Microsoft word - emea-combined-h2022en.doc


One ml of suspension contains 20 mg mercaptopurine (as monohydrate).
One ml of suspension contains 3 mg aspartame, 1 mg methyl hydroxybenzoate (as the sodium salt),
0.5 mg ethyl hydroxybenzoate (as the sodium salt) and sucrose (trace).
For a full list of excipients, see section 6.1.

Oral suspension.
The suspension is pink to brown in colour.
Therapeutic indications

Xaluprine is indicated for the treatment of acute lymphoblastic leukaemia (ALL) in adults,
adolescents and children.
Posology and method of administration

Xaluprine treatment should be supervised by a physician or other healthcare professional experienced
in the management of patients with ALL.
The dose is governed by cautiously monitored haematotoxicity and the dose should be carefully
adjusted to suit the individual patient in accordance with the employed treatment protocol. Depending
on phase of treatment, starting or target doses generally vary between 25-75 mg/m2 body surface area
(BSA) per day, but should be lower in patients with reduced or absent Thiopurine Methyl Transferase
(TPMT) enzyme activity (see section 4.4).
6–mercaptopurine is metabolised by the polymorphic TPMT enzyme. Patients with little or no inherited TPMT activity are at increased risk for severe toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. TPMT testing cannot substitute for haematological monitoring in patients receiving Xaluprine. The optimal starting dose for homozygous deficient patients has not been established (see section 4.4). Special populations Dose in the elderly No specific studies have been carried out in the elderly. However, it is advisable to monitor renal and hepatic function in these patients, and if there is any impairment, consideration should be given to reducing the Xaluprine dose. Dose in renal impairment Since 6–mercaptopurine pharmacokinetics has not been formally studied in renal impairment, no specific dose recommendations can be given. Since impaired renal function may result in slower elimination of mercaptopurine and its metabolites and therefore a greater cumulative effect, consideration should be given to reduced starting doses in patients with impaired renal function. Patients should be closely monitored for dose related adverse reactions. Dose in hepatic impairment Since 6–mercaptopurine pharmacokinetics has not been formally studied in hepatic impairment, no specific dose recommendations can be given. Since there is a potential for reduced elimination of mercaptopurine, consideration should be given to reduced starting doses in patients with impaired hepatic function. Patients should be closely monitored for dose related adverse reactions (see section 4.4). Switching between tablet and oral suspension and vice versa A tablet form of 6–mercaptopurine is also available. The 6-mecaptopurine oral suspension and tablet are not bioequivalent with respect to peak plasma concentration, and therefore intensified haematological monitoring of the patient is advised on switching formulations (see section 5.2). Combination with xanthine oxidase inhibitors Allopurinol and other xanthine oxidase inhibitors decrease the rate of catabolism of 6-mercaptopurine. When allopurinol and 6–mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of 6–mercaptopurine is given. Other xanthine oxidase inhibitors should be avoided (see section 4.5). Method of administration Xaluprine is for oral use and requires redispersing (by shaking vigorously at least for 30 seconds) prior to dosing. Two dosing syringes (a purple syringe graduated to 1 ml and a white syringe graduated to 5 ml) are provided for accurate measurement of the prescribed dose of the oral suspension. It is recommended that the healthcare professional advises the patient or carer which syringe to use to ensure that the correct volume is administered. Xaluprine may be taken with food or on an empty stomach, but patients should standardise the method of administration. The dose should not be taken with milk or dairy products (see section 4.5). Xaluprine should be taken at least 1 hour before or 2 hours after milk or dairy products. 6–mercaptopurine displays diurnal variation in pharmacokinetics and efficacy. Administration in the evening compared to morning administration may lower the risk of relapse. Therefore the daily dose of Xaluprine should be taken in the evening. To assist accurate and consistent dose delivery to the stomach water should be taken after each dose of Xaluprine. Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Concomitant use with yellow fever vaccine (see section 4.5)
Special warnings and precautions for use
