Normicron 200 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Normicron 200 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains:
Rifaximin 200 mg
Excipients:
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet
Pink circular biconvex film-coated tablets, with “AW” printed on both sides.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Normicron is indicated for the treatment of traveller’s diarrhoea that is not associated with any of:
Fever
Bloody diarrhoea
Eight or more unformed stools in the previous 24 h Occult blood or leucocytes in the stool.
Normicron may shorten the duration of diarrhoea when this is associated with noninvasive strains of E.coli (see sections 4.4 and 5.1).
4.2 Posology and method of administration
Posology 200 mg every 8 hours for three days (total 9 doses).
Rifaximin must not be used for more than 3 days even if symptoms continue and a second course of treatment must not be taken (see section 4.4).
Rifaximin can be administered with or without food.
Paediatric population
The safety and efficacy of Normicron 200 mg film-coated tablets in children (aged less than 18 years) have not been established.
Elderly
No dosage adjustment is necessary as the safety and efficacy data of Normicron 200 mg film-coated tablets showed no differences between the elderly and the younger patients.
Hepatic impairment
A dosage adjustment for patients with hepatic insufficiency is not necessary (see section 5.2).
Renal impairment
Although dosing change is not anticipated, caution should be used in patients with impaired renal function (see section 5.2).
Method of administration Orally with a glass of water.
4.3 Contraindications
Hypersensitivity to the active substance, to any rifamycin (e.g. rifampicin or rifabutin) or to any of the excipients (listed in section 6.1).
Cases of intestinal obstruction.
4.4 Special warnings and precautions for use
Clinical data have shown that rifaximin is not effective in the treatment of traveller’s diarrhoea caused by invasive enteric pathogens such as Campylobacter, Salmonella and Shighella, which typically produce dysenterylike diarrhoea characterised by fever, blood in the stool and high stool frequency.
If symptoms worsen treatment with rifaximin should be interrupted.
If symptoms have not resolved after 3 days of treatment, or recur shortly afterwards, a second course of rifaximin should not be administered. Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including rifaximin. The potential association of rifaximin treatment with CDAD and pseudomembranous colitis (PMC) cannot be ruled out.
Patients should be informed that despite the negligible absorption of the drug (less than 1%), like all rifamycin derivatives, rifaximin may cause a reddish discolouration of the urine.
Due to the effects on the gut flora, the effectiveness of oral oestrogenic contraceptives could decrease after rifaximin administration. However, such interactions have not been commonly reported. It is recommended to take additional contraceptive precautions, in particular if the oestrogen content of oral contraceptives is less than 50 pg (see also section 4.5).
Caution should be exercised when concomitant use of rifaximin and a P-glycoprotein inhibitor such as ciclosporin is needed (see section 4.5).
Both decreases and increases in international normalized ratio (in some cases with bleeding events) have been reported in patients maintained on warfarin and prescribed rifaximin. If co-administration is necessary, the international normalized ratio should be carefully monitored with the addition or withdrawal of treatment with rifaximin. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5).
Paediatric population
Normicron 200 mg film-coated tablets are not recommended for use in children (<18 years old).
4.5 Interaction with other medicinal products and other forms of interaction
There is no experience regarding administration of rifaximin to subjects who are taking another rifamycin antibacterial agent to treat a systemic bacterial infection.
In vitro data show that rifaximin did not inhibit the major cytochrome P-450 (CYP) drug metabolizing enzymes (CYPs1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4).
In vitro data show that rifaximin did not induce CYP1A2 and CYP 2B6 but is a weak inducer of the CYP3A4 isoenzyme of the P450 cytochrome.
In healthy subjects, clinical drug interaction studies demonstrated that rifaximin did not significantly affect the pharmacokinetics of CYP3A4 substrates. However, in hepatic impaired patients it cannot be excluded that rifaximin may decrease the exposure of concomitant CYP3A4 substrates administered (e.g. warfarin, antiepileptics, antiarrhythmics) due to the higher systemic exposure with respect to healthy subjects.
An in vitro study suggested that rifaximin is a moderate substrate of P-glycoprotein (P-gp) and metabolized by CYP3A4. It is unknown whether concomitant drugs which inhibit CYP3A4 can increase the systemic exposure of rifaximin.
Both decreases and increases in international normalized ratio have been reported in patients maintained on warfarin and prescribed rifaximin. If co-administration is necessary, the international normalized ratio should be carefully monitored with the addition or withdrawal of rifaximin. Adjustments in the dose of oral anticoagulants may be necessary.
The potential for drug-drug interactions to occur at the level of gut transporter systems has been evaluated.
In healthy subjects, co-administration of a single dose of ciclosporin (600 mg), a potent P-glycoprotein inhibitor, with a single dose of rifaximin (550mg) resulted in 83-fold and 124-fold increases in rifaximin mean Cmax and AUC co respectively.
The clinical significance of this increase in systemic exposure is unknown.
