Meloxicam Winthrop may be available in the countries listed below.
Meloxicam is reported as an ingredient of Meloxicam Winthrop in the following countries:
International Drug Name Search
Zitrolid may be available in the countries listed below.
Azithromycin is reported as an ingredient of Zitrolid in the following countries:
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Lidocaïne Aguettant may be available in the countries listed below.
Lidocaine hydrochloride monohydrate (a derivative of Lidocaine) is reported as an ingredient of Lidocaïne Aguettant in the following countries:
International Drug Name Search
Celeston may be available in the countries listed below.
Betamethasone 21-acetate and 21-(disodium phosphate) (a derivative of Betamethasone) is reported as an ingredient of Celeston in the following countries:
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Eucardic may be available in the countries listed below.
UK matches:
Carvedilol is reported as an ingredient of Eucardic in the following countries:
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Glossary
| SPC | Summary of Product Characteristics (UK) |
Zesun may be available in the countries listed below.
Timepidium Bromide is reported as an ingredient of Zesun in the following countries:
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Bisoprolol ratiopharm may be available in the countries listed below.
Bisoprolol is reported as an ingredient of Bisoprolol ratiopharm in the following countries:
Bisoprolol fumarate (a derivative of Bisoprolol) is reported as an ingredient of Bisoprolol ratiopharm in the following countries:
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Velmetia may be available in the countries listed below.
Metformin hydrochloride (a derivative of Metformin) is reported as an ingredient of Velmetia in the following countries:
Sitagliptin phosphate hydrate (a derivative of Sitagliptin) is reported as an ingredient of Velmetia in the following countries:
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Zolastrol may be available in the countries listed below.
Anastrozole is reported as an ingredient of Zolastrol in the following countries:
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Zofecard may be available in the countries listed below.
Zofenopril is reported as an ingredient of Zofecard in the following countries:
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In the US, Glynase (glyburide systemic) is a member of the drug class sulfonylureas and is used to treat Diabetes, Type 2.
US matches:
Glibenclamide is reported as an ingredient of Glynase in the following countries:
Glipizide is reported as an ingredient of Glynase in the following countries:
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Dermon may be available in the countries listed below.
Miconazole nitrate (a derivative of Miconazole) is reported as an ingredient of Dermon in the following countries:
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Zocort may be available in the countries listed below.
Hydrocortisone 21-acetate (a derivative of Hydrocortisone) is reported as an ingredient of Zocort in the following countries:
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Metrolyl* (Metronidazole) Suppositories 1g
Each 1g suppository contains metronidazole BP 1g
For a full list of excipients, see section 6.1
Suppository
White opaque suppository
Metrolyl* is indicated in adults and children for the following indications:
Treatment of infections in which anaerobic bacteria have been identified or are suspected as pathogens, particularly Bacteroides fragilis and other species of Bacteroides and including other species for which metronidazole is bactericidal e.g.: Fusobacteria, Eubacteria, Clostridia and anaerobic cocci.
Metrolyl* can be used in septicaemia, bacteraemia, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, peritonitis and post operative wound infection from which one or more of these anaerobes have been isolated.
Prevention of post operative infections due to anaerobic bacteria,particularly species of Bacteroides and anaerobic Streptococci.
.
Route of administration: Rectal
Treatment of Anaerobic Infections:
Adults and children over 10 years of age: 1 g suppository inserted into the rectum 8 hourly for 3 days. Oral medication with 400 mg 3 times a day should be substituted as soon as feasible. If rectal medication has to be continued for more than 3days then the suppositories should be inserted at 12 hourly intervals.
Children (5 -10 years): As for adults but with 500 mg suppositories and oral medication with 7.5 mg/kg bodyweight 3 times a day.
Infants and children under 5 years: As for children of 5-10 years but with a reducted dose of suppositories (1½ of a 500 mg suppository for 1-5 years and ¼ of a 500 mg suppository for under 1 year).
Prevention of Anaerobic Infections:
Used in appendectomy and post-operative medication for elective colonic surgery.
Adults and children over 10 years of age: 1 g suppository inserted into the rectum 2 hours before surgery and repeat at 8 hourly intervals until oral medication (200-400 mg 3 times a day) can be given to complete a 7day course.
If rectal medication is necessary after the third post-operative day, the frequency of administration should be reduced to 12 hourly.
Children (5-10 years): 500 mg suppositories administered as for adults until oral medication, 3.7 to 7.5 mg/kg bodyweight three times daily becomes a possibility.
Known sensitivity to metronidazole or any of the excipients.
Metronidazole has no direct activity against aerobic or facultative anaerobic bacterium.
Clinical and laboratory monitoring e.g. leucocyte count, are advised if administration with Metrolyl for more than 10 days is considered to be necessary. Patients should be monitored for adverse reactions, such as peripheral or central neuropathy e.g. paraesthesia, ataxia, dizziness, convulsive seizures.
Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of neurological aggravation.
There is a possibility that after Trichomonas vaginalis has been eliminated a gonococcal infection might be persistant.
The half-life elimination of metronidazole remains the same in patients with renal failure, therefore there is no needs for dose reduction. However, such patients retain the metabolites of metronidazole, the clinical significance of this is not known.
In patients undergoing haemodialysis metronidazole and its metabolites are efficiently removed during an eight hour dialysis period. Therefore, Metronidazole should be re-administered immediately after haemodialysis.
