Active ingredients: Chlorambucil
LEUKERAN 2 mg film-coated tablets
Why is Leukeran used? What is it for?
LEUKERAN contains the active substance chlorambucil which belongs to a class of medicines called antineoplastics (medicines used in the treatment of malignant tumors).
LEUKERAN is indicated in the treatment of:
- Hodgkin's disease (malignant tumor of the lymph nodes)
- Certain forms of non-Hodgkin's lymphomas (another type of malignant tumor of the lymph nodes)
- Chronic lymphocytic leukemia (malignant tumor of lymphocytes, blood cells belonging to the white blood cell group)
- Waldenström's macroglobulinemia (type of lymphoma in which cancer cells produce a large amount of an abnormal protein called macroglobulin)
Contraindications When Leukeran should not be used
Do not take LEUKERAN - if you are allergic to chlorambucil or any of the other ingredients of this medicine.
Precautions for use What you need to know before taking Leukeran
LEUKERAN is an active cytotoxic (cell-killing) agent for use only under the supervision of physicians experienced in administering such medicines.
Talk to your doctor before you are given LEUKERAN if:
- have had or are undergoing a vaccination with so-called "live" vaccines. Leukeran causes a lowering of the immune system and concomitant administration of this type of vaccine should be avoided as serious or fatal infections can occur.
- is a potential candidate for a bone marrow transplant (autologous stem cell transplant), because long-term use of chlorambucil can decrease the number of stem cells available.
- you have recently (at least 4 weeks) received radiotherapy or if you have received other cytotoxic agents, you should not be given LEUKERAN
- have liver disease as signs and symptoms of toxicity must be closely monitored. Also, if you have severe hepatic insufficiency your doctor will take this into account when determining the dose of Leukeran that is best for you.
- have kidney disease
Interactions Which drugs or foods can modify the effect of Leukeran
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Particularly:
- you have had or are due to undergo a vaccination (see section Warnings and precautions).
- fludarabine, pentostatin and cladribine (anticancer medicines that block cell multiplication), because taking these medicines together with LEUKERAN increased the cytotoxicity of chlorambucil in vitro.
LEUKERAN with food, drink and alcohol
Chlorambucil tablets should be administered orally and should be taken daily on an empty stomach (at least one hour before meals or three hours after meals).
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
Whenever possible, do not take chlorambucil during pregnancy, particularly during the first trimester.
The physician for each patient will evaluate the risk to the fetus against the expected therapeutic benefits for the mother.
Feeding time
Mothers on LEUKERAN therapy should not breastfeed.
Fertility
This medicine can cause disappearance of the normal menstrual cycle and suppression of ovarian function (blocks ovulation, which is the release of the egg from the ovaries) in women.
In humans, this medicine may cause cessation of sperm production, although a total dose of at least 400 mg is believed to be required.
A resumption of spermatogenesis (production of spermatozoa) of varying degrees has been observed in patients with lymphoma after treatments with total doses of chlorambucil equal to 410-2600 mg.
Adequate contraceptive precautions should be used when either partner is given LEUKERAN.
Driving and using machines
There are no data on the effects on the ability to drive and use machines.
LEUKERAN contains lactose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dosage and method of use How to use Leukeran: Dosage
Always take this medicine exactly as described in this leaflet or as directed by your doctor. If in doubt, consult your doctor.
Hodgkin's disease
Adults
Used as a single drug, in the palliative treatment (acts on the symptoms but not on the cause of the disease) of the disease in advanced state, it is generally administered at doses of 0.2 mg / kg / day for 4-8 weeks.
LEUKERAN is normally used in combination therapy and various treatment regimens have been used. LEUKERAN was used as an alternative to nitrogen mustard, with a reduction in toxicity but with similar therapeutic effects.
Children
LEUKERAN can be used to treat Hodgkin's disease in children. Treatment schemes are similar to those used for adults.
Non-Hodgkin's lymphomas
Adults
Used as a single agent in the palliative treatment of advanced disease it is initially administered at doses of 0.1-0.2 mg / kg / day for 4-8 weeks, maintenance therapy is carried out by reducing the daily dosage or with intermittent courses of therapy.
LEUKERAN is useful in the treatment of advanced and diffuse lymphocytic lymphomas and in cases of relapse after radiotherapy. There is no significant difference in the response rate obtained with chlorambucil alone or in combination chemotherapy in the case of advanced non-Hodgkin's lymphocytic lymphomas.
