SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nitrofurantoin 50mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 50 mg Nitrofurantoin Ph Eur in macrocrystalline form. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Yellow coloured free flowing granules filled in hard gelatine capsule with white body printed with “50” in black and yellow cap printed with “NTF” in black.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Nitrofurantoin is indicated for the treatment of and prophylaxis against acute or recurrent, uncomplicated lower urinary tract infections when due to susceptible micro-organisms (see section 4.4 and 5.1)

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Dosage:

Adults

Acute Uncomplicated Urinary Tract Infections (UTIs): 50 mg four times daily for seven days.

Severe chronic recurrence (UTIs): 100 mg four times daily for seven days.

Long term suppression: 50-100 mg once a day.

Prophylaxis: 50 mg four times daily for the duration of procedure and for three days thereafter.

Children and Infants over three months of age

Acute Urinary Tract Infections: 3mg/kg day in four divided doses for seven days. Suppressive - 1mg/kg, once a day.

For children under 25kg body weight other formulations of nitrofurantoin should be considered

Elderly

Provided there is no significant renal impairment, in which Nitrofurantoin is contraindicated, the dosage should be that for any normal adult. See precaution and risks to elderly patients associated with long-term therapy (Section 4.8).

4.3 Contraindications

Patients with known hypersensitivity to nitrofurantoin or other nitrofurans.

Patients suffering from renal dysfunction with an eGFR of less than 45 ml/minute. Nitrofurantoin may be used with caution as short-course therapy only for the treatment of uncomplicated lower urinary tract infection in individual cases with an eGFR between 30-44 ml/min to treat resistant pathogens, when the benefits are expected to outweigh the risks.

G6PD deficiency (see also Section 4.6)

Acute porphyria.

In infants under three months of age as well as pregnant patients at term (during labour and delivery) because of the theoretical possibility of haemolytic anaemia in the foetus or in the newborn infant due to immature erythrocyte enzyme systems.

4.4 Special warnings and precautions for use

Nitrofurantoin is not effective for the treatment of parenchymal infections of unilaterally nonfunctioning kidney. A surgical cause for infection should be excluded in recurrent or severe cases.

Since pre-existing conditions may mask adverse reactions, Nitrofurantoin should be used with caution in patients with pulmonary disease, hepatic dysfunction, neurological disorders, and allergic diathesis.

Peripheral neuropathy and susceptibility to peripheral neuropathy which may become severe or irreversible has occurred and may be life threatening. Therefore, treatment should be stopped at the first signs of neural involvement (paraesthesiae).

Nitrofurantoin should be used in caution with patients with anaemia, diabetes mellitus, electrolyte imbalance, debilitating conditions and vitamin B (particularly folate) deficiency.

Acute, subacute and chronic pulmonary reactions have been observed in patients treated with nitrofurantoin. If these reactions occur, nitrofurantoin should be discontinued immediately.

Chronic pulmonary reactions (including pulmonary fibrosis and diffuse interstitial pneumonitis ) can develop insidiously, and may occur commonly in elderly patients. Close monitoring of the pulmonary conditions of patients receiving long-term therapy is warranted (especially in the elderly).

Patient should be monitored closely for signs of hepatitis (particularly in long term use). Urine may be coloured yellow or brown after taking Nitrofurantoin. Patients on Nitrofurantoin are susceptible to false positive urinary glucose (if tested for reducing substances).

Nitrofurantoin should be discontinued at any sign of haemolysis in those with suspected glucose-6-phosphate dehydrogenase deficiency.

Gastrointestinal reactions may be minimised by taking the drug with food or milk, or by adjustment of dosage.

For long-term treatment, monitor patients closely for evidence of hepatitis or pulmonary symptoms or other evidence of toxicity.

Discontinue treatment with Nitrofurantoin if otherwise unexplained pulmonary, hepatic, haematological or neurological syndromes occur.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

1.    Increased absorption with food or agents delaying gastric emptying.

2.    Decreased absorption with magnesium trisilicate.

3.    Decreased renal excretion of Nitrofurantoin by probenecid and sulphinpyrazone.

4.    Decreased anti-bacterial activity by carbonic anhydrase inhibitors and urine alkalisation.

5.    Anti-bacterial antagonism by quinolone anti-infectives.

6.    Interference with some tests for glucose in urine.

7.    As Nitrofurantoin belongs to the group of Antibacterials, it will have the following interactions:

•    Oestrogens: In common with other antibiotics, nitrofurantoin may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of oestrogen-containing contraceptive products. Therefore, patients should be warned appropriately and extra contraceptive precautions taken.

•    Typhoid Vaccine (oral): Antibacterials inactivate oral typhoid vaccine.

4.6 Fertility, pregnancy and lactation

Animal studies with Nitrofurantoin have shown no teratogenic effects. Nitrofurantoin has been in extensive clinical use since 1952, and its suitability in human pregnancy has been well documented. However, as with all other drugs, the maternal side effects may adversely affect course of pregnancy. The drug should be used at the lowest dose as appropriate for a specific indication, only after careful assessment.

Nitrofurantoin is however contraindicated in infants under three months of age and in pregnant women during labour and delivery, because of the possible risk of haemolysis of the infants' immature red cells. Breast feeding an infant known or suspected to have an erythrocyte enzyme deficiency (including G6PD deficiency), must be temporarily avoided, since Nitrofurantoin is detected in trace amounts in breast milk.

4.7 Effects on ability to drive and use machines

Nitrofurantoin may cause dizziness and drowsiness and the patient should not drive or operate machinery if affected this way.

