Co-Trimoxazole Tablets Bp
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-trimoxazole Tablets BP
2 Qualitative and quantitative composition
Each tablet contains 80 mg of trimethoprim and 400 mg of sulfamethoxazole.
For excipients, see 6.1
3 Pharmaceutical form
Tablet.
White normal convex tablets engraved with Crescent moon logo on one side, a breakline and A286 on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment and prophylaxis (primary and secondary) of Pneumocystis jirovecii (pneumocystis carinii) pneumonia in adults and children.
Treatment and prophylaxis of toxoplasmosis, treatment of nocardiasis.
Treatment of urinary tract infections and acute exacerbations of chronic bronchitis, where there is bacterial evidence of sensitivity to co-trimoxazole and good reason to prefer this combination to a single antibiotic.
Treatment of acute otitis media in children, where there is good reason to prefer co-trimoxazole to a single antibiotic.
4.2 Posology and method of administration
Route of administration: To be swallowed whole or taken with a little water.
Adults and children over 12 years
Standard dosage: two tablets twice daily.
For severe infection: three tablets twice daily
Children
Children under 6 years: not recommended.
6 - 12 years: 1 tablet twice daily.
In acute infections, dose should be administered for 5 days or until the patient has been symptom-free for two days. If clinical improvement is not evident after 7 days therapy, the patient should be reassessed.
As an alternative to standard dosage for acute uncomplicated lower urinary tract infections, short term therapy of 1 to 3 days duration has been shown to be effective.
Impaired hepatic function:
No data are available relating to dosage in patients with impaired hepatic function.
Impaired renal function
Adults and children over 12 years (no information is available for children under 12 years of age);
The following dosage scheme is suggested:
Creatinine clearance above 30 ml/min: standard dosage Creatinine clearance 15-30 ml/min: half the standard dosage.
Creatinine clearance below 15 ml/min: Not recommended
Measurement of plasma sulfamethoxazole should be undertaken at intervals of 2-3 days, after 12 hours of Co-trimoxazole administration.
If the concentration of sulfamethoxazole exceeds 150 mcg/ml then treatment should be interrupted until the value falls below 120 mcg/ml.
Long term prophylaxis of recurrent or suppression of chronic infection following sterilisation of the urine:
Adults and children over 12 years: 1 tablet at night
Children under 12 years: single nightly dose of 2 mg trimethoprim and 10 mg sulfamethoxazole per kg body weight.
Treatment may be continued for 3 to 12 months or more if necessary.
Pneumocystis jirovecii (Pneumocystis carinii) pneumonia:
Treatment 120 mg per kg body weight per day in two or more divided doses for two weeks. The steady state or serum level of trimethoprim should be maintained at 5 microgram/ml or higher for maximum efficacy.
Prevention: The following dose schedules may be used:
Adults and children over 12 years:
Two tablets once daily.
Two tablets three times per week on alternate days.
Two tablets twice daily three times per week on alternate days.
Children 6 - 12 years:
One tablet twice daily on 3 consecutive or alternate days per week or on 7 days per week.
Nocardiosis: There is no consensus on the most appropriate dosage. Adult doses of 6 to 8 tablets daily for up to 3 months have been used.
Toxoplasmosis: There is no consensus on the most appropriate dosage for the treatment or prophylaxis of this condition. The decision should be based on clinical experience. For prophylaxis, however, the dosages suggested for prevention of Pneumocystis jirovecii pneumonitis may be appropriate.
Elderly:
See Special Warnings and Precautions for Use. Unless otherwise specified standard dosage applies.
No specific studies have been carried out in the elderly, although it has been widely used in older people. However, caution is advised when treating the elderly because, as a group, they are more susceptible to adverse reactions.
4.3 Contra-indications
Co-trimoxazole tablets should not be administered to patients with:
Severe renal insufficiency where repeated measurements of the plasma concentration can not be performed.
A history of sulphonamide, trimethoprim or Co-trimoxazole hypersensitivity or any of the ingredients.
Marked liver parenchymal damage or blood dyscrasias.
Serious haematological disorders.
Co-trimoxazole should not be given to premature babies and infants under 6 weeks of age, except in the management of pneumocystis carinii pneumonia where this may be from 4 weeks of age.
4.4 Special warnings and precautions for use
Fatalities may occur due to severe skin, liver and blood disorders and respiratory hypersensitivity. Co-trimoxazole should be discontinued immediately if a skin rash or blood disorders develop.
Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Co-trimoxazole.
Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.
