This information is intended for use by health professionals

1. Name of the medicinal product

Macrobid 100mg Prolonged-release Capsules.

2. Qualitative and quantitative composition

Macrobid is a modified release, hard gelatin capsule containing the equivalent of 100mg of Nitrofurantoin in the form of nitrofurantoin macrocrystals and nitrofurantoin monohydrate.

Excipient(s) with known effect-Lactose 194.60 mg per capsule

For the full list of excipients, see section 6.1

3. Pharmaceutical form

The 100mg capsule has an opaque blue cap and opaque yellow body and bears the monogram “GS 100”.

4. Clinical particulars
4.1 Therapeutic indications

For the treatment of and prophylaxis against acute or recurrent, uncomplicated lower urinary tract infections or pyelitis either spontaneous or following surgical procedures. It is indicated in adults, children and infants over 12 years of age.

Macrobid is specifically indicated for the treatment of infections when due to susceptible strains of Escherichia coli, Enterococci, Staphylococci, Citrobacter, Klebsiella and Enterobacter.

Most strains of Proteus and Serratia are resistant. All Pseudomonas strains are resistant.

Macrobid is not indicated for the treatment of associated renal cortical or perinephric abscesses.

4.2 Posology and method of administration

Posology

Adults and children over 12 years of age.

The dose should be taken with food or milk (e.g. at meal times).

Acute or recurrent uncomplicated UTI and pyelitis -100mg twice daily for seven days.

Surgical Prophylaxis - 100 mg twice daily on the day of the procedure and 3 days thereafter.

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 (see section 4.8).

Children under 12 years

Macrobid is a fixed dosage and is therefore not suitable for children under 12 years

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

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)

• 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 a unilaterally 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 hepatic or pulmonary 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 (paraesthesia).

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).

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 signs 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.

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.

For long term treatment monitor the patient closely for appearance of hepatic or pulmonary symptoms and other evidence of toxicity.

Discontinue treatment with nitrofurantoin if otherwise unexplained pulmonary, hepatotoxic, haematological or neurological syndromes occur.

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 sulfinpyrazone.

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:

• 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 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

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

Macrobid 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, megaloblasticanaemia and eosinophilia

Immune system disorders

Not known

Allergic skin reactions, angioneuroticoedema 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 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

**Can be fatal

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 MHRA 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 specific antidote. However, Nitrofurantoin can be haemodialysed. Standard treatment is by induction of emesis or by gastric lavage in cases of recent ingestion. Monitoring of full blood count, liver function tests and pulmonary function, 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, nitrofuran derivatives

ATC code: J01XE01

Mechanism of action

Nitrofurantoin is a broad spectrum antibacterial agent, active against the majority of urinary pathogens. It is bactericidal in renal tissue and throughout the urinary tract. The wide range of organisms sensitive to the bacterial activity include Escherichia coli, Enteroccus faecalis, Klebsiella species, Enterobacter species, Staphylococcus species: (eg S. aureus, S. saprophyticus, S. epidermidis)

Clinically, most common urinary pathogens are sensitive to nitrofurantoin. Some strains of Enterobacter and Klebsiella are resistant. Nitrofurantoin is not active against most strains of Proteus species or Serratia species. It has no activity against Pseudomonas species.

5.2 Pharmacokinetic properties

Absorption:

Each Macrobid capsule contains two forms of nitrofurantoin. 25% of the dose is macrocrystalline nitrofurantoin which has slower dissolution and absorption than nitrofurantoin microcrystals. The remaining 75% of the dose is microcrystalline nitrofurantoin contained in a powdered blend which on exposure to gastric and intestinal fluids forms a gel matrix resulting in a modified release of active ingredient over time. Combined these systems provide a clinically effective bactericidal urine concentration at therapeutic doses.

Distribution:

Plasma nitrofurantoin concentrations at therapeutic doses of the Macrobid capsule are low, with peak levels usually less than 1 mcg/ml. Nitrofurantoin is highly soluble in urine to which it may impart a brown colour. Unlike many drugs the presence of food or agents delaying gastric emptying increases the bioavailability of the Macrobid capsule.

Elimination:

Approx. 20-25% of the total single dose of nitrofurantoin is recovered from the urine unchanged over 24 hours.

5.3 Preclinical safety data

None stated.

6. Pharmaceutical particulars
6.1 List of excipients

Macrobid Capsules contain talc, corn starch, lactose carbopol, povidone, sugar, magnesium stearate, gelatin and colouring agents (E104, E171, E132).

Printing ink contains Shellac, Propylene Glycol (E1520), Titanium Dioxide (E171), Black iron oxide (E172), Ammonium Hydroxide (E527) and Simethicone.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

The expiry date for the product should not exceed 2 years from the date of its manufacture.

6.4 Special precautions for storage

Capsules should be stored in light and moisture resistant containers.

Storage temperature should not exceed 30°C (aluminium/ aluminium).

Do not store above 25°C (For PVC/ polyethylene/aclar/aluminium blisters)

6.5 Nature and contents of container

There are two pack sizes, one consists of 14 capsules and the other is a sample pack containing 2 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.

7. Marketing authorisation holder

Mercury Pharmaceuticals Ltd,

Capital House,

85 King William Street,

London EC4N 7BL, UK

8. Marketing authorisation number(s)

PL 12762/0052

9. Date of first authorisation/renewal of the authorisation

31/03/2000

10. Date of revision of the text

18/03/2019