No adjustment in the dosage of Metrolyl is required in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD).
Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. Significant cumulation may occur in patients with hepatic encephalopathy, resulting in high plasma concentrations of metronidazole may contribute to the symptoms of the encephalopathy. Therefore, Metrolyl should, be administered with caution in patients with hepatic encephalopathy, the daily dosage should be reduced to one third and administered once daily.
Metronidazole may cause darkened urine.
Due to inadequate evidence, the mutagenicity risk in humans (see section 5.3), with the use of Metrolyl for longer treatment than usually required should be carefully considered.
Alcohol
The consumption of alcohol during metronidazole therapy should be avoided since there could be a disulfiram-like reaction. Psychotic reactions have been reported in patients who were using metronidazole and disulfiram concurrently.
Anticoagulant
Potentiation of warfarin-type anticoagulant therapy (except with heparin) has been reported so that dose adjustment of the anticoagulant may be needed.
Barbiturates
Phenobarbitone: The half-life of metronidazole is reduced from 7-8 hours to about 3 hours in patients receiving phenobarbitone.
In patients taking metronidazole, the assay of aspartate amino transferase may give spuriously low values; this depends on the method used.
Lithium
Lithium retention with evidence of possible renal damage has been reported where this compound and metronidazole have been used concurrently. Preferably, apart from monitoring lithium, creatinine and electrolyte concentrations, lithium therapy should be tapered and or withdrawn before use of metronidazole.
Anti-epileptics
Patients taking phenobarbital or phenytoin metabolise metronidazole at a much greater rate than normally reducing the half-life to approximately 3 hours.
Primidone: accelerates the metabolism of metronidazole resulting in a reduced plasma concentration.
Cytotoxics:
Busulfan: Increased risk of toxicity due to increased busulfan plasma concentration levels which may lead to severe busulfan toxicity.
Fluorouracil: Metronidazole reduces the clearance of 5-fluorouracil resulting in increased toxicity of 5-fluorouracil.
Ulcer-healing drugs:
Cimetidine increases the plasma concentration of metronidazole by inhibiting its metabolism.
Disulfiram
Administration of metronidazole may lead to psychoses and confusion.
Ciclosporin: Patients receiving ciclosporin are at risk of elevated ciclosporin serum levels. Serum ciclosporin and serum creatinine should be closely monitored when coadministration is necessary.
There is inadequate data of the safety of metronidazole in pregnancy. Metrolyl should not be given during pregnancy or lactation unless the physician considers it essential, should this be the case then short, high-dosage regimens are not recommended.
Patients should be warned that drowsiness, dizziness, confusion, hallucinations, convulsions or transient visual disorders could occur, and advised them not to drive or operate machinery if they get the se symptoms.
The frequency of adverse events listed below is defined using the following convention:
very common (
Serious adverse reactions occur rarely with standard recommended regimens. Clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods longer than those recommended, are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.
Blood and lymphatic system disorders:
Very rare: agranulocytosis, neutropenia, thrombocytopenia, pancytopenia,
Not known: leucopenia.
Immune system disorders:
Rare: anaphylaxis
Not known: angiodema, urticaria, fever.
Metabolism and nutrition disorders:
Not known: anorexia.
Psychiatric disorders:
Very rare: psychotic disorders, including confusion and hallucinations.
Not known: depressed mood.
Nervous system disorders:
Uncommon: drowsiness, dizziness, convulsions, headaches
Very rare: encephalopathy (e.g. confusion, fever, headache, hallucinations, paralysis, light sensitivity, disturbances in sight and movement, stiff neck) and subacute cerebellar syndrome (e.g. ataxia, dysathria, gait impairment, nystagmus and tremor) which may resolve on discontinuation of the drug.
Not known: during intensive and/or prolonged metronidazole therapy, peripheral sensory neuropathy or transient epileptiform seizures have been reported. In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced.
Eye disorders:
Very rare: vision disorders such as diplopia and myopia, which in most cases, is transient.
Gastrointestinal disorders:
Not known: taste disorders, oral mucositis, furry tongue, nausea, vomiting, gastro-intestinal disturbances such as epigastric pain and diarrhoea.
Hepatobiliary disorders:
Very rare: abnormal liver function tests, cholestatic hepatitis, jaundice and pancreatitis reversible on drug withdrawal.
Skin and subcutaneous tissue disorders:
Very rare: skin rashes, pustular eruptions, pruritis, flushing
Not known: erythema multiforme.
Musculoskeletal, connective tissue and bone disorders:
Uncommon: asthenia
Very rare: myalgia, arthralgia.
Renal and urinary disorders:
Very rare: darkening of urine (due to metronidazole metabolite).
After single doses up to 12 g metronidazole have been reported in suicidal attempts and accidental overdoses, vomiting, nausea, ataxia and disorientation were observed.
There is no specific antidote for metronidazole overdose. symptomatic and supportive treatment should be instituted.
Pharmacotherapeutic code: Antibacterials for systemic use, ATC code J01X D01.
Metronidazole has antiprotozoal and antibacterial properties and is effective against Trichomonas vaginalis and other protozoa including Entamoeba histolytica and Giardia lamblia, and against anaerobic bacteria.
Metronidazole is readily absorbed from the rectal mucosa and widely distributed in body, maximum concentrations occur in the serum after about 1 hour and traces can be detected after 24 hours.