If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Co-trimoxazole treatment should be discontinued.
The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.
If the patient has developed SJS or TEN with the use of Co-trimoxazole, Co-trimoxazole must not be re-started in this patient at any time.
Care should be taken when administering to folate deficient patients such as the elderly who may require folate supplements. For prolonged treatment with this drug, in particular for those patients with suspected impairment of folate metabolism, monitoring of blood counts, including thromocytes, is recommended at monthly intervals.
Particular care is always advised when treating elderly patients because, as a group, they are more susceptible to adverse reactions and more likely to suffer serious effects as a result particularly when complicating conditions exist, e.g. impaired kidney and/or liver function and/or concomitant use of other drugs.
In the elderly, regular monthly blood counts are advisable particularly if prolonged administration is given (i.e. exceeding 3 months) since it has been suggested that elderly patients are more susceptible to blood dyscrasias.
Use with caution in patients with hepatic or renal impairment, and avoid in severe cases. In patients with renal impairment the plasma concentration of the drug should be measured. An adequate urinary output should be maintained by adequate fluid intake to avoid the risk of crystallisation. The risk may be increased in patients suffering from malnutrition.
Haemolysis may occur in patients with G6PD (glucose-6-phosphate-dehydrogenase) deficiency.
Co-trimoxazole should be administered with care to patients with severe allergy or bronchial asthma and should be avoided in patients known or suspected to be at risk of acute porphyria as both trimethoprim and sulphonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria. Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in patients with phenylketonuria on appropriate dietary restrictions.
Co-trimoxazole should not be used to treat streptococcal pharyngitis due to group A beta-haemolytic streptococci; eradication of these organisms from the oropharynx is less effective than with penicillin.
Use with caution in patients at risk of hyperkalaemia. Close monitoring of serum potassium is warranted.
Except under careful supervision Co-trimoxazole tablets should not be given to patients with serious haematological disorders (see 4.8 Undesirable effects).
Co-trimoxazole has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.
The combination of antibiotics in Co-trimoxazole should only be used where, in the judgement of the physician, the benefits of treatment outweigh any possible risks; consideration should be given to the use of a single effective antibacterial agent.
Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Trimethoprim may interfere with the estimation of serum/plasma creatinine when the alkaline picrate reaction is used. This may result in overestimation of serum/plasma creatinine in the order of 10%. The creatinine clearance is reduced; the renal tubular secretion of creatinine is decreased from 23% to 9% whilst the glomerular filtration remains unchanged.
Megaloblastic anaemia has occasionally been reported in patients receiving pyrimethamine in doses in excess of 25 mg weekly, who are also being treated with this product.
In some situations, concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to co-trimoxazole. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters.
Co-trimoxazole tablets should not be given to patients receiving warfarin, acenocoumarol, phenytoin, sulphonylureas and hypoglycaemics as the action of these drugs may be potentiated.
Caution should be exercised in patients taking any other drugs that can cause hyperkalaemia.
In elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.
Concurrent use with rifampicin may significantly increase the elimination and shorten the elimination half-life of trimethoprim.
The plasma concentration of both trimethoprim and dapsone is possibly increased with concomitant use.
Co-trimoxazole, given together with ciclosporin may cause a reversible deterioration in renal function following renal transplantation.
Simultaneous administration of co-trimoxazole with drugs that form cations at physiological pH, and are also excreted by active renal secretion e.g. procainamide and amantadine, may lead to an increase in plasma concentration of one or both of the drugs.
Increased levels of digoxin may result in a proportion of elderly patients with concomitant use of trimethoprim and digoxin.
There is an increased risk of haematological toxicity with azathioprine, methotrexate and mercaptopurine. Megaloblastic anaemia may occur with concurrent use of co-trimoxazole and antifolate drugs such as methotrexate. The antifolate effect of methotrexate is increased by co-trimoxazole and concomitant use of these two drugs should be avoided. If Co-trimoxazole is considered appropriate therapy in patients receiving other anti-folate drugs such as methotrexate, a folate supplement should be considered.
Co-trimoxazole may increase the free plasma levels of methotrexate. Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobillus casei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.
Co-trimoxazole increases the risk of ventricular arrhythmias with amiodarone (concomitant use should be avoided).
Co-trimoxazole increases the plasma concentration of lamivudine and possible zalcitabine. It is therefore advisable to avoid administering a high-dose of co-trimoxazole with lamivudine. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.
The effect of thiopental is enhanced following co-administration with co-trimoxazole.
