4.1. Therapeutic indications

Fomicyt is indicated in all age groups for the treatment of the following infections when it is considered inappropriate to use antibacterial agents that are commonly recommended for their initial treatment (see sections 4.2, 4.4 and 5.1):

- complicated urinary tract infections

- infective endocarditis

- bone and joint infections

- hospital-acquired pneumonia, including ventilator-associated pneumonia

- complicated skin and soft tissue infection

- bacterial meningitis

- complicated intra-abdominal infections

- bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

The daily dose of fosfomycin is determined based on the indication, severity and site of the infection, susceptibility of the pathogen(s) to fosfomycin and the renal function. In children, it is also determined by age and body weight.

Adults and adolescents (≥ 12 years of age) (≥ 40 kg):

The general dosage guidelines for adults and adolescents with estimated creatinine clearance > 80 ml/min are as follows:

Table 1 – dosing in adults and adolescents with CrCl >80 ml/min

Indication

Daily dose

Complicated urinary tract infection

12–24 g a in 2–3 divided doses

Infective endocarditis

12–24 g a in 2–3 divided doses

Bone and joint infections

12–24 g a in 2–3 divided doses

Hospital-acquired pneumonia, including ventilator-associated pneumonia

12–24 g a in 2–3 divided doses

Complicated skin and soft tissue infections

12–24 g a in 2–3 divided doses

Bacterial meningitis

16–24 g a in 3–4 divided doses

Complicated intra-abdominal infections

12–24 g a in 2–3 divided doses

Bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above

12–24 g a in 2–3 divided doses

Individual doses must not exceed 8 g.

a The high-dose regimen in 3 divided doses should be used in severe infections expected or known to be caused by less susceptible bacteria.

There are limited safety data in particular for doses in excess of 16 g/day. Special caution is advised when such doses are prescribed.

Duration of treatment

Treatment duration should take into account the type of infection, the severity of the infection as well as the patient's clinical response.

Elderly patients

The recommended doses for adults should be used in elderly patients. Caution is advised when considering the use of doses at the higher end of the recommended range (see also recommendations on dosage for patients with impaired renal function).

Renal impairment

No dose adjustment is recommended in patients within estimated creatinine clearance between 40–80 ml/min. However, caution should be exercised in these cases, particularly if doses at the higher end of the recommended range are considered

In patients with impaired renal function the dose of fosfomycin must be adjusted to the degree of renal impairment.

Dose titration should be based on creatinine clearance values.

Table 2 shows the recommended dose adjustments for patients with a CrCL less than 40 mL/min:

Table 2 – Dose adjustments for patients with a CrCL less than 40 mL/min

CLCR patient

CLCR patient/CLCR normal

Daily dosage recommendeda

40 mL/min

0.333

70% (in 2-3 divided doses)

30 mL/min

0.250

60% (in 2-3 divided doses)

20 mL/min

0.167

40% (in 2-3 divided doses)

10 mL/min

0.083

20% (in 1-2 divided doses)

a The dose is expressed as a proportion of the dose that would have been considered appropriate if the patient's renal function were normal as calculated according to Cockgroft-Gault formula.

The first dose (loading dose) should be increased by 100%, but must not exceed 8 g.

Patients undergoing renal replacement therapy

Patients undergoing chronic intermittent dialysis (every 48 hours) should receive 2 g of fosfomycin at the end of each dialysis session.

During continuous veno-venous hemofiltration (post-dilution CVVHF), fosfomycin is effectively eliminated. Patients undergoing post-dilution CVVHF will not require any dose adjustment (see section 5.2).

Hepatic impairment

No dose adjustment is necessary in patients with hepatic impairment.

Paediatric population

Dose recommendations are based on very limited data.

