Ethylpapaverine may be available in the countries listed below.
Ethaverine hydrochloride (a derivative of Ethaverine) is reported as an ingredient of Ethylpapaverine in the following countries:
International Drug Name Search
Uropan may be available in the countries listed below.
Oxybutynin hydrochloride (a derivative of Oxybutynin) is reported as an ingredient of Uropan in the following countries:
International Drug Name Search
Carbamazépine Mylan LP may be available in the countries listed below.
Carbamazepine is reported as an ingredient of Carbamazépine Mylan LP in the following countries:
International Drug Name Search
Salofalk 1g Suppositories
Each suppository contains 1 g mesalazine.
For a full list of excipients, see section 6.1
Suppositories
Appearance: light beige coloured, torpedo-shaped suppositories
Treatment of acute mild to moderate ulcerative colitis that is limited to the rectum (ulcerative proctitis).
Adults and elderly:
One Salofalk 1g Suppository once daily (equivalent to 1g mesalazine daily) inserted into the rectum.
Children
There is little experience and only limited documentation for an effect in children.
General instructions for use:
Salofalk 1g Suppositories should be administered preferably at bedtime.
Treatment with Salofalk 1g Suppositories must be administered regularly and consistently, because only in this way can healing be successfully achieved.
The duration of use is determined by the physician.
Salofalk 1g Suppositories are contraindicated in patients with:
- known hypersensitivity to salicylates or the excipient
- severe impairment of hepatic or renal function
Blood tests (differential blood count; liver function tests such as ALT or AST; serum creatinine) and dip-stick urinalysis should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, further testing is recommended 14 days after commencement of treatment, then a further two to three times at intervals of 4 weeks.
If the findings are normal, further testing should be carried out every 3 months. If additional symptoms occur, tests should be performed immediately.
Caution is recommended in patients with impaired hepatic function.
Salofalk 1g Suppositories are not recommended in patients with impaired renal function. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment.
Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment with Salofalk 1g Suppositories.
Patients with a history of adverse drug reactions to preparations containing sulphasalazine should be kept under close medical surveillance on commencement of a course of treatment with Salofalk 1g Suppositories. Should Salofalk 1g Suppositories cause acute intolerability reactions such as cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.
Specific interaction studies have not been performed.
Interactions may occur during treatment with Salofalk 1g Suppositories and concomitant administration of the following medicinal products. Most of these possible interactions are based on theoretical reasons:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
In patients who are concomitantly treated with azathioprine or 6-mercaptopurine, possible enhanced myelosuppressive effects of azathioprine or 6-mercaptopurine should be taken into account.
There are no adequate data from the use of Salofalk 1g Suppositories in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on pregnancy or on the health of the fetus/newborn child. To date no other relevant epidemiologic data are available. In one single case after long-term use of a high dose mesalazine (2-4 g, orally) during pregnancy, renal failure in a neonate was reported.
Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
Salofalk 1g Suppositories should only be used during pregnancy if the potential benefit outweighs the possible risk.
N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. Only limited experience during lactation in women is available to date. Hypersensitivity reactions like diarrhea can not be excluded. Therefore, Salofalk 1g Suppositories should only be used during breast-feeding if the potential benefit outweighs the possible risk. If the suckling neonate develops diarrhea, the breast-feeding should be discontinued.
No effects on ability to drive and use machines have been observed
In clinical studies involving 248 participants, approximately 3% experienced adverse reactions while receiving Salofalk 1g Suppositories. The most commonly reported ADRs were headache, in approximately 0.8%, and gastrointestinal side effects (constipation in approximately 0.8%; nausea, vomiting and abdominal pain in 0.4% each).
The following side effects have been reported with the use of mesalazine:
|
| |
|
|
|
|
| |
|
|
|
|
|
|
|
| |
|
| |
|
| |
|
| |
|
| |
|
|
No cases of intoxication have been reported to date and no specific antidotes are known.
If necessary, intravenous infusion of electrolytes (forced diuresis) should be considered in cases of overdose.
Pharmacotherapeutic group: Aminosalicylic acid and similar agents
ATC code: A07EC02
The mechanism of the anti-inflammatory action is unknown. The results of in vitro studies indicate that inhibition of lipoxygenase may play a role.
Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated. Mesalazine (5-Aminosalicylic acid / 5-ASA) may also function as a radical scavenger of reactive oxygen compounds.
On reaching the intestinal lumen, rectally administered mesalazine has largely local effects on the intestinal mucosa and submucosal tissue.