There is an increased risk of methaemoglobinaemia with prilocaine.
Potassium aminobenzoate inhibits the action of sulphonamides.
Avoid concomitant use of sulphonamides with clozapine.
4.6 Fertility, pregnancy and lactation
Both sulfamethoxazole and trimethoprim cross the placenta. The safety of co-trimoxazole in human pregnancy has not been established. Case control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans. Teratogenic effects have been seen in animals. Trimethoprim may interfere with folic acid metabolism. Co-trimoxazole should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Co-trimoxazole is used in pregnancy.
There is a risk of neonatal haemolysis and methaemoglobinaemia during the third trimester of pregnancy following administration of Co-trimoxazole.
Sulfamethoxazole competes with bilirubin for binding to plasma albumin. As significantly maternally derived drug levels persist for several days in the newborn, there may be a risk of precipitating or exacerbating neonatal hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when Co-trimoxazole is administered to the mother near the time of delivery. This theoretical risk is particularly relevant in infants at increased risk of hyperbilirubinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency.
Approximately 1 percent of maternal dose of sulphonamides and approximately 0.2 percent of maternal dose of trimethoprim appear in breast milk. Sulphonamides may cause haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient neonates. There is a small risk of kernicterus in jaundiced infants.
Administration of Co-trimoxazole should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinaemia. Additionally, administration of Co-trimoxazole should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia
4.7. Effects on ability to drive and use machines
Since co-trimoxazole tablets have been reported (on the basis of subjective experiences only) to have caused headache, depression, dizziness and hallucinations, operating machines and driving while taking this medicine is forbidden.
4.8 Undesirable effects
The frequency categories associated with the adverse events below are estimates. For most events, suitable data for estimating incidence were not available. In addition, adverse events may vary in their incidence depending on the indication.
Data from large published clinical trials were used to determine the frequency of very common to rare adverse events. Very rare adverse events were primarily determined from post-marketing experience data and therefore refer to reporting rate rather than a “true” frequency.
The following convention has been used for the classification of adverse events in terms of frequency:- Very common > 1/10, common > 1/100 and < 1/10, uncommon > 1/1000 and < 1/100, rare > 1/10,000 and < 1/1000, very rare < 1/10,000.
Infections and infestations
Common: Monilial overgrowth Blood and lymphatic system disorders
Very rare: Thrombocytopenia, purpura, leucopenia, neutropenia, eosinophilia, agranulocytosis, megaloblastic anaemia, aplastic anaemia, haemolytic anaemia, methaemoglobinaemia, haemolysis in certain susceptible G-6-PD deficient patients. The majority of haematological changes are mild and have proved to be reversible on withdrawal of the drug. Most of the changes cause no clinical symptoms although they may become severe in isolated cases, especially in the elderly, in those with hepatic or renal failure, or poor folate status. Fatalities have been recorded in at-risk patients and these patients should be observed carefully (see 4.3 contra-indications).
Immune system disorders
Very rare: Serum sickness, anaphylaxis, allergic myocarditis; angiodema, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, peri-arteritis nodosa; systemic lupus erythematosus (SLE).
Very common: Hyperkalaemia
Very rare: Hyponatraemia, hypoglycaemia, anorexia.
Close supervision is recommended when co-trimoxazole is used in elderly patients or in patients taking high doses of co-trimoxazole as these patients may be more susceptible to hyperkalaemia and hyponatraemia.
Psychiatric disorders
Very rare: Depression, hallucinations Nervous system disorders
Common: Headache
Very rare: Aseptic meningitis, convulsions, peripheral neuropathy, ataxia, vertigo, tinnitus, dizziness
Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either co-trimoxazole or to trimethoprim alone.
Eye disorders
Very rare: Uveitis
Respiratory, thoracic and mediastinal disorders
Very rare: Cough, dyspnoea, pulmonary infiltration which may indicate respiratory hypersensitivity which, while very rare, has been fatal.
Gastrointestinal disorders
Common: Nausea, diarrhoea.
Uncommon: Vomiting
Very rare: Glossitis, stomatitis, pseudomembranous colitis, pancreatitis Hepatobiliary disorders
Very rare: Raised hepatic transaminases and bilirubin, cholestatic jaundice and hepatic necrosis.
Cholestatic jaundice and hepatic necrosis may be fatal.
Skin and subcutaneous tissue disorders
Common: Skin rashes
Very rare: Photosensitivity, exfoliative dermatitis, fixed drug eruption; erythema multiforme, severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4)
Very rare: Arthralgia, myalgia Renal and urinary disorders
Very rare: Impaired renal function (sometimes reported as renal failure), electrolyte disturbances, crystalluria and renal disorders including interstitial nephritis.
