Nitrofurantoin 50 mg Hard Capsules

Capsule, hard (hard capsule) A hard gelatin capsule with a yellow cap and white body, size 3 (15.9 x 5.82 mm).

4.1 Therapeutic indications Nitrofurantoin is indicated in diseases of the urinary tract that are caused by micro-organisms sensitive to nitrofurantoin (see section 5.1). • In acute uncomplicated lower urinary tract infections; • For short-term prophylaxis after surgical procedures, transurethral interventions, catheterization, cystoscopy and indwelling catheter; • For long-term treatment of urinary tract infections up to 6 months; longer than 6 months only if the benefits clearly outweigh the potential risks. In view of the side effects, long-term therapy should only be used if no suitable alternative is available (see section 4.4). Consideration should be given to official guidance on the appropriate use of antibacterial agents.4.2 Posology and method of administration **Posology** **Treatment of acute uncomplicated lower urinary tract infections** Adults and children aged over 12 years: one 50 mg capsule 4 times a day. General use: 5 to 7 days or at least 3 days after no infection is detectable in the urine. In girls aged 5 to 12 years: the usual dose is 3 to 6 mg/kg body weight per day divided into 4 doses; for 7 days or at least 3 days after no infection is detectable in the urine. This pharmaceutical form (capsules) may not be suitable for use in children in this age group. **Short-term prophylaxis for urinary tract surgery** Adults and children from 12 years of age: 50 mg 4 times per day on the day of surgery and for 3 days after. **Long-term treatment of urinary tract infections** Adults and children from 12 years: 50 to 100 mg once a day, usually in the evening before sleep. **Method of administration** For oral use. This medicinal product should always be taken with food or milk. Taking Nitrofurantoin with a meal improves absorption and is important for optimal efficacy.4.3 Contraindications Nitrofurantoin is contraindicated: • for patients with hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • for patients with renal impairment (eGFR below 45 ml/min) or with an increased serum creatinine • for patients with G6PD deficiency • for patients with acute porphyria • for infants younger than three months because of the theoretical possibility of haemolytic anaemia in the foetus or in the newborn (less than 3 months old) due to immature erythrocyte enzyme systems • for patients who have previously had a lung or liver reaction other than a peripheral neuropathy after use of nitrofurantoin or other nitrofurans.4.4 Special warnings and precautions for use Prolonged use of Nitrofurantoin is not recommended. During nitrofurantoin treatment there may be lung and liver complications that could be life-threatening (see section 4.8). If this happens treatment should be stopped immediately and the necessary measures should be taken. Acute, subacute and chronic pulmonary reactions have been observed in patients treated with nitrofurantoin. If these reactions occur, nitrofurantoin must be discontinued immediately. Chronic pulmonary reactions (including pulmonary fibrosis and diffuse interstitial pneumonitis) can develop insidiously and can often occur in elderly patients. Close monitoring of the lung disease of patients receiving long-term therapy is indicated (especially in the elderly). **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, this medicinal product should be withdrawn immediately and appropriate measures should be taken. Existing conditions can mask pulmonary and hepatic side effects. Caution should be exercised when nitrofurantoin is used in patients with pulmonary diseases, disturbed hepatic function, neurological disorders and allergic diathesis. Peripheral neuropathy, which can become serious or irreversible, has occurred (usually within two months) and can become life-threatening. Therefore, treatment should be discontinued at the first signs of neural infection (paraesthesia, weakness). Conditions such as renal insufficiency, anaemia, diabetes mellitus, alcoholism, electrolyte disorder, vitamin B deficiency (especially folate deficiency) and exhaustive conditions increase the risk of developing peripheral neuropathy. Urine can be coloured yellow or brown after taking nitrofurantoin. Patients taking nitrofurantoin can test false positive for urine glucose (if tested for urine reducing substances). Nitrofurantoin should be discontinued if there is evidence of haemolysis in suspected persons of glucose-6-phosphate dehydrogenase deficiency (ten percent of individuals with dark skin colour of Afro-Caribbean origin and a small percentage of ethnic groups coming from the