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Salofalk rectal suspension

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Salofalk 4g/60ml enemas
Rectal suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One Salofalk 4g/60ml enema (= 60 g rectal suspension) contains 4 g mesalazine.

Excipients with known effects: potassium metabisulphite (Ph.Eur.) (E224) and sodium benzoate (E211).

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Rectal suspension

Appearance: cream-coloured to light, pale-brown homogeneous suspension

4.  CLINICAL PARTICULARS

4.1 Therapeutic indications

 Acute attacks of ulcerative colitis (a chronic inflammatory disease of the large bowel)

4.2 Posology and method of administration

Posology

Adults and elderly:

In patients with symptoms of acute inflammation, the content of one enema bottle (60 g rectal suspension) is administered into the intestine as a clyster once daily at bedtime.

 Children and adolescents:
There is little experience and  only limited documentation for an effect in children.

General instructions for use:
Salofalk enemas are used once daily at bedtime.

Treatment with Salofalk enemas 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.

Method of administration:

Rectal use.
The best results are achieved if the bowel is emptied before administration of the Salofalk enema.

Preparation:
• The bottle should be shaken for 30 seconds.
• Then the protective cap of the applicator is removed.
• The bottle should be held at the top and bottom.

The correct position for administration is as follows:
• The patient should lie down on his/her left side with his/her left leg stretched out and right leg bent. This makes it easier for the rectal suspension to be administered and for the enema to be effective.

Administration of the rectal suspension:
• The tip of the applicator should be inserted deep into the rectum.
• The bottle should be tipped downwards slightly and then squeezed slowly.
• Once the bottle is empty, the applicator tip should be slowly withdrawn from the rectum.
• The patient should remain lying down in this position for at least 30 minutes to allow the contents of the enema to spread throughout the rectum.
• If possible, the rectal suspension should be allowed to exert its effects all night.

4.3 Contraindications

Salofalk enemas 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 enemas should not be used 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 enemas.

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 enemas. Should Salofalk enemas cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.

Due to their potassium metabisulphite content, Salofalk enemas can provoke allergic reactions with anaphylactic symptoms and bronchial constriction (bronchospasm) in sensitive patients, particularly in those with asthma or a history of allergies. 

Because the product contains sodium benzoate, it may provoke hypersensitivity reactions in suitably predisposed patients in the form of irritation of the skin, eyes and mucous membranes. 

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

Pregnancy
There are no adequate data from the use of Salofalk enemas 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 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 enemas should only be used during pregnancy if the potential benefit outweighs the possible risk.

Breast-feeding
N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. Only limited experience with mesalazine during lactation in women is available to date. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Salofalk enemas 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 4g/60ml enemas have no or negligible influence on the ability to drive or 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
 rare
(≥ 1/10,000;  <1/1,000) very rare 
(< 1/10,000)
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,
pericarditis 
Respiratory, thoracic and mediastinal disorders  Allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis)
Gastrointestinal disorders Abdominal pain,
diarrhoea,
flatulence,
nausea,
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)

Photosensitivity 
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)
Abt. Pharmakovigilanz
Kurt-Georg-Kiesinger-Allee 3
53175 Bonn
www.bfarm.de

4.9 Overdose

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 the 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.

Pharmacodynamic effects
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:

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 4g/60ml enemas specific:

Distribution:
An imaging study in patients with mild-to-moderate acute ulcerative colitis showed that the rectal suspension at the start of treatment and at remission after 12 weeks is distributed mainly in the rectum and sigmoid colon and to a lesser extent in the descending colon.

Absorption and elimination:
In a study in ulcerative colitis patients in remission, peak plasma concentrations of 0.92 µg/ml 5-ASA and 1.62 µg/ml N-Ac-5-ASA were achieved after approximately 11-12 hours under steady-state conditions. The elimination rate was approximately 13% (45-hour value), with most (approximately 85%) being eliminated in the form of the metabolite, N-Ac-5-ASA.
The steady-state plasma concentrations of 5-ASA and N-Ac-5-ASA in children with chronic inflammatory bowel disease under treatment with Salofalk® 4g/60ml enemas were 0.5-2.8 µg/ml and 0.9-4.1 µg/ml respectively.

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 tubule (pars convoluta) 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. Carbomer 35 000
2. Potassium acetate
3. Potassium metabisulphite (Ph.Eur.) (E 224, max. 0.28 g, equivalent to max. 0.16 g SO2)
4. Sodium benzoate (E 211)
5. Disodium edetate (Ph.Eur.)
6. Water, purified
7. Xanthan gum

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

 2 years

6.4 Special precautions for storage

 Store in the original sealed blister packs in order to protect from light.

6.5 Nature and contents of the container

Container:
Round, white, concertina-shaped LDPE bottle with a green protective LDPE cap
Pack sizes:
Packs containing 7 (N1) and 21 (N2) enemas

6.6 Special precautions for disposal and other handling

 No special requirements.

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