Children
LEUKERAN can be used to treat non-Hodgkin's lymphomas in children. Treatment schemes are similar to those used for adults.
Chronic lymphocytic leukemia
Adults
Leukeran therapy is usually started after you experience symptoms or when there are signs of impaired bone marrow function (but not bone marrow failure), as indicated by peripheral blood counts. LEUKERAN is initially administered at a dose of 0.15 mg / kg / day until the white blood cell count has fallen below 10,000 per mm3.
Therapy can be resumed 4 weeks after the end of the first course and continued at a dose of 0.1 mg / kg / day.
Normally, in a number of patients after about 2 years of therapy the white blood cell count tends to normalize, the spleen and lymph nodes become impalpable and the percentage of lymphocytes in the bone marrow is reduced to less than 20%.
If you have evidence of bone marrow failure they should be treated with prednisolone initially and there should be signs of recovery of bone marrow function before starting treatment with LEUKERAN. Intermittent high-dose therapy was compared with daily doses of LEUKERAN, but no significant differences were observed in therapeutic response or in the frequency of undesirable effects between the two treatment groups.
Waldenström macroglobulinemia
Adults
LEUKERAN is the treatment of choice for Waldenström's macroglobulinemia.
Initial doses are approximately 6-12 mg / day until leukopenia is observed; subsequently dosages of 2-8 mg / day are adopted.
Safe handling of LEUKERAN tablets
The handling of LEUKERAN tablets must follow the recommendations described for cytotoxic drugs in accordance with current regulations.
As long as the outer coating of the tablet is intact, there is no risk in handling LEUKERAN tablets.
LEUKERAN tablets must not be divided.
Overdose What to do if you have taken too much Leukeran
Reversible pancytopenia (decrease in all blood cells) is the main sign of accidental chlorambucil overdose.
Severe central nervous system reactions such as agitated behavior and ataxia (loss of movement control) up to generalized convulsions can occur.
Treatment
Since there is no antidote, blood status should be carefully monitored and all general supportive measures taken in conjunction with blood transfusions when necessary.
In case of accidental ingestion / intake of an excessive dose of Leukeran, notify your doctor immediately or go to the nearest hospital.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Leukeran
Like all medicines, this medicine can cause side effects, although not everybody gets them.
There is no current clinical documentation for this product to be used to support the determination of the frequency of adverse reactions.
Undesirable effects may vary in their incidence depending on the dose received and also on whether chlorambucil is administered in combination with other therapeutic agents. The undesirable effects reported with Leukeran are ranked below in order of frequency:
Very common (may affect more than 1 in 10 people)
- Leukopenia (decreased white blood cells), neutropenia (decreased neutrophils), thrombocytopenia (decreased platelets), pancytopenia (decreased all blood cells), or bone marrow failure (bone marrow block)
Common (may affect up to 1 in 10 people)
- Acute secondary blood malignancies (especially leukemia and myelodysplastic syndrome, which is an alteration in the function of the bone marrow manifested by poor formation or malfunction of blood cells), particularly after long-term treatment.
- Anemia
- Seizures in children with a kidney problem known as nephrotic syndrome.
- Gastrointestinal disorders such as nausea, vomiting, diarrhea and oral ulcerations.
Uncommon (may affect up to 1 in 100 people)
- Dermatitis
Rare (may affect up to 1 in 1,000 people)
- Allergic reactions such as urticaria and angioneurotic edema following the first or subsequent administration. Stevens-Johnson syndrome and toxic epidermal necrolysis. On rare occasions, skin rash progression to severe conditions including Stevens-Johnson syndrome and toxic epidermal necrolysis has been reported.
- Seizures (patients with a history of seizure disorders may be particularly susceptible), partial and / or generalized focal seizures in children and adults who were given chlorambucil with daily therapeutic doses or with intermittent high dose regimens.
- Hepatotoxicity, jaundice.
- Drug fever.
Very rare (may affect up to 1 in 10,000 people)
- Irreversible bone marrow failure. Although myelosuppression (decreased bone marrow activity) occurs frequently, this is usually reversible, provided that therapy is stopped in time.