Mediterranean, Middle Eastern or Western Asian origin suffer from a G6PD deficiency). **Excipients** This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.4.5 Interaction with other medicinal products and other forms of interaction The effect of other medicinal products on nitrofurantoin: • Food or medicinal products that delays gastric emptying increase the bioavailability of nitrofurantoin, probably due to better dissolution in the gastric juice. • Carbonic anhydrase inhibitors and alkalising agents can reduce the antibacterial activity of nitrofurantoin. • Magnesium trisilicate co-administered with nitrofurantoin reduces the absorption of nitrofurantoin. • There may be an antagonism between quinolones and nitrofurantoin: simultaneous application is not recommended. • Probenecid and sulfinpyrazone can reduce the renal clearance of nitrofurantoin. The effect of nitrofurantoin on other medicines/laboratory tests: • Typhoid fever vaccine (oral): antibacterial agents make the oral typhoid fever vaccine ineffective. • Nitrofurantoin can affect certain laboratory tests. False positive results or incorrect high reading can occur with urinary glucose tests based on the reduction of copper sulphate, such as Benedict's reagent and Clinitest (Ames). However, there is no interference with the Clinistix test.4.6 Fertility, pregnancy and lactation **Pregnancy** A large amount of data in pregnant women has no teratogenicity or foetal/neonatal toxicity. Animal studies do not show reproductive toxicity at clinically relevant doses. If prescribed by a doctor, nitrofurantoin can be used during pregnancy. However, because of the possible risk of haemolysis of immature red blood cells in the baby, it is best not to be administered just before and during the delivery. **Breast-feeding** Nitrofurantoin is excreted in breast milk. The quantities in milk are so small that it is unlikely that these amounts can cause haemolytic anaemia in a G6PD-deficient infant. Nitrofurantoin can be used during breastfeeding. **Fertility** In men, a temporary stoppage in spermatogenesis and reduced sperm counts were observed at supratherapeutic doses. Clinical doses are not associated with male infertility. No reduced fertility was observed in animal studies. In rats, at high doses observed a temporary stoppage in spermatogenesis.4.7 Effects on ability to drive and use machines Nitrofurantoin may cause dizziness and drowsiness. If this happens the patient should not drive or operate machinery until the symptoms disappear.4.8 Undesirable effects Reported adverse reactions for nitrofurantoin are listed below according to organ system class. The frequency of the adverse reactions listed below is defined according to the following convention: very common (≥1/10), rare (≥1/10,000 to <1/1,000), not known (frequency cannot be estimated from the available data). | | | | | --- | --- | --- | | **MedDRA System Organ Class (SOC)** | **Frequency** | **Side effects** | | Infections and infestations | Not known | Sialadenitis. | | Blood and lymphatic system-diseases | Rare | Agranulocytosis, eosinophilia, leucopenia, granulocytopenia, thrombocytopenia, aplastic anaemia and megaloblastic anaemia1. | | Immune system disorders | Rare | Exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome. | | Not known | Maculo-papular rash, rash erythematous, eczema, urticaria, angioedema. Lupus syndrome (associated with lung reactions), anaphylactic reactions, DRESS syndrome, cutaneous vasculitis. | | Metabolism and nutrition disorders | Rare | Anorexia. | | Psychiatric disorders 2 | Not known | Depression, euphoria, confusion, psychotic reactions, headaches2**.** | | Nervous system disorders | Very common | Idiopathic intracranial hypertension. | | Not known | Peripheral motor neuropathy, peripheral sensory neuropathy. Neuritis optics. Nystagmus, dizziness, somnolence. | | Cardiac disorders | Rare | Circulatory collapse and cyanosis. | | Respiratory, thoracic and mediastinal conditions | Not known | Acute lung reactions3, fever, chills4, chest pain, dyspnoea, cough, lung infiltration with consolidation or pleural effusion5 and eosinophilia. Subacute lung reactions, fever and eosinophilia. Chronic lung reactions, fever, chills, cough and dyspnoea6. | | Gastrointestinal disorders | Rare | Nausea. | | Not known | Vomiting, abdominal pain, diarrhoea, pancreatitis. | | Hepatobiliary disorders | Rare | Cholestatic icterus and chronic hepatitis7. | | Not known | Autoimmune hepatitis. | | Skin and subcutaneous tissue disorders | Very common | Short-lived alopecia. | | Renal and urinary disorders | Very common | Superinfections by fungi or resistant organisms (i.e. *Pseudomonas*). | | Not known | Interstitial nephritis | | Congenital, familial and genetic disorders | Rare | Haemolytic anaemia/G6PD deficiency anaemia. | | General disorders and administration site conditions | Not known | Asthenia, arthralgia. | 1 Treatment should be discontinued when the blood count returns to normal. 