At least half the dose is excreted in the urine as metronidazole and its metabolites, including an acid oxidation product, a hydroxy derivative and glucoronide. Metronidazole diffuses across the placenta and is found in breast milk in concentrations equivalent to those in serum.
Metronidazole has been shown to be carcinogenic in mice and rats following chronic oral administration, however, similar studies in the hamster have given negative results. Epidemiological studies have not provided clear evidence of a carcinogenic risk in humans.
Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent or humans in vivo, there was inadequate evidence of a mutagenic effect of metronidazole, with some studies reporting mutagenic effects while other studies were negative.
Hard fat (Witepsol E75 and W35).
Not known.
36 months.
Do not store above 25°C. Protect from light.
Sealed PVC moulds containing the suppositories inside a cardboard carton.
Pack size: 10
Not applicable.
Sandoz Ltd
Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR.
United Kingdom
PL 04416/0054
25 May 1982/30 April 1997
10 May 2011
* trade mark
Zitroneo may be available in the countries listed below.
Azithromycin is reported as an ingredient of Zitroneo in the following countries:
International Drug Name Search
Anibesol may be available in the countries listed below.
Bezafibrate is reported as an ingredient of Anibesol in the following countries:
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Protopic 0.1% ointment
1 g of Protopic 0.1% ointment contains 1.0 mg of tacrolimus as tacrolimus monohydrate (0.1%).
For a full list of excipients, see section 6.1.
Ointment
A white to slightly yellowish ointment.
Protopic 0.1 % ointment is indicated in adults and adolescents (16 years of age and above)
Flare treatment
Adults and adolescents (16 years of age and above)
Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids.
Maintenance treatment
Treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation of flare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e. occurring 4 or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).
Protopic treatment should be initiated by physicians with experience in the diagnosis and treatment of atopic dermatitis.
Protopic is available in two strengths, Protopic 0.03 % and Protopic 0.1 % ointment.
Posology
Flare treatment
Protopic can be used for short-term and intermittent long-term treatment. Treatment should not be continuous on a long-term basis.
Protopic treatment should begin at the first appearance of signs and symptoms. Each affected region of the skin should be treated with Protopic until lesions are cleared, almost cleared or mildly affected. Thereafter, patients are considered suitable for maintenance treatment (see below). At the first signs of recurrence (flares) of the disease symptoms, treatment should be re-initiated.
Adults and adolescents (16 years of age and above)
Treatment should be started with Protopic 0.1% twice a day and treatment should be continued until clearance of the lesion. If symptoms recur, twice daily treatment with Protopic 0.1% should be restarted. An attempt should be made to reduce the frequency of application or to use the lower strength Protopic 0.03% ointment if the clinical condition allows.
Generally, improvement is seen within one week of starting treatment. If no signs of improvement are seen after two weeks of treatment, further treatment options should be considered.
Elderly patients
Specific studies have not been conducted in elderly patients. However, the clinical experience available in this patient population has not shown the necessity for any dosage adjustment.
Paediatric population
Only Protopic 0.03 % ointment should be used in children from the age of 2 to 16 years.
Protopic ointment should not be used in children aged below 2 years until further data are available.
Maintenance treatment
Patients who are responding to up to 6 weeks treatment using tacrolimus ointment twice daily (lesions cleared, almost cleared or mildly affected) are suitable for maintenance treatment.
Adults and adolescents (16 years of age and above)
Adult patients (16 years of age and above) should use Protopic 0.1% ointment. Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected by atopic dermatitis to prevent progression to flares. Between applications there should be 2–3 days without Protopic treatment.
After 12 months treatment, a review of the patient`s condition should be conducted by the physician and a decision taken whether to continue maintenance treatment in the absence of safety data for maintenance treatment beyond 12 months.
If signs of a flare reoccur, twice daily treatment should be re-initiated (see flare treatment section above).
Elderly patients
Specific studies have not been conducted in elderly patients (see flare treatment section above).
Paediatric population
Only Protopic 0.03 % ointment should be used in children from the age of 2 to 16 years.
Protopic ointment should not be used in children aged below 2 years until further data are available.
Method of administration
Protopic ointment should be applied as a thin layer to affected or commonly affected areas of the skin. Protopic ointment may be used on any part of the body, including face, neck and flexure areas, except on mucous membranes. Protopic ointment should not be applied under occlusion because this method of administration has not been studied in patients (see section 4.4).
Hypersensitivity to the active substance, macrolides in general, or to any of the excipients.
Protopic should not be used in patients with congenital or acquired immunodeficiencies or in patients on therapy that cause immunosuppression.
Exposure of the skin to sunlight should be minimised and the use of ultraviolet (UV) light from a solarium, therapy with UVB or UVA in combination with psoralens (PUVA) should be avoided during use of Protopic ointment (see section 5.3). Physicians should advise patients on appropriate sun protection methods, such as minimisation of the time in the sun, use of a sunscreen product and covering of the skin with appropriate clothing. Protopic ointment should not be applied to lesions that are considered to be potentially malignant or pre-malignant.
Emollients should not be applied to the same area within 2 hours of applying Protopic ointment. Concomitant use of other topical preparations has not been assessed. There is no experience with concomitant use of systemic steroids or immunosuppressive agents.