Effects associated with Pneumocystis jirovecii (P.carinii) Pneumonitis (PCP) management
Very rare: Severe hypersensitivity reactions, rash, fever, neutropenia, thrombocytopenia, raised liver enzymes, hyperkalaemia, hyponatraemia
At the high doses used for PCP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. If signs of bone marrow depression occur, the patient should be given calcium folinate supplementation (5-10 mg/day). Severe hypersensitivity reactions have been reported in PCP patients on re-exposure to co-trimoxazole, sometimes after a dosage interval of a few days.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
I. Acute overdosages are likely to result in nausea, vomiting, abdominal pain, dizziness, confusion and bone marrow depression.
II. Treatment for overdose within an hour of ingestion should consist of gastric lavage. The benefit of gastric decontamination is uncertain. Consider activated charcoal (charcoal dose: 50 g for adults; 1 g/kg for children) if the patient presents within 1 hour of ingestion of a toxic dose, provided the airway can be protected. If urine output is low, adequate fluid intake is necessary.
III. The elimination of sulfamethoxazole can be hastened with increased fluid intake plus alkinisation of the urine by administration of sodium bicarbonate.
IV. Folate deficiency effect of trimethoprim on the bone marrow can be reversed by oral or intramuscular administration of calcium folinate 3-6 mg, for five to seven days.
V. Both trimethoprim and active sulfamethoxazole are moderately dialysable by haemolysis. Peritoneal dialysis is not effective.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Combinations of sulphonamides and trimethoprim, including derivatives
ATC Code: J01E E01
Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole in a 1:5 ratio. This combination interferes with two consecutive steps in the normal bacterial metabolism of folic acid.
Trimethoprim belongs to the diaminopyrimidine group. It inhibits enzyme dihydrofolate reductase which catalyses the reduction of dihydrofolate to tetrahydrofolate. This is a crucial step in the synthesis of folate.
It also exerts a remarkable degree of selective toxicity despite the fact that it inhibits metabolic step which is common to man and bacteria. Dihydrofolate reductases of man, bacteria and protoxoa differ markedly in their affinity for the different diaminopyrimidines.
Man and parasites obtain their folate requirements by quite a different mechanism. Man obtains his folates pre-formed from the diet and can absorb ready-made folinic acid - the metabolite just distal to the point of blockade by the drug, thereby bypassing the drug’s action.
Micro-organisms can not utilize preformed folate therefore must synthesize their requirements using p-aminobenzoate as starting material which they cannot manufacture and must obtain from their environment.
The differential toxicity of sulfamethoxazole for bacteria and man results from the competitive inhibition by sulfamethoxazole of the uptake of the chemically closely related p-aminobenzoate which is required by bacteria for the synthesis of dihydrofolic acid and not by the invaded host.
Sulfamethoxazole and trimethoprim act sequentially on a single metabolic pathway concerned with the generation of crucial folate, a co-factor in the synthesis of purines required for the assembly of nucleic acids without which the bacteria can not survive.
Due to sequential blockade, the action of each of the compounds is greatly potentiated and together they show a striking degree of antimicrobial synergy. Trimethoprim is the more active agent. Trimethoprim and sulfamethoxazole alone are both essentially bacteriostatic agents, but when used in combination they exert a bactericidal effect against some strains.
The use of drugs in combination might be expected to confer not only synergic interaction but protection against the emergence of resistant mutants. The synergistic, bactericidal effect of the combination has been demonstrated, in a wide variety of gram-positive and gram-negative organisms.
5.2 Pharmacokinetic properties
Trimethoprim is almost completely absorbed from the gastrointestinal tract within 23 hours and 90 percent of which is recoverable from urine almost all in the active form. Approximately 85 percent of sulfamethoxazole is absorbed during the same period. Antibacterially it is one of the most active sulphonamides and behaves pharmacokinetically similar to trimethoprim. About the same fraction of sulfamethoxazole is recoverable from urine, about half of it is in the active form.
Following an oral dose of 160 mg trimethoprim (TMP) and 800 mg sulfamethoxazole (SMX), significant levels of both drugs appear in plasma within 1 hour and after 2-4 hours, peak plasma levels attained for TMP, total SMX (active + metabolised) and active SMX of 1.2-1.9, 35-65 and 25-60 pg/ml respectively. An effective plasma concentration is maintained for 6-8 hours so that MIC is exceeded for the majority of bacteria isolated from clinical infections.
