Quofenix - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Quofenix 300 mg powder for concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains delafloxacin meglumine equivalent to 300 mg delafloxacin.

After reconstitution each ml contains 25 mg of delafloxacin.

Excipient(s) with known effect:

Each vial contains 2480 mg of sulfobutylbetadex sodium.

Each vial contains 175 mg of sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion (powder for concentrate).

Light yellow to tan cake, which may exhibit cracking and shrinkage and slight variation in texture and colour.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

• • acute bacterial skin and skin structure infections (ABSSSI)
• • community-acquired pneumonia (CAP)

when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the initial treatment of these infections (see sections 4.4 and 5.1).

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 Sjogren’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

Very rare cases of prolonged (continuing months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. 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.

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

System Organ Class	Common	Uncommon	Rare
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 Gammaglutamyl­transferase increased
Skin and subcutaneous tissue disorders	Pruritus	Dermatitis allergic Urticaria Rash Hyperhidrosis	Alopecia Cold sweat Night sweat

System Organ Class	Common	Uncommon	Rare
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

• * Very rare 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, depression, fatigue, memory impairment, sleep disorders, and 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).

• * * 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 national reporting system listed in

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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, fluoroquinolones, ATC code: J01MA23

Mechanism of action

Delafloxacin inhibits bacterial topoisomerase IV and DNA gyrase (topoisomerase II), enzymes required for bacterial DNA replication, transcription, repair, and recombination.

Resistance

Resistance to fluoroquinolones, including delafloxacin, can occur due to mutations in defined regions of the target bacterial enzymes topoisomerase IV and DNA gyrase referred to as Quinolone-Resistance Determining Regions (QRDRs), or through other resistance mechanisms such as efflux mechanisms.

Cross-resistance between delafloxacin and other fluoroquinolones may be observed, although some isolates resistant to other fluoroquinolone may retain susceptibility to delafloxacin.

Susceptibility testing breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for delafloxacin are as follows:

Organism	MIC breakpoints (mg/L)
	Susceptible (S <)	Resistant (R >)
Staphylococcus aureus (ABSSSI)	0.25	0.25
Staphylococcus aureus (CAP)	0.016	0.016
Streptococcus pneumoniae	0.06	0.06
Streptococcus pyogenes	0.03	0.03
Streptococcus dysgalactiae	0.03	0.03
Streptococcus agalactiae	0.03	0.03
Streptococcus anginosus group	0.03	0.03
Escherichia coli	0.125	0.125
Haemophilus influenzae	0.004	0.004

Pharmacokinetic/phar­macodynamic relationship

The fAUC24/MIC ratio, as for other quinolone antibiotics, resulted in the pharmacokinetic/ pharmacodynamic parameter most closely associated with the efficacy of delafloxacin.

Clinical efficacy against specific pathogens

Efficacy has been demonstrated in clinical studies against the pathogens listed under each indication that were susceptible to delafloxacin in vitro.

Acute bacterial skin and skin structure infections

Gram-positive microorganisms:

• • Staphylococcus aureus (including methicillin-resistant [MRSA])
• • Staphylococcus haemolyticus
• • Staphylococcus hominis
• • Staphylococcus lugdunensis
• • Streptococcus agalactiae
• • Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus

intermedius, and Streptococcus constellatus)

• • Streptococcus dysgalactiae
• • Streptococcus mitis group (including Streptococcus cristatus, Streptococcus gordonii, Streptococcus oralis, Streptococcus mitis, and Streptococcus sanguinis)
• • Streptococcus pyogenes
• • Enterococcus faecalis

Gram-negative microorganisms:

• • Escherichia coli
• • Enterobacter cloacae
• • Klebsiella pneumoniae
• • Pseudomonas aeruginosa

Community-acquired pneumonia

Gram-positive microorganisms:

• • Streptococcus pneumoniae
• • Staphylococcus aureus (MSSA)

Gram-negative microorganisms:

• • Haemophilus influenzae
• • Escherichia coli

Atypical:

• • Chlamydia pneumoniae
• • Legionella pneumophila
• • Mycoplasma pneumoniae

The European Medicines Agency has waived the obligation to submit the results of studies with Quofenix in all subsets of the paediatric population in the treatment of local infections of skin and subcutaneous tissues and community-acquired pneumonia (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Following intravenous use of 300 mg delafloxacin every 12 hours, steady state concentrations are achieved after approximately 3–5 days with about 10% accumulation after multiple administrations.