Protopic ointment has not been evaluated for its efficacy and safety in the treatment of clinically infected atopic dermatitis. Before commencing treatment with Protopic ointment, clinical infections at treatment sites should be cleared. Patients with atopic dermatitis are predisposed to superficial skin infections. Treatment with Protopic may be associated with an increased risk of folliculitis and herpes viral infections (herpes simplex dermatitis [eczema herpeticum], herpes simplex [cold sores], Kaposi's varicelliform eruption) (see section 4.8). In the presence of these infections, the balance of risks and benefits associated with Protopic use should be evaluated.
The potential for local immunosuppression (possibly resulting in infections or cutaneous malignancies) in the long term (i.e. over a period of years) is unknown (see section 5.1).
Protopic contains the active substance tacrolimus, a calcineurin inhibitor. In transplant patients, prolonged systemic exposure to intense immunosuppression following systemic administration of calcineurin inhibitors has been associated with an increased risk of developing lymphomas and skin malignancies. In patients using tacrolimus ointment, cases of malignancies, including cutaneous and other types of lymphoma, and skin cancers have been reported (see section 4.8). Patients with atopic dermatitis treated with Protopic have not been found to have significant systemic tacrolimus levels.
Lymphadenopathy was uncommonly (0.8%) reported in clinical trials. The majority of these cases were related to infections (skin, respiratory tract, tooth) and resolved with appropriate antibiotic therapy. Transplant patients receiving immunosuppressive regimens (e.g. systemic tacrolimus) are at increased risk for developing lymphoma; therefore patients who receive Protopic and who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves. Lymphadenopathy present at initiation of therapy should be investigated and kept under review. In case of persistent lymphadenopathy, the aetiology of the lymphadenopathy should be investigated. In the absence of a clear aetiology for the lymphadenopathy or in the presence of acute infectious mononucleosis, discontinuation of Protopic should be considered.
Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied to these areas, the ointment should be thoroughly wiped off and/or rinsed off with water.
The use of Protopic ointment under occlusion has not been studied in patients. Occlusive dressings are not recommended.
As with any topical medicinal product, patients should wash their hands after application if the hands are not intended for treatment.
Tacrolimus is extensively metabolised in the liver and although blood concentrations are low following topical therapy, the ointment should be used with caution in patients with hepatic failure (see section 5.2).
The use of tacrolimus ointment is not recommended in patients with a skin barrier defect, such as Netherton's syndrome, lamellar ichthyosis, generalized erythroderma or cutaneous Graft Versus Host Disease. These skin conditions may increase systemic absorption of tacrolimus. Oral use of tacrolimus is also not recommended to treat these skin conditions. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions.
Care should be exercised if applying Protopic to patients with extensive skin involvement over an extended period of time, especially in children (see section 4.2).
The development of any new change different from previous eczema within a treated area should be reviewed by the physician.
Formal topical drug interaction studies with tacrolimus ointment have not been conducted.
Tacrolimus is not metabolised in human skin, indicating that there is no potential for percutaneous interactions that could affect the metabolism of tacrolimus.
Systemically available tacrolimus is metabolised via the hepatic Cytochrome P450 3A4 (CYP3A4). Systemic exposure from topical application of tacrolimus ointment is low (< 1.0 ng/ml) and is unlikely to be affected by concomitant use of substances known to be inhibitors of CYP3A4. However, the possibility of interactions cannot be ruled out and the concomitant systemic administration of known CYP3A4 inhibitors (e.g. erythromycin, itraconazole, ketoconazole and diltiazem) in patients with widespread and/or erythrodermic disease should be done with caution.
Paediatric population
An interaction study with protein-conjugated vaccine against Neisseria menigitidis serogroup C has been investigated in children aged 2-11 years. No effect on immediate response to vaccination, the generation of immune memory, or humoral and cell-mediated immunity has been observed (see section 5.1).
Fertility
There are no fertility data available.
Pregnancy
There are no adequate data from the use of tacrolimus ointment in pregnant women. Studies in animals have shown reproductive toxicity following systemic administration (see section 5.3). The potential risk for humans is unknown.
Protopic ointment should not be used during pregnancy unless clearly necessary.
Breastfeeding
Human data demonstrate that, after systemic administration, tacrolimus is excreted into breast milk. Although clinical data have shown that systemic exposure from application of tacrolimus ointment is low, breast-feeding during treatment with Protopic ointment is not recommended.
Protopic ointment is administered topically and is unlikely to have an effect on the ability to drive or use machines.
In clinical studies approximately 50% of patients experienced some type of skin irritation adverse reaction at the site of application. Burning sensation and pruritus were very common, usually mild to moderate in severity and tended to resolve within one week of starting treatment. Erythema was a common skin irritation adverse reaction. Sensation of warmth, pain, paraesthesia and rash at the site of application were also commonly observed. Alcohol intolerance (facial flushing or skin irritation after consumption of an alcoholic beverage) was common.
Patients may be at an increased risk of folliculitis, acne and herpes viral infections.
Adverse reactions with suspected relationship to treatment are listed below by system organ class. Frequencies are defined as very common ( 1/10), common ( 1/100 to < 1/10) and uncommon (1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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* The adverse reaction has been reported during post-marketing experience
Maintenance treatment
In a study of maintenance treatment (twice weekly treatment) in adults and children with moderate and severe atopic dermatitis the following adverse events were noted to occur more frequently than in the control group: application site impetigo (7.7% in children) and application site infections (6.4% in children and 6.3% in adults).
