Nitrofurantoin 25mg-5ml oral suspension

Oral Suspension A yellow suspension with characteristic apricot odour.

4.1 Therapeutic indications Nitrofurantoin Oral Suspension 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). It is indicated in adults and children over 3 months of age. 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** 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). **Renal impairment** Nitrofurantoin is contraindicated in patients with renal dysfunction and in patients with an eGFR of less than 45 ml/minute (see sections 4.3 & 4.4). Method of administration: For oral use. It is recommended to shake well before use, until complete resuspension. This medicine should always be taken with food or milk. Taking Nitrofurantoin with a meal improves absorption and is important for optimal efficacy.4.3 Contraindications 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). 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 **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. **Pulmonary adverse reactions** Acute, subacute and chronic pulmonary reactions have been observed in patients treated with nitrofurantoin. If these reactions occur, nitrofurantoin should be discontinued immediately. Signs of pulmonary damage include difficulty and or pain when breathing, shortness of breath and coughing up blood or mucus. **Chronic pulmonary reactions** 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). **Acute pulmonary reactions** Pulmonary reactions may be acute and usually occur within the first week of treatment. Increased vigilance for respiratory symptoms in patients who have just started therapy is warranted (especially in the elderly). Nitrofurantoin Oral Suspension 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. 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. Since pre-existing conditions may mask adverse reactions, Nitrofurantoin Oral Suspension 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 (paraesthesia). Nitrofurantoin Oral Suspension should be used with caution in patients with anaemia, diabetes mellitus, electrolyte imbalance, debilitating conditions and Vitamin B (particularly folate) deficiency. Patients should be monitored closely for signs of hepatitis (particularly in long terms use). Urine may be coloured yellow or brown after taking Nitrofurantoin Oral Suspension. Patients on Nitrofurantoin Oral Suspension are susceptible to false positive urinary glucose (if tested for reducing substances). Nitrofurantoin Oral Suspension should be discontinued at any sign of haemolysis in those with suspected glucose-6-phosphate dehydrogenase deficiency. 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 diarrhoea4.5 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 Oral Suspension belongs to the group of Antibacterials it will have the following resulting interactions: 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. Breastfeeding 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 Oral Suspension 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 A tabulated list of undesirable effects is outlined below: The undesirable effects are listed according to organ systems and following frequencies: Rare (≥1/10,000 to <1/1,000) Not known (cannot be estimated from the available data) | | | | | --- | --- | --- | | System organ class | 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 | Not known | depression, euphoria, confusion, psychotic reactions | | Nervous system disorders | 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 | Not known | Acute pulmonary reactions, Subacute pulmonary reactions\* Chronic pulmonary reactions Cough, Dyspnoea, Pulmonary fibrosis; possible association with lupus-erythematous-like syndrome. | | Gastrointestinal disorders | Not known | Sialadenitis, Pancreatitis, Nausea, Anorexia, Emesis, Abdominal pain and Diarrhea. | | Hepatobiliary disorders | Not known | Cholestatic jaundice, Chronic active hepatitis\\, Hepatic necrosis, Autoimmune hepatitis | | Skin and subcutaneous tissue disorders | Not known | Transient alopecia Exfoliative dermatitis and erythema multiforme (including Stevens-Johnson Syndrome), 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 | | Investigations | Not known | False positive urinary glucose | \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. \\*Fatal events have been reported 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose Symptoms Symptoms and signs of overdose include gastric irritation, nausea and vomiting. Management 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.

5.1 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. 8.1, valid from 2018-05-15*) | | | | | --- | --- | --- | | | ***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.

6.1 List of excipients Methyl parahydroxybenzoate Propyl parahydroxybenzoate Polysorbate 20 Glycerol Carbomer Sucralose Apricot flavour Sodium hydroxide6.2 Incompatibilities None known6.3 Shelf life 3 years After first opening: 3 months6.4 Special precautions for storage This medicinal product does not require any special storage conditions before opening. After first opening do not store above 25oC and use within 3 months.6.5 Nature and contents of container | | | | --- | --- | | Bottle: | 300 ml in Amber (Type III) glass | | Closure: | LDPE, child-resistant and tamper evident 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.