The half-life of IV delafloxacin is approximately 10 hours. Delafloxacin pharmacokinetic is comparable in patients with ABSSSI or CAP and healthy volunteers.

Absorption

Peak plasma delafloxacin concentrations are achieved at the end of the 1 hour intravenous infusion. The 300-mg IV formulation and 450 mg tablet are bioequivalent with regard to total exposure (AUC).

Distribution

The steady state volume of distribution of delafloxacin is about 40 L which approximates total body water. The plasma protein binding of delafloxacin is approximately 84%; it primarily binds to albumin. Plasma protein binding of delafloxacin is not significantly affected by the degree of renal impairment.

Following IV administration of 7 doses of 300 mg of delafloxacin to 30 healthy volunteers, the mean delafloxacin AUC0–12 (3.6 hr*pg/mL) in alveolar macrophages was 83% of the free-plasma

AUC0–12, and the mean delafloxacin AUC0–12 (2.8 hr*pg/mL) in epithelial lining fluid was 65% of the free-plasma AUC0–12.

Biotransformation

Glucuronidation of delafloxacin is the primary metabolic pathway with oxidative metabolism representing <1% of an administered dose. The glucuronidation of delafloxacin is mediated mainly by UGT1A1,UGT1A3 and UGT2B15. Unchanged parent drug is the predominant component in plasma. There are no significant circulating metabolites (mean=9.6%) in humans.

In vitro data indicate that delafloxacin at clinically relevant concentrations does not inhibit cytochrome P450 CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 nor UDP glucuronosyltran­sferases isoforms UGT1A1 and UGT2B7. Delafloxacin does not induce CYP1A2, CYP2B6, CYP2C9, CYP2C8, CYP2C19 or CYP3A4/5.

Likewise at clinically relevant concentrations delafloxacin does not inhibit the transporters MDR1, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2K and BSEP. Delafloxacin is a probable substrate of BCRP.

Elimination

After single intravenous dose of 14C-labeled delafloxacin, 65% of the radioactivity is excreted in the urine and 28% is excreted in the faeces. Delafloxacin is excreted both unchanged and as glucuronide metabolites in urine. The radioactivity recovered from faeces is unchanged delafloxacin.

Obese patients (> 30 kg/m2 BMI)

Pharmacokinetic parameters are not altered in obese patients (BMI > 30 kg/m2).

Hepatic impairment

No clinically meaningful changes in delafloxacin Cmax and AUC, were observed, following administration of a single 300 mg intravenous dose of delafloxacin into patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C) compared to matched healthy control subjects.

Renal impairment

Following single intravenous (300 mg) administration to patients with mild, moderate, or severe renal impairment or ESRD on haemodialysis with and without haemodialysis after dosing, mean total exposure (AUCt) were 1.3, 1.7, 2.1, 3.5 and 4.1-fold higher than values for matched control subjects. Peak concentrations for the mild and moderate renal impairment patients were similar to that of healthy subjects, whereas peak concentrations were 2.1-fold, 5.9-fold and 6.4-fold higher for patients with severe renal impairment and ESRD on haemodialysis with and without haemodialysis after dosing, respectively.

In patients with moderate, or severe renal impairment or ESRD on haemodialysis, accumulation of the intravenous vehicle sulfobutylbetadex sodium occurs. The mean systemic exposure (AUC) increased 2.2-fold, 5.3-fold, 8.5-fold and 29.8-fold for patients with moderate impairment, severe impairment and ESRD with and without haemodialysis after dosing, respectively compared to the normal control group. The mean peak exposure (Cmax) increased about 2-fold, 5-fold and 7-fold for patients with severe impairment and ESRD with and without haemodialysis after dosing, respectively compared to the normal control group.

For dosing instructions in subjects with renal impairment refer to section 4.2.

Elderly

The pharmacokinetics of delafloxacin is not significantly altered with age; therefore, dose adjustment is not necessary based on age.

Paediatric population

No clinical trials have been conducted with delafloxacin in paediatric patients.

Gender

Clinically significant gender-related differences in delafloxacin pharmacokinetics have not been observed in healthy subjects or in patients with ABSSSI or CAP. No dose adjustment is recommended based on gender.

5.3 Preclinical safety data

In repeat dose toxicity studies in rats and dogs, gastrointestinal effects were the main findings: these included dilated cecum (oral only), abnormal stool, and decreased food intake and / or body weight in rats, and emesis, salivation and abnormal stool / diarrhoea in dogs. In addition increases in serum ALT and ALP, and reduced total protein and globulin values were recorded at the end of the treatment period in the pivotal 4-week IV dog study at the high dose (75 mg/kg) in individual dogs. Importantly, gastrointestinal effects and slightly elevated liver enzymes in dogs were not associated with histopathological changes of gastrointestinal and annexed tissues (pancreas, liver). No adverse effects were seen in rats at exposures about 2-fold higher than humans, or in dogs at exposures approximately equal to humans.

In embryo-fetal development studies carried out in rats and rabbits, delafloxacin was devoid of teratogenic effects but induced foetal growth retardation and ossification delays at levels of dose producing maternal toxicity. In rats foetal effects occurred at a level of exposure exceeding about 2fold that observed in humans based on the AUC, but in rabbits, a species known to be extremely sensitive to maternal toxicity of antibacterial drugs, the effects on foetuses were recorded at levels of exposure well below that observed in humans. As delafloxacin is excreted in milk, severe toxicity was observed in newborn rats during lactation when mothers were treated during pregnancy and lactation with delafloxacin at a dose producing a systemic exposure about 5-fold higher than observed in humans. However, no such effects and no other developmental abnormalities occurred in the progeny of mothers exposed up to a level about 2-fold higher than observed in humans. No effects were detected on rat male and female fertility at a level of exposure about 5-fold higher than that observed in humans.

Long-term carcinogenicity studies have not been conducted with delafloxacin.

No genotoxicity hazard was identified in vitro and it was negative in vivo at the highest possible dose > 15 times the estimated human plasma exposure based on AUC.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Meglumine

Sulfobutylbetadex sodium

Disodium edetate

Sodium hydroxide (for pH-adjustment)

Hydrochloric acid, concentrated (for pH-adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

4 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 20 to 25°C or at 2 to 8°C. From a microbiological point of view, the product should be used immediately after reconstitution and dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.

Do not freeze.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

20 ml clear type I glass vials outfitted with 20 mm type I rubber stoppers and 20 mm flip-off caps. Pack-size: 10 vials.

6.6 Special precautions for disposal

Quofenix must be reconstituted under aseptic conditions, using 10.5 mL of dextrose 50 mg/ml (5%) solution for injection (D5W) or sodium chloride 9 mg/ml (0.9%) solution for injection for each 300 mg vial.

• • The vial should be vigorously shaken until contents are completely dissolved. The

reconstituted vial contains 300 mg per 12 mL of delafloxacin as a clear yellow to amber coloured solution.

• • The reconstituted solution must be then diluted in 250mL IV bag (either 0.9% Sodium Chloride Injection or D5W) prior to administration.
• • Prepare the required dose for intravenous infusion by withdrawing the volume of 12 ml for Quofenix 300 mg or 8 ml for Quofenix 200 mg from the reconstituted vial.
• • The required dose of Quofenix reconstituted solution should be aseptically transferred from the vial to a 250 mL intravenous bag. (Any unused portion of the reconstituted solution should be discarded).
• • After reconstitution and dilution, Quofenix is to be administered via intravenous infusion,

using a total infusion time of 60 minutes.

Quofenix must not be co-infused with other medications. If a common intravenous line is being used to administer other medicinal products in addition to Quofenix the line should be flushed before and after each Quofenix infusion with sodium chloride 9 mg/ml (0.9%) solution for injection or D5W. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

• A. Menarini – Industrie Farmaceutiche Riunite – s.r.l.

Via Sette Santi 3, 50131 Florence, Italy

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1393/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 December 2019