Post-marketing
Cases of malignancies, including cutaneous and other types of lymphoma, and skin cancers, have been reported in patients using tacrolimus ointment (see section 4.4).
Overdosage following topical administration is unlikely.
If ingested, general supportive measures may be appropriate. These may include monitoring of vital signs and observation of clinical status. Due to the nature of the ointment vehicle, induction of vomiting or gastric lavage is not recommended.
Pharmacotherapeutic group: Other dermatologicals, ATC code: D11AH01
Mechanism of action and pharmacodynamic effects
The mechanism of action of tacrolimus in atopic dermatitis is not fully understood. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known.
Via its binding to a specific cytoplasmic immunophilin (FKBP12), tacrolimus inhibits calcium-dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesis of IL-2, IL-3, IL-4, IL-5 and other cytokines such as GM-CSF, TNF-α and IFN-γ.
In vitro, in Langerhans cells isolated from normal human skin, tacrolimus reduced the stimulatory activity towards T cells. Tacrolimus has also been shown to inhibit the release of inflammatory mediators from skin mast cells, basophils and eosinophils.
In animals, tacrolimus ointment suppressed inflammatory reactions in experimental and spontaneous dermatitis models that resemble human atopic dermatitis. Tacrolimus ointment did not reduce skin thickness and did not cause skin atrophy in animals.
In patients with atopic dermatitis, improvement of skin lesions during treatment with tacrolimus ointment was associated with reduced Fc receptor expression on Langerhans cells and a reduction of their hyperstimulatory activity towards T cells. Tacrolimus ointment does not affect collagen synthesis in humans.
Clinical efficacy and safety
The efficacy and safety of Protopic was assessed in more than 18,500 patients treated with tacrolimus ointment in Phase I to Phase III clinical trials. Data from six major trials are presented here.
In a six-month multicentre double-blind randomised trial, 0.1% tacrolimus ointment was administered twice-a-day to adults with moderate to severe atopic dermatitis and compared to a topical corticosteroid based regimen (0.1% hydrocortisone butyrate on trunk and extremities, 1% hydrocortisone acetate on face and neck). The primary endpoint was the response rate at month 3 defined as the proportion of patients with at least 60% improvement in the mEASI (modified Eczema Area and Severity Index) between baseline and month 3. The response rate in the 0.1% tacrolimus group (71.6%) was significantly higher than that in the topical corticosteroid based treatment group (50.8%; p<0.001; Table 1). The response rates at month 6 were comparable to the 3-month results.
Table 1 Efficacy at month 3
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§ Topical corticosteroid regimen = 0.1% hydrocortisone butyrate on trunk and extremities, 1% hydrocortisone acetate on face and neck
§§ higher values = greater improvement
The incidence and nature of most adverse events were similar in the two treatment groups. Skin burning, herpes simplex, alcohol intolerance (facial flushing or skin sensitivity after alcohol intake), skin tingling, hyperaesthesia, acne and fungal dermatitis occurred more often in the tacrolimus treatment group. There were no clinically relevant changes in the laboratory values or vital signs in either treatment group throughout the study.
In the second trial, children aged from 2 to 15 years with moderate to severe atopic dermatitis received twice daily treatment for three weeks of 0.03% tacrolimus ointment, 0.1% tacrolimus ointment or 1% hydrocortisone acetate ointment. The primary endpoint was the area-under-the-curve (AUC) of the mEASI as a percentage of baseline averaged over the treatment period. The results of this multicentre, double-blind, randomised trial showed that tacrolimus ointment, 0.03% and 0.1%, is significantly more effective (p<0.001 for both) than 1% hydrocortisone acetate ointment (Table 2).
Table 2 Efficacy at week 3
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§ lower values = greater improvement
The incidence of local skin burning was higher in the tacrolimus treatment groups than in the hydrocortisone group. Pruritus decreased over time in the tacrolimus groups but not in the hydrocortisone group. There were no clinically relevant changes in the laboratory values or vital signs in either treatment group throughout the clinical trial.
The purpose of the third multicentre, double-blind, randomised study was the assessment of efficacy and safety of 0.03% tacrolimus ointment applied once or twice a day relative to twice daily administration of 1% hydrocortisone acetate ointment in children with moderate to severe atopic dermatitis. Treatment duration was for up to three weeks.
Table 3 Efficacy at week 3
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§ higher values = greater improvement
The primary endpoint was defined as the percentage decrease in mEASI from the baseline to end of treatment. A statistically significant better improvement was shown for once daily and twice daily 0.03% tacrolimus ointment compared to twice daily hydrocortisone acetate ointment (p<0.001 for both). Twice daily treatment with 0.03% tacrolimus ointment was more effective than once daily administration (Table 3). The incidence of local skin burning was higher in the tacrolimus treatment groups than in the hydrocortisone group. There were no clinically relevant changes in the laboratory values or vital signs in either treatment group throughout the study.
In the fourth trial, approximately 800 patients (aged
The efficacy and safety of tacrolimus ointment in maintenance treatment of mild to severe atopic dermatitis was assessed in 524 patients in two Phase III multicentre clinical trials of similar design, one in adult patients (
The primary endpoint in both studies was the number of disease exacerbations requiring a “substantial therapeutic intervention” during the DCP, defined as an exacerbation with an IGA of 3-5 (i.e. moderate, severe and very severe disease) on the first day of the flare, and requiring more than 7 days treatment. Both studies showed significant benefit with twice weekly treatment with tacrolimus ointment with regard to the primary and key secondary endpoints over a period of 12 months in a pooled population of patients with mild to severe atopic dermatitis. In a subanalysis of a pooled population of patients with moderate to severe atopic dermatitis these differences remained statistically significant (Table 4). No adverse events not reported previously were observed in these studies.