Cytotoxicity and haematological monitoring Treatment with 6–mercaptopurine causes bone marrow suppression leading to leucopenia and thrombocytopenia and, less frequently, to anaemia. Careful monitoring of haematological parameters should be conducted during therapy. The leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in the counts, treatment should be interrupted immediately. Bone marrow suppression is reversible if 6–mercaptopurine is withdrawn early enough. There are individuals with an inherited deficiency of the TPMT enzyme activity who are very sensitive to the myelosuppresive effect of 6–mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with 6–mercaptopurine. This problem could be exacerbated by coadministration with active substances that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is necessary. Substantial dose reductions are generally required for homozygous-TPMT deficiency patients to avoid the development of life threatening bone marrow suppression. A possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6–mercaptopurine in combination with other cytotoxics (see section 4.8). Immunosuppression Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended. Hepatotoxicity Xaluprine is hepatotoxic and liver function tests should be monitored weekly during treatment. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. The patient should be instructed to discontinue Xaluprine immediately if jaundice becomes apparent (see section 4.8). Renal toxicity During remission induction when rapid cell lysis is occurring, uric acid levels in blood and urine should be monitored as hyperuricaemia and/or hyperuricosuria may develop, with the risk of uric acid nephropathy. Hydration and urine alkalinisation may minimize potential renal complications. Pancreatitis in off-label treatment of patients with inflammatory bowel disease Pancreatitis has been reported to occur at a frequency of ≥ 1/100 to < 1/10 (“common”) in patients treated for inflammatory bowel disease. Mutagenicity and carcinogenicity Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a renal cell carcinoma patient who received an unstated dose of 6–mercaptopurine and in patients with chronic renal disease treated at doses of 0.4 – 1.0 mg/kg/day. In view of its action on cellular deoxyribonucleic acid (DNA) 6–mercaptopurine is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenesis with this treatment.
When oral anticoagulants are coadministered with 6–mercaptopurine, a reinforced monitoring of INR
(International Normalised Ratio) is recommended (see section 4.5).
This medicinal product contains aspartame (E951), a source of phenylalanine. May be harmful for
people with phenylketonuria.
It also contains sodium methyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate which
may cause allergic reaction (possibly delayed).
As this medicine contains sucrose, patients with rare hereditary problems of fructose intolerance,
glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Long term use increases the risk of dental caries and it is essential that adequate dental hygiene is
Safe handling of the suspension
Parents and care givers should avoid Xaluprine contact with skin or mucous membrane. If the
suspension comes into contact with skin or mucosa, it should be washed immediately and thoroughly
with soap and water (see section 6.6).
Interaction with other medicinal products and other forms of interaction
The administration of 6–mercaptopurine with food may decrease systemic exposure slightly but this is unlikely to be of clinical significance. Therefore, Xaluprine may be taken with food or on an empty stomach, but patients should standardise the method of administration. The dose should not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme which metabolises 6–mercaptopurine and might therefore lead to reduced plasma concentrations of mercaptopurine. Effects of mercaptopurine on other medicinal products Concomitant administration of yellow fever vaccine is contraindicated, due to the risk of fatal disease in immunocompromised patients (see section 4.3) Vaccinations with other live organism vaccines are not recommended in immunocompromised individuals (see section 4.4). Inhibition of the anticoagulant effect of warfarin, when given with 6–mercaptopurine, has been reported. Monitoring of the INR (International Normalised Ratio) value is recommended during concomitant administration with oral anticoagulants. Cytotoxic agents may decrease the intestinal absorption of phenytoin. Careful monitoring of the phenytoin serum levels is recommended. It is possible that the levels of other anti-epileptic medicinal products may also be altered. Serum antiepileptic levels should be closely monitored during treatment with Xaluprine, making dose adjustments as necessary. Effects of other medicinal products on mercaptopurine When allopurinol and Xaluprine are administered concomitantly it is essential that only a quarter of the usual dose of Xaluprine is given since allopurinol decreases the rate of metabolism of 6–mercaptopurine via xanthine oxidase. Also other xanthine oxidase inhibitors, such as febuxostat, may decrease the metabolism of mercaptopurine and concomitant administration is not recommended as data are insufficient to determine an adequate dose reduction. As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme, which metabolises 6–mercaptopurine, they should be administered with caution to patients receiving concurrent Xaluprine therapy (see section 4.4). Fertility, pregnancy and lactation

