SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One suppository contains mesalazine as the medically active ingredient.
Excipient with known effect: cetyl alcohol (Ph.Eur.)
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Appearance: white to cream-coloured, torpedo-shaped suppositories
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of acute episodes of ulcerative colitis that is limited to the rectum.
4.2 Posology and method of administration
Adults and elderly:
One Salofalk suppository three times daily (equivalent to 1500 mg mesalazine daily) inserted into the rectum, according to the individual clinical requirement.
As soon as remission has occurred, the dose in prevention of recurrence
should be reduced to one suppository with 250 mg mesalazine three times daily (e.g. Salofalk 250mg Suppositories).
Children and adolescents:
There is little experience and only limited documentation for an effect in children.
Method of administration:
When used three times daily, Salofalk Suppositories should be inserted into the rectum in the morning, at midday and at bedtime.
Treatment with Salofalk 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 500mg Suppositories are contraindicated in patients with:
– hypersensitivity to the active substance, salicylates or to any of the excipients listed in section 6.1
– severe impairment of hepatic or 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, follow-up tests are recommended 14 days after commencement of treatment, then a further two to three tests at intervals of 4 weeks.
If the findings are normal, follow-up tests should be carried out every 3 months. If additional symptoms occur, these tests should be performed immediately.
Caution is recommended in patients with impaired hepatic function.
Salofalk 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 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 500mg Suppositories. Should Salofalk Suppositories cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.
Cetyl alcohol, an excipient of Salofalk Suppositories can cause local skin irritation (e.g. contact dermatitis).
4.5 Interaction with other medicinal products and other forms of interaction
Specific interaction studies have not been performed.
In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or thioguanine, a possible increase in the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine should be taken into account.
There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.
4.6 Fertility, pregnancy and lactation
There are no adequate data on the use of Salofalk Suppositories in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the foetus/newborn child. To date no other relevant epidemiologic data are available. In one single case after long-term use of a high dose of 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, embryonic/foetal development, parturition or postnatal development.
Salofalk 500mg 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 such as diarrhoea in the infant cannot be excluded. Therefore, Salofalk Suppositories should only be used during breast-feeding, if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, the breast-feeding should be discontinued.
4.7 Effects on ability to drive and use machines
Salofalk 500mg Suppositories have no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The following undesirable effects have been observed after administration of mesalazine:
System organ class Frequency according to MedDRA convention
(≥ 1/10,000; <1/1,000) Very rare
Blood and lymphatic system disorders Altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia)
Nervous system disorders Headache, dizziness Peripheral neuropathy
Cardiac disorders Myocarditis,
Respiratory, thoracic and mediastinal disorders Allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis)
Gastrointestinal disorders Abdominal pain,
vomiting Acute pancreatitis
Renal and urinary disorders Impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency
Skin and subcutaneous tissue disorders Photosensitivity Alopecia
Musculoskeletal and connective tissue disorders Myalgia, arthralgia
Immune system disorders Hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis
Hepatobiliary disorders Changes in liver function parameters (increase in transaminases and parameters of cholestasis), hepatitis, cholestatic hepatitis
Reproductive system disorders Oligospermia (reversible)
More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.
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
Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medical Devices)
There are rare data on overdosage (e.g. intended suicide with high oral doses of mesalazine), which do not indicate renal or hepatic toxicity. There is no specific antidote and treatment is symptomatic and supportive.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: intestinal anti-inflammatory agents; aminosalicylic acid and similar agents
ATC code: A07EC02
Mechanism of action
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.
5.2 Pharmacokinetic Properties
General considerations of mesalazine:
Mesalazine absorption is highest in proximal gut regions and lowest in distal gut areas.
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.
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 Suppositories specific:
Scintigraphic studies with technetium-labelled Salofalk 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. Salofalk Suppositories are thus particularly suitable for treating proctitis (ulcerative colitis of the rectum).
After both a single administration and after several weeks of long-term treatment with 500 mg mesalazine three times daily as Salofalk Suppositories, peak plasma concentrations of 5-ASA were in the range of 0.1 to 1.0 µg/ml, those of the main metabolite N-Ac-5-ASA were in the range of 0.3 to 1.6 µg/ml. Peak plasma concentrations of 5-ASA are partially reached within the first hour of application.
After a single rectal dose of 500 mg mesalazine as Salofalk Suppositories, approx. 11% (within 72 hours) was recovered in the urine, and after several weeks of long-term treatment with 500 mg mesalazine three times daily as Salofalk Suppositories approx. 13% of the 5-ASA dose administered was recovered in the urine. Approximately 10 % of a single administered dose was eliminated via the bile.
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
1. Hard fat
2. Docusate sodium
3. Cetyl alcohol (Ph.Eur.)
6.3 Shelf life
6.4 Special precautions for storage
Store in the original container in order to protect contents from light.
Do not store above 30C.
6.5 Nature and contents of container
Packs of 10 (N1), 30 (N2) and 120 (N3) suppositories
6.6 Special precautions for disposal and other handling
No special requirements.