In vitro studies suggest that a clinical interaction between rifaximin and other compounds that undergo efflux via P-gp and other transport proteins is unlikely (MRP2, MRP4, BCRP and BSEP).
No drug interaction studies investigating the concomitant intake of rifaximin and other drugs that might be used during an episode of travellers’ diarrhoea (e.g. loperamide, charcoal) are available.
In case of administration of charcoal, rifaximin should be taken at least 2 hours after that administration.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is no or limited data from the use of rifaximin in pregnant women.
Animal studies showed transient effects on ossification and skeletal variations in the foetus (see section 5.3). The clinical relevance of these findings in humans is unknown.
As a precautionary measure, use of rifaximin during pregnancy is not recommended. Breast-feeding
It is unknown whether rifaximin/metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from rifaximin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility
Animal studies do not indicate direct or indirect harmful effects with respect to male and female fertility.
4.7 Effects on ability to drive and use machines
In clinical controlled trials dizziness and somnolence have been reported but rifaximin has negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
In clinical studies in subjects who received rifaximin for treatment of travellers’ diarrhoea Adverse Reactions considered as being at least possibly related to rifaximin have been categorised by organ system and frequency.
|
MedDRA System Organ Class |
Common |
Uncommon |
Frequency not Known |
|
Infections and infestations |
Candidiasis, Herpes simplex, Nasopharyngitis, Pharyngitis, Upper respiratory tract infection |
Clostridial infections | |
|
Blood and lymphatic system disorders |
Lymphocytosis, Monocytosis, Neutropenia |
Thrombocytopenia | |
|
Immune system disorders |
Anaphylactic responses, Angioedemas, Hypersensitivity | ||
|
Metabolism and nutrition disorders |
Decreased appetite, Dehydration | ||
|
Psychiatric disorders |
Abnormal dreams, Depressed mood, Insomnia, Nervousness | ||
|
Nervous system disorders |
Dizziness, Headache |
Hypoesthesia, Migraine, Paraesthesia, Sinus headache, Somnolence |
Presyncope |
|
Eye disorders |
Diplopia | ||
|
Ear and labyrinth disorders |
Ear pain, Vertigo | ||
|
Cardiac disorders |
Palpitations | ||
|
Vascular disorders |
Blood pressure increased, Hot flush | ||
|
Respiratory, thoracic, and mediastinal disorders |
Cough, Dry throat, Dyspnoea, Nasal congestion, Oropharyngeal pain, Rhinorrhea | ||
|
Gastrointestinal disorders |
Abdominal pain, Constipation, Defecation urgency, Diarrhoea, Flatulence, bloating and distension Nausea and vomiting symptoms, Rectal tenesmus’ |
Abdominal pain upper, Dry lips, Dyspepsia, Gastrointestinal motility disorder, Faeces hard, Haematochezia, Mucous stools, Taste disorders | |
|
Hepatobiliary disorders |
Aspartate aminotransferase increased |
Liver function test abnormalities | |
|
Skin and subcutaneous tissue disorders |
Rashes, eruptions and exanthemas, Sunburn |
Dermatitis Dermatitis exfoliative Eczema Erythemas Pruritus Purpura |
|
MedDRA System Organ Class |
Common |
Uncommon |
Frequency not Known |
|
Urticarias | |||
|
Musculoskeletal and connective tissue disorders |
Back pain, Muscle spasms, Muscular weakness, Myalgia, Neck pain, | ||
|
Renal and urinary disorders |
Blood in urine present, Glycosuria, Pollakiuria, Polyuria, Proteinuria | ||
|
Reproductive system and breast disorders |
Polymenorrhoea | ||
|
General disorders and administration site conditions |
Pyrexia |
Asthenic conditions, Chills, Cold sweat, Hyperhidrosis, Influenza like illness, Oedema peripheral, Pain and discomfort | |
|
Investigations |
International normalised ratio abnormalities |
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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
In clinical trials with patients suffering from traveller’s diarrhoea doses of up to 1800 mg/day have been tolerated without any severe clinical signs.
Dosages of up to 2400 mg/day for 7 days in patients/subjects with normal bacterial flora rifaximin did not result in any relevant clinical symptoms related to the high dosage.
In case of overdose symptomatic treatments and supportive care are recommended.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: intestinal, anti-infective agents- antibiotics- ATC code: A07AA11.
The product Normicron contains rifaximin (4-desoxy-4’methyl pyrido (1’,2’1,2) imidazo (5,4-c) rifamycin SV), in the polymorphic form a.
Mode of action
Rifaximin is an antibacterial agent of the rifamycin class that binds irreversibly to the beta sub-unit of the bacterial enzyme DNA-dependent RNA polymerase and consequently inhibits bacterial RNA synthesis.
Rifaximin has a broad antimicrobial spectrum against most of the Grampositive and -negative, aerobic and anaerobic bacteria responsible for intestinal infections.
Due to the very low absorption from the gastro-intestinal tract rifaximin in the polymorph a form is locally acting in the intestinal lumen and clinically not effective against invasive pathogens.