Clinical efficacy and safety of Salofalk® 1 g suppositories was evaluated in a multicentre phase III study, which included 403 patients with endoscopically and histologically confirmed mild to moderately active ulcerative proctitis. The mean disease activity index (DAI) at base line was 6.2 ± 1.5 (range: 3 – 10). Patients were randomised to treatment with one Salofalk® 1 g suppository (1 g OD group) or 3 suppositories containing 0.5 g mesalazine (0.5 g TID group per day for 6 weeks. The primary efficacy variable was clinical remission defined as DAI < 4 at the final visit or withdrawal. At the final per protocol analysis, 87.9% of the patients in the 1 g OD group and 90.7% of the 0.5 g TID group were in clinical remission (Intention-to-treat analysis: 1 g OD group: 84.0%; 0.5 g TID group: 84.7%). The mean change in DAI from baseline was -4.7 in both treatment groups. No drug-related serious AEs occurred.
General considerations of mesalazine:
Absorption:
Mesalazine absorption is highest in proximal gut regions and lowest in distal gut areas.
Biotransformation:
Mesalazine is metabolised both pre-systemically by the intestinal mucosa and in the liver to the pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria. Protein binding of mesalazine and N-Ac-5-ASA is 43% and 78%, respectively.
Elimination:
Mesalazine and its metabolite N-Ac-5-ASA are eliminated via the faeces (major part), renally (varies between 20 and 50 %, dependent on kind of application, pharmaceutical preparation and route of mesalazine release, respectively), and biliary (minor part). Renal excretion predominantly occurs as N-Ac-5-ASA. About 1 % of total orally administered mesalazine dose is excreted into the breast milk mainly as N-Ac-5-ASA.
Salofalk 1g suppositories specific:
Distribution:
Scintigraphic studies with a similar medicinal product, technetium-labelled mesalazine 500mg suppositories showed peak spread of the suppository that had melted due to body temperature after 2 – 3 hours. The spread was limited primarily to the rectum and rectosigmoid junction. It is assumed that Salofalk 1g suppositories act very similar and thus are particularly suitable for treating proctitis (ulcerative colitis of the rectum).
Absorption:
In healthy subjects mean peak plasma concentrations of 5-ASA after a single rectal dose of 1g mesalazine (Salofalk 1 g Suppository) were 192 ± 125 ng/ml (range 19 – 557 ng/ml), those of the main metabolite N-Ac-5-ASA were 402 ± 211 ng/ml (range 57 – 1070 ng/ml). Time to reach the peak plasma concentration of 5-ASA was 7.1 ± 4.9 h (range 0.3 – 24 h).
Elimination:
In healthy subjects, after a single rectal dose of 1g mesalazine (Salofalk 1g Suppository) approx. 14 % of the administered 5-ASA dose were recovered in the urine during 48 hours.
With the exception of a local tolerance study in dogs, which demonstrated good rectal tolerance, no preclinical studies have been performed with Salofalk 1g Suppositories.
Preclinical data on mesalazine reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenicity (rat) or toxicity to reproduction.
Kidney toxicity (renal papillary necrosis and epithelial damage in the proximal convoluted tubule or the whole nephron) has been seen in repeat-dose toxicity studies with high oral doses of mesalazine. The clinical relevance of this finding is unknown.
Hard fat
Not applicable.
3 years
Store in the original container in order to protect contents from light.
Do not store above 25°C.
Container (strip): PVC/polyethylene film
Package sizes: 10, 12, 15, 20, 30, 60, 90
Not all package sizes may be marketed.
Any unused product or waste material should be disposed of in accordance with local requirements.
Dr. Falk Pharma GmbH
Leinenweberstr. 5
79108 Freiburg
Germany
Tel: +49 (0)761 1514-0
PL 08637/0018; PA573/4/4
17 May 2010
17 May 2010
In some countries, this medicine may only be approved for veterinary use.
Rec.INN
0481658-94-0
C40-H33-F3-N4-O3
674
Antiobesity agent
N-{(1S)-2-[Benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4'-(trifluoromethyl)biphenyl-2-carboxamido]-1H-indol-2-carboxamide (WHO)
1H-Indole-2-carboxamide, 1-methyl-N-[(1S)-2-[methyl(phenylmethyl)amino]-2-oxo-1-phenylethyl]-5-[[[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino]- (USAN)
1-Methyl-5-[(4'-trifluormethylbiphenyl-2-carbonyl)amino]-1H-indol-2-carbonsäure-[(S)-(benzylmethylcarbamoyl)phenylmethyl]amid (IUPAC)
5-[4'-(Trifluoromethylbiphenyl-2-carbonyl)amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide
International Drug Name Search
Glossary
| IUPAC | International Union of Pure and Applied Chemistry |
| IS | Inofficial Synonym |
| OS | Official Synonym |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
| WHO | World Health Organization |
Salicylic Acid Ointment BP
Salicylic acid BP 2.0% w/w
Ointment.
For the treatment of hyperkeratotic and scaling conditions such as psoriasis.
Topical.