- Movement disorders including tremors, muscle twitching and myoclonus (short and involuntary muscle contraction) in the absence of seizures. Peripheral neuropathies (malfunction or problems of the peripheral nerves).
- Interstitial pulmonary fibrosis (transformation of lung tissue into scar tissue), interstitial pneumonia (inflammation and progressive scarring of the lungs). Severe interstitial pulmonary fibrosis has occasionally been reported in patients with chronic lymphocytic leukemia on long-term therapy with chlorambucil, but may regress after discontinuation of therapy.
- Abacterial cystitis (inflammation of the bladder not caused by bacteria).
Not known (frequency cannot be estimated from the available data)
- Absence of menstruation (amenorrhea)
- Absence of spermatozoa (azoospermia).
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/ it / responsible. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the package after EXP. The expiry date refers to the unopened, correctly stored product.
Store in a dry place.
Store in a refrigerator (2 ° C - 8 ° C).
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
Composition
- The active ingredient is chlorambucil. One film-coated tablet contains 2 mg of chlorambucil.
- The other ingredients are: Tablet core: microcrystalline cellulose, anhydrous lactose, anhydrous colloidal silica, stearic acid.
- Tablet coating: hypromellose, titanium dioxide, synthetic yellow iron oxide, synthetic red iron oxide, macrogol.
Description of what LEUKERAN looks like and contents of the pack
Film-coated tablets in bottles of 25 tablets.
The following information is intended for healthcare professionals only
Monitoring
Since LEUKERAN can cause irreversible bone marrow aplasia (total block of bone marrow activity), blood tests of patients being treated should be closely monitored through comprehensive weekly checks. At therapeutic doses, LEUKERAN reduces the number of lymphocytes and has less effect on blood counts. of neutrophils, platelets and hemoglobin levels. It is not necessary to stop therapy at the first sign of a reduction in neutrophils, but it should be noted that the reduction may continue for 10 days or more after the last dose.
When there is lymphocytic infiltration of the bone marrow (replacement of the bone marrow with lymphocytes) or when it is hypoplastic (poorly functioning in the production of blood cells), the daily dose should not exceed 0.1 mg / kg body weight.
Children with nephrotic syndrome (kidney disease involving loss of protein in the urine), patients prescribed intermittent high dose regimens and patients with a history of seizure disorders should be closely monitored after administration of LEUKERAN. as they may present a higher risk of seizures.
Mutagenesis and carcinogenesis
Chlorambucil has been shown to cause chromatid or chromosomal damage in humans.
Secondary blood malignancies have been reported (especially leukemia, which is a cancer of the white blood cells and myelodysplastic syndrome, which is an alteration in the function of the bone marrow, manifested by a reduction in blood cells), particularly after treatment long-term (see section "Possible side effects").
A comparison between patients with ovarian cancer treated with alkylating agents compared to other untreated ones showed that the use of alkylating agents including chlorambucil markedly increases the incidence of acute leukemia.
The onset of acute myelogenous leukemia has also been reported in a small fraction of patients on long-term treatment with chlorambucil as adjuvant therapy for breast cancer. The risk of developing leukemia must be weighed against the potential therapeutic benefits of using chlorambucil.
Teratogenesis
LEUKERAN, like other cytotoxic agents, is potentially teratogenic (can cause malformations).
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
LEUKERAN 2 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains:
Active ingredient: chlorambucil 2 mg.
Excipient with known effects:
each tablet also contains 67.65 mg of lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
LEUKERAN is indicated in the treatment of:
- Hodgkin's disease
- Some forms of non-Hodgkin's lymphomas
- Chronic lymphocyte leukemia
- Waldenström's macroglobulinemia
04.2 Posology and method of administration
For a detailed picture of the protocols used, it is advisable to consult the relevant literature.
LEUKERAN is an active cytotoxic agent to be used only under the supervision of physicians experienced in the administration of such drugs.
Dosage
Hodgkin's disease
• Adults
Used as a single drug, in the palliative treatment of advanced disease, it is generally administered at doses of 0.2 mg / kg / day for 4-8 weeks.
LEUKERAN is normally used in combination therapy and various treatment regimens have been used. LEUKERAN was used as an alternative to nitrogen mustard, with a reduction in toxicity but with similar therapeutic effects.
• Pediatric population
LEUKERAN can be used to treat Hodgkin's disease in children. Treatment schemes are similar to those used for adults.