Table 4 Efficacy (moderate to severe subpopulation)
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DE: disease exacerbation
P<0.001 in favour of tacrolimus ointment 0.1% (adults) and 0.03% (children) for the primary and key secondary endpoints
A seven-month, double blind, randomised parallel group study of paediatric patients (2-11 years) with moderate to severe atopic dermatitis was performed. In one arm patients received Protopic 0.03% ointment (n=121) twice a day for 3 weeks and thereafter once a day until clearance. In the comparator arm patients received 1% hydrocortisone acetate ointment (HA) for head and neck and 0.1% hydrocortisone butyrate ointment for trunk and limbs (n=111) twice a day for 2 weeks and subsequently HA twice a day to all affected areas. During this period all patients and control subjects (n=44) received a primary immunisation and a rechallenge with a protein-conjugate vaccine against Neisseria menigitidis serogroup C.
The primary endpoint of this study was the response rate to vaccination, defined as the percentage of patients with a serum bactericidal antibody (SBA) titre
The primary response to vaccination was not affected.
Clinical data have shown that tacrolimus concentrations in systemic circulation after topical administration are low and, when measurable, transient.
Absorption
Data from healthy human subjects indicate that there is little or no systemic exposure to tacrolimus following single or repeated topical application of tacrolimus ointment.
Most atopic dermatitis patients (adults and children) treated with single or repeated application of tacrolimus ointment (0.03-0.1%), and infants from age of 5 months treated with tacrolimus ointment (0.03%) had blood concentrations < 1.0 ng/ml. When observed, blood concentrations exceeding 1.0 ng/ml were transient. Systemic exposure increases with increasing treatment areas. However, both the extent and the rate of topical absorption of tacrolimus decrease as the skin heals. In both adults and children with an average of 50% body surface area treated, systemic exposure (i.e. AUC) of tacrolimus from Protopic is approximately 30-fold less than that seen with oral immunosuppressive doses in kidney and liver transplant patients. The lowest tacrolimus blood concentration at which systemic effects can be observed is not known.
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated for prolonged periods (up to one year) with tacrolimus ointment.
Distribution
As systemic exposure is low with tacrolimus ointment, the high binding of tacrolimus (> 98.8%) to plasma proteins is considered not to be clinically relevant.
Following topical application of tacrolimus ointment, tacrolimus is selectively delivered to the skin with minimal diffusion into the systemic circulation.
Metabolism
Metabolism of tacrolimus by human skin was not detectable. Systemically available tacrolimus is extensively metabolised in the liver via CYP3A4.
Elimination
When administered intravenously, tacrolimus has been shown to have a low clearance rate. The average total body clearance is approximately 2.25 l/h. The hepatic clearance of systemically available tacrolimus could be reduced in subjects with severe hepatic impairment, or in subjects who are co-treated with drugs that are potent inhibitors of CYP3A4.
Following repeated topical application of the ointment the average half-life of tacrolimus was estimated to be 75 hours for adults and 65 hours for children.
Paediatric population
The pharmacokinetics of tacrolimus after topical application are similar to those reported in adults, with minimal systemic exposure and no evidence of accumulation (see above).
Repeated dose toxicity and local tolerance
Repeated topical administration of tacrolimus ointment or the ointment vehicle to rats, rabbits and micropigs was associated with slight dermal changes such as erythema, oedema and papules.
Long-term topical treatment of rats with tacrolimus led to systemic toxicity including alterations of kidneys, pancreas, eyes and nervous system. The changes were caused by high systemic exposure of rodents resulting from high transdermal absorption of tacrolimus. Slightly lower body weight gain in females was the only systemic change observed in micropigs at high ointment concentrations (3%).
Rabbits were shown to be especially sensitive to intravenous administration of tacrolimus, reversible cardiotoxic effects being observed.
Mutagenicity
In vitro and in vivo tests did not indicate a genotoxic potential of tacrolimus.
Carcinogenicity
Systemic carcinogenicity studies in mice (18 months) and rats (24 months) revealed no carcinogenic potential of tacrolimus.
In a 24-month dermal carcinogenicity study performed in mice with 0.1% ointment, no skin tumours were observed. In the same study an increased incidence of lymphoma was detected in association with high systemic exposure.
In a photocarcinogenicity study, albino hairless mice were chronically treated with tacrolimus ointment and UV radiation. Animals treated with tacrolimus ointment showed a statistically significant reduction in time to skin tumour (squamous cell carcinoma) development and an increase in the number of tumours. It is unclear whether the effect of tacrolimus is due to systemic immunosuppression or a local effect. The risk for humans cannot be completely ruled out as the potential for local immunosuppression with the long-term use of tacrolimus ointment is unknown.
Reproduction toxicity
Embryo/foetal toxicity was observed in rats and rabbits, but only at doses that caused significant toxicity in maternal animals. Reduced sperm function was noted in male rats at high subcutaneous doses of tacrolimus.
White soft paraffin
Liquid paraffin
Propylene carbonate
White beeswax
Hard paraffin
Not applicable.
