4.1. Therapeutic indications

Because of the risk of prolonged, disabling and potentially irreversible serious adverse drug reactions (see section 4.4 and section 4.8) this product must only be prescribed when other antibiotics that are commonly recommended for the infection are inappropriate. This applies to all indications listed below. Situations where other antibiotics are considered to be inappropriate are where:

• there is resistance to other first-line antibiotics recommended for the infection;

• other first-line antibiotics are contraindicated in an individual patient;

• other first-line antibiotics have caused side effects requiring treatment to be stopped;

• treatment with other first-line antibiotics has failed.

Quofenix is indicated for the treatment of the following infections in adults:

• acute bacterial skin and skin structure infections (ABSSSI)

• community-acquired pneumonia (CAP)

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

4.2. Posology and method of administration

Posology

The recommended dose is 300 mg delafloxacin every 12 hours administered over 60 minutes by intravenous infusion. Switch to delafloxacin 450 mg tablet orally every 12 hours is possible at the discretion of the physician. The total duration of treatment is 5 to 14 days for ABSSSI and 5 to 10 days for CAP.

Special population

Elderly

No dose adjustment is required. As per fluoroquinolone class patients aged over 60 years are at increased risk for developing severe tendon disorders including tendon rupture (see sections 4.4 and 5.2).

Renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (CrCl of ≥30 mL/min). Dosing in patients with severe renal impairment (CrCl of <30 mL/min) should be decreased to 200 mg intravenously every 12 hours; alternatively patients should receive 450 mg delafloxacin orally every 12 hours (see section 4.4 and 5.2).

Quofenix is not recommended in patients with End Stage Renal Disease (ESRD).

Hepatic impairment

No dosage adjustment is necessary (see section 5.2).

Paediatric population

Quofenix is contraindicated in children and adolescents (see section 4.3).

Method of administration

Intravenous use.

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.

Hypersensitivity to any fluoroquinolone or quinolone antibacterial medicinal product.

Previous history of tendon disorders related to fluoroquinolone administration.

Pregnancy, women of childbearing potential not using contraception and breast-feeding (see section 4.6).

Children or growing adolescents below 18 years of age (see section 4.2).

4.4. Special warnings and precautions for use

The use of delafloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products (see section 4.8). Treatment of these patients with delafloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).

Contraception

If women of a sexually mature age are treated, effective contraception must be used during treatment (see section 4.6).

Aortic dissection and aneurysm, and heart valve regurgitation/incompetence

Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones.

Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.8).

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease or congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection or heart valve disease, or in presence of other risk factors or conditions predisposing

- for both aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behcet's disease, hypertension, rheumatoid arthritis) or additionally

- for aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome) or additionally

- for heart valve regurgitation/incompetence (e.g. infective endocarditis).

The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.

In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Patients should be advised to seek immediate medical attention in case of acute dyspnoea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, and those treated concurrently with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided. At the first sign of tendinitis (e.g. painful swelling, inflammation) the treatment with delafloxacin should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g. immobilisation). Corticosteroids should not be used if signs of tendinopathy occur (see section 4.8).

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with delafloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially irreversible condition (see section 4.8).

Central nervous system effects

Fluoroquinolones have been associated with an increased risk of central nervous system (CNS) reactions, including: convulsions and increased intracranial pressure (including pseudotumor cerebri) and toxic psychosis. Fluoroquinolones may also cause CNS reactions of nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or acts. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving delafloxacin, delafloxacin should be discontinued immediately and appropriate measures should be instituted. Delafloxacin should be used when the benefits of treatment exceed the risks in patients with known or suspected CNS disorders (e.g. severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold.

Exacerbation of myasthenia gravis

Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse reactions, including deaths and requirement for ventilator support, have been associated with fluoroquinolone use in persons with myasthenia gravis. The use of delafloxacin is not recommended in patients with known history of myasthenia gravis.

Clostridioides difficile-associated disease

Clostridioides difficile-associated disease has been reported in users of nearly all systemic antibacterial medicinal products, with severity ranging from mild diarrhoea to fatal colitis. Clostridioides difficile-associated disease must be considered in all patients who present with diarrhoea. If Clostridioides difficile-associated disease is suspected or confirmed treatment with delafloxacin should be discontinued and appropriate supportive measures together with the specific antibacterial treatment of C. difficile should be considered.

Medicinal products inhibiting the peristalsis are contraindicated if Clostridioides difficile-associated disease is suspected.