Non-Hodgkin's lymphomas
• Adults
Used as a single agent in the palliative treatment of advanced disease, it is initially administered at doses of 0.1 - 0.2 mg / kg / day for 4-8 weeks, maintenance therapy is carried out by reducing the daily dosage or with intermittent courses of therapy.
LEUKERAN is useful in the treatment of patients with advanced and diffuse lymphocytic lymphomas and in cases of relapse after radiotherapy. There is no significant difference in the overall response rate obtained with chlorambucil alone or in combination chemotherapy in the case of advanced non-Hodgkin's lymphocytic lymphomas.
• Pediatric population
LEUKERAN can be used in the treatment of non-Hodgkin's lymphomas in pediatric patients. Treatment schemes are similar to those used for adults.
Chronic lymphocytic leukemia
• Adults
Leukeran therapy is usually started after the patient has developed symptoms or when there are signs of impaired bone marrow function (but not bone marrow failure), as indicated by peripheral blood counts.
LEUKERAN is initially administered at a dose of 0.15 mg / kg / day until the white blood cell count has fallen below 10,000 per microliter.
Therapy can be resumed 4 weeks after the end of the first course and continued at a dose of 0.1 mg / kg / day.
Normally in a number of patients after about 2 years of therapy the white blood cell count tends to normalize, the spleen and lymph nodes become impalpable and the percentage of lymphocytes in the bone marrow is reduced to less than 20%. Patients with evidence of bone marrow failure should initially be treated with prednisolone and there should be signs of recovery of bone marrow function prior to initiating treatment with LEUKERAN.
Intermittent high-dose therapy was compared with daily doses of LEUKERAN, but no significant differences were observed in therapeutic response or in the frequency of undesirable effects between the two treatment groups.
Waldenström macroglobulinemia
• Adults
LEUKERAN is one of the first choice treatments for Waldenström's macroglobulinemia. Initial doses are approximately 6-12 mg / day until leukopenia is observed; subsequently dosages of 2-8 mg / day are adopted.
Special populations
Kidney failure
No dose adjustment is considered necessary in patients with renal insufficiency.
Hepatic insufficiency
Patients with hepatic insufficiency should be carefully monitored for signs and symptoms of toxicity. Since chlorambucil is mainly metabolised in the liver, a dose reduction should be considered in patients with severe hepatic impairment. However, in patients with hepatic insufficiency there are insufficient data to make a specific dosing recommendation.
Elderly patients
No specific studies have been conducted in elderly patients. However, monitoring of renal and hepatic function is recommended. Caution should be exercised if these functions are compromised. Although clinical experience has not shown age-related differences in response, the dosage of the medicinal product should still be carefully titrated in elderly patients, usually starting therapy with the lowest available dosage.
Method of administration
Chlorambucil tablets should be administered orally and should be taken daily on an empty stomach (at least one hour before meals or three hours after meals).
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Immunization with live organism vaccine has the potential to cause infection in immunocompromised patients. Therefore, immunization with live organism vaccines is not recommended.
Patients who may undergo an autologous stem cell transplant should not be treated with long-term chlorambucil.
Safe handling of LEUKERAN : see section 6.6.
Monitoring
As LEUKERAN can cause irreversible bone marrow aplasia, the blood counts of patients being treated should be carefully monitored through comprehensive weekly checks. At therapeutic doses, LEUKERAN reduces the number of lymphocytes and has less effect on neutrophil and platelet counts and hemoglobin levels.
It is not necessary to stop therapy at the first sign of a reduction in neutrophils, but it should be noted that the reduction may continue for 10 days or more after the last dose.
LEUKERAN should not be given to patients who have recently (at least four weeks) undergone radiotherapy or who have received other cytotoxic agents.
When there is lymphocytic infiltration of the bone marrow or when this is hypoplastic, the daily dose should not exceed 0.1 mg / kg of body weight.
Pediatric patients with nephrotic syndrome, patients prescribed intermittent high dose regimens and patients with a history of seizure disorders should be closely monitored following administration of Leukeran as they may be at a higher risk for seizures.
Mutagenesis and carcinogenesis
Chlorambucil has been shown to cause chromatid or chromosomal damage in humans.
Secondary blood malignancies (especially leukemia and myelodysplastic syndrome) have been reported, particularly after long-term treatment (see section 4.8).
