СииНУ

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 chemotherapy)

- malignant melanoma (metastatic)

СииНУ "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.

СииНУ has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following:

Brain tumors - both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures.

Hodgkin's disease - secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

Posology

Adults

СииНУ "medac" is given by mouth. The recommended dose in patients with normally functioning bone marrow receiving СииНУ "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 СииНУ "medac" is given as part of a drug regimen which includes other marrow-depressant medicinal products.

- in the presence of leucopenia below 3,000/mm³ or thrombocytopenia below 75,000/mm³.

Marrow depression after СииНУ "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 СииНУ "medac" dosage.

Paediatric population

Until further data is available, administration of СииНУ "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).

Method of administration

СииНУ "medac" is given by mouth.

The recommended dose of СииНУ in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m² as a single oral dose every 6 weeks (see PATIENT INFORMATION and HOW SUPPLIED: Directions to the Pharmacist). In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m² every 6 weeks. When СииНУ is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly.

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:

A repeat course of СииНУ should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm³; leukocytes above 4000/mm³), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.

СииНУ can cause birth defects. Men and women are recommended to take contraceptive precautions during therapy with СииНУ and for 6 months after treatment. Men should be informed about the risk for an irreversible infertility due to treatment with СииНУ.

СииНУ "medac" should not be administered to patients who are pregnant or to mothers who are breastfeeding.

Other contraindications are:

- ;

- Previous hypersensitivity to nitrosoureas;

- Previous failure of the tumour to respond to other nitrosoureas;

- Severe bone marrow depression;

- Severe renal impairment;

- Coeliac disease or wheat allergy;

- Concomitant use of yellow fever vaccine or other live vaccines is contraindicated in immunosuppressed patients.

СииНУ should not be given to individuals who have demonstrated a previous hypersensitivity to it.

Patients receiving СииНУ "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 СииНУ.

Therefore, blood counts should be carried out before starting the medicinal product and at frequent intervals 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 СииНУ than recommended by a physician and should be told that СииНУ is taken as a single oral dose and will not be repeated for at least 6 weeks.

The bone marrow toxicity of СииНУ is cumulative and therefore dose adjustments must be considered on the basis of nadir blood counts from prior dose.

Caution should be used in administering СииНУ to patients with decreased circulating platelets, leukocytes, or erythrocytes.

Pulmonary toxicity from СииНУ appears to be dose-related. 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 СииНУ may cause liver dysfunction, it is recommended that liver function tests be monitored periodically.

Renal function tests should also be monitored periodically.

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.

WARNINGS

Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of СииНУ should not be given more frequently than every 6 weeks.

The bone marrow toxicity of СииНУ is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION).

Pulmonary toxicity from СииНУ appears to be dose related (see ADVERSE REACTIONS).

Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies.

Liver and renal function tests should be monitored periodically (see ADVERSE REACTIONS).

Pregnancy Category D

СииНУ can cause fetal harm when administered to a pregnant woman. СииНУ is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. There are no adequate and well controlled studies in pregnant women. 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 fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

General

In all instances where the use of СииНУ is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of СииНУ therapy should be carried out with caution and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.

Laboratory Tests

Due to delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose.

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 СииНУ may cause liver dysfunction, it is recommended that liver function tests be monitored periodically.

Renal function tests should also be monitored periodically.

Carcinogenesis, Mutagenesis, Impairment of Fertility

СииНУ is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans (see ADVERSE REACTIONS). СииНУ also affects fertility in male rats at doses somewhat higher than the human dose.

Pregnancy

Pregnancy Category D

See WARNINGS.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from СииНУ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

See ADVERSE REACTIONS: Pulmonary Toxicity, and DOSAGE AND ADMINISTRATION.

Geriatric Use

No data from clinical studies of СииНУ are available for patients 65 years of age and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Lomustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

The list is presented by system organ class and frequency

- 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)

- Not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

The principal adverse effect is marrow toxicity of a delayed or prolonged nature. It usually occurs four to six weeks after administration of the medicinal product and is dose-related. Thrombocytopenia appears about four weeks after a dose of СииНУ "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 medicinal product. Approximately 65 % of patients receiving 130 mg/m² develop white blood cell 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 leukaemia 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 disorders

Nausea and vomiting usually occur four to six hours after a full single dose of СииНУ "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.

Nervous system disorders

Mild neurological symptoms, like e.g. apathy, disorientation, confusion and stuttering can occur uncommonly in combination therapy with other antineoplastic medicinal products or radiation.

Respiratory, thoracic and mediastinal disorders

Interstitial pneumonia or lung fibrosis have been reported rarely.

Renal and urinary disorders

Renal failure, decrease in kidney size, and progressive azotaemia have been reported in single cases after prolonged treatment with СииНУ and related nitrosoureas reaching a high cumulative total dose. Therefore it is recommended not to exceed a maximum cumulative total СииНУ dose of 1,000 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 СииНУ 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.

Hematologic Toxicity

The most frequent and most serious toxicity of СииНУ is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of СииНУ and persists for 1 to 2 weeks. Approximately 65% of patients receiving 130 mg/m² develop white blood counts below 5000 wbc/mm³. Thirty-six percent developed white blood counts below 3000 wbc/mm³. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.

СииНУ may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses.

The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following long-term nitrosourea therapy.

Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia.

Pulmonary Toxicity

Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported rarely with СииНУ. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of СииНУ usually greater than 1100 mg/m². There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg.

Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received related nitrosoureas in childhood and early adolescence (1-16 years) combined with cranial radiotherapy for intracranial tumors. There appeared to be some late reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be slowly progressive and has resulted in death in some cases. In this long-term study of carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary fibrosis.

Gastrointestinal Toxicity

Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. Prior administration of antiemetics is effective in diminishing and sometimes preventing this side effect. Nausea and vomiting can also be reduced if СииНУ is administered to fasting patients.

Hepatotoxicity

A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase, and bilirubin levels, has been reported in a small percentage of patients receiving СииНУ.

Nephrotoxicity

Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal failure have been reported in patients who received large cumulative doses after prolonged therapy with СииНУ. Kidney damage has also been reported occasionally in patients receiving lower total doses.

Other Toxicities

Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been reported infrequently.

Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted in some patients receiving СииНУ. However, the relationship to medication in these patients is unclear.

Symptoms

Accidental overdose with СииНУ has been reported, including fatal cases. Symptoms of overdose with СииНУ "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

Overdose should be treated immediately by gastric lavage.

Antidote

There is no specific antidote to overdose with СииНУ "medac". Treatment should be symptomatic and supportive. Appropriate blood product replacement should be given as clinically required.

Accidental overdose with lomustine has been reported, including fatal cases. Accidental overdose has been associated with bone marrow suppression, abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath.

No proven antidotes have been established for СииНУ overdosage. In case of overdose, appropriate supportive measures should be taken.