Contraception in males and females
Evidence of the teratogenicity of 6–mercaptopurine in humans is equivocal. Both sexually active men
and women should use effective methods of contraception during treatment and for at least three
months after receiving the last dose. Animal studies indicate embryotoxic and embryolethal effects
(see section 5.3).
Xaluprine should not be given to patients who are pregnant or likely to become pregnant without
careful assessment of risk versus benefit.
There have been reports of premature birth and low birth weight following maternal exposure to 6–
mercaptopurine. There have also been reports of congenital abnormalities and spontaneous abortion
following either maternal or paternal exposure. Multiple congenital abnormalities have been reported
following maternal 6-mercatopurine treatment in combination with other chemotherapy agents.
A more recent epidemiological report suggests that there is no increased risk of preterm births, low
birth weight at term, or congenital abnormalities in women exposed to mercaptopurine during
It is recommended that newborns of women exposed to mercaptopurine during pregnancy are
monitored for haematological and immune system disturbances.
6–mercaptopurine has been identified in the colostrum and breast-milk of women receiving
azathioprine treatment and thus women receiving Xaluprine should not breast-feed.
The effect of 6–mercaptopurine therapy on human fertility is unknown but there are reports of
successful fatherhood/motherhood after receiving treatment during childhood or adolescence.
Transient profound oligospermia has been reported following exposure to 6–mercaptopurine in
combination with corticosteroids.
Effects on ability to drive and use machines

No studies on the effect on the ability to drive and use machines have been performed. A detrimental
effect on these activities cannot be predicted from the pharmacology of the active substance.
Undesirable effects
The main adverse reaction of treatment with 6–mercaptopurine is bone marrow suppression leading to leucopenia and thrombocytopenia. For mercaptopurine there is a lack of modern clinical documentation which can serve as support for accurately determining the frequency of adverse reactions. The following events have been identified as adverse reactions. The adverse reactions are displayed by system organ class and frequency: very common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥1/1000 to < 1/100), rare (≥1/10,000 to < 1/1000) and very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System organ class
Adverse reaction

6–mercaptopurine is hepatotoxic in animals and man. The histological findings in man have shown
hepatic necrosis and biliary stasis
The incidence of hepatotoxicity varies considerably and can occur with any dose but more frequently
when the recommended dose is exceeded.
Monitoring of liver function tests may allow early detection of hepatotoxicity. This is usually
reversible if 6–mercaptopurine therapy is stopped soon enough but fatal liver damage has occurred.
Symptoms and signs Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of overdose having occurred. The principal toxic effect is on the bone marrow, resulting in myelosuppression. Haematological toxicity is likely to be more profound with chronic overdose than with a single ingestion of Xaluprine. Liver dysfunction and gastroenteritis may also occur. The risk of overdose is also increased when xanthine oxidase inhibitors is being given concomitantly with 6–mercaptopurine (see section 4.5). Management As there is no known antidote the blood picture should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary. Active measures (such as the use of activated charcoal or gastric lavage) may not be effective in the event of 6-mercaptopurine overdose unless the procedure can be undertaken within 60 minutes of ingestion. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, antimetabolites, purine analogues, ATC code:
6–mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular
uptake and intracellular anabolism to thioguanine nucleotides for cytotoxicity. The 6–mercaptopurine
metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The thioguanine
nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the
active substance.
Cross-resistance usually exists between 6–mercaptopurine and 6-thioguanine.
Pharmacokinetic properties

