Anti-infectives

Therapeutic indications

Fleming® is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1): Acute bacterial sinusitis (adequately diagnosed); Acute otitis media; Acute exacerbations of chronic bronchitis (adequately diagnosed); Community acquired pneumonia; Cystitis; Pyelonephritis; Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with spreading cellulitis; Bone and joint infections, in particular osteomyelitis.

Fleming® powder for injectable solution or infusion (IV use)

In addition to the above listed indications.
Severe infections of the ear, nose and throat (such as mastoiditis, peritonsillar infections, epiglottitis, and sinusitis when accompanied by severe systemic signs and symptoms); Intra-abdominal infections; Female genital infections.
Prophylaxis against infections associated with major surgical procedures in adults, such as those involving the: Gastrointestinal tract, Pelvic cavity, Head and neck, Biliary tract surgery.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

POSOLOGY AND METHOD OF ADMINISTRATION

Posology

Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component.
The dose of Fleming® that is selected to treat an individual infection should take into account:

• The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)
• The severity and the site of the infection
• The age, weight and renal function of the patient as shown below.

The use of alternative presentations of Fleming® (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1).

The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy).

Adults and children ≥ 40 kg

Recommended doses:
Standard dose: (for all indications)
One 500mg/125mg dose taken three times a day.
One 875 mg/125 mg two times a day;

Higher dose - (particularly for infections such as otitis media, sinusitis, lower respiratory tract infections and urinary tract infections): 875 mg/125 mg three times a day.

Children < 40 kg

Children may be treated with Fleming® tablets or suspensions.
Recommended doses:
• 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day given as two divided doses;
• up to 70 mg/10 mg/kg/day given as two divided doses may be considered for some infections (such as otitis media, sinusitis and lower respiratory tract infections).

As the tablets cannot be divided, children weighing less than 25 kg must not be treated with Fleming® tablets.
Children weighing less than 25 kg should preferably be treated with Fleming® suspension. No clinical data are available for Fleming® 7:1 formulations regarding doses higher than 45 mg/6.4 mg per kg per day in children under 2 years.
There are no clinical data for Fleming® 7:1 formulations for patients under 2 months of age. Dosing recommendations in this population therefore cannot be made.

Method of administration

leming is for oral use.
Fleming® should be administered with a meal to minimise potential gastrointestinal intolerance.
Therapy can be started parenterally according to the SmPC of the IV-formulation and continued with an oral preparation.

Fleming® powder for injectable solution or infusion (IV use)

Adults and children ≥ 40 kg

For treatment of infections as indicated in section 4.1:1000 mg/ 200 mg every 8 hours.
Children < 40 kg Recommended doses:
• Children aged 3 months and over: 25 mg/5 mg per kg every 8 hours
• Children aged less than 3 months or weighing less than 4 kg: 25 mg/5 mg per kg every 12 hours.

Elderly

No dose adjustment is considered necessary.

Renal impairment

No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min. In patients with creatinine clearance less than 30 ml/min, the use of Fleming® presentations with an amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as no recommendations for dose adjustments are available.

Hepatic impairment

Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4).

Method of administration

Fleming® is for intravenous use. Fleming® may be administered either by slow intravenous injection over a period of 3 to 4 min directly into a vein or via a drip tube or by infusion over 30 to 40 min. Fleming® is not suitable for intramuscular administration.

Children aged less than 3 months should be administered Fleming® by infusion only.
Treatment with Fleming® may be initiated by the use of an intravenous preparation and completed with an appropriate oral presentation as considered appropriate for the individual patient.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

CONTRA-INDICATIONS

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.
History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).
History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8).

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

See full prescribing information

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents (see sections 4.3 and 4.8).

Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).

Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.

Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see section 4.8). This reaction requires Fleming® discontinuation and contraindicates any subsequent administration of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8). In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9).

During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods.
The presence of clavulanic acid in Fleming® may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

Fleming® powder for oral suspension contains aspartame

Which is a source of phenylalanine. This may be harmful for children born with a condition called ’phenylketonuria’.

Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

INTERACTION

Oral anticoagulants, Methotrexate, Probenecid, Mycophenolate mofetil.

PREGNANCY AND LACTATION

Pregnancy: Use should be avoided during pregnancy, unless considered essential by the physician.

Lactation: Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

UNDERSIRABLE EFECTS

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting.

For uncommon, rare and very rare side effects see full prescribing information

OVERDOSE

Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.
Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors;
ATC code: J01CR02.

Date of SmPC text revision: 24 May 2017; 29 July 2015; 01 August 2014; 17 March 2016; 17 December 2015;
Date of abbreviated prescribing information: November 2017.
More detailed Information on request: Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, Volta Place,
35 Patrice Lumumba Road, Airport Residential Area, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.

THERAPEUTIC INDICATIONS IN ADULTS

Tarivid® film coated tablets are indicated in adults for the treatment of the following bacterial infections (see sections 4.4 and 5.1):

• acute Pyelonephritis and complicated urinary tract infections
• bacterial Prostatitis, epididymo-orchitis
• Pelvic inflammatory disease, in combination with other antibacterial agents

In the below-mentioned infections Tarivid® film-coated tablets should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections (see section 4.4).

• Uncomplicated cystitis
• urethritis
• bone and joint infections.
• complicated skin and soft-tissue infections.
• acute bacterial sinusitis.
• acute exacerbation of chronic obstructive pulmonary disease including bronchitis.
• community acquired pneumonia.
• prophylaxis of bacterial infection in neutropenic patients.

Ofloxacin has no activity against Treponema pallidum.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

POSOLOGY AND METHOD OF ADMINISTRATION

CONTRA-INDICATIONS

Tarivid® must not be administered:
• in patients who are hypersensitive to ofloxacin, other quinolones or any of the excipients listed in section 6.1,
• in patients with epilepsy or a lowered CNS seizure threshold,
• in patients with tendon disease/damage associated with previous quinolone therapy,
• in children and adolescents up to 18 years of age*,
• during pregnancy^*,
• during lactation^*.

^*because, judging from animal experiments, a risk of damage to the growth-plate cartilage in the growing organism cannot be entirely excluded.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

The use of ofloxacin 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 ofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).

Risks of resistance

Methicillin-resistant S. aureus

Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including ofloxacin. Therefore ofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to ofloxacin (and commonly recommended antibacterial agents for the treatment of MRSA-infections are considered inappropriate).