Recommended dose and dosage schedule
Adults, children and the elderly: apply twice daily to the affected area.
Contraindicated in patients displaying salicylate hypersensitivity, or sensitivity to any other ingredient in the preparation.
For external use only.
Avoid contact with broken or inflamed skin.
Salicylate toxicity may occur if applied to large areas of skin or to the skin of neonates.
There are no known interactions when used as indicated. However, topical salicylic acid may increase the absorption of other topically applied medicines. Concomitant use of Salicylic Acid Ointment BP and other topical medicines on the same area of skin should therefore be avoided.
Whilst there are no known contra-indications to the use of Salicylic Acid Ointment BP during pregnancy and lactation, the safety has not been established. Salicylic Acid Ointment BP should therefore be used with caution or following professional advice.
None likely.
Possible sensitivity reactions, drying and irritation.
Symptoms of systemic salicylate poisoning (tinnitus, dizziness and deafness) have been reported after the application of salicylic acid to large areas of skin and for prolonged periods. Salicylism may also occur in the unlikely event of large quantities being ingested. Salicylism is unlikely to occur if Salicylic Acid Ointment BP is used as indicated.
Salicylate poisoning is usually associated with plasma concentrations >350mg/L (2.5mmol/L). Most adult deaths occur in patients whose concentrations exceed 700mg/L (5.1mmol/L). Single doses less than 100mg/kg are unlikely to cause serious poisoning.
Symptoms
Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases.
A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of four years. In children aged four years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier.
Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.
Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.
Management
Give activated charcoal if an adult presents within one hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema.
Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations >700 mg/L (5.1 mmol/L), or lower concentrations associated with severe clinical or metabolic features. Patients under ten years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.
Salicylic acid has a keratolytic action.
Salicylic acid may be percutaneously absorbed. However, there is no evidence of any systemic absorption from the use of Salicylic Acid Ointment BP.
No other information relevant to the prescriber other than that already stated in other sections of the SPC.
White petroleum jelly BP, hard paraffin BP, wool alcohols BP, liquid paraffin BP.
None known.
36 months unopened.
Store below 25°C.
700ml securitub polypropylene white with cap.
No special requirements.
Thornton & Ross Ltd.
Huddersfield
HD7 5QH
England.
PL 00240/6616R
22/11/85 / 30/01/2004
20/01/2011
Generic Name: carbinoxamine, dextromethorphan, and pseudoephedrine (kar bi NOX a meen/dex troe meh THOR fan/soo doe eh FEH drin)
Brand Names: Andehist DM NR, Carb PSE 12 DM, Carbaxef-DM, Carbodex DM, Carbofed DM Drops, Cordron-12 DM, Cordron-DM NR, Mintex DM, Pediatex 12 DM, Pediatex-DM, PSE Allergy DM, PSE Carb DM Drops, PSE Carbinoxamine DM, Pseudo Carb DM
Carbinoxamine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.
Dextromethorphan is a cough suppressant. It suppresses an area in the brain that causes coughing.
Pseudoephedrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).
The combination of carbinoxamine, dextromethorphan, and pseudoephedrine is used to treat sneezing, cough, runny or stuffy nose, itchy or watery eyes, hives, skin rash, itching, and other symptoms of allergies and the common cold.
Carbinoxamine, dextromethorphan, and pseudoephedrine may also be used for other purposes not listed in this medication guide.
Call your doctor if you have a fever, or if your symptoms get worse or do not improve after taking this medicine for 7 days.
Do not take this product for cough caused by smoking, asthma, or emphysema. Do not take this medicine if your cough produces a lot of mucus, unless your doctor has told you to.
Before taking this medication, tell your doctor if you are allergic to carbinoxamine, dextromethorphan, or pseudoephedrine, or if you have:
diabetes;
glaucoma;
heart disease or high blood pressure;
thyroid disease;
a stomach ulcer or a stomach obstruction,
emphysema or chronic bronchitis; or
an enlarged prostate or urination problems.
If you have any of these conditions, you may need a dose adjustment or special tests to safely take this medication.
Artificially-sweetened liquid forms of cold medicine may contain phenylalanine. This would be important to know if you have phenylketonuria (PKU). Check the ingredients and warnings on the medication label if you are concerned about phenylalanine.
Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label. Cold medicine is usually taken only for a short time until your symptoms clear up.
Measure the liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.
Call your doctor if you have a fever, or if your symptoms get worse or do not improve after taking this medicine for 7 days.
Since cough and cold medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.
Overdose symptoms may include extreme drowsiness, confusion, feeling restless or nervous, blurred vision, dry mouth, nausea, vomiting, restlessness, hallucinations, fainting, and seizure (convulsions).
Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.
feeling light-headed, fainting;
urinating less than usual or not at all;
wheezing, tightness in your chest;
severe dizziness, anxiety, restless feeling, or nervousness;
easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms; or
increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure).
Less serious side effects may include:
drowsiness, dizziness;
lack of coordination;
upset stomach;
stuffy nose, chest congestion;
sleep problems (insomnia);
feeling restless or excited (especially in children);
dry mouth or nose; or
blurred vision.
This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect.
Before taking carbinoxamine, dextromethorphan, and pseudoephedrine, tell your doctor if you are using any of the following drugs:
a diuretic (water pill), or blood pressure medicine;
medication to treat irritable bowel syndrome;
bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol);
aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others);
a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others; or
antidepressants such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others.
This list is not complete and there may be other drugs that can interact with carbinoxamine, dextromethorphan, and pseudoephedrine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.
See also: Pediatex-DM side effects (in more detail)
Famotab may be available in the countries listed below.
Famotidine is reported as an ingredient of Famotab in the following countries:
International Drug Name Search
Salazopyrin Tablets
Sulfasalazine EP 500 mg
Yellow round tablets embossed “KPh” on one side and “101” and a score line on the other.
Induction and maintenance of remission of ulcerative colitis; treatment of active Crohn's Disease.
The dose is adjusted according to the severity of the disease and the patient's tolerance to the drug, as detailed below.
Elderly Patients
No special precautions are necessary.
A) Ulcerative colitis
Adults
Severe Attacks
Salazopyrin 2-4 tablets four times a day may be given in conjunction with steroids as part of an intensive management regime. Rapid passage of the tablets may reduce effect of the drug.
Night-time interval between doses should not exceed 8 hours.
Moderate Attack
2-4 tablets four times a day may be given in conjunction with steroids.
Maintenance Therapy
With induction of remission reduce the dose gradually to 4 tablets per day. This dosage should be continued indefinitely since discontinuance even several years after an acute attack is associated with a four fold increase in risk of relapse.
Children
The dose is reduced in proportion to body weight.
Acute Attack or Relapse
40-60mg/kg per day
Maintenance Dosage
20-30mg/kg per day
Salazopyrin Suspension may provide a more flexible dosage form.
B) Crohn's Disease
In active Crohn's Disease, Salazopyrin should be administered as in attacks of ulcerative colitis (see above).
Sulfasalazine is contraindicated in:
Infants under the age of 2 years.
Patients with a known hypersensitivity to sulfasalazine, its metabolites or any of the excipients as well as sufonamides or salicylates.
Patients with porphyria.
Complete blood counts (including differential white cell count), liver function tests and assessment of renal function (including urinalysis) should be performed in all patients before starting therapy with sulfasalazine, and frequently during the first 3 months of therapy. Thereafter, monitoring should be performed as clinically indicated. The patient should also be counselled to report immediately with any sore throat, fever, malaise, pallor, purpura, jaundice or unexpected non-specific illness during sulfasalazine treatment, this may indicate myelosuppression, haemolysis or hepatoxicity. Treatment should be stopped immediately while awaiting the results of blood tests. .
Sulfasalazine should not be given to patients with impaired hepatic or renal function or with blood dyscrasias, unless the potential benefit outweighs the risk.
Sulfasalazine should be given with caution to patients with severe allergy or bronchial asthma.
Use in children with the concomitant condition systemic onset juvenile rheumatoid arthritis may result in a serum sickness like reaction; therefore sulfasalazine is not recommended in these patients.
Since sulfasalazine may cause haemolytic anaemia, it should be used with caution in patients with G-6-PD deficiency.
Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency potentially resulting in serious blood disorders (e.g., macrocytosis and pancytopenia), this can be normalised by administration of folic acid or folinic acid (leucovorin).
Because sulfasalazine causes crystalluria and kidney stone formation, adequate fluid intake should be ensured during treatment.
Oligospermia and infertility may occur in men treated with sulfasalazine. Discontinuation of the drug appears to reverse these effects within 2 to 3 months.
Reduced absorption of digoxin , resulting in non-therapeutic serum levels, has been reported when used concomitantly with oral sulfasalazine.
Sulfonamides bear certain chemical similarities to some oral hypoglycemic agents. Hypoglycemia has occurred in patients receiving sulfonamides. Patients receiving sulfasalazine and hypoglycemic agents should be closely monitored.
Due to inhibition of thiopurine methyltransferase by salazopyrin, bone marrow suppression and leucopenia have been reported when the thiopurine 6-mercaptopurine or it's prodrug, azathioprine, and oral salazopyrin were used concomitantly.
Coadministration of oral sulfasalazine and methotrexate to rheumatoid arthritis patients did not alter the pharmacokinetic disposition of the drugs. However, an increased incidence of gastrointestinal adverse events, especially nausea, was reported.