Neonates, infants and children < 12 years of age (< 40 kg)

The dosage of fosfomycin in children should be based on age and body weight (BW):

Table 3 – Dosing in children and neonates

Age/weight

Daily dose

Premature neonates (age a <40 weeks)

100 mg/kg BW in 2 divided doses

Neonates (age a 40-44 weeks)

200 mg/kg BW in 3 divided doses

Infants 1-12 months (up to 10 kg BW)

200-300 b mg/kg BW in 3 divided doses

Infants and children aged 1≤12 years (10≤40 kg BW)

200-400 b mg/kg BW in 3-4 divided doses

a Sum of gestational and postnatal age

b The high-dose regimen may be considered for severe infections and or serious infections (such as meningitis), in particular when known or suspected to be caused by organisms with moderate susceptibility.

No dose recommendations can be made for children with renal impairment.

Method of administration

Fomicyt is intended for intravenous use.

The duration of infusion should be at least 15 minutes for the 2 g pack size, at least 30 minutes for the 4 g pack size and at least 60 minutes for the 8 g pack size.

As damaging effects can result from inadvertent intra-arterial administration of products not specifically recommended for intra-arterial therapy, it is essential to ensure that fosfomycin is only administered into veins.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Risk of selecting for resistance and the need for combination therapy

In vitro, fosfomycin has been found to rapidly select for resistant mutants. Also, the use of intravenous fosfomycin alone has been associated with selection of resistance in clinical studies. Whenever possible, it is recommended that fosfomycin is administered as part of a combination antibacterial drug regimen to reduce the risk of selecting for resistance.

Limitations of the clinical data

The clinical data to support the use of intravenous fosfomycin for treatment of some of the listed indications is limited by a lack of adequate randomised controlled trials. Furthermore, various dose regimens have been used and no single intravenous dose regimen has been strongly supported by clinical trial data. It is recommended that fosfomycin is selected to treat the listed indications only when it is considered inappropriate to use antibacterial agents that are commonly recommended for their initial treatment.

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during fosfomycin treatment (see sections 4.3 and 4.8). If such reactions occur, treatment with fosfomycin must be discontinued immediately and adequate emergency measures must be initiated.

Clostridioides difficile-associated diarrhea

Clostridioides difficile-associated colitis and pseudo-membranous colitis have been reported with fosfomycin and may range in severity from mild to life-threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhea during or subsequent to the administration of fosfomycin. Discontinuation of therapy with fosfomycin and the administration of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Sodium and potassium levels and risk of sodium overload

Sodium and potassium levels should be monitored regularly in patients receiving fosfomycin, in particular during prolonged treatment. Given the high content of sodium (0.32 grams) per gram of fosfomycin, the risk of hypernatraemia and fluid overload should be assessed before starting treatment, especially in patients with a history of congestive heart failure or underlying comorbidities such as nephrotic syndrome, liver cirrhosis, hypertension, hyperaldosteronism, pulmonary oedema or hypoalbuminemia as well as in neonates under sodium restriction. A low-sodium diet is recommended during treatment. An increase in the infusion length and/or a reduction to the individual dose (with more frequent administration) could also be considered. Fosfomycin may decrease potassium levels in serum or plasma, therefore potassium supplementation should be always considered.

Haematological reactions (including agranulocytosis)

In patients receiving fosfomycin intravenously haematological reactions including neutropenia or agranulocytosis have occurred (see section 4.8). Therefore, the leukocyte count should be monitored at regular intervals and if such reactions occur, an adequate medical treatment should be initiated.

Renal impairment

In patients with impaired renal function, adjust the dosage according to the grade of renal insufficiency (see section 4.2).

Excipients

1 g fosfomycin (equivalent to 1.32 g disodium fosfomycin) contains 14 mmol (320 mg) sodium, equivalent to 16 % of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult. One bottle with 2 g of fosfomycin contains 28 mmol (640 mg) sodium, one bottle with 4 g fosfomycin contains 56 mmol (1280 mg) sodium and one bottle with 8 g of fosfomycin contains 111 mmol (2560 mg) sodium.