E. coli

Resistance to fluoroquinolones of E. coli – the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.

Neisseria gonorrhoeae infections

Due to increase in resistance to N. gonorrhoeae, ofloxacin should not be used as empirical treatment option in suspected gonococcal infection (urethral gonococcal infection, pelvic inflammatory disease and epididymo-orchitis), unless the pathogen has been identified and confirmed as susceptible to ofloxacin. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.

Pelvic inflammatory disease

For pelvic inflammatory disease, ofloxacin should only be considered in combination with anaerobe coverage.

P. aeruginosa

Nosocomial and other severe infections caused by P. aeruginosa may require combination therapy. In cases of specific infections caused by P. aeruginosa in particular, resistance levels must be tested in order to ensure targeted therapy.

Streptococci

Tarivid® is not indicated for the treatment of acute angina tonsillaris caused by beta-haemolytic streptococci.

Risk of resistance

The prevalence of acquired resistance may vary geographically and over time for selected species.
Therefore, local information on resistance is required; microbiological diagnosis with isolation of the pathogen and demonstration of its susceptibility should be sought, especially for severe infections or failure to respond to treatment.

Bone and joint infections

For bone and joint infections, consideration must be given to the need for a combined treatment with other anti-infectives.

Severe bullous reactions

Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with ofloxacin (see section 4.8). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

Hypersensitivity reactions

Hypersensitivity and allergic reactions following the initial administration of fluoroquinolones have been reported. Anaphylactic and anaphylactoid reactions may progress to life-threatening shock, even after the initial administration. In this case, ofloxacin must be discontinued and appropriate emergency procedures (e.g. shock treatment, including administration of antihistamines, corticosteroids, sympathomimetics and, if required, ventilation) must be initiated.

Diseases caused by Clostridium difficile

The occurrence of diarrhoea, particularly if it is severe, persistent and/or contains blood, during or after treatment with Tarivid® (including several weeks after treatment), may indicate a disease triggered by Clostridium difficile (CDAD). CDAD may range in severity from mild to life threatening, the most severe form of which is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with ofloxacin. If pseudomembranous colitis is suspected, treatment with Tarivid® must be discontinued immediately and an appropriate therapy initiated without delay (e.g. oral treatment with specific antibiotics/chemotherapeutic agents, as oral vancomycin, oral teicoplanin or metronidazole, with proven clinical efficacy). Medicines that inhibit intestinal peristalsis must not be taken.

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. Ofloxacin 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.

Patients with a tendency for seizures

Quinolones may lower the seizure threshold and may trigger seizures. Tarivid® is contraindicated in patients with known epilepsy or a known lowered CNS seizure threshold (see section 4.3). As with other quinolones, Tarivid® should be used only with extreme caution in patients otherwise predisposed to epileptic seizures, e.g. patients with existing CNS lesions, during concurrent treatment with fenbufen or comparable non-steroidal anti-inflammatory drugs, or with medicines that lower the seizure threshold, such as theophylline (see also section 4.5).

Treatment with Tarivid® must be discontinued at the onset of seizures. Appropriate standard emergency procedures are indicated (e.g. maintenance of airway patency and administration of anticonvulsants such as diazepam or barbiturates).

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 ofloxacin 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.

Patients with impaired renal function

Ofloxacin is mainly excreted via the kidneys. In patients with impaired renal function, Tarivid® should therefore only be administered after a dose adjustment (see section 4.2), together with medical monitoring of the renal function.

Psychotic reactions

During treatment with quinolones including ofloxacin, depression and psychotic reactions have been reported in patients. In some cases these have developed into suicidal ideation and self-endangering behaviour including suicide attempt (see section 4.8) – sometimes already after a single dose of ofloxacin. If the patient develops such reactions, ofloxacin must be discontinued immediately at the first signs or symptoms of these reactions and patients should be advised to contact their prescriber for advice. Alternative nonfluoroquinolone antibacterial therapy should be considered and appropriate measures initiated. Caution should be exercised if ofloxacin is used in patients with psychotic disorders or a medical history of psychiatric disorders.

Patients with impaired hepatic function

Hepatic damage may occur during treatment with Tarivid. In patients with impaired hepatic function, Tarivid® should be administered only if hepatic function is medically monitored. Cases of fulminant hepatitis, which may lead to liver failure (sometimes fatal), have been reported with fluoroquinolones. Patients should be instructed to suspend treatment and seek advice from their doctor if signs of hepatic disease develop, e.g. loss of appetite, jaundice, dark discolouration of the urine, pruritus or abdominal tenderness (see section 4.8).

Patients on treatment with vitamin K antagonists

Due to a possible increase in coagulation values (PT/INR) and/or bleeding in patients on concomitant treatment with fluoroquinolones, including ofloxacin, and a vitamin K antagonist (e.g. warfarin), coagulation values should be monitored (see section 4.5).

Myasthenia gravis

Fluoroquinolones, including ofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and the requirement for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Ofloxacin is not recommended in patients with a known history of myasthenia gravis.

Prevention of photosensitization

Photosensitisation has been reported with ofloxacin (see section 4.8). It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp, solarium), during treatment and for 48 hours following treatment discontinuation in order to prevent photosensitisation.

Secondary infection

As with other antibiotics, the use of ofloxacin, especially if prolonged, may result in overgrowth of non-susceptible organisms. The patient’s condition should therefore be monitored at regular intervals. Appropriate measures must be taken if a secondary infection occurs.

Heart disorders

Cases of QT interval prolongation have been reported in patients taking fluoroquinolones, including ofloxacin (see section 4.8).

When using fluoroquinolones, including ofloxacin, caution should be taken in patients with known risk factors for QT interval prolongation, for example:
• congenital long QT syndrome,
• concomitant administration of other medicines that are known to prolong the QT interval (e.g. class IA and III antiarrhythmics, tricyclic
and tetracyclic antidepressants, macrolides, imidazole antifungal agents and antimalarial agents, some non-sedative antihistamines [e.g. astemizole, terfenadine, ebastine], antipsychotics). • uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia),
• elderly patients,
• cardiac disease (heart failure, myocardial infarction, bradycardia).

