MIMS Revision Date: 01 December 2020

1 Name of Medicine

Mutaflor Capsules.

2 Qualitative and Quantitative Composition

1 gastro-resistant hard capsule contains:
Escherichia coli strain Nissle 1917 2.5 x 10⁹ viable cells (CFU).
Australian labelling - corresponding to not less than 250 million viable cells (CFU).
For a full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Gastro-resistant hard capsule.

4 Clinical Particulars

4.1 Therapeutic Indications

For the relief/management of chronic constipation.
To increase the number of bowel movements per day and the number of days on which bowel movements occur in patients with chronic constipation.

4.2 Dose and Method of Administration

Posology. Adults and adolescents. Take 3 to 4 Mutaflor capsules daily.
Method of administration. The dose should be taken with a meal, if possible with breakfast, and an appropriate amount of fluid. Avoid chewing the capsules.
With onset of flatulence the daily dose may be split and administered with meals spread evenly throughout the day.
Duration of administration. Mutaflor may be taken for up to 8 weeks. In constipation which persisted for many years Mutaflor should be regarded as a health-maintenance treatment and the therapy therefore be repeated periodically.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients.

4.4 Special Warnings and Precautions for Use

None.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Antibiotics directed against Gram-negative bacteria and sulphonamides may reduce the efficacy of Mutaflor.

4.6 Fertility, Pregnancy and Lactation

Use in pregnancy. E. coli strain Nissle 1917 is a commensal gut inhabitant of human beings and is not being absorbed. Therefore, effects on pregnancy and lactation are not to be expected.
Use in lactation. E. coli strain Nissle 1917 is a commensal gut inhabitant of human beings and is not being absorbed. Therefore, effects on pregnancy and lactation are not to be expected.

4.7 Effects on Ability to Drive and Use Machines

Not relevant.

4.8 Adverse Effects (Undesirable Effects)

The assessment of undesirable effects was based on the following frequencies:
Very common (≥ 1/10).
Common (≥ 1/100, < 1/10).
Uncommon (≥ 1/1,000, < 1/100).
Rare (≥ 1/10,000, < 1/1,000).
Very rare (< 1/10,000), including isolated reports.
Gastrointestinal disorders. Frequently (≥ 1/100, < 1/10), initial flatulence occurs. Changes in stool consistency or stool frequency, abdominal pain, borborygmi, meteorism, nausea or vomiting were observed very rarely (< 1/10,000, including isolated reports).
Skin and subcutaneous disorders. Skin efflorescences, erythema or skin flaking were observed very rarely (< 1/10,000, including isolated reports).
Nervous system disorders. Very rarely, headache was reported.

