This information is intended for use by health professionals

1. Name of the medicinal product

Nitrofurantoin 25mg/5ml Oral Suspension

2. Qualitative and quantitative composition

Each 5 ml oral suspension contains 25 mg Nitrofurantoin (as monohydrate)

Excipients with known effect:

Methyl parahydroxybenzoate

Propyl parahydroxybenzoate

Glycerol

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Oral Suspension

A yellow suspension with characteristic apricot odour.

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 either spontaneous or following surgical procedures 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

Posology

Dosage:

Adults

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

Severe Chronic Recurrence: 100mg four times day for seven days.

Long Term Suppression: 50mg - 100mg once a day.

Prophylaxis: 50mg four times daily for the duration of procedure and 3 days thereafter.

Paediatric population

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.

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. It is recommended to shake well before use, until complete resuspension.

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 (including pregnancy at term, and breast-feeding of affected infants, Third trimester: May produce neonatal haemolysis if used at term, only small amounts are present in milk but could be enough to produce haemolysis in G6PD deficient infants), 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.

4.4 Special warnings and precautions for use

Nitrofurantoin is not effective for the treatment of parenchymal infections of unilaterally non-functioning 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 terms 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.

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.

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

Excipient Warnings

This product contains:

Methyl parahydroxybenzoate which may cause allergic reaction (possibly delayed)

Propyl parahydroxybenzoate which may cause allergic reaction (possibly delayed)

Glycerol which may cause headache, stomach upset and diarrhoea

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 resulting interactions:

Oestrogens: Antibacterials that do not induce liver enzymes possibly reduce contraceptive effect of oestrogens (risk probably small, Interactions of combined oral contraceptives may also apply to combined contraceptive patches).

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

4.6 Fertility, pregnancy and lactation

Pregnancy

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 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

Caution should be exercised while breast-feeding an infant known or suspected to have an erythrocyte enzyme deficiency, 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. Patients should be advised not to drive or operate machinery if affected in this way until such symptoms go away.

4.8 Undesirable effects

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1000 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)

System organ class MedDRA

Frequency

Adverse reaction

Infections and infestations

Not known

Superinfections by fungi or resistant organisms such as Pseudomonas. However, these are limited to the genitourinary tract

Blood and lymphatic system disorders

Rare

Not known

Aplastic anaemia

Agranulocytosis, leucopenia, granulocytopenia, haemolytic anaemia, thrombocytopenia,glucose-6-phosphatedehydrogenase deficiency anaemia, megaloblastic anaemia and eosinophilia

Immune system disorders

Not known

Allergic skin reactions, angioneurotic oedema and anaphylaxis, Cutaneous vasculitis

Psychiatric disorders

Rare

Depression, euphoria, confusion, psychotic reactions

Nervous system disorders

Rare

 

Not known

Peripheral neuropathy including optic neuritis (sensory as well as motor involvement), nystagmus, vertigo, dizziness, headache and drowsiness.

Benign intracranial hypertension

Cardiac disorders

Rare

Collapse and cyanosis

Respiratory, thoracic and mediastinal disorders

Rare

Not known

Chronic pulmonary reactions

Acute pulmonary reactions*, Subacute pulmonary reactions, Cough, Dyspnoea, Permanent impairment of pulmonary function, Pulmonary fibrosis; possible association with lupus-erythematous-like syndrome. Bronchiolitis obliterans organizing pneumonia.

Gastrointestinal disorders

Uncommon

Not known

Emesis, Abdominal pain and Diarrhoea.

Sialadenitis, Pancreatitis, Nausea, Anorexia,

Hepatobiliary disorders

Rare
 

Not known

Liver failure (which maybe fatal), Cholestatic jaundice, Chronic active hepatitis (fatalities have been reported)

Hepatic necrosis, Autoimmune hepatitis

Skin and subcutaneous tissue disorders

Rare
 

Not known

Exfoliative dermatitis and erythema multiforme (including Stevens-Johnson Syndrome)

Transient alopecia, maculopapular, erythematous or eczematous eruptions,urticaria, rash, and pruritis. Lupus-like syndrome associated with pulmonary reaction.