3 years
Do not store above 25°C.
Laminate tube with an inner lining of low-density-polyethylene fitted with a white polypropylene screw cap.
Package sizes: 10 g, 30 g and 60 g. Not all pack sizes may be marketed.
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
EU/1/02/201/003
EU/1/02/201/004
EU/1/02/201/006
Date of first authorisation: 28/02/2002
Date of renewal: 20/11/2006
23/06/2011
POM
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.
Zoiplon may be available in the countries listed below.
Zopiclone is reported as an ingredient of Zoiplon in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
JAN
A03AX12
0000108-73-6
C6-H6-O3
126
Antispasmodic agent
1,3,5-Benzenetriol
1,3,5-Trihydroxybenzene
1,3,5-Trihydroxybenzol (IUPAC)
Benzene-1,3,5-triol (BAN)
International Drug Name Search
Glossary
| BAN | British Approved Name |
| DCF | Dénomination Commune Française |
| IUPAC | International Union of Pure and Applied Chemistry |
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
Allopurinolo may be available in the countries listed below.
Allopurinolo (DCIT) is known as Allopurinol in the US.
International Drug Name Search
Glossary
| DCIT | Denominazione Comune Italiana |
In some countries, this medicine may only be approved for veterinary use.
Methoprene is reported as an ingredient of Zodiac in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
Tiabendazole is reported as an ingredient of Omnizole in the following countries:
International Drug Name Search
Zobistat may be available in the countries listed below.
Aciclovir is reported as an ingredient of Zobistat in the following countries:
International Drug Name Search
Puri-Nethol® 50 mg tablets
Each tablet contains 50 mg of 6-mercaptopurine.
For a full list of excipients, see section 6.1.
Tablets
Pale yellow, round tablets, biconvex, scored on one side, engraved GX above the score and EX2 below the score and plain on the other side
Cytotoxic agent.
Puri-Nethol is indicated for the treatment of acute leukaemia. It may be utilised in remission induction and it is particularly indicated for maintenance therapy in: acute lymphoblastic leukaemia; acute myelogenous leukaemia. Puri-Nethol may be used in the treatment of chronic granulocytic leukaemia.
For oral administration
Dosage in adults and children:
For adults and children the usual starting dose is 2.5 mg/kg bodyweight per day, or 50-75 mg/m2 body surface area per day, but the dose and duration of administration depend on the nature and dosage of other cytotoxic agents given in conjunction with Puri-Nethol.
The dosage should be carefully adjusted to suit the individual patient.
Puri-Nethol has been used in various combination therapy schedules for acute leukaemia and the literature should be consulted for details.
Dosage 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 Puri-Nethol dosage.
Dosage in renal impairment:
Consideration should be given to reducing the dosage in patients with impaired renal function.
Dosage in hepatic function:
Consideration should be given to reducing the dosage in patients with impaired hepatic function.
In general:
When Zyloric (allopurinol) and 6-mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of 6-mercaptopurine is given since Zyloric (allopurinol) decreases the rate of catabolism of 6-mercaptopurine.
Hypersensitivity to any component of the preparation.
In view of the seriousness of the indications there are no other absolute contra-indications.
Puri-Nethol is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
Safe handling of Puri-Nethol Tablets:
See section 6.6 Instructions for Use/Handling
Monitoring:
Treatment with Puri-Nethol causes bone marrow suppression leading to leucopenia and thrombocytopenia and, less frequently, to anaemia. Full blood counts must be taken daily during remission induction and careful monitoring of haematological parameters should be conducted during maintenance 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 Puri-Nethol is withdrawn early enough.
During remission induction in acute myelogenous leukaemia the patient may frequently have to survive a period of relative bone marrow aplasia and it is important that adequate supportive facilities are available.
There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppresive effect of 6-mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with Puri-Nethol. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfazalazine. Also 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 Undesirable Effects). 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 still necessary.
Puri-Nethol 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 Puri-Nethol immediately if jaundice becomes apparent.
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.
Cross resistance usually exists between 6-mercaptopurine and 6-tioguanine.
The dosage of 6-mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.
Mutagenicity and carcinogenicity:
Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a hypernephroma 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 carcinogenisis with this treatment.
Two cases have been documented of the occurrence of acute nonlymphatic leukaemia in patients who received 6-mercaptopurine, in combination with other drugs, for non-neoplastic disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with 6-mercaptopurine and later developed acute nonlymphatic leukaemia, but it is not clear whether this was part of the natural history of the disease or if the 6-mercaptopurine played a causative role.
A patient with Hodgkins Disease treated with 6-mercaptopurine and multiple additional cytotoxic agents developed acute myelogenous leukaemia.
Twelve and a half years after 6-mercaptopurine treatment for myasthenia gravis a female patient developed chronic myeloid leukaemia.
Reports of hepatosplenic T-cell lymphoma in the inflammatory bowel disease (IBD) population have been received when 6-mercaptopurine is used (an unlicensed indication) in combination with anti-TNF agents (see section 4.8 Undesirable Effects).
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special Warnings and Precautions for Use).
When Zyloric (allopurinol) and Puri-Nethol are administered concomitantly it is essential that only a quarter of the usual dose of Puri-Nethol is given since Zyloric decreases the rate of catabolism of Puri-Nethol.
Inhibition of the anticoagulant effect of warfarin, when given with Puri-Nethol, has been reported.