Mechanism of resistance
The main mechanism of acquiring resistance to rifaximin appears to involve a mutation in the rpoB gene encoding the bacterial RNA polymerase.
The incidence of resistant subpopulations among bacteria isolated from patients with traveller’s diarrhoea was very low.
Clinical studies that investigated changes in the susceptibility of intestinal flora of subjects affected by traveller’s diarrhoea, failed to detect the emergence of drug resistant Gram-positive (e.g. enterococci) and Gramnegative (E. coli) organisms during a three-day course of treatment with rifaximin.
Development of resistance in the normal intestinal bacterial flora was investigated with repeated, high doses of rifaximin in healthy volunteers and Inflammatory Bowel Disease patients. Strains resistant to rifaximin developed, but were unstable and did not colonise the gastrointestinal tract or replace rifaximin-sensitive strains. When treatment was discontinued resistant strains disappeared rapidly.
Experimental and clinical data suggest that the treatment of traveller’s diarrhoea with rifaximin of patients harbouring strains of Mycobacterium tuberculosis or Neisseria meningitidis will not select for rifampicin resistance.
Susceptibility
Rifaximin is a non-absorbed antibacterial agent. In vitro susceptibility testing cannot be used to reliably establish susceptibility or resistance of bacteria to rifaximin. There are currently insufficient data available to support the setting of a clinical breakpoint for susceptibility testing.
Rifaximin has been evaluated in vitro on pathogens causing traveller’s diarrhoea. These pathogens were: ETEC (Enterotoxigenic E. coli), EAEC (Enteroaggregative E. coli), Non-V cholerae vibrios. The MIC90, for the bacterial isolates tested, was 32 pg/ml, which can easily be achieved in the intestinal lumen due to high faecal concentrations of rifaximin.
5.2 Pharmacokinetic properties
Absorption
Pharmacokinetic studies in rats, dogs and humans demonstrated that after oral administration rifaximin in the polymorph a form is virtually not absorbed (less than 1%). Following the administration of therapeutic doses of rifaximin in healthy volunteers and patients with damaged intestinal mucosa (Inflammatory Bowel Disease), plasma levels are negligible (less than 10 ng/ml). Systemic absorption of rifaximin is increased but not by a clinically relevant extent by administration within 30 minutes of a high-fat breakfast.
Distribution
Rifaximin is moderately bound to human plasma proteins. In vivo, the mean protein binding ratio was 67.5% in healthy subjects and 62% in patients with hepatic impairment when rifaximin was administered.
Biotransformation
Analysis of faecal extracts demonstrated that rifaximin is found as the intact molecule, implying that it is neither degraded nor metabolised during its passage through the gastrointestinal tract.
In a study using radio-labelled rifaximin, urinary recovery of rifaximin was 0.025% of the administered dose, while <0.01% of the dose was recovered as 25-desacetylrifaximin, the only rifaximin metabolite that has been identified in humans.
Elimination
A study with radio-labelled rifaximin suggested that 14C-rifaximin is almost exclusively and completely excreted in faeces (96.9 % of the administered dose). The urinary recovery of 14C rifaximin does not exceed 0.4% of the administered dose.
Linearity/non-linearity
The rate and extent of systemic exposure of humans to rifaximin appeared to be characterized by non-linear (dose-dependent) kinetic which is consistent with the possibility of dissolution-rate-limited absorption of rifaximin.
Special Populations
Renal impairment
No clinical data are available on the use of rifaximin in patients with impaired renal function.
Hepatic impairment
Clinical data available for patients with hepatic impairment showed a systemic exposure higher than that observed in healthy subjects.
The systemic exposure of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers.
The increase in systemic exposure to rifaximin in subjects with hepatic impairment should be interpreted in light of rifaximin gastrointestinal local action and its low systemic bioavailability, as well as the available rifaximin safety data in subjects with cirrhosis.
Therefore no dosage adjustment is recommended because rifaximin is acting locally.
Paediatric population
The pharmacokinetics of rifaximin has not been studied in paediatric patients of any age.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In a rat embryofetal development study, a slight and transient delay in ossification that did not affect the normal development of the offspring, was observed at 300 mg/kg/day. In the rabbit, following oral administration of rifaximin during gestation, an increase in the incidence of fetal skeletal variations was observed at clinically relevant doses.
The clinical relevance of these findings is unknown.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Sodium starch glycolate type A glycerol distearate colloidal anhydrous silica talc
microcrystalline cellulose
Tablet coating: hypromellose,
titanium dioxide E171 disodium edetate propylene glycol red iron oxide E172.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Original packing: 3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PE/PVDC-Aluminium blister packs containing 9 tablets.
6.6 Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Alfa Wassermann S.p.A.
Via E. Fermi, 1 65020 Alanno (Pescara),
ITALY
8 MARKETING AUTHORISATION NUMBER(S)
PL 13687/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/12/2010 / 20/07/2016
10 DATE OF REVISION OF THE TEXT
20/07/2016