4.8 Undesirable effects

The ADRs derived from clinical studies and post-marketing surveillance with nitrofurantoin, sorted by MedDRA System Organ Class are listed below.

The following terminologies have been used in order to classify the occurrence of undesirable effects.

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Infections and infestations
Overgrowth of non-susceptible organisms1	Not known
2 Blood and lymphatic system disorders
Agranulocytosis	Not known
Leucopenia	Not known
Granul ocytopenia	Not known
Thrombocytopenia	Not known
Megaloblastic anaemia	Not known
Glucose-6-phosphate dehydrogenase deficiency anaemia	Not known
Eosinophilia	Not known
Aplastic anaemia	Rare
Immune system disorders
Sialadenitis	Not known

Pruritus	Not known
Raculopapular	Not known
Erythematous or eczematous eruptions	Not known
Urticaria	Not known
Stevens-Johnson syndrome	Rare
Exfoliative dermatitis	Rare
Erythema multiforme	Rare
Lupus-like syndrome	Not known
Transient alopecia	Not known
Respiratory, thoracic and mediastinal disorders
7 Acute pulmonary disorder	Not known
7 Chronic pulmonary disorder	Not known
1    As with other antimicrobial agents, superinfections by fungi or resistant organisms such as Pseudomonas may occur. However, these are limited to the genito-urinary tract because suppression of normal bacterial flora does not occur elsewhere in the body. 2 Cessation of therapy has generally returned the blood picture to normal 3 Treatment should be stopped at the first sign of neurological involvement 4    With symptoms of sensory as well as motor involvement, which may become severe or irreversible 5    Treatment should be stopped at the first sign of hepatotoxicity 6    Cholestatic jaundice is generally associated with short-term therapy (usually up to two weeks). Chronic active hepatitis, occasionally leading to hepatic necrosis is generally associated with long-term therapy (usually after six months). The onset may be insidious 7 If any of the following reactions occur the drug should be discontinued. Acute pulmonary reactions usually occur within the first week of treatment and are reversible with cessation of therapy. Acute pulmonary reactions are commonly manifested by fever, chills, cough, chest pain, dyspnoea, pulmonary infiltration with consolidation or pleural effusion on chest x-ray, and eosinophilia. In subacute pulmonary reactions, fever and eosinophilia

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 the national reporting system, the Yellow card scheme: website www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms and signs of overdose include gastric irritation, nausea and vomiting.

There is no known specific antidote. However, Nitrofurantoin can be haemodialysed in cases of recent ingestion. Standard treatment is by induction of emesis or by gastric lavage. Monitoring of full blood count, liver function, and pulmonary function tests are recommended. A high fluid intake should be maintained to promote urinary excretion of the drug.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, Nitrofuran derivatives ATC Code: J01XE01 Mode of action

Nitrofurantoin is bactericidal in urine at therapeutic doses. The mechanism of the antimicrobial action of nitrofurantoin is unusual among antibacterials.

Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates which inactivate or alter bacterial ribosomal proteins and other macromolecules. As a result of such inactivations, the vital biochemical processes of protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis are inhibited.

PK/PD relationship

Efficacy is mainly dependent upon the Cmax (maximum serum concentration): MIC (minimum inhibitory concentration) ratio of the pathogen and the AUC (area under the curve)

Mechanism (s) of resistance

The broad-based nature of this mode of action may explain the lack of acquired bacterial resistance to nitrofurantoin, as the necessary multiple and simultaneous mutations of the target macromolecules would likely be lethal to the bacteria. Resistance to nitrofurantoin may be chromosomal or plasmid mediated, and involves inhibition of nitrofuran reductase. Nitrofurantoin resistance confers a reduction in fitness in E. coli in the absence of antibiotic. In the presence of therapeutic levels of nitrofurantoin, even resistant mutants are so disturbed in growth that they are probably unable to become enriched and establish an infection, and viability is decreased.

Cross-resistance with antibiotics and sulfonamides has not been observed, and transferable resistance is, at most, a very rare phenomenon

Breakpoints

According to the EUCAST (European Committee on Antimicrobial Susceptibility Testing) the following breakpoints have been defined for nitrofurantoin:

-Enterobacteriaceae: S < 64 mg/l and R > 64 mg/l

-    Escherichia coli : S < 64 mg/l and R > 64 mg/l

-    Enterococcus spp: S < 64 mg/l and R > 64 mg/l

-    Streptococcus agalactiae: S < 64 mg/l and R > 64 mg/l

-    Staphylococcus saprophyticus : S < 64.0 mg/l and R > 64.0 mg/l

Susceptibility

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infection is questionable.

5.3 Preclinical safety data

Carcinogenic effect of nitrofurantoin in animal studies was observed. However, human data and extensive use of nitrofurantoin over 50 years do not support such observations.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate Maize starch Purified talc Capsule Shell Gelatin

Sodium lauryl sulphate Iron oxide yellow (E172)

Titanium dioxide (E171)

6.2 Incompatibilities

Not known.

6.3 Shelf life

30 months.

6.4 Special precautions for storage

Store in the original container in order to protect from light.

6.5 Nature and contents of container

PVC /aluminium blisters of 10, 14, 15, 20, 28, 30 and 100 capsules.

Not all pack sizes may be marketed.

Special precautions for disposal

Nitrofurantoin Capsules should be used as directed by physician.

A patient information leaflet is provided with details of use and handling of the product.

MARKETING AUTHORISATION HOLDER

Morningside Healthcare Ltd 115 Narborough Road Leicester LE30PA United Kingdom

15/08/2014