Pregnancy
Reproduction studies in rats and rabbits have revealed no evidence of harm to the fetus. Published data regarding use of sulfasalazine in pregnant women have revealed no evidence of teratogenic hazards. If sulfasalazine is used during pregnancy, the possibility of fetal harm appears remote. Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency. Because the possibility of harm cannot be completely ruled out, sulfasalazine should be used during pregnancy only if clearly needed.
Lactation
Sulfasalazine and sulfapyridine are found in low levels in breast milk. Caution should be used, particularly if breastfeeding premature infants or those deficient in G-6-PD.
No specific effects.
Overall, about 75% of ADRs occur within 3 months of starting therapy, and over 90% by 6 months. Some undesirable effects are dose-dependent and symptoms can often be alleviated by reduction of the dose.
General
Sulfasalazine is split by intestinal bacteria to sulfapyridine and 5-amino salicylate so ADRs to either sulfonamide or salicylate are possible. Patients with slow acetylator status are more likely to experience ADRs related to sulfapyridine. The most commonly encountered ADRs are nausea, headache, rash, loss of appetite and raised temperature.
Specific
The adverse reactions observed during clinical studies conducted with Sulfasalazine have been provided in a single list below by class and frequency (very common (
Additional reactions reported from post-marketing experience are included as frequency Not known (cannot be estimated from the available data) in the list below.
|
|
| |
|
|
| |
|
|
|
|
|
|
| |
|
|
| |
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
| |
|
|
|
|
| |
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
* See Section 4.4 for further information
The drug has low acute per oral toxicity in the absence of hypersensitivity. There is no specific antidote and treatment should be supportive.
Around 90% of a dose reaches the colon where bacteria split the drug into sulfapyridine (SP) and mesalazine (ME). These are active, and the unsplit sulfasalazine (SASP) is also active on a variety of symptoms. Most SP is absorbed, hydroxylated or glucuronidated and a mix of unchanged and metabolised SP appears in the urine. Some ME is taken up and acetylated in the colon wall, such that renal excretion is mainly ac-me. SASP is excreted unchanged in the bile and urine. Overall the drug and its metabolites exert immunomodulatory effects, antibacterial effects, effects on the arachidonic acid cascade and alteration of activity of certain enzymes. The net result clinically is a reduction in activity of the inflammatory bowel disease. The enteric coated SASP is registered for the treatment of rheumatoid arthritis, where the effect resembles penicillamine or gold.
With regard to the use of salazopyrin in bowel disease there is no evidence that systemic levels are of any relevance other than with regard to ADR incidence. Here levels of SP over about 50µg/ml are associated with a substantial risk of ADRs, especially in slow acetylators. For SASP given as a single 3g oral dose, peak serum levels of SASP occurred in 3-5 hours, elimination half life was 5.7 ±0.7 hours, lag time 1.5 hours. During maintenance therapy renal clearance of SASP was 7.3 ±1.7ml/min, for SP 9.9 ±1.9 and AC-ME 100 ±20. Free SP first appears in plasma in 4.3 hours after a single dose with an absorption half life of 2.7 hours. The elimination half life was calculated as 18 hours. Turning to mesalazine, in urine only AC-ME (not free ME) was demonstrable, the acetylation probably largely achieved in the colon mucosa. After a 3g SASP dose lag time was 6.1 ±2.3 hours and plasma levels kept below 2µg/ml total ME. Urinary excretion half-life was 6.0 ±3.1 hours and absorption half life based on these figures 3.0 ±1.5 hours. Renal clearance constant was 125 ml/min corresponding to the GFR.
In two-year carcinogenicity studies in rats and mice, sulfasalazine showed some evidence of carcinogenicity. In rats, there was a small increase in the incidence of transitional cell papillomas in the urinary bladder and kidney. The tumours were judged to be induced mechanically by calculi formed in the urine rather than through a direct genotoxic mechanism. In the mouse study, there was a significant increase in the incidence of hepatocellular adenoma or carcinoma. The mechanism of induction of hepatocellular neoplasia has been investigated and attributed to species-specific effects of sulfasalazine that are not relevant to humans.
Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) or in the L51784 mouse lymphoma cell assay at the HGPRT gene. It did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, and in vivo mouse bone marrow chromosomal aberration tests were negative. However, sulfasalazine showed positive or equivocal mutagenic responses in rat and mouse micronucleus assays, and in human lymphocyte sister chromatid exchange, chromosomal aberration and micronucleus assays. The ability of sulfasalazine to induce chromosome damage has been attributed to perturbation of folic acid levels rather than to a direct genotoxic mechanism.
Based on information from non-clinical studies, sulfasalazine is judged to pose no carcinogenic risk to humans. Sulfasalazine use has not been associated with the development of neoplasia in human epidemiology studies.