The bioavailability of oral 6–mercaptopurine shows considerable inter-individual variability, which
probably results from its first-pass metabolism. When administered orally at a dosage of 75 mg/m2
to 7 paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5
to 37%.
In a comparative bioavailability study in healthy adult volunteers (n=60), 50mg of Xaluprine oral
suspension was demonstrated to be bioequivalent to the reference 50mg tablet for AUC, but not Cmax.
The mean (90% CI) Cmax with the oral suspension was 39% (22% - 58%) higher than the tablet
although there was less between-subject variability (%C.V) with the oral suspension (46%) than the
tablet (69%).
The elimination half-life of 6–mercaptopurine is 90 ± 30 minutes, but the active metabolites have a
longer half-life (approximately 5 hours) than the parent compound. The apparent body clearance is
4832 ± 2562 ml/min/m2. There is low entry of 6–mercaptopurine into the cerebrospinal fluid.
The main route of elimination for 6–mercaptopurine is by metabolism. The intracellular anabolism of
6-merpactopurine is catalysed by several enzymes to eventually form 6-thioguanine nucleotides
(TGNs), but a variety of intermediary TGNs are formed en route to the TGNs. The first step is
catalysed by hypoxanthine-guanine phosphoribosyl transferase yielding thioinosine monophosphate
(TIMP). 6–mercaptopurine is also subject to S-methylation by the enzyme thiopurine S-
methyltransferase (TPMT), yielding methylmercaptopurine, which is inactive. However, TPMT also
catalyses the S-methylation of the principle nucleotide metabolite, TIMP, to form methylthioinosine
monophosphate (mTIMP). Both TIMP and mTIMP are inhibitors of phosphoribosyl pyrophosphate
amidotransferase, an enzyme which is important in de novo purine synthesis. Xanthine oxidase is the
main catabolic enzyme and it converts the 6–mercaptopurine into the inactive metabolite, 6-thiouric
acid. This is excreted in the urine. Approximately 7% of an oral dose is excreted as unchanged 6–
mercaptopurine within 12 hours after administration.
Preclinical safety data
Genotoxicity 6–mercaptopurine, in common with other antimetabolites, is mutagenic and causes chromosomal aberrations in vitro and in vivo in mice and rats. Carcinogenicity Given its genotoxic potential, 6–mercaptopurine is potentially carcinogenic. Teratogenicity
6–mercaptopurine causes embryolethality and severe teratogenic effects in the mouse, rat, hamster
and rabbit at doses that are non-toxic to the mother. In all species, the degree of embryotoxicity and
the type of malformations are dependent on the dose and stage of the gestation at the time of
List of excipients

Xanthan gum
Aspartame (E951)
Concentrated Raspberry juice
Sodium methyl parahydroxybenzoate (E219)
Sodium ethyl parahydroxybenzoate (E215)
Potassium sorbate (E202)
Sodium hydroxide
Purified water

Not applicable.
Shelf life

1 year
After first opening: 56 days.
Special precautions for storage

Do not store above 25ºC.
Keep the bottle tightly closed (see section 6.6).
Nature and contents of container

Amber type III glass bottle with tamper evident child-resistant closure (HDPE with expanded
polyethylene liner) containing 100 ml of oral suspension.
Each pack contains one bottle, an HDPE bottle adaptor and 2 polyethylene dosing syringes (a purple
syringe graduated to1 ml and a white syringe graduated to 5 ml).
Special precautions for disposal and other handling
Safe handling Anyone handling Xaluprine should wash their hands before and after administering a dose. To decrease the risk of exposure, parents and care givers should wear disposable gloves when handling Xaluprine. Xaluprine contact with skin or mucous membrane must be avoided. If Xaluprine comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water. Spillages must be wiped immediately. Women who are pregnant, planning to be or breastfeeding should not handle Xaluprine. Parents / care givers and patients should be advised to keep Xaluprine out of the reach and sight of
children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.
Keep the bottle tightly closed to protect the integrity of the product and minimise the risk of
accidental spillage.
The bottle should be shaken vigorously for at least 30 seconds to ensure the oral suspension is well
Cytotoxic. Any unused product or waste material should be disposed of in accordance with local

Nova Laboratories Limited
Martin House
Gloucester Crescent
Wigston, Leicester
LE18 4YL
United Kingdom


9th April 2012
11th March 2013 Detailed information on this product is available on the website of the European Medicines Agency


Microsoft word - hypothesis english version.doc

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