Drug Rash With Eosinophilia And Systemic Symptoms (DRESS syndrome), cutaneous vasculitis

Renal and urinary disorders

Not known

Yellow or brown discolouration of urine, Interstitial nephritis

General disorders and administration site conditions

Not known

Asthenia, fever, chills, drug fever and arthralgia

Congenital, familial and genetic disorders

Not Known

Acute porphyria

Investigations

Not known

False positive urinary glucose

*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 occur less often than in the acute form. 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.

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

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
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use – other antibacterials

ATC code: J01XE01

Mode of action: Nitrofurantoin is reduced by a wide range of enzymes including bacterial flavoproteins 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 pharmacodynamic (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. 9.0, valid from 2019-01-01)

MIC breakpoint (mg/L)

S ≤

R >

E. coli*

64

64

S. saprophyticus*

64

64

E. faecalis*

64

64

S. agalactiae (group B streptococci)*

64

64

Aerococcus sanguinicola and urinae *

16

16

*Uncomplicated UTI only

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.

Commonly susceptible species:

Aerobic gram-positive microorganisms

Enterococcus species

Staphylococcus aureus

Coagulase-negative staphylococci (including Staphylococcus epidermidis and Staphylococcus saprophyticus)*

Streptococcus agalactiae*

Viridans group streptococci*

Aerobic gram-negative microorganisms

Citrobacter koseri*

Citrobacter freundii*

Escherichia coli

Klebsiella oxytoca*

* In vitro data are available, but their clinical significance is unknown. Nitrofurantoin exhibits in vitro activity against these bacteria; however, the safety and effectiveness of nitrofurantoin in treating clinical infections due to these bacteria have not been established in adequate and well controlled clinical trials.

Species for which acquired resistance may be a problem

Aerobic gram-negative microorganisms

Klebsiella oxytoca*

Enterobacter spp

Inherently resistant organisms

Aerobic gram-negative microorganisms

Proteus spp

Pseudomonas spp

Serratia spp

Morganella spp

Providencia spp

5.2 Pharmacokinetic properties

Absorption

Orally administered Nitrofurantoin is readily absorbed in the upper gastrointestinal tract and is rapidly excreted in the urine. Blood concentrations at therapeutic dosages are usually low.

Elimination

Maximum urinary excretion usually occurs 2-4 hours after administration of Nitrofurantoin. Urinary drug dose recoveries of about 40-45% are obtained. It has an elimination half-life of about 30 minutes

5.3 Preclinical safety data

A carcinogenic effect of Nitrofurantoin in animal studies was observed. However, human data and extensive use of Nitrofurantoin over 50 years do not support such observation.

6. Pharmaceutical particulars
6.1 List of excipients

Methyl parahydroxybenzoate

Propyl parahydroxybenzoate

Polysorbate 20

Glycerol

Carbomer

Sucralose

Apricot flavour

Sodium hydroxide

6.2 Incompatibilities

None known

6.3 Shelf life

3 years

After first opening: 3 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions before opening.

After first opening do not store above 25°C and use within 3 months.

6.5 Nature and contents of container

Bottle: 300 ml in Amber (Type III) glass

Closure: LDPE child-resistant screw cap

Dosing devices: One 5 ml oral medication syringe (plastic dosing pipette) with 0.1ml graduation and

the neck fitted syringe adaptor for the bottle or one double plastic 2.5/5.0 ml spoon

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

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

7. Marketing authorisation holder

Aspire Pharma Ltd

Unit 4 Rotherbrook Court,

Bedford Road

Petersfield

GU32 3QG

8. Marketing authorisation number(s)

PL 35533/0138

9. Date of first authorisation/renewal of the authorisation

16/07/2019

10. Date of revision of the text

16/07/2019