. Symptoms of overdosage with Lomustine "medac" will probably include bone-marrow toxicity, haematological toxicity, abdominal pain, nausea and vomiting, diarrhoea, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath.
Emergency Procedures
Overdosage should be treated immediately by gastric lavage.
Antidote
There is no specific antidote to overdosage with Lomustine "medac". Treatment should be symptomatic and supportive. Appropriate blood product replacement should be given as clinically required.
5.1 Pharmacodynamic properties
The mode of action is believed to be partly as an alkylating agent and partly by inhibition of several steps in the synthesis of nucleic acid and inhibition of the repair of single strand breaks in DNA chains.
5.2 Pharmacokinetic properties
Lomustine "medac" is readily absorbed from the intestinal tract. A maximum plasma concentration of 0.5-2 ng/ml is reached after 3 hours following an oral dose of 30-100 mg/m2
The plasma-disappearance of the chloroethyl-group follows by a single phased course with a half-life of 72 hours. The cyclohexyl-group disappears according to a twofold plasma-disappearance with half-lives of 4 hours (t / a) and 50 hours (t / P). After oral application of radioactive marked lomustine the blood-brain-barrier is passed. Approximately 15 to 30 % of the measured radioactivity in the plasma can be detected in the cerebrospinal fluid.
Lomustine "medac" is rapidly metabolised and metabolites are excreted mainly via the kidneys. Lomustine "medac" cannot be detected in its active form in the urine at any time.
5.3 Preclinical safety data
None available.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule Contents:
Lactose Wheat Starch Talc
Magnesium Stearate
Capsule Shell:
Gelatin
Indigo carmine E132 Titanium Dioxide E171
6.2 Incompatibilities
None stated.
6.3 Shelf life
3 years as packaged for sale.
6.4 Special precautions for storage
Do not store above 25 °C.
Store in the original container protected from light and moisture.
6.5 Nature and contents of container
Securitainers containing 20 capsules.
6.6 Special precautions for disposal
None.
7 MARKETING AUTHORISATION HOLDER
medac - Gesellschaft fuer klinische Spezialpraeparate mbH
Theaterstr. 6
22880 Wedel, Germany
MARKETING AUTHORISATION NUMBER(S)
PL 11587/0003
9
10
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29/09/1977 / 25/08/2006
DATE OF REVISION OF THE TEXT
29/05/2015