Hypersensitivity reactions

Patients with known hypersensitivity to delafloxacin or other fluoroquinolones must not take Quofenix (see section 4.3). Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving fluoroquinolone antibacterial medicinal products. Before initiating therapy with Quofenix, careful inquiry should be made about previous hypersensitivity reactions to other quinolone or fluoroquinolone antibacterial medicinal products. If an anaphylactic reaction to Quofenix occurs, the medicinal product should be discontinued immediately and appropriate therapy should be instituted.

Patients with renal impairment

Dose adjustment is needed in patients with severe renal impairment (see section 4.2).

The safety and efficacy of the dose adjustment guidance in patients with severe renal impairment has not been clinically evaluated and is based on pharmacokinetic modelling data. Delafloxacin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk. Clinical response to treatment and renal function should be closely monitored in these patients.

Accumulation of the intravenous vehicle sulfobutylbetadex sodiumoccurs in patients with moderate to severe renal impairment; therefore serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to switch to Quofenix 450 mg tablet every 12 hours.

Quofenix is not recommended in patients with End Stage Renal Disease (ESRD).

Limitations of the clinical data

In the two major trials in ABSSSI the types of infections treated were confined to cellulitis/erysipelas, abscesses and wound infections only. Other types of skin infections have not been studied. Patients with toxic shock, neutropenia (neutrophil counts < 500 cells/mm3) or severely immunocompromised patients were not included in the studies. There is limited experience in patients aged > 75 years. However, the CAP population was older than the one studied in ABSSSI (48.3 % of subjects were ≥ 65 years and 23.9% ≥ 75 years). In the CAP study 90.7% of patients had CURB-65 score of ≤2. However 69.3% of patients were categorised to PORT class III and 30.7% of patients had a PORT score >III.

Prolonged, disabling and potentially irreversible serious adverse drug reactions

Cases of prolonged (continuing for months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (including musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. There are no pharmacological treatments established to be effective treatments of the symptoms of long lasting or disabling side effects associated with fluoroquinolones. Delafloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice, so that symptoms can be appropriately investigated and to avoid further exposure which could potentially worsen adverse reactions.

Superinfection

Fluoroquinolone non-susceptible microorganisms may result in superinfection with the use of delafloxacin. If superinfection occurs during therapy, appropriate measures should be taken.

Dysglycaemia

As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported (see section 4.8), usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.

There are no data available on severe cases of hypoglycaemia resulting in coma or death after delafloxacin use.

Serious bullous skin reactions

Cases of bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with other fluoroquinolones. Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with a family history of, or actual glucose-6-phosphate dehydrogenase deficiency are prone to haemolytic reactions when treated with other quinolones. Therefore, delafloxacin should be used with caution in these patients.

Excipients

This medicinal product contains sulfobutylbetadex sodium. In patients with moderate to severe renal impairment, accumulation of cyclodextrins occurs.

This medicinal product contains 175 mg sodium per vial, equivalent to 8.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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

Effect of other medicinal products on delafloxacin

There are no available data concerning specific effects of other medicinal products on delafloxacin. Known fluoroquinolones-associated possible interactions shall be considered.

Effect of delafloxacin on other medicinal products

Chelation active substance: antacids, sucralfate, metal cations, multivitamins

There are no data concerning an interaction of intravenous delafloxacin with multivitamins, didanosine, or metal cations. However, delafloxacin should not be co-administered with any solution containing multivalent cations, e.g. magnesium, through the same intravenous line (see section 4.2 and 6.2).

Based on in vitro data on metabolising enzymes and transporters delafloxacin possesses a low potential to alter the disposition of other medicinal products (see section 5.2).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment with delafloxacin.

Pregnancy

There are no or limited amount of data from the use of delafloxacin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). In the absence of human data and findings in non-clinical studies at human therapeutic exposures, delafloxacin is contraindicated during pregnancy and in women of childbearing potential not using contraception (see sections 4.3 and 4.4).

Breast-feeding

It is unknown whether delafloxacin/metabolites are excreted in human milk.

Available pharmacodynamic/toxicological data in animals have shown excretion of delafloxacin/metabolites in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. Breast-feeding is contraindicated during treatment with delafloxacin.

Fertility

The effects of delafloxacin on fertility in humans have not been studied. Nonclinical studies conducted with delafloxacin in rats do not indicate harmful effects with respect to fertility or reproductive performance (see section 5.3).