4.9 Overdose

No case of overdose has been reported.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Modes of action. Mutaflor capsules contain as the active substance a defined non-pathogenic bacterial strain of human origin, of the species Escherichia coli (E. coli), in a viable form capable of proliferation: E. coli strain Nissle 1917. By means of special adhesive organelles (Type F-1A, F-1C, and "curli" fimbriae) the strain is able to attach to the mucin layer of the gut wall and to form microcolonies in the form of biofilms. The strain is well mobile by possessing flagella, which is an advantage when colonizing the colon.
The effects of Mutaflor or E. coli strain Nissle 1917 were determined by in vitro experiments and in vivo examinations as well as by clinical studies. Hence, the following properties and modes of action were detected:
Antagonism. E. coli strain Nissle 1917 forms antimicrobial substances (microcins) and multiple iron-acquisition systems (siderophores), which are responsible for its direct antagonism against pathogens on the one hand and for its assertiveness, following oral administration, in the intestinal tract on the other hand. Moreover, the strain inhibits invasion of the colon mucosa by enteroinvasive pathogens.
Stabilization of the mucosal barrier in the gut. E. coli strain Nissle 1917, in cell-culture experiments on human colonocytes, stabilizes the barrier function of the epithelial cell layer and normalizes increased permeability of the gut mucosa. This strengthening of the gut barrier is based on stimulation of synthesis of an anchor protein (ZO-2) and its reorganization in tight junctions.
Immunomodulating properties. Effects on humoral immune response. Newborn infants, on colonization with E. coli strain Nissle 1917, show a significant raise of IgA and IgM levels in stool filtrates and serum. Isolated reports indicate an increase of IgA in saliva. In germ-free newborn piglets oral administration of E. coli strain Nissle 1917 leads to stimulation of development of immunocompetent cells of the gut-associated immune system (IgA and IgG producing lymphocytes, MHC-class-II-expressing cells), without showing signs of inflammation (no influx of granulocytes).
Effects on cellular immune response. In-vitro experiments revealed immunomodulating properties for E. coli strain Nissle 1917. Thus, enhanced secretory output of mouse macrophages (interleukin 6 [IL-6], tumour necrosis factor [TNF], oxygen radicals) and of human mononuclear cells from peripheral blood (interleukin 10) were detected. However, an enhanced production of TNF was not confirmed by in vivo examinations in mice and other animal models.
Moreover, enhanced cytotoxicity of mouse macrophages against intracellular parasites and thus a stronger defence against intracellular infectious agents was demonstrated ex vivo. The cell cycle and proliferation of human T lymphocytes from peripheral blood were inhibited by E. coli strain Nissle 1917, but not of T lymphocytes from gut. New recruitment of activated T lymphocytes to the gut-associated immune system may thus be blocked.
Effects on innate immunity. E. coli strain Nissle 1917 inducers the synthesis of antimicrobial peptides. Thus, the synthesis of inducible defensins in human colonocytes in vitro and, in vivo in the gut after oral administration to germ-free piglets, the production of calprotectin is stimulated. In newborn (premature) infants the innate and adaptive immune response is stimulated by oral administration of Mutaflor.
Anti-inflammatory properties. Mutaflor possesses anti-inflammatory properties. Both in in-vitro experiments in human gut epithelial cells and in in-vivo experiments in established animal models if inflammatory bowel disease, anti-inflammatory properties of E. coli strain Nissle 1917 were detected.
Properties promoting motility. E. coli strain Nissle 1917 produces short-chain fatty acids as metabolites, which are important for the energy balance of the colon mucosa. They stimulate colonic motility and blood circulation of the gut mucosa as well as enhancing sodium and chloride absorption. Stimulation of colonic motility, probably caused by acetic acid of microbial origin, is important for the treatment of chronic constipation.
Metabolic properties. The Mutaflor strain possesses multifunctional metabolic properties and is able to catabolize different carbohydrates, sugar alcohols, amino acids, and other substrates by consuming oxygen. Thus, an anaerobic milieu is created and maintained in the colon in vivo, which is important for the stability of the intestinal ecosystem.

5.2 Pharmacokinetic Properties

Due to their coating, Mutaflor capsules are resistant to gastric juice and will not dissolve before the terminal ileum. The active substance E. coli strain Nissle 1917 as a commensal bacterium colonizes the colon, is not absorbed and not metabolized. It is excreted via the faeces.

5.3 Preclinical Safety Data

E. coli strain Nissle 1917 has no toxic or pathogenic properties, neither in vitro nor in vivo. It does not form enterotoxins such as hemolysin, is not enteroinvasive, has no pathogenic adhesion characteristics and no uropathogenic properties. It is sensitive to antibiotics frequently used against Gram-negative bacteria and does not show any immunotoxic effects. In addition, E. coli strain Nissle 1917 is not serum-resistant, i.e. it is rapidly killed by human serum.
This is due to the possession of a special lipopolysaccharide with an extremely abridged side chain of the O6 antigen. The strain is thus unable to act as a sepsis causing agent.
No examinations have been done regarding reproduction toxicology. Since E. coli strain Nissle 1917 is a normal, non-pathogenic and non-invasive inhabitant of the human gut, toxic effects on reproduction or on the embryo were never detected so far and are not expected.

6 Pharmaceutical Particulars

6.1 List of Excipients

Maltodextrin, talc, methacrylic acid-methyl methacrylate copolymer (1:1), macrogol (4000), triethyl citrate, glycerol 85%, titanium dioxide, iron (III)-oxide, gelatin, white beeswax, carnauba wax, shellac, purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

12 months.

6.4 Special Precautions for Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze.).

6.5 Nature and Contents of Container

Nature of container. Blisters: Cupping strips made from PVC/PVDC foil, closed by aluminium foil.
Package sizes. Packs with 20 gastro-resistant hard capsules.
Packs with 50 gastro-resistant hard capsules.
Packs with 100 gastro-resistant hard capsules.

6.6 Special Precautions for Disposal

No special requirements.

6.7 Physicochemical Properties

No data available.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Date of First Approval

28 February 2012

Date of Revision

15 August 2018