A comparison between patients with ovarian cancer treated with alkylating agents compared to other untreated ones showed that the use of alkylating agents including chlorambucil markedly increases the incidence of acute leukemia.
The onset of acute myelogenous leukemia has also been reported in a small fraction of patients on long-term treatment with chlorambucil as adjuvant therapy for breast cancer.
The leukemogenic risk must be weighed against the potential therapeutic benefits when considering the use of chlorambucil (see section 5.3).
Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4).
Purine analogs (such as fludarabine, pentostatin and cladribine) increased the cytotoxicity of chlorambucil ex vivo; however, the clinical significance of this finding is unknown.
04.6 Pregnancy and breastfeeding
Pregnancy
The use of chlorambucil in pregnancy should be avoided wherever possible and particularly during the first trimester. For each individual case it is good to evaluate the risk for the fetus with the therapeutic benefits expected for the mother.
As with all other cytotoxic chemotherapy treatments, adequate contraceptive precautions should be used when either partner is given LEUKERAN.
Feeding time
Mothers on LEUKERAN therapy should not breastfeed
Fertility
Chlorambucil can cause suppression of ovarian function and amenorrhea has been reported following drug therapy. Azoospermia has also been observed as a result of chlorambucil therapy, although a total dose of at least 400 mg is believed to be required.
A resumption of spermatogenesis of varying degrees has been observed in patients with lymphoma after treatments with total doses of chlorambucil equal to 410-2600 mg.
Teratogenicity
LEUKERAN, like other cytotoxic agents, is potentially teratogenic (see section 5.3).
04.7 Effects on ability to drive and use machines
There are no data on the effects of chlorambucil on the ability to drive and use machines.
04.8 Undesirable effects
There is no current clinical documentation for this product to be used to support the determination of the frequency of adverse reactions. Undesirable effects may vary in their incidence depending on the dose received and also on whether chlorambucil is administered in combination with other therapeutic agents.
Adverse reactions have been classified according to system organ class and according to the frequency convention: very common (≥1 / 10), common (≥1 / 100,
1 Although bone marrow failure occurs frequently, this is usually reversible, provided that therapy is stopped in time.
3 Patients with a history of seizure disorders may be particularly susceptible.
3 Severe interstitial pulmonary fibrosis has occasionally been reported in patients with chronic lymphocytic leukemia on long-term therapy with chlorambucil, but may regress after discontinuation of therapy.
4 Progression of skin rash to severe conditions including Stevens-Johnson syndrome and toxic epidermal necrolysis has been reported.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Symptoms
Reversible pancytopenia is the main sign of accidental overdosing of chlorambucil. Manifestations of neurological toxicity range from agitated behavior and ataxia to generalized convulsions.
Treatment
Since there is no antidote, blood status should be carefully monitored and all general supportive measures taken in conjunction with blood transfusions when necessary.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic and immunomodulatory drugs - cytostatics - alkylating substances - analogues of nitrogen mustard.
ATC code: L01AA02.
Mechanism of action
Chlorambucil is a derivative of the aromatic nitrogenous mustard which acts as a bifunctional alkylating agent. In addition to interference with DNA replication, chlorambucil induces cellular apoptosis through the accumulation of cytosolic p53 and the subsequent activation of the apoptosis promoter (Bax).
Pharmacodynamic effects
The cytotoxic effect of chlorambucil is due to both chlorambucil itself and its major metabolite, phenylacetic acid mustard (see section 5.2).
Resistance mechanism
Chlorambucil is a derivative of nitrogenous aromatic mustard, and resistance to nitrogenous mustards has been reported secondary to: alterations in the transport of these agents and their metabolites through various multi-resistant proteins, alterations in the kinetics of cross-link DNA formed by these agents and modifications of apoptosis and altered DNA repair activity. Chlorambucil is not a substrate of multi-resistant protein 1 (MRP1 or ABCC1), but its conjugated glutathione are substrates of MRP1 (ABCC1) and MRP2 (ABCC2).
05.2 Pharmacokinetic properties
Absorption
Chlorambucil is well absorbed by passive diffusion from the gastrointestinal tract and is measurable within 15-30 minutes of administration. The bioavailability of oral chlorambucil is approximately 70% -100% following administration of single doses of 10-200 mg. In a study with 12 patients who received approximately 0.2 mg / kg of oral chlorambucil, the mean dose-adjusted maximum plasma concentration (492 + 160 nanograms / ml) ranged from 0.25 to 2. hours after administration.