Elderly patients and women may be more sensitive to QTc-prolonging medications: Therefore, caution should be taken when using fluoroquinolones, including ofloxacin, in these populations (see also sections 4.2 “Elderly patients”, 4.5, 4.8 and 4.9).

Dysglycaemia

Disturbances in blood glucose including both hyperglycemia and hypoglycemia have been reported with fluoroquinolones including ofloxacin which occurred more frequently in the elderly. 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 (see section 4.8).

Treatment with Tarivid® should be stopped immediately if a patient reports blood glucose disturbance and alternative nonfluoroquinolone antibacterial therapy should be considered.

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 ofloxacin 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).

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency may be predisposed to haemolytic reactions if they are treated with quinolones. Therefore, if ofloxacin has to be used in these patients, potential occurrence of haemolysis should be monitored.

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).

Interference with laboratory tests

In patients treated with ofloxacin, determination of opiates or porphyrin in urine may give false-positive results. It may be necessary to confirm positive opiate screens by more specific method.

Aortic Aneurysm and Dissection

Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.

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 in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).

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

Other notes

Patients who have reacted to other quinolones with severe undesirable effects (e.g. severe neurological reactions) are at greater risk of experiencing similar reactions to ofloxacin.

Tarivid® contains lactose

Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take Tarivid® film-coated tablets.

INTERACTIONS

Antacids, Sucralate, Metal Cations: Concurrent intake of magnesium or aluminium containing antacids or sucralfate can attenuate the effects of Tarivid® film-coated tablets. The same applies to other preparations that contain metal ions (aluminium, iron, magnesium or zinc). Tarivid® film-coated tablets must therefore be taken approximately 2 hours before such preparations.

Theophylline, fenbufen or similar non-steroidal antiinflammatory drugs: No pharmacokinetic interactions of ofloxacin were found with theophylline in a clinical study. However, a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, nonsteroidal antiinflammatory drugs, or other agents, which lower the seizure threshold.

Medicinal products that prolong the QT-interval

Ofloxacin, like other quinolones, should be used with caution in patients taking medicines known to prolong the QT interval (e.g. class IA and III antiarrhythmics, tricyclic and tetracyclic antidepressants, macrolides, imidazole antifungal agents and antimalarial agents, some non-sedative antihistamines [e.g. astemizole, terfenadine, ebastine], antipsychotics) (see section 4.4).

Vitamin K antagonists: Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in patients treated with ofloxacin in combination with a vitamin K antagonist (e.g. warfarin). Close monitoring of the coagulation status of patients undergoing concurrent treatment with Vitamin K antagonists is thus recommended.

Glibenclamide- Ofloxacin can cause a slight increase in serum glibenclamide levels. As hypoglycaemia is then more likely to occur, close monitoring of blood glucose levels is thus recommended with concomitant administration of ofloxacin and glibenclamide.

Probenecid, cimetidine, furosemide and methotrexate: Probenecid decreased the total clearance of ofloxacin by 24%, and increased AUC by 16%. The proposed mechanism is a competition or inhibition for active transport at the renal tubular excretion. Caution should be exercised when ofloxacin is coadministered with drugs that affect the tubular renal secretion such as probenecid, cimetidine, furosemide and methotrexate, because it can cause elevated serum levels and increased undesirable effects.

UNDESIRABLE EFFECTS

For uncommon, rare and very rare side effects see full prescribing information

OVERDOSE

To eliminate any non-absorbed ofloxacin, measures such as gastric lavage, administration of absorbing agents and sodium sulphate (if possible within the first 30 minutes) are recommended, as well as antacids to protect the gastric mucosa; furthermore, therapy by diuresis to promote the elimination of any absorbed substance.

PHARMACOLOGICAL PROPERTIES

Ofloxacin is a bactericidal antibiotic from the fluoroquinolone group. ATC code: J01MA01.

Date of SmPC approval: November 2019;
Date of abbreviated prescribing information: November 2020.
More detailed Information on request: Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, Volta Place,
35 Patrice Lumumba Road, Airport Residential Area, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.

Therapeutic indications

Tavanic® is indicated in adults for the treatment of the following infections (see sections 4.4 and 5.1):
• acute pyelonephritis and complicated urinary tract infections (see section 4.4),
• chronic bacterial prostatitis,
• inhalation anthrax: for post-exposure prophylaxis and as curative treatment (see section 4.4).

In the below-mentioned infections Tavanic® should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.
• acute bacterial sinusitis,
• acute exacerbation of chronic obstructive pulmonary disease including bronchitis,
• community-acquired pneumonia,
• complicated skin and soft-tissue infections.
• uncomplicated cystitis (see section 4.4).

Tavanic® can also be used to continue a course of treatment in patients who have shown improvement during initial treatment with intravenous levofloxacin.
Consideration should be given to the official guidance on the appropriate use of antibacterial agents.

POSOLOGY AND METHOD OF ADMINISTRATION

CONTRA-INDICATIONS

Levofloxacin film-coated tablets must not be used:
• in patients with hypersensitivity to levofloxacin or other quinolones, or to any of the excipients listed in section 6.1,
• in patients with epilepsy,
• in patients with a known history of tendon disorders after previous fluoroquinolone use,
• in children and growing adolescents,
• during pregnancy,
• in breast-feeding women.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

The use of levofoxacin 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 levofoxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).

Risks of resistance

Methicillin-resistant S. aureus are likely to possess co-resistance to fluoroquinolones (including levofloxacin). In known or suspected MRSA infections, levofloxacin is therefore not recommended for treatment, unless laboratory results confirm susceptibility of the pathogen to levofloxacin (and commonly recommended antibiotics for the treatment of MRSA are not considered to be indicated). Levofloxacin can be used for the treatment of acute bacterial sinusitis or acute exacerbation of chronic bronchitis when these infections have been professionally diagnosed. Resistance of E. coli – the most common pathogen in urinary tract infections – to fluoroquinolones varies within the European Union. When prescribing, physicians should consider the local prevalence of resistance in E. coli to fluoroquinolones. Inhalation anthrax: Use in humans is based on in vitro Bacillus anthracis susceptibility data and on experimental data in animals together with limited human data. Treating physicians should refer to national or international consensus papers when treating anthrax.

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. Levofloxacin 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.

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, in patients receiving daily doses of 1000 mg levofloxacin 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 levofloxacin 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.