2 Treatment should be discontinued at the first signs of neurological and/or psychological involvement.3 If any of the following respiratory reactions occur, the use of this medicinal product should be stopped.4 Acute pulmonary reactions usually occur within the first week of treatment and are reversible after discontinuation of treatment.5 Demonstrated through X-ray diagnosis.6 Chronic pulmonary reactions are rare in patients receiving continuous treatment for 6 months or more get longer and are more common in older patients.7 Fatalities are reported. Cholestatic icterus is generally associated with short-term treatment (usually up to 2 weeks). Chronic active hepatitis, which occasionally leads to necrosis, is generally associated with long-term treatment (usually 6 months). Treatment should be discontinued at the first signs of hepatotoxicity. See section 4.4. **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.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 within one hour after ingestion. 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 this medicinal product.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: antibacterials for systemic use ATC code: J01XE01 **Mechanism of action** Nitrofurantoin belongs to the nitrofurans. Therapeutically active concentrations are only achieved in the urine. Nitrofurantoin is most active in acidic urine and if the pH value is higher than 8 the majority of the antibacterial activity is lost. The exact mechanism of action is not known. Multiple working mechanisms are described. Nitrofurantoin inhibits a number of bacterial enzymes. It also inhibits bacterial ribosomal proteins and thus causes a complete inhibition of bacterial protein synthesis. It is possible that nitrofurantoin also causes damage to the DNA. **Resistance** Resistance rarely develops during treatment with nitrofurantoin, possibly because nitrofurantoin has different mechanisms of action. Resistance can occur with long-term treatment. Plasmid-encoded resistance is reported in *Escherichia coli*. Reduced sensitivity has been observed among ESBL-producing intestinal bacteria. Resistance can be due to the loss of nitrofuran reductases that generate the active intermediates. **Susceptibility testing breakpoints** MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for nitrofurantoin and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints\_en.xlsx The following table contains an overview of relevant micro-organisms for the indication. Commonly sensitive species: *Staphylococcus aureus* *Staphylococcus epidermis* *Staphylococcus saprophyticus* *Enterococcus faecalis* *Escherichia coli* Types where acquired resistance can be a problem: *Citrobacter* species *Enterobacter* species *Klebsiella* species Inherently resistant organisms: *Proteus* species *Pseudomonas* species *Serratia* species5.2 Pharmacokinetic properties **Absorption** Each capsule contains macrocrystalline nitrofurantoin, that dissolves and absorbs slower than the nitrofurantoin microcrystals. Nitrofurantoin is rapidly absorbed in the upper part of the small intestine. Ingestion with food or milk promotes absorption. Plasma concentrations are low at therapeutic doses, with peaks usually lower than 1 μg/ml. **Distribution** 60 to 77% of nitrofurantoin is loosely bound to plasma albumin. Distribution takes place between intra- and extracellular tissue components. Minor amounts of nitrofurantoin pass through the placenta. **Biotransformation** Approximately 60% of an administered dose of nitrofurantoin is primarily metabolised enzymatically to microbiologically inactive aminofurans, which can discolour the urine. **Elimination** The half-life in blood or plasma is estimated at about 60 minutes. In patients with normal kidney function and average dose, average values are 50 to 200 micrograms/ml nitrofurantoin in the urine.5.3 Preclinical safety data No data available.

6.1 List of excipients **Capsule content** Maize starch Lactose monohydrate Talc **Capsule shell** Titanium dioxide (E171) Gelatin Yellow iron oxide (E172)6.2 Incompatibilities Not applicable6.3 Shelf life 3 years6.4 Special precautions for storage This medicinal product does not require any special storage conditions.6.5 Nature and contents of container PVC/Aluminium foil blister pack containing 20 or 30 capsules and HDPE opaque bottle containing 500 capsules. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.