As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Puri-Nethol therapy (see Section 4.4 Special Warnings and Precautions for Use).
Pregnancy:
6-mercaptopurine is potentially teratogenic. The use of Puri-Nethol should be avoided whenever possible during pregnancy. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised if either partner is receiving Puri-Nethol tablets.
Maternal Exposure:
Studies of 6-mercaptopurine in animals have shown reproductive toxicity (see Section 5.3 Preclinical Safety Data). The potential risk for humans is unclear.
Normal offspring have been born after mercaptopurine therapy administered as a single chemotherapy agent during human pregnancy. Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported following maternal 6-mercatopurine treatment in combination with other chemotherapy agents.
Paternal Exposure:
Congenital abnormalities and spontaneous abortion have been reported after paternal exposure to 6-mercaptopurine.
Effects on fertility:
The effect of Puri-Nethol therapy on human fertility is largely unknown but there are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence. Transient profound oligospermia was observed in a young man who received 6-mercaptopurine 150 mg/day plus prednisone 80 mg/day for acute leukaemia. Two years after cessation of the chemotherapy, he had a normal sperm count and he fathered a normal child.
Lactation:
6-Mercaptopurine has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with azathioprine, a pro-drug of 6-mercaptopurine and thus mothers receiving Puri-Nethol should not breast-feed.
There are no data on the effect of 6-mercaptopurine on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.
For mercaptopurine there is a lack of modern clinical documentation which can serve as support for accurately determining the frequency of undesirable effects.
The following convention has been utilised for the classification of undesirable effects:- Very common
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Very Rare: secondary leukaemia and myelodysplasia (see Section 4.4 Special Warnings and Precautions for Use); hepatosplenic T-cell lymphoma in patients with IBD (an unlicensed indication) when used in combination with anti-TNF agents (see Section 4.4 Special Warnings and Precautions for Use).
Blood and lymphatic system disorders | |
Very common | Bone marrow suppression; leucopenia and thrombocytopenia. |
The main side effect of treatment with 6-mercaptopurine is bone marrow suppression leading to leucopenia and thrombocytopenia. | |
Uncommon | anaemia |
Immune system disorders | |
Hypersensitivity reactions with the following manifestations have been reported: | |
Rare: | Arthralgia; skin rash; drug fever |
Very Rare: | Facial oedema |
Metabolism and nutrition disorders | |
Uncommon | Anorexia |
Gastrointestinal disorders | |
Common | Nausea; vomiting; pancreatitis in the IBD population* (an unlicensed indication) |
Rare | Oral ulceration; pancreatitis (in the licensed indications) |
Very rare | Intestinal ulceration |
Hepato-biliary disorders | |
Common | Biliary stasis; hepatotoxicity |
Rare | Hepatic necrosis |
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 of 2.5 mg/kg bodyweight daily or 75 mg/m2 body surface area per day 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.
Skin and subcutaneous tissue disorders | |
Rare | alopecia |
Reproductive system and breast disorders | |
Very Rare | Transient oligospermia |
Symptoms and signs:
Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of overdosage having occurred. The principal toxic effect is on the bone marrow, resulting in myelosuppression. Haematological toxicity is likely to be more profound with chronic overdosage than with a single ingestion of Puri-Nethol. Liver dysfunction and gastroenteritis may also occur.
The risk of overdosage is also increased when Zyloric is being given concomitantly with Puri-Nethol (see Section 4.5 Interactions with other Medicaments and other forms of Interaction).
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) may not be effective in the event of 6-mercaptopurine overdose unless the procedure can be undertaken within 60 minutes of ingestion.
Further management should be as clinically indicated or as recommended by the national poisons centre.
ATC Code: L01BB02
Pharmacotherapeutic group:
6-Mercaptopurine is sulphydryl analogue of the purine base hypoxanthine and acts as a cytotoxic antimetabolite.
Mode of Action:
6-Mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular uptake and intracellular anabolism to tioguanine nucleotides for cytotoxicity. The 6-mercaptopurine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The tioguanine nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the drug.
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%).
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 drug. The apparent body clearance is 4832 ± 2562 ml/min/m2. There is low entry of 6-mercaptopurine into the cerebrospinal fluid.
The main method of elimination for 6-mercaptopurine is by metabolic alteration. The kidneys eliminate approximately 7% of 6-mercaptopurine unaltered within 12 hours of the drug being administered. Xanthine oxidase is the main catabolic enzyme of 6-mercaptopurine and it converts the drug into the inactive metabolite, 6-thiouric acid. This is excreted in the urine.
6-Mercaptopurine, in common with other antimetabolites, is potentially mutagenic in man and chromosome damage has been reported in mice, rats and man.
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 administration.
Lactose
Maize Starch
Hydrolysed Starch
Stearic Acid
Magnesium Stearate
Purified Water
None known
60 months
Store below 25ºC. Keep the bottle tightly closed.
Amber glass bottles with child resistant high density polyethylene closures with induction heat seal liners.
Pack size: 25 tablets
Safe handling and disposal:
It is recommended that 6-mercaptopurine tablets should be handled following the prevailing local recommendations and/or regulations for the handling and disposal of cytotoxic drugs.
ALKOPHARMA SARL
45-47, rte d'Arlon
L – 1140 Luxembourg
PL 36637/0006
29 August 2006
September 2010
POM