Following completion of absorption, the ratio in the plasma of active, non protein bound TMP to active non protein bound SMX lies between 1:5-1:40. This ratio from bacteriologic point of view is the most useful range which also holds in for slightly reduced renal function and at all times following drug administration. Plasma concentration of SMX is considerably higher than those obtained from a corresponding dose of trimethoprim. This is because volume distribution of trimethoprim approximate to (in fact exceeds because of concentration in some organs) the total body water volume whereas sulfamethoxazole is restricted to the extracellular fluid. Nevertheless the plasma profile, of the two drugs are very similar if 5 times as much SMX as TMP is administered, plasma concentrations in a ratio of about 20:1 will be attained.
The bacteriologically active (diffusible) concentration of the drug depends on the degree of protein binding. About 45 percent of TMP is bound to plasma proteins and 58-66 percent SMX. The addition of TMP does not interfere with protein binding of SMX.
There are 6 metabolites of SMP that have been identified and these account for approximately 10-15 percent of the total plasma TMP concentration. In urine 20 percent of TMP is excreted in the form of its metabolites both unconjugated and conjugated in the form of glucuronides. Some of the metabolites are bacteriostatically inactive and some possess a lesser degree of activity.
The metabolites of SMX are important quantitatively, N4 - acetyl SMX and N1 -glucuronide SMX, these are bacteriostatically inactive. In urine 60-70 percent of SMX is present in the form of its metabolites, mainly N4 - acetyl derivative. At equilibrium metabolites of SMX in plasma account for 20-35 percent of the total SMX. With intact renal function, plasma half life of SMX and TMP is 10-12 hours.
After a single dose of the combined drug, the cumulative urinary recovery after 72-96 hours amounts to 70-85 percent and 80-95 percent of the dose for total TMP and SMX respectively. The amount of the active SMX recovery is about 30 percent. The urinary concentration of drugs depend upon urinary flow rate, pH and time of collection. The approximate urinary concentration of TMP is 100 times the plasma concentrations, for SMX the level is 5 times the concentration in plasma. The active SMX content in urine is equal to the plasma concentration. Decrease in the ratio SMX:TMP is counteracted by high content of TMP in the urine.
The cumulative recovery in urine is decreased with impaired renal function, being most marked for TMP. Despite decreased recovery of the drug from the urine, urinary concentrations are usually maintained above the MIC of each drug for most urinary pathogens. TMP and active SMX are removed by haemodialysis. SMX metabolites are retained. The kidneys are the organs of excretion for both drugs. Extrarenal excretion amounts to only a small percentage. Some 4 percent of the ingested TMP dose is detected in the faeces. Urinary excretion of trimethoprim is pH dependent, as it is a weak base with pKa 7.3 of which ionization and consequently trapping in the renal tubular lumen depends on the acidity of the urine.
5.3. Pre-clinical safety data
There are no pre-clinical data of relevance to the prescriber that are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose
Sodium starch glycolate Magnesium stearate Pregelatinised maize starch Purified water
6.2. Incompatibilities
None reported.
6.3. Shelf life
Plastic containers: Blister packs:
36 months (3 years), as packaged for sale 24 months (2 years), as packaged for sale
6.4. Special precautions for storage
Keep out of the reach of children. Protect from heat, light and moisture.
6.5 Nature and contents of container
The product is packed in:
(i) Opaque plastic containers composed of polypropylene tubes and polyethylene made tamper evident closures for pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500 and 1000 tablets.
(ii) Opaque plastic container composed of either HDPP or HDPE with a tamper evident or child-resistant tamper evident closure composed of HDPE with a packaging inclusion of standard polyether foam or polyethylene or polypropylene made filler in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 50,
56, 84, 100, 250, 500 and 1000 tablets.
(iii) HDPE container with PP lid and induction seal wad in pack sizes of 9, 10, 14,
15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500 and 1000 tablets
(iv) Blister packs of aluminium/opaque PVC in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 56 and 84 tablets.
Not all pack sizes may be marketed.
6.6. Instructions for use, handling and disposal
No special instructions for use/handling
7. MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited Units 3 and 4
Quidhampton Business Units Polhampton Lane Overton
Hants RG25 3ED
PL 20416/0052
9. DATE OF FIRST AUTHORISATION/RENEWAL OF
AUTHORISATION
28 May 2004
10 DATE OF REVISION OF THE TEXT
26/11/2014