4.5. Interaction with other medicinal products and other forms of interaction

Specific concerns relating to INR imbalance:

Numerous cases of increased oral anticoagulant activity have been reported in patients receiving antibiotic therapy. The severity of the infection or inflammation, patient age and general state of health appear to be risk factors. Under these circumstances, it is difficult to determine to what extent the infection itself or its treatment play a role in the INR imbalance. However, certain classes of antibiotics are more involved, particularly: fluoroquinolones, macrolides, cyclins, cotrimoxazole, and certain cephalosporins.

4.6. Fertility, pregnancy and lactation

Pregnancy:

There are no data from the use of intravenously administered fosfomycin in pregnant women. Fosfomycin crosses the placenta. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Fosfomycin should therefore not be prescribed to pregnant women unless the benefit outweighs the risk.

Breast-feeding:

After the administration of fosfomycin, low quantities were found in human milk. Only scarce information about fosfomycin use during breastfeeding is available, therefore this treatment is not recommended as first choice for a breastfeeding woman, especially if she is breastfeeding a premature or new-born baby. No specific risk for a breastfed child was demonstrated, however, as with any other antibiotics a potential risk of changes in infant bowel flora should be taken into consideration.

Fertility:

No data in humans are available. In male and female rats oral administration of fosfomycin up to 1000 mg/kg/day did not impair fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

No specific studies have been performed but patients should be informed that confusion and asthenia have been reported. This may influence some patients' ability to drive and use machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions during treatment are erythematous skin eruption, ion disbalances (see section 4.4), injection site reactions, dysgeusia and gastrointestinal disturbances. Other important adverse reactions include anaphylactic shock, antibiotic associated colitis and decreases in white blood cell counts (see section 4.4).

Tabulated list of adverse reactions

Undesirable effects are listed by body system and frequency using the following convention:

Very common: ≥ 1/10

Common: ≥ 1/100 to < 1/10

Uncommon: ≥ 1/1,000 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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Frequency

Adverse reaction

Blood and lymphatic system disorders

Not known

Agranulocytosis (transient), leucopenia, thrombocytopenia, neutropenia

Immune system disorders

Very rare

Anaphylactic reactions including anaphylactic shock and hypersensitivity (see section 4.4)

Nervous system disorders

Common

Dysgeusia,

Uncommon

Headache

Investigations

Common

Hypernatremia, hypokalemia* (see section 4.4)

Gastrointestinal disorders

Uncommon

Nausea, vomiting, diarrhea

Not known

Antibiotic-associated colitis (see section 4.4)

Hepatobiliary disorders

Uncommon

Blood alkaline phosphatase increased (transient), Transaminases increased (ALAT, ASAT), gamma-GT increased

Not known

Hepatitis

Skin and subcutaneous tissue disorders

Common

Erythematous eruption

Uncommon

Rash

Not known

Angioedema, pruritus, urticaria

General disorders and administration site conditions

Common

Injection site phlebitis

Uncommon

Asthenia

* see section below (Description of selected adverse reactions)

Description of selected adverse reactions:

Hypokalemia may result in diffuse symptoms such as weakness, tiredness or oedema and/or muscle twitching. Severe forms may cause hyporeflexia and cardiac arrhythmia. Hypernatremia may be associated with thirst, hypertension and signs of fluid overload such as oedema (see section 4.4). Severe forms may cause confusion, hyperreflexia, seizures and coma.

Paediatric population

Limited safety information is available from the paediatric population. Frequency, type and severity of adverse reactions may be expected to be similar to the adult population.

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

Experience regarding the overdose of fosfomycin is limited. Cases of hypotonia, somnolence, electrolytes disturbances, thrombocytopenia and hypoprothrombinemia have been reported with parenteral use of fosfomycin. In the event of overdose, the patient must be monitored (particularly for plasma/serum electrolyte levels), and treatment should be symptomatic and supportive. Rehydration is recommended to promote urinary elimination of the active substance. Fosfomycin is effectively cleared from the body by haemodialysis with a mean elimination half-life of approximately 4 hours.