Nitrofurantoin

Nitrofurantoin 50mg Capsules, Hard

Each capsule contains 50mg of nitrofurantoin in macrocrystalline form.

It also contains lactose monohydrate (see section 4.4).

For the full list of excipients, see section 6.1.

Hard, gelatin capsules.

Size '3' opaque yellow cap and opaque white body hard gelatin capsules, imprinted with “EM28” with 360 deg. thin band, in black ink on cap.

Dimension (Length): 15.80 mm ± 0.40 mm

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.

Posology

Adults

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

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

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

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

Children and Infants over three months of age

For children under 25 kg body weight consideration should be given to the use of Nitrofurantoin Suspension.

Acute Urinary Tract Infections: 3mg/kg day in four divided doses for seven days.

Suppressive - 1mg/kg, once a day.

Nitrofurantoin should not be used in children under three months of age (see section 4.3).

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).

Method of administration

For oral use.

This medicine should always be taken with food or milk. Taking Nitrofurantoin with a meal improves absorption and is important for optimal efficacy.

Hypersensitivity to nitrofurantoin, other nitrofurans or to any of the excipients listed in section 6.1.

Patients suffering from renal dysfunction with an eGFR below 45 ml/minute.

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.

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 with caution in 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).

Patients 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.

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.

Nitrofurantoin 50mg Capsules contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hepatotoxicity

Hepatic reactions, including hepatitis, autoimmune hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis, occur rarely. Fatalities have been reported. The onset of chronic active hepatitis may be insidious, and patients should be monitored periodically for changes in biochemical tests that would indicate liver injury. If hepatitis occurs, the drug should be withdrawn immediately and appropriate measures should be taken.

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 the oral typhoid vaccine.

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 the 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.

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

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 (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).

Chronic pulmonary reactions occur rarely in patients who have received continuous therapy for six months or longer and are more common in elderly patients. Changes in ECG have occurred, associated with pulmonary reactions. Minor symptoms such as fever, chills, cough and dyspnoea may be significant. Collapse and cyanosis have been reported rarely. The severity of chronic pulmonary reactions and their degree of resolution appear to be related to the duration of therapy after the first clinical signs appear. It is important to recognise symptoms as early as possible. Pulmonary function may be impaired permanently, even after cessation of therapy.

⁶ Treatment should be stopped at the first sign of hepatotoxicity.

⁷ Fatalities have been reported. 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.

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store.

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.

Pharmacotherapeutic group: Antibacterials for systemic use – other antibacterials

ATC code: J01XE01

Mode of action

Nitrofurantoin is reduced by various bacterial enzymes to reactive intermediates which bind to bacterial ribosomes and inhibit several bacterial enzymes involved in the synthesis of DNA, RNA and other metabolic enzymes.

PK/PD relationship

There are no recent pharmacokinetic data available or studies that link pharmacokinetic (PK) with pharmacodynamics (PD) information. The PK/PD index and correlation with outcome is not known.

Mechanism (s) of resistance

Nitrofurantoin acts at multiple targets in the bacterial cell and resistance is uncommon. Resistance is thought to be due to loss of intracellular nitroreductase activity via sequential mutations in the DNA regions encoding these enzymes.

Breakpoints

Susceptibility interpretive Criteria for Nitrofurantoin (EUCAST v. 8.1, valid from 2018-05-15)

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.

* In vitro data are available, but their clinical significance is unknown

Clinically, most common urinary pathogens are sensitive to nitrofurantoin.

Most strains of proteus and serratia are resistant. All pseudomonas strains are resistant.

The nitrofurantoin macrocrystals are specially formulated. The controlled crystal size is designed to control the speed of absorption and thus reduce the incidence of nausea. Clinical and animal studies indicate that nitrofurantoin therapy decreases the likelihood of nausea in patients who might experience these symptoms on nitrofurantoin therapy. This special formulation of nitrofurantoin had not caused any decrease in antibacterial efficacy.

Orally administered nitrofurantoin is readily absorbed in the upper gastrointestinal tract at a slower rate and to a reduced extent when compared to microcrystalline nitrofurantoin. Blood concentrations at therapeutic dosage are usually low with an elimination half-life of approximately 30 minutes or less.

Maximum urinary excretion usually occurs 4-5 hours after administration of macrocrystalline nitrofurantoin. Urinary drug dose recoveries of approximately 25-30% are obtained.

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.

Capsule content:

Lactose Monohydrate

Pregelatinized starch

Talc

Capsule shell:

Gelatin

Purified water

Quinoline yellow (E104)

Iron oxide yellow (E172)

Titanium dioxide (E171)

Printing ink:

Shellac

Propylene glycol

Potassium hydroxide

Black iron oxide (E172)

Not applicable.

2 years.

This medicinal product does not require any special storage conditions.

Nitrofurantoin 50mg Capsules, Hard are supplied in PVC white opaque/aluminium foil blisters.

Nitrofurantoin 50mg Capsules are available in packs of 20 and 30 capsules.

Not all pack sizes may be marketed.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Tillomed Laboratories Ltd220 Butterfield, Great Marlings,

Luton, LU2 8DL

United Kingdom

PL 11311/0573

13/02/2019

23/01/2020