Clostridium difficile-associated disease

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with levofloxacin (including several weeks after the end of treatment), may be indicative of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to its most severe (life-threatening) form, i.e. pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis if serious diarrhoea develops in patients during or after treatment with levofloxacin. If CDAD is suspected or confirmed, treatment with levofloxacin must be halted immediately and appropriate treatment initiated. Antiperistaltic agents are contraindicated in such cases.

Patients predisposed to seizures

Quinolones can lower the seizure threshold and may trigger seizures. Levofloxacin is contraindicated in patients with known epilepsy (see section 4.3) and, as with other quinolones, should be used only with extreme caution in patients predisposed to epileptic seizures or receiving concomitant treatment with medicinal products that lower the seizure threshold, such as theophylline (see section 4.5). If convulsive seizures occur (see section 4.8), treatment with levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or existing glucose-6-phosphate dehydrogenase deficiency may be prone to haemolytic reactions when treated with quinolones. When treating such patients with levofloxacin, potential occurrence of haemolysis should therefore be closely monitored.

Patients with impaired renal function

Since levofloxacin is excreted mainly by the kidneys, the dose should be adjusted in patients with impaired renal function (see section 4.2).

Hypersensitivity reactions

Levofloxacin can induce serious, potentially life-threatening hypersensitivity reactions (e.g. angioedema and even anaphylactic shock), occasionally even after the first dose (see section 4.8). Patients should discontinue treatment immediately and inform their physician or an emergency physician, who will initiate appropriate emergency measures.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN: also known as Lyell's syndrome), Stevens Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with levofloxacin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. If signs and symptoms suggestive of these reactions appear, levofloxacin should be discontinued immediately and an alternative treatment should be considered. If the patient has developed a serious reaction such as SJS, TEN or DRESS with the use of levofloxacin, treatment with levofloxacin must not be restarted in this patient at any time.

Dysglycaemia

As with all quinolones, abnormal blood glucose levels (including hyperglycaemia and hypoglycaemia) have been reported, occurring more frequently in the elderly and usually in diabetics receiving concomitant treatment with an oral antidiabetic (e.g. glibenclamide) or with insulin. There are known cases of hypoglycaemic coma. In diabetic patients, careful monitoring of blood glucose levels is recommended (see section 4.8).

Treatment with Tavanic® should be stopped immediately if a patient reports blood glucose disturbance and alternative nonfluoroquinolone antibacterial therapy should be considered.

Prevention of photosensitisation

Photosensitisation has been reported with levofloxacin (see section 4.8). It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp, solarium) during and for up to 48 hours after treatment, in order to avoid photosensitisation.

Patients on treatment with vitamin K antagonists

Due to possible elevation of coagulation values (PT/INR) and/or bleeding in patients treated with levofloxacin in combination with vitamin K antagonists (e.g. warfarin), coagulation values should be monitored when these medicines are used concomitantly (see section 4.5).

Psychotic reactions

Psychotic reactions have been reported in patients on treatment with quinolones, including levofloxacin. In very rare cases, these have progressed to suicidal thoughts and self-endangering behaviour – sometimes after only a single dose of levofloxacin (see section 4.8). If any patient develops such reactions, levofloxacin must be discontinued immediately at the first signs or symptoms of these reactions and patients should be advised to contact their prescriber for advice. Alternative nonfluoroquinolone antibacterial therapy should be considered and appropriate measures instituted. Caution is indicated when using levofloxacin in psychotic patients or those with a history of psychiatric illness.

QT interval prolongation

Fluoroquinolones, including levofloxacin, should only be used with caution in patients with known risk factors for prolongation of the QT interval such as, for example: congenital long QT syndrome, concomitant use of medicinal products that are known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics), uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia), cardiac disease (e.g. heart failure, myocardial infarction, bradycardia). Elderly patients and women may be more sensitive to QTc-prolonging medications. Fluoroquinolones, including levofloxacin, should therefore be used with caution in these patients (see sections 4.2 “Elderly patients”, 4.5, 4.8, and 4.9).

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 levofloxacin 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)

Hepatobiliary disorders

Cases of hepatic necrosis and even fatal hepatic failure have been reported with levofloxacin, especially in patients with severe underlying diseases/comorbidities, e.g. sepsis (see section 4.8). Patients should be advised to stop treatment and consult their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus and tender abdomen.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, may trigger neuromuscular blockade and exacerbate muscle weakness in patients with myasthenia gravis. Severe postmarketing adverse reactions (including death or the requirement for respiratory support) are associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is therefore not recommended for patients with known myasthenia gravis.

Visual disturbances

If vision becomes impaired or other effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).

Superinfection

In prolonged treatment with levofloxacin, overgrowth of non-susceptible organisms may occur. In the event of superinfection, appropriate measures should be undertaken.

Interference with laboratory results

In patients treated with levofloxacin, opiate detection in urine may give false-positive results. Positive results may have to be confirmed by more specific methods. Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and hence lead to false-negative results in the bacteriological diagnosis of tuberculosis.

Aortic Aneurysm and Dissection

Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.

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 in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis). In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

INTERACTIONS

Effects of other medicinal products on Tavanic

Iron salts, zinc salts, magnesium- or aluminium-containing antacids, didanosine: Levofloxacin absorption is significantly reduced when iron salts, magnesium- or aluminium-containing antacids or didanosine (applies only to didanosine formulations with aluminium- or magnesium-containing buffering agents are administered concomitantly with Tavanic® tablets. Concurrent use of fluoroquinolones with multi-vitamin preparations containing zinc appears to reduce absorption. It is recommended that preparations containing divalent or trivalent cations, such as iron- or zinc salts, or magnesium- or aluminium-containing antacids or didanosine (applies only to didanosine formulations with aluminium- or magnesium-containing buffering agents) should not be taken 2 hours before and for up to 2 hours after the administration of Tavanic® film-coated tablets (see section 4.2). Calcium salts have been shown to have a minimal effect on the absorption of levofloxacin after oral administration.

Sucralfate: The bioavailability of Tavanic® film-coated tablets is significantly reduced when co-administered with sucralfate. If the patient must be treated concurrently with sucralfate and Tavanic® film-coated tablets, it is best to administer sucralfate 2 hours after Tavanic® film-coated tablets (see section 4.2).

