1. Name Of The Medicinal Product
Salofalk 500mg gastro-resistant tablets
2. Qualitative And Quantitative Composition
Each tablet of Salofalk 500mg gastro-resistant tablets contains 500 mg mesalazine.
Excipients: sodium carbonate and croscarmellose sodium
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Gastro-resistant tablets
Appearance: oval, light yellow to ochre, gastro-resistant tablets, matt with smooth surface; not scored.
4. Clinical Particulars
4.1 Therapeutic Indications
• For the treatment of acute episodes and the maintenance of remission of ulcerative colitis.
4.2 Posology And Method Of Administration
Adults and elderly
Depending upon the clinical requirements in individual cases, the following daily doses are recommended:
For the treatment of acute episodes: 1.5 g to 3.0 g mesalazine in three divided doses (1 or 2 tablets of Salofalk 500mg three times daily).
For the maintenance of remission: 1.5 g mesalazine in three divided doses (1 tablet of Salofalk 500mg three times daily).
Children:
There is only limited documentation for an effect in children (age 6-18 years).
Children 6 years of age and older
Active disease: To be determined individually, starting with 30-50 mg/kg/day in divided doses. Maximum dose: 75 mg/kg/day. The total dose should not exceed the maximum adult dose.
Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed the recommended adult dose.
It is generally recommended that half the adult dose may be given to children up to a body weight of 40 kg; and the normal adult dose to those above 40 kg.
General instructions for use:
Salofalk 500mg tablets should be taken in the morning, at midday and in the evening, 1 hour before meals. They should be swallowed whole, not chewed, and taken with plenty of fluid.
Treatment with Salofalk 500mg tablets should be administered regularly and consistently, both in the acute inflammatory stage and during maintenance therapyin order to achieve the desired therapeutic effect.
The duration of use is determined by the physician.
For maintenance of remission in ulcerative colitis, the dose can usually be reduced to 1.5 g mesalazine/day (adults and adolescents with a body weight over 40 kg) and 0.75 g mesalazine/day (children/adolescents).
4.3 Contraindications
Salofalk 500mg tablets are contraindicated in cases of:
- pre-existing hypersensitivity to salicylic acid and its derivatives or to any of the other constituents
- severe impairment of hepatic and renal function.
4.4 Special Warnings And Precautions For Use
Blood tests (differential blood count; liver function parameters like ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, controls are recommended 14 days after commencement of treatment, then a further two to three times at intervals of 4 weeks.
If the findings are normal, control examinations should be carried out every 3 months. If additional symptoms occur, control examinations should be performed immediately.
Caution is recommended in patients with impaired hepatic function.
Salofalk 500mg tablets 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 500mg tablets.
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 500mg tablets. Should Salofalk 500mg tablets cause acute intolerability reactions such as cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.
Note:
In rare cases, in patients who have undergone bowel resection/bowel surgery in the ileocoecal region with removal of the ileocoecal valve, it has been observed that Salofalk 500mg tablets were excreted undissolved in the stool, due to an excessively rapid intestinal passage.
1 Salofalk 500 mg tablet contains 2.1 mmol (49 mg) sodium. This must be taken into consideration in patients on a sodium-controlled (low-sodium/low-salt) diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Specific interaction studies have not been performed.
Interactions may occur during treatment with Salofalk 500mg tablets and concomitant administration of the following medicinal products. Most of these possible interactions are based on theoretical reasons:
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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.
4.6 Pregnancy And Lactation
There are no adequate data from the use of Salofalk 500mg tablets 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 epidmiologic 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 500mg tablets 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. Hypersensivity reactions like diarrhea can not be excluded. Therefore, Salofalk 500mg tablets 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.
4.7 Effects On Ability To Drive And Use Machines
No effects on the ability to drive and use machines have been observed
4.8 Undesirable Effects
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4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Intestinal anti-inflammatory agent
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.
Mesalazine, orally administered, acts predominantly locally at the gut mucosa and in the submucous tissue from the luminal side of the intestine. It is important, therefore, that mesalazine is available at the regions of inflammation. Systemic bioavailability / plasma concentrations of mesalazine therefore are of no relevance for therapeutic efficacy, but rather a factor for safety. In order to fulfil these criteria, Salofalk 500mg tablets are coated with Eudragit L; they are thus gastro-resistant and release of mesalazine is pH-dependent.
5.2 Pharmacokinetic Properties
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 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 500mg tablets specific:
Distribution:
A combined pharmacoscintigraphic/pharmacokinetic study showed that Salofalk 500mg tablets, reach the ileocoecal region after approximately 3-4 hours in fasting subjects and reach the ascending colon within approximately 4–5 hours. The total transit time in the colon is approximately 17 hours.
Absorption:
Release of mesalazine from Salofalk 500mg tablets, begins after a lag-phase of approximately 3–4 hours. Peak plasma concentrations are reached after approximately 5 hours (ileocoecal region) and, at 3 x 500 mg mesalazine/ day under steady-state conditions, are 3.0 ± 1.6 µg/ml for mesalazine and 3.4 ± 1.6 µg/ml for the metabolite, N-Ac-5-ASA.
Elimination:
The total renal elimination rate for mesalazine and N-Ac-5-ASA over 24 hours during multiple intake (3 x 1 Salofalk 500mg tablets, for 2 days; 1 tablet on the third day=examination day) was approximately 60%. The non-metabolised mesalazine fraction after oral administration was approximately 10%.
5.3 Preclinical Safety Data
Preclinical data 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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Basic butylated methylacrylate copolymer (Ph.Eur.) (=Eudragit E)
Calcium stearate (Ph.Eur.)
Cellulose, microcrystalline
Croscarmellose sodium
Glycine
Hypromellose
Macrogol 6000
Methacrylic acid-methyl methacrylate copolymer (1:1) (Ph.Eur.) (=Eudragit L)
Povidone K25
Silica, colloidal anhydrous
Sodium carbonate, anhydrous
Talc
Colouring agents: titanium dioxide (E 171), iron oxide hydrate (E 172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
No special precautions for storage.
6.5 Nature And Contents Of Container
Blister : PVC/PVDC (orange-transparent) /aluminium blister foil
Package sizes: 20, 45, 50, 90, 100 and 300 Salofalk 500mg tablets
Not all package sizes will be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Dr. Falk Pharma GmbH
Leinenweberstr. 5
79108 Freiburg
Germany
Tel: +49 (0)761 1514-0
8. Marketing Authorisation Number(S)
PL 08637/0019
9. Date Of First Authorisation/Renewal Of The Authorisation
23 June 2009
10. Date Of Revision Of The Text
August 2010
11 DOSIMETRY
(IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS
(IF APPLICABLE)
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