Consistent with the expected rapid absorption of chlorambucil, the interindividual variability in plasma chlorambucil pharmacokinetics has been shown to be relatively small following oral doses ranging from 15 to 70 mg (2-fold variability in intra-patient AUC to 2-4 fold inter-patient variability).
Absorption of chlorambucil is reduced when taken after food. In a ten-patient study, food intake increased the median time to reach a Cmax greater than 100%, reduced peak plasma concentrations by more than 100%. 50% and reduced the mean AUC (0-?) By approximately 27% (see section 4.2).
Distribution
Chlorambucil has a volume of distribution of approximately 0.14-0.24 L / kg.
Chlorambucil covalently binds to plasma proteins, mainly albumin (98%) and covalently binds to red blood cells.
Biotransformation
Chlorambucil is extensively metabolised in the liver by monodichloroethylation and? -Oxidation, forming phenylacetic acid mustard (PAAM) as the main metabolite, which possesses alkylating activity in animals. Chlorambucil and PAAM degrade. in vivo forming monohydroxy and dihydroxy derivatives. It also reacts with glutathione to form mono- and diglutathionyl conjugates of chlorambucil.
Following administration of approximately 0.2 mg / kg of oral chlorambucil, PAAM was detected in the plasma of some patients as soon as 15 minutes and the mean dose-adjusted plasma concentration (Cmax) was 306 ± 73 nanograms. / ml was observed within 1-3 hours.
Elimination
The terminal phase of the elimination half-life for chlorambucil is in the range of 1.3 to 1.5 hours and is approximately 1.8 hours for PAAM. The extent of renal excretion of unchanged chlorambucil and PAAM is very low; less than 1% of the administered dose of each is excreted in the urine over 24 hours, with the remaining dose eliminated primarily as monohydroxy and dihydroxy derivatives.
05.3 Preclinical safety data
Carcinogenicity and mutagenesis
Like other cytotoxic agents, chlorambucil is mutagenic in genotoxicity tests in vitro and in vivo, and is carcinogenic in animals and humans.
Reproductive toxicology
Chlorambucil has been shown in rats to damage spermatogenesis and cause testicular atrophy.
Teratogenicity
Chlorambucil has been shown to induce developmental abnormalities such as short or twisted tail, microcephaly or exencephaly, digital abnormalities including ectro-, brachi-, syn- and polydactyly, and long bone abnormalities such as reduction in length, absence of one or more components, total absence of ossification sites in the mouse and rat embryo following a single oral administration of 4-20 mg / kg. Chlorambucil has also been shown to induce renal abnormalities in the offspring of rats following a single intraperitoneal injection of 3- 6 mg / kg.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet core: microcrystalline cellulose, anhydrous lactose, anhydrous colloidal silica, stearic acid. Tablet coating: hypromellose, titanium dioxide, synthetic yellow iron oxide, synthetic red iron oxide, macrogol.
06.2 Incompatibility
Incompatibilities with other medicines are unknown.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store in a dry place.
Store in a refrigerator (2 ° C - 8 ° C).
06.5 Nature of the immediate packaging and contents of the package
LEUKERAN 2 mg is supplied as brown, round, biconvex tablets in amber glass bottles with a child resistant closure of 25 tablets.
06.6 Instructions for use and handling
Safe handling of LEUKERAN Tablets
The handling of LEUKERAN tablets must follow the recommendations referring to cytotoxic drugs in accordance with the regulations in force.
As long as the outer coating of the tablet is intact, there is no risk in handling LEUKERAN tablets.
LEUKERAN tablets must not be divided.
07.0 MARKETING AUTHORIZATION HOLDER
Aspen Pharma Trading Limited
3016 Lake Drive,
Citywest Business Campus,
Dublin 24, Ireland.
08.0 MARKETING AUTHORIZATION NUMBER
Bottle of 25 film-coated tablets of 2 mg: A.I.C. 024790026
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Bottle of 25 film-coated tablets of 2 mg: March 28, 2001 / May 2010
10.0 DATE OF REVISION OF THE TEXT
October 2015
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