Povidone; Maize starch; magnesium stearate; colloidal silicon dioxide.
Certain types of extended wear soft contact lenses may be permanently stained during therapy.
The tablets are stable for 5 years.
None
Square or rectangular HDPE jar with easy to open tamper-evisent polypropylene screw-cap. To contain 112 tablets.
Take with water
Pfizer Limited
Ramsgate Road
Sandwich
Kent, CT13 9NJ
United Kingdom
PL 00057/1044
17 August 2010
17 August 2010
POM.
SZ 6_0 Tabs UK
Septrin 80 mg/400 mg Tablets
Each tablet contains 400 mg Sulfamethoxazole and 80 mg Trimethoprim
Excipients,
For a full list of excipients, see Section 6.1
Tablets.
White, biconvex tablets marked “GX Y2B” with scoreline on one side.
Septrin tablets are indicated for the treatment of the following infections when owing to sensitive organisms (see section 5.1):
Treatment and prevention of Pneumocystis jiroveci (P. carinii) pneumonitis
Treatment and prophylaxis of toxoplasmosis
Treatment of nocardiosis
The following infections may be treated with Septrin where there is bacterial evidence of sensitivity to Septrin and good reason to prefer the combination of antibiotics in Septrin to a single antibiotic:
Acute uncomplicated urinary tract infection
Acute otitis media
Acute exacerbation of chronic bronchitis
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Method of administration: oral
It may be preferable to take Septrin with some food or drink to minimise the possibility of gastrointestinal disturbances.
Standard dosage recommendations for acute infections
Adults and children over 12 years:
|
|
This dosage approximates to 6 mg trimethoprim and 30 mg sulfamethoxazole per kilogram body weight per 24 hours.
Treatment should be continued until the patient has been symptom free for two days; the majority will require treatment for at least 5 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.
The elderly:
See Special Warnings and Precautions for Use. Unless otherwise specified standard dosage applies.
Impaired hepatic function:
No data are available relating to dosage in patients with impaired hepatic function.
Special Dosage Recommendations
(Standard dosage applies unless otherwise specified)
Where dosage is expressed as "tablets" this refers to the adult tablet, i.e. 80 mg Trimethoprim BP and 400 mg Sulfamethoxazole BP. If other formulations are to be used appropriate adjustment should be made.
Impaired renal function:
Adults and children over 12 years (no information is available for children under 12 years of age):
|
|
|
|
|
|
|
|
Measurements of plasma concentration of sulfamethoxazole at intervals of 2 to 3 days are recommended in samples obtained 12 hours after administration of Septrin. If the concentration of total sulfamethoxazole exceeds 150 microgram/ml then treatment should be interrupted until the value falls below 120 microgram/ml.
Pneumocystis jiroveci (P.carinii) pneumonitis:
Treatment: A higher dosage is recommended, using 20 mg trimethoprim and 100 mg sulfamethoxazole per kg of body weight per day in two or more divided doses for two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous Septrin). (See 4.8 Undesirable Effects).
Prevention:
Adults: The following dose schedules may be used:
160 mg trimethoprim/800 mg sulfamethoxazole daily 7 days per week.
160 mg trimethoprim/800 mg sulfamethoxazole three times per week on alternate days.
320 mg trimethoprim/1600 mg sulfamethoxazole per day in two divided doses three times per week on alternate days.
Children:
The following dose schedules may be used for the duration of the period at risk (see Standard dosage recommendations for acute infections subsection of 4.2):
− Standard dosage taken in two divided doses, seven days per week
− Standard dosage taken in two divided doses, three times per week on alternate days
− Standard dosage taken in two divided doses, three times per week on consecutive days
− Standard dosage taken as a single dose, three times per week on consecutive days
The daily dose given on a treatment day approximates to 150 mg trimethoprim/m2/day and 750 mg sulfamethoxazole/m2/day. The total daily dose should not exceed 320 mg trimethoprim and 1600 mg sulfamethoxazole.
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 jiroveci pneumonitis may be appropriate.
Septrin should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimoxazole or any excipients of Septrin.
Contra-indicated in patients showing marked liver parenchymal damage.
Contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.
Septrin should not be given to premature babies nor to full-term infants during the first 6 weeks of life except for the treatment/prophylaxis of PCP in infants 4 weeks of age or greater.
Fatalities, although very rare, have occurred due to severe reactions including Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.
Septrin should be discontinued at the first appearance of skin rash.(see 4.8 Undesirable Effects).
Particular care is always advisable 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.
An adequate urinary output should be maintained at all times. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients. In patients suffering from malnutrition the risk may be increased.
Regular monthly blood counts are advisable when Septrin is given for long periods, or to folate deficient patients or to the elderly; since there exists a possibility of asymptomatic changes in haematological laboratory indices due to lack of available folate. These changes may be reversed by administration of folinic acid (5 to 10 mg/day) without interfering with the antibacterial activity.
In glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients haemolysis may occur.
Septrin should be given with caution to patients with severe allergy or bronchial asthma.
Septrin should not be used in the treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci; eradication of these organisms from the oropharynx is less effective than with penicillin.
Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction.
The administration of Septrin to patients known or suspected to be at risk of acute porphyria should be avoided. Both trimethoprim and sulphonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.
Close monitoring of serum potassium is warranted in patients at risk of hyperkalaemia.
Except under careful supervision Septrin should not be given to patients with serious haematological disorders (see 4.8 Undesirable Effects). Septrin 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 Septrin 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.
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 of 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.
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.
Reversible deterioration in renal function has been observed in patients treated with co-trimoxazole and cyclosporin following renal transplantation.
Concurrent use of rifampicin and Septrin results in a shortening of the plasma half-life of trimethoprim after a period of about one week. This is not thought to be of clinical significance.
When trimethoprim is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine), there is the possibility of competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.
In elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.
Occasional reports suggest that patients receiving pyrimethamine at doses in excess of 25 mg weekly may develop megaloblastic anaemia should co-trimoxazole be prescribed concurrently.
Co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with Septrin is advisable.
Co-trimoxazole prolongs the half-life of phenytoin and if co-administered could result in excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels are advisable.
Concomitant use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients.
Co-trimoxazole may increase the free plasma levels of methotrexate.
Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.
Administration of trimethoprim/sulfamethoxazole 160mg/800mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.
Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported.
Caution should be exercised in patients taking any other drugs that can cause hyperkalaemia.
If Septrin is considered appropriate therapy in patients receiving other anti-folate drugs such as methotrexate, a folate supplement should be considered.
Pregnancy
There are not any adequate data from the use of Septrin in pregnant women. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans.
Trimethoprim is a folate antagonist and, in animal studies, both agents have been shown to cause foetal abnormalities (see 5.3 Preclinical Safety Data).
Septrin should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Septrin is used in pregnancy.
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 Septrin 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.
Lactation
The components of Septrin (trimethoprim and sulfamethoxazole) are excreted in breast milk. Administration of Septrin 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 Septrin should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia.
There have been no studies to investigate the effect of Septrin on driving performance or the ability to operate machinery. Further a detrimental effect on such activities cannot be predicted from the pharmacology of the drug. Nevertheless the clinical status of the patient and the adverse events profile of Septrin should be borne in mind when considering the patients ability to operate machinery.
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
Infections and Infestations
|
|
Blood and lymphatic system disorders
|
|
The majority of haematological changes are mild and reversible when treatment is stopped. 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 dysfunction or in those with 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
|
|
Metabolism and nutrition disorders
|
|
|
|
|
|
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
|
|
Nervous system disorders
|
|
|
|
|
|
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.
Respiratory, thoracic and mediastinal disorders
|
|
Cough, shortness of breath and pulmonary infiltrates may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.
Gastrointestinal disorders
|
|
|
|
|
|
|
|
|
|
Eye Disorders
|
|
Hepatobiliary disorders
|
|
Cholestatic jaundice and hepatic necrosis may be fatal.
Skin and subcutaneous tissue disorders
|
|
|
|
|
|
Lyell's syndrome carries a high mortality.
Musculoskeletal and connective tissue disorders
|
|
Renal and urinary disorders
|
|
Effects associated with Pneumocystis jiroveci (P.carinii) Pneumonitis (PCP) management
|
|
At the high dosages 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.
Nausea, vomiting, dizziness and confusion are likely signs/symptoms of overdosage. Bone marrow depression has been reported in acute trimethoprim overdosage.
If vomiting has not occurred, induction of vomiting may be desirable. Gastric lavage may be useful, though absorption from the gastrointestinal tract is normally very rapid and complete within approximately two hours. This may not be the case in gross overdosage. Dependant on the status of renal function administration of fluids is recommended if urine output is low.
Both trimethoprim and active sulfamethoxazole are moderately dialysable by haemodialysis. Peritoneal dialysis is not effective.
Pharmacotherapeutic group: Combinations of sulfonamides and trimethoprim, incl. derivatives; ATC code: J01EE01
Mode of Action
Septrin is an antibacterial drug composed of two active principles, sulfamethoxazole and trimethoprim. Sulfamethoxazole is a competitive inhibitor of dihydropteroate synthetase enzyme. Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid (PABA) in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim binds to and reversibly inhibits bacterial dihydrofolate reductase (DHFR) and blocks the production of tetrahydrofolate. Depending on the conditions the effect may be bactericidal. Thus trimethoprim and sulfamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents.
Mechanism of resistance
In vitro studies have shown that bacterial resistance can develop more slowly with both sulfamethoxazole and trimethoprim in combination that with either sulfamethoxazole or trimethoprim alone.
Resistance to sulfamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase the concentration of PABA and thereby out-compete with sulfamethoxazole resulting in a reduction of the inhibitory effect on dihydropteroate synthetase enzyme. Another resistance mechanism is plasmid-mediated and results from production of an altered dihydropteroate synthetase enzyme, with reduced affinity for sulfamethoxazole compared to the wild-type enzyme.
Resistance to trimethoprim occurs through a plasmid-mediated mutation which results in production of an altered dihydrofolate reductase enzyme having a reduced affinity for trimethoprim compared to the wild-type enzyme.
Trimethoprim binds to plasmodial DHFR but less tightly than to bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.
Many common pathogenic bacteria are susceptible in vitro to trimethoprim and sulfamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antibiotics, however, in vitro activity does not necessarily imply that clinical efficacy has been demonstrated and it must be noted that satisfactory susceptibility testing is achieved only with recommended media free from inhibitory substances, especially thymidine and thymine.
Breakpoints
EUCAST
Enterobacteriaceae: S
S. maltophilia: S
Acinetobacter: S
Staphylococcus: S
Enterococcus: S
Streptococcus ABCG: S
Streptococcus pneumoniae: S
Hemophilus influenza: S
Moraxella catarrhalis: S
Psuedomonas aeruginosa and other non-enterobacteriaceae: S
S = susceptible, R = resistant. *These are CLSI breakpoints since no EUCAST breakpoints are currently available for these organisms.
Trimethoprim: sulfamethoxazole in the ratio 1:19. Breakpoints are expressed as trimethoprim concentration.
Antibacterial Spectrum
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. This information gives only an approximate guidance on probabilities whether microorganisms will be susceptible to trimethoprim/sulfamethoxazole or not.
Trimethoprim/sulfamethoxazole susceptibility against a number of bacteria are shown in the table below:
|
|
|
|
|
|
|
|
After oral administration trimethoprim and sulfamethoxazole are rapidly and nearly completely absorbed. The presence of food does not appear to delay absorption. Peak levels in the blood occur between one and four hours after ingestion and the level attained is dose related. Effective levels persist in the blood for up to 24 hours after a therapeutic dose. Steady state levels in adults are reached after dosing for 2-3 days. Neither component has an appreciable effect on the concentrations achieved in the blood by the other.
Trimethoprim is a weak base with a pKa of 7.4. It is lipophilic. Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, saliva, sputum and vaginal secretions. Levels in the aqueous humor, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (intestinal) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and foetal tissues reaching concentrations approximating those of maternal serum.
Approximately 50% of trimethoprim in the plasma is protein bound. The half-life in man is in the range 8.6 to 17 hours in the presence of normal renal function. It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10 ml/minute. There appears to be no significant difference in the elderly compared with young patients.
The principal route of excretion of trimethoprim is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged drug. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely.
Sulfamethoxazole is a weak acid with a pKa of 6.0. The concentration of active sulfamethoxazole in a variety of body fluids is of the order of 20 to 50% of the plasma concentration.
Approximately 66% of sulfamethoxazole in the plasma is protein bound . The half-life in man is approximately 9 to 11 hours in the presence of normal renal function. There is no change in the half-life of active sulfamethoxazole with a reduction in renal function but there is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 ml/minute.
The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form. In elderly patients there is a reduced renal clearance of sulphamethoxazole.
Reproductive toxicology:
At doses in excess of recommended human therapeutic dose, trimethoprim and sulfamethoxazole have been reported to cause cleft palate and other foetal abnormalities in rats, findings typical of a folate antagonist. Effects with trimethoprim were preventable by administration of dietary folate. In rabbits, foetal loss was seen at doses of trimethoprim in excess of human therapeutic doses.
Tablets
Sodium starch glycollate
Povidone
*Dioctyl sodium sulphosuccinate
*Docusate sodium
Magnesium stearate
*alternative ingredients
See drug interactions.
5 years.
Do not store above 25°C. Keep container in the outer carton.
Amber glass bottles with low density polyethylene snap-fit closures and PVC/Al foil blister pack.
Pack size: 50 and 100
Round enamelled tins with lever lids.
Pack size: 5000
Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.
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 of the order of 10%. Functional inhibition of the renal tubular secretion of creatinine may product a spurious fall in the estimated rate of creatinine clearance.
The Wellcome Foundation Ltd
Glaxo Wellcome House
Berkeley Avenue
Greenford
Middlesex UB6 ONN
Trading as:
GlaxoSmithKline UK
Stockley Park West
Uxbridge
Middlesex UB11 1BT
PL 00003/0109R
|
|
|
|
21 July 2009