4.7. Effects on ability to drive and use machines

Quofenix has moderate influence on the ability to drive and use machines. Some adverse drug reactions (e.g. dizziness, headache, visual disorders) may impair the patient's ability to concentrate and react, and therefore may constitute a risk in situations where the patient operates an automobile or machinery or engages in other activities requiring mental alertness and coordination.

4.8. Undesirable effects

Summary of safety profile

The most common adverse drug reactions reported in ABSSSI (Phase 2 and 3 studies) and CAP (Phase 3 study) involving a total of 1,297 patients (868 subjects in acute bacterial skin and skin structure infections and 429 subjects in community-acquired pneumonia), exposed to delafloxacin, intravenous or oral formulation, were diarrhoea, nausea and hypertransaminasaemia (5.86%, 5.47% and 2.85% respectively) which were mild to moderate in intensity.

Tabulated list of adverse reactions

The following adverse reactions have been identified in four comparative ABSSSI Phase 2 and 3 studies and in one CAP Phase 3 study classified by preferred term and System Organ Class, and by frequency. Frequencies are defined as: 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).

System Organ Class

Common

Uncommon

Rare

Infections and infestations

Fungal infection

Clostridioides difficile infection (see section 4.4)

Urinary tract infection

Sinusitis

Blood and lymphatic system disorders

Anaemia

Leukopenia

Thrombocytopenia

Neutropenia

International normalised ratio increased

Immune system disorders

Hypersensitivity (see section 4.4)

Seasonal allergy

Metabolism and nutrition disorders

Hyperglycaemia (see section 4.4)

Decreased appetite

Hypoglycaemia (see section 4.4)

Hyperuricaemia

Hypokalaemia

Blood potassium increased

Psychiatric disorders*

Insomnia

Hallucination, auditory

Anxiety

Abnormal dreams

Confusional state

Nervous system disorders*

Headache

Peripheral neuropathy (including paraesthesia and hypoaesthesia) (see section 4.4)

Dizziness

Dysgeusia

Presyncope

Somnolence

Eye disorders*

Vision blurred

Dry eye

Ear and labyrinth disorders*

Vertigo

Tinnitus

Vestibular disorder

Cardiac disorders**

Palpitations

Sinus tachycardia

Bradycardia

Vascular disorders**

Hypertension

Hypotension

Flushing

Deep vein thrombosis

Phlebitis

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Cough

Dry throat

Gastrointestinal disorders

Diarrhoea

Vomiting

Nausea

Stomatitis

Abdominal pain

Dyspepsia

Dry mouth

Flatulence

Constipation

Gastritis erosive

Gastrooesophageal reflux disease

Paraesthesia oral

Hypoaesthesia oral

Glossodynia

Faeces discoloured

Hepatobiliary disorders

Hypertransaminasaemia

Blood alkaline phosphatase increased

Blood albumin decreased

Gamma-glutamyltransferase increased

Skin and subcutaneous tissue disorders

Pruritus

Dermatitis allergic

Urticaria

Rash

Hyperhidrosis

Alopecia

Cold sweat

Night sweat

Musculoskeletal and connective tissue disorders*

Arthralgia

Myalgia

Tendonitis (see section 4.4)

Musculoskeletal pain (e.g. pain in extremity, back pain, neck pain), muscle weakness

Blood creatine phosphokinase increased

Arthritis reactive

Myositis

Muscle spasm

Renal and urinary disorders

Renal impairment

Haematuria

Crystal urine present

General disorders and administration site conditions*

Infusion site reaction

Pyrexia

Local swelling

Fatigue

Oedema peripheral

Chills

Medical device complication

Injury, poisoning and procedural complications

Wound complication

Description of selected adverse drug reactions

* Cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, fatigue, psychiatric symptoms, memory impairmentand impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors (see section 4.4). A range of psychiatric symptoms may occur as part of these side effects, which may include, but are not necessarily limited to, sleep disorders, anxiety, panic attacks, confusion, or depression. There are no pharmacological treatments established to be effective treatments of the symptoms of long lasting or disabling side effects associated with fluoroquinolones. The frequency of these prolonged, disabling and potentially irreversible serious drug reactions cannot be estimated with precision using available data, but the reporting incidence from adverse drug reaction reports indicates the frequency is at minimum between 1/1,000 and 1/10,000 (corresponding to the Rare frequency category).

** Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (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.

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

4.9. Overdose

The highest daily intravenous dose administered in clinical studies was 1200 mg; the patients who receive this dose did not have any adverse drug reactions or notable clinical laboratory test findings during the study. Treatment of overdose with delafloxacin should consist of observation and general supportive measures.