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs No pharmacokinetic interactions of levofloxacin were demonstrated with theophylline in a clinical study. However, a pronounced lowering of the seizure threshold may occur when quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs or other agents that lower the cerebral seizure threshold.
Levofloxacin concentrations were about 13% higher during co-medication with fenbufen than when administered alone

Probenecid and cimetidine: Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%), as both medicines are capable of blocking the renal tubular secretion of levofloxacin. However, at the doses tested in the study, the statistically significant kinetic differences are unlikely to be of clinical relevance.

Levofloxacin should be used with caution when co-administering medicinal products that affect tubular renal secretion, e.g. probenecid and cimetidine. This particularly applies to patients with renal insufficiency.

Other information: In clinical pharmacology studies, no clinically relevant effect on the pharmacokinetics of levofloxacin was shown when the following medicinal products were co-administered: calcium carbonate, digoxin, glibenclamide, ranitidine.

Effect of Tavanic® on other medicinal products

Ciclosporin: The half-life of ciclosporin was prolonged by 33% upon co-administration of levofloxacin.

Vitamin K antagonists: Prolongation of the prothrombin time (increase in INR/decrease in thromboplastin time) and/or even bleeding have been reported in patients concurrently treated with levofloxacin and vitamin K antagonists (e.g. warfarin). Such bleeding may even be severe. Coagulation values should therefore be monitored in patients treated with vitamin K antagonists (see section 4.4).

Medicinal products known to prolong the QT interval: Levofloxacin, like other fluoroquinolones, should only be used with caution in patients concurrently taking other medicinal products known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4 “QT interval prolongation”).

Other information: A pharmacokinetic study showed that levofloxacin exerts no effect on the pharmacokinetics of theophylline (a test substrate for CYP1A2), indicating that levofloxacin is not a CYP1A2 inhibitor.

Other forms of interaction

Food: There is no clinically relevant interaction with food. Tavanic® film-coated tablets can therefore be taken irrespective of food intake.

UNDESIRABLE EFFECTS

Psychiatric disorders: Insomnia
Nervous system disorders: Headache, light-headedness
Vascular disorders: (after IV administration only:) Phlebitis
Gastrointestinal disorders: Diarrhoea, vomiting. nausea
Hepatobiliary disorders: Elevated liver enzyme values (ALT/AST, alkaline phosphatase, GGT)
General disorders and administration site conditions: (After IV administration only:) Infusion site reactions (pain, reddening)
Other undesirable effects that have occurred with fluoroquinolones:− porphyria attacks in patients with porphyria.

OVERDOSE

In the event of an overdose, symptomatic treatment should be instituted. ECG monitoring should be undertaken due to the possible occurrence of QT interval prolongation. Antacids may be used for protection of the gastric mucosa. Haemodialysis, including peritoneal dialysis and CAPD, are unable to eliminate levofloxacin effectively. No specific antidote exists.

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: quinolone antibacterials, fluoroquinolones.
ATC code: J01MA12

Date of SmPC approval: November 2019;
Date of abbreviated prescribing information: November 2020.
More detailed Information on request: Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, Volta Place,
35 Patrice Lumumba Road, Airport Residential Area, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.

THERAPEUTIC INDICATIONS

The therapeutic indications of cefpodoxime are based on its antibacterial activity and pharmacokinetic properties.
In children, they are limited to the treatment of infections due to bacteria susceptible to cefpodoxime, in particular:
• Acute sinusitis media.
• Documented group A beta-hemolytic streptococcal sore throat.
• Sinusitis.
• Lower respiratory tract infections.

In adults, they are limited to the treatment of infections due to susceptible bacteria, in particular:
• documented group A beta-hemolytic streptococcal sore throat.
• acute sinusitis.
• acute bronchial suppuration in at-risk patients (particularly alcoholics, smokers, patients over 65 years of age, etc.).
• exacerbation of chronic obstructive pulmonary disease, particularly in repeat episodes or in at-risk patients.
• bacterial lung diseases, particularly in at-risk patients.

Orelox® 200 are indicated for use in the short-term treatment of upper and lower respiratory tract infections due to susceptible micro-organisms (sensitivity tests must be performed):
• Acute bronchitis due to: Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis.
• Pharyngitis and tonsillitis due to: Streptococcus pyogenes.
• Acute exacerbations of chronic bronchitis due to: Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis.
• Bacterial pneumonia and community-acquired bronchopneumonia due to: Haemophilus influenza, Streptococcus pneumoniae, Moraxella catarrhalis.
• Acute sinusitis due to: Haemophilus influenzae (non-typeable), Streptococcus pneumoniae, Methicillin-sensitive Staphylococcus aureus, Moraxella catarrhalis.

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

POSOLOGY AND METHOD OF ADMINISTRATION

Children with normal kidney function

The mean dosage is 8 mg/kg/day, without exceeding the adult dose (200 mg/day for sore throat and 400 mg/day for all other indications), administered in 2 divided doses at 12-hour intervals. The amount per dose for oral administration is indicated, according to the child’s Duration of treatment for sore throat is 5 days.

Adults

200 mg or 400 mg to be taken as 2 divided doses, 12 hours apart during meals, i.e.:

2 x 200 mg per day, i.e. 2 tablets morning and evening in:
• acute sinusitis,
In acute maxillary sinusitis, a 5-day treatment has been shown to be effective.

• acute bronchial suppuration in at-risk patients,
• exacerbation of chronic obstructive pulmonary disease, particularly in repeat episodes or in at-risk patients,
• bacterial lung diseases, particularly in at-risk patients,

2 x 100 mg per day, i.e. 1 tablet morning and evening in sore throat.
The duration of treatment for sore throat is 5 days.

Elderly

No dose adjustment is required if the elderly subject has normal renal function.

Patients with kidney failure

No dose adjustment is required if creatinine clearance is over 40 ml/min.

Acute sinusitis, acute exacerbations of chronic bronchitis, pneumonia

One Orelox® 200 tablet (200 mg) every 12 hours with meals (400 mg/day)

CONTRA-INDICATIONS

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

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Treatment must be discontinued if any signs of allergy occur.
• Before prescribing cephalosporins, patient history should be investigated, due to the 5-10% occurrence of cross-allergy between penicillins and cephalosporins.

• - Extreme caution should be exercised when administering cephalosporins in penicillin-sensitive patients: strict medical monitoring is necessary as of the first dose.
• - Use of cephalosporins is absolutely contraindicated in patients with a history of immediate allergy to cephalosporins. If in doubt, the physician must absolutely remain with the patient during administration of the first dose, in order to treat any potential anaphylactic events.

• Hypersensitivity reactions (anaphylaxis) observed with these two types of beta-lactam antibiotics can be serious and occasionally fatal.
• The occurrence of an episode of diarrhea may, in exceptional cases, be symptomatic of pseudomembranous colitis, diagnosis of which is based on colonoscopy.
• Although rare with cephalosporins, if this event occurs, treatment must be discontinued immediately and appropriate specific antibiotic therapy (vancomycin) instituted. In this case, administration of drugs promoting fecal stasis must be absolutely avoided.
• This medicinal product contains lactose, and is therefore contraindicated in patients with galactose intolerance, Lapp lactase deficiency or glucose and galactose malabsorption syndrome (rare hereditary disorders).
• Blood disorders
• As with other beta-lactam antibiotics, neutropenia and, more rarely, agranulocytosis may develop during treatment with cefpodoxime, particularly if given over long periods, in which case blood monitoring should be considered.
• Bullous eruptions
• As with other cephalosporins, cases of bullous eruptions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. If any skin and/or mucosal disorder occur, patients should contact their doctor immediately and prior to continuing treatment.
• Superinfection
• As with other antibiotics, the use of cefpodoxime proxetil, especially if prolonged, may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.
• Encephalopathy
• Beta-lactams, including cefpodoxime, predispose the patient to encephalopathy risk (which may include convulsions, confusion, impairment of consciousness, movement disorders), particularly in case of overdose or renal impairment.

Precautions for use

• In patients who are allergic to other beta-lactam antibiotics, the possibility of cross-allergy should be taken into account.
• In patients with severe renal failure, it may be necessary to adjust the daily dose based on creatinine clearance (see “At-risk patients” and section 4.2).
• As with other broad-spectrum antibiotics, long-term use of cefpodoxime proxetil may result in overgrowth of non-susceptible organisms, which may require treatment discontinuation.
• Interactions with laboratory tests.
• Positive Coombs tests have been reported during treatment with cephalosporins.
• A false positive reaction for glucose in the urine may occur with reducing substances, but not when glucose oxidase methods are used.

INTERACTIONS

Food: A study has shown that regardless of the type of food, the bioavailability of cefpodoxime increases when the medicinal product is administered during meals.

Gastric pH changes: Increased gastric pH: H2 antagonists (ranitidine) and antacids (aluminum hydroxide, sodium bicarbonate) lead to reduced bioavailability.

Conversely, reduced gastric pH (pentagastrin) induces an increase in bioavailability.
The clinical implications of these effects have yet to be determined.

PREGNANCY AND LACTATION

Pregnancy

Due to the expected benefit, use of cefpodoxime can be considered during pregnancy if necessary, despite insufficient data in animals and man.

Breast-feeding

Excretion in breast milk is low, and the amounts ingested by the infant are far lower than therapeutic doses. Consequently, breast-feeding is possible during use of the antibiotic.

However, breast-feeding (or the medicinal product) should be discontinued if diarrhea, candidiasis or skin eruption occurs in the infant.

UNDESIRABLE EFFECTS

Adverse effects mainly include the following:
• diarrhea,
• vomiting,
• abdominal pain,
• rash, angioedema.

There have also been rare cases of the following:
• Gastrointestinal effects: as with other broad-spectrum antibiotics, rare cases of enterocolitis with bloody diarrhea have been reported, as well as rare cases of pseudomembranous colitis.
• Hepatobiliary effects: moderate elevation in ASAT and ALAT transaminase concentrations.
• Allergic effects: skin eruptions, pruritus, urticaria, anaphylactic shock.

Cutaneous effects: various types of eruption, localized bullous eruption, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.
• Headache.
• Dizziness.
• Beta-lactam antibiotics, including cefpodoxime, predispose patients to encephalopathy (which can include seizure, confusion, consciousness disorders or abnormal movements), particularly if they have had an overdose or if they have renal failure.
• Renal effects: moderate increase in creatinine concentrations.
• Hematological effects: decrease in hemoglobin levels, thrombocytopenia, neutropenia and hypereosinophilia and, in exceptional cases, agranulocytosis.

For uncommon, rare and very rare side effects see full prescribing information

OVERDOSE

Given the lack of experience to date, the usual symptomatic treatment should be instituted.

PHARMACODYNAMIC PROPERTIES

Antibacterials for systemic use
ATC code: J01DA33 (Third-generation cephalosporins).

Date of SmPC approval: April 2017.
Date of abbreviated prescribing information: November 2019.
More detailed Information on request: Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, Volta Place,
35 Patrice Lumumba Road, Airport Residential Area, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.

THERAPEUTIC INDICATIONS

Axacef® is indicated for the treatment of the infections listed below in adults and children from the age of 3 months (see sections 4.4 and 5.1).
• Acute streptococcal tonsillitis and pharyngitis.
• Acute bacterial sinusitis.
• Acute otitis media.
• Acute exacerbations of chronic bronchitis.
• Cystitis.
• Pyelonephritis.
• Uncomplicated skin and soft tissue infections.
• Treatment of early Lyme disease.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

POSOLOGY AND METHOD OF ADMINISTRATION

Posology

The usual course of therapy is seven days (may range from five to ten days).

Table 1. Adults and children (≥40 kg)

Table 2. Children (<40 kg)

There is no experience of using Axacef®in children under the age of 3 months.

Renal impairment: The safety and efficacy of Cefuroxime Axetil in patients with renal failure have not been established. Cefuroxime is primarily excreted by the kidneys. In patients with markedly impaired renal function it is recommended that the dosage of Cefuroxime should be reduced to compensate for its slower excretion. Cefuroxime is effectively removed by dialysis.

Hepatic impairment : There are no data available for patients with hepatic impairment. Since Cefuroxime is primarily eliminated by the kidney, the presence of hepatic dysfunction is expected to have no effect on the pharmacokinetics of cefuroxime.

Method of administration

Oral use.
Axacef®tablets should be taken after food for optimum absorption. Axacef®tablets should not be crushed and are therefore unsuitable for treatment of patients who cannot swallow tablets.

CONTRA-INDICATIONS

Hypersensitivity to Cefuroxime or to any of the excipients listed in section 6.1.
Patients with known hypersensitivity to Cephalosporin antibiotics.

History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of Betalactam antibacterial agent (Penicillins, Monobactams and Carbapenems).

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Hypersensitivity reactions

Special care is indicated in patients who have experienced an allergic reaction to Penicillins or other Beta-lactam antibiotics because there is a risk of cross-sensitivity.
As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with Cefuroxime must be discontinued immediately and adequate emergency measures must be initiated.
Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to cefuroxime, to other Cephalosporins or to any other type of beta-lactam agent. Caution should be used if Cefuroxime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction has been seen following Cefuroxime Axetil treatment of Lyme disease. It results directly from the bactericidal activity of Cefuroxime Axetil on the causative bacteria of Lyme disease, the spirochaete Borrelia burgdorferi.
Patients should be reassured that this is a common and usually self-limiting consequence of antibiotic treatment of Lyme disease (see section 4.8).

Overgrowth of non-susceptible microorganisms

As with other antibiotics, use of Cefuroxime Axetil may result in the overgrowth of Candida. Prolonged use may also result in the overgrowth of other non-susceptible microorganisms (e.g. enterococci and Clostridium difficile), which may require interruption of treatment (see section 4.8).

Antibacterial agent–associated pseudomembranous colitis have been reported with nearly all antibacterial agents, including Cefuroxime and may range in severity from mild to life threatening. This diagnosis should be considered in patients with diarrhoea during or subsequent to the administration of Cefuroxime (see section 4.8).

Discontinuation of therapy with Cefuroxime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given (see section 4.8).

Interference with diagnostic tests

The development of a positive Coomb’s Test associated with the use of cefuroxime may interfere with cross matching of blood (see section 4.8).
As a false negative result may occur in the Ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving Cefuroxime Axetil.

INTERACTIONS

Drugs which reduce gastric acidity may result in a lower bioavailability of Cefuroxime axetil compared with that of the fasting state and tend to cancel the effect of enhanced absorption after food.

Cefuroxime Axetil may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

Cefuroxime is excreted by glomerular filtration and tubular secretion. Concomitant use of probenicid is not recommended. Concurrent administration of Probenecid significantly increases the peak concentration, area under the serum concentration time curve and elimination half-life of Cefuroxime.

Concomitant use with oral anticoagulants may give rise to increased INR.

PREGNANCY AND LACTATION

Cefuroxime axetil should be administered with caution during early months of pregnancy. Caution should be exercised when cefuroxime axetil is administered to a nursing mother.

UNDESIRABLE EFFECTS

Pregnancy: There are limited data from the use of Cefuroxime in pregnant women. Studies in animals have shown no harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development. Axacef®should be prescribed to pregnant women only if the benefit outweighs the risk.

Lactation: Cefuroxime is excreted in human milk in small quantities. Adverse effects at therapeutic doses are not expected, although a risk of diarrhoea and fungus infection of the mucous membranes cannot be excluded. Breastfeeding might have to be discontinued due to these effects. The possibility of sensitisation should be taken into account. Cefuroxime should only be used during breastfeeding after benefit/risk assessment by the physician in charge.

UNDESIRABLE EFFECTS

The most common adverse reactions are Candida overgrowth, eosinophilia, headache, dizziness, gastrointestinal disturbances and transient rise in liver enzymes.

For uncommon, rare and very rare side effects see full prescribing information.

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: antibacterials for systemic use, second-generation cephalosporins, ATC code: J01DC02.

Date of SmPC approval: November 2015;
Date of abbreviated prescribing information: November 2019.
More detailed Information on request:
Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, Volta Place,
35 Patrice Lumumba Road, Airport Residential Area, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.

THERAPEUTIC INDICATIONS

Zoxon® is indicated for the treatment of the following infections in adults and children including term neonates (from birth):
Bacterial Meningitis, Community acquired pneumonia, Hospital acquired pneumonia, Acute otitis media, Intra-abdominal infections, Complicated urinary tract infections (including pyelonephritis), Infections of bones and joints, Complicated skin and soft tissue infections, Gonorrhoea, Syphilis, Bacterial endocarditis.

Zoxon® may be used:
• For treatment of acute exacerbations of chronic obstructive pulmonary disease in adults
• For treatment of disseminated Lyme borreliosis (early (stage II) and late (stage III)) in adults and children including neonates from 15 days of age.
• For pre-operative prophylaxis of surgical site infections
• In the management of neutropenic patients with fever that is suspected to be due to a bacterial infection
• In the treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Zoxon® should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum (see section 4.4).
Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

POSOLOGY AND METHOD OF ADMINISTRATION

The dose depends on the severity, susceptibility, site and type of infection and on the age and hepato-renal function of the patient.
The doses recommended in the tables below are the generally recommended doses in these indications. In particularly severe cases, doses at the higher end of the recommended range should be considered.

Adults and children over 12 years of age (≥50 kg)

^* In documented bacteraemia, the higher end of the recommended dose range should be considered.
^** Twice daily (12 hourly) administration may be considered where doses greater than 2 g daily are administered.

Indications for adults and children over 12 years of age (≥ 50 kg) that require specific dosage schedules:

Acute Otitis Media: A single intramuscular dose of Zoxon1-2 g can be given.
Limited data suggest that in cases where the patient is severely ill or previous therapy has failed, Zoxon® may be effective when given as an intramuscular dose of 1-2 g daily for 3 days.

Pre-operative prophylaxis of surgical site infections: 2 g as a single pre-operative dose.

Gonorrhoea: 500 mg as a single intramuscular dose.

Syphilis: The generally recommended doses are 500 mg-1 g once daily increased to 2 g once daily for neurosyphilis for 10-14 days. The dose recommendations in syphilis, including neurosyphilis, are based on limited data. National or local guidance should be taken into consideration.

Disseminated Lyme borreliosis (early [Stage II] and late [Stage III]) 2 g once daily for 14-21 days. The recommended treatment durations vary and national or local guidelines should be taken into consideration.

Paediatric population

Neonates, infants and children 15 days to 12 years of age (< 50 kg)

^* In documented bacteraemia, the higher end of the recommended dose range should be considered.
^** Twice daily (12 hourly) administration may be considered where doses greater than 2 g daily are administered.

Indications for neonates, infants and children 15 days to 12 years (< 50 kg) that require specific dosage schedules:

Acute otitis media: For initial treatment of acute otitis media, a single intramuscular dose of Zoxon® 50 mg/kg can be given. Limited data suggest that in cases where the child is severely ill or initial therapy has failed, Zoxon® may be effective when given as an intramuscular dose of 50 mg/kg daily for 3 days.

Pre-operative prophylaxis of surgical site infections: 50-80 mg/kg as a single pre-operative dose

Syphilis: The generally recommended doses are 75-100 mg/kg (max 4 g) once daily for 10-14 days. The dose recommendations in syphilis, including neurosyphilis, are based on very limited data. National or local guidance should be taken into consideration.

Disseminated Lyme borreliosis (early [Stage II] and late [Stage III]): 50–80 mg/kg once daily for 14-21 days. The recommended treatment durations vary and national or local guidelines should be taken into consideration.

Neonates 0-14 days
Zoxon® is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age).

^* In documented bacteraemia, the higher end of the recommended dose range should be considered.
A maximum daily dose of 50 mg/kg should not be exceeded.

Indications for neonates 0-14 days that require specific dosage schedules:

Acute otitis media: For initial treatment of acute otitis media, a single intramuscular dose of Zoxon® 50 mg/kg can be given.

Pre-operative prophylaxis of surgical site infections: 20-50 mg/kg as a single pre-operative dose.

Syphilis: The generally recommended dose is 50 mg/kg once daily for 10-14 days. The dose recommendations in syphilis, including neurosyphilis, are based on very limited data. National or local guidance should be taken into consideration.

Duration of therapy: The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of ceftriaxone should be continued for 48 - 72 hours after the patient has become afebrile or evidence of bacterial eradication has been achieved.

Older people: The dosages recommended for adults require no modification in older people provided that renal and hepatic function is satisfactory.

Patients with hepatic impairment: Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment provided renal function is not impaired.
There are no study data in patients with severe hepatic impairment (see section 5.2).

Patients with renal impairment: In patients with impaired renal function, there is no need to reduce the dosage of ceftriaxone provided hepatic function is not impaired. Only in cases of preterminal renal failure (creatinine clearance < 10 ml/min) should the ceftriaxone dosage not exceed 2 g daily.
In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Ceftriaxone is not removed by peritoneal or haemodialysis. Close clinical monitoring for safety and efficacy is advised.

Patients with severe hepatic and renal impairment: In patients with both severe renal and hepatic dysfunction, close clinical monitoring for safety and efficacy is advised.

Method of administration

Intramuscular administration: Zoxon® can be administered by deep intramuscular injection. Intramuscular injections should be injected well within the bulk of a relatively large muscle and not more than 1 g should be injected at one site.
As the solvent used is lidocaine, the resulting solution should never be administered intravenously (see section 4.3). The information in the Summary of Product Characteristics of lidocaine should be considered.

Intravenous administration: Zoxon® can be administered by intravenous infusion over at least 30 minutes (preferred route) or by slow intravenous injection over 5 minutes. Intravenous intermittent injection should be given over 5 minutes preferably in larger veins.

Intravenous doses of 50 mg/kg or more in infants and children up to 12 years of age should be given by infusion. In neonates, intravenous doses should be given over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see section 4.3 and 4.4). Intramuscular administration should be considered when the intravenous route is not possible or less appropriate for the patient. For doses greater than 2 g intravenous administration should be used.

Ceftriaxone is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition, because of the risk of precipitation of ceftriaxone-calcium (see section 4.3).

Diluents containing calcium, (e.g. Ringer’s solution or Hartmann’s solution), should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously (see sections 4.3, 4.4 and 6.2).

For pre-operative prophylaxis of surgical site infections, ceftriaxone should be administered 30-90 minutes prior to surgery.

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

CONTRA-INDICATIONS

Hypersensitivity to ceftriaxone, to any other cephalosporin or to any of the excipients listed in section 6.1.
History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems).

Ceftriaxone is contraindicated in

Premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age)^*

Full-term neonates (up to 28 days of age)

• with hyperbilirubinaemia, jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired^*
• if they require (or are expected to require) intravenous calcium treatment, or calcium-containing infusions due to the risk of precipitation of a ceftriaxone-calcium salt (see sections 4.4, 4.8 and 6.2).

^* In vitro studies have shown that ceftriaxone can displace bilirubin from its serum albumin binding sites leading to a possible risk of bilirubin encephalopathy in these patients.

Contraindications to lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine solution is used as a solvent (see section 4.4). See information in the Summary of Product Characteristics of lidocaine, especially contraindications.

Ceftriaxone solutions containing lidocaine should never be administered intravenously.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Hypersensitivity reactions

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported (see section 4.8). In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if ceftriaxone is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Severe cutaneous adverse reactions (Stevens Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) have been reported; however, the frequency of these events is not known (see section 4.8).

Interaction with calcium containing products

Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term neonates aged less than 1 month have been described. At least one of them had received ceftriaxone and calcium at different times and through different intravenous lines. In the available scientific data, there are no reports of confirmed intravascular precipitations in patients, other than neonates, treated with ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups.

In patients of any age ceftriaxone must not be mixed or administered simultaneously with any calcium-containing intravenous solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing total parenteral nutrition (TPN) solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If the use of ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion and the infusion lines flushed between solutions (see sections 4.3, 4.8, 5.2 and 6.2).

Paediatric population

Safety and effectiveness of Zoxon® in neonates, infants and children have been established for the dosages described under Posology and Method of Administration (see section 4.2). Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.

Zoxon® is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section 4.3).

Immune mediated haemolytic anaemia: An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including Zoxon® (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during Zoxon® treatment in both adults and children.

If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporin-associated anaemia should be considered and ceftriaxone discontinued until the aetiology is determined.

Long term treatment

During prolonged treatment complete blood count should be performed at regular intervals.

Colitis/Overgrowth of non-susceptible microorganisms

Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftriaxone (see section 4.8). Discontinuation of therapy with ceftriaxone and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents.

Severe renal and hepatic insufficiency

In severe renal and hepatic insufficiency, close clinical monitoring for safety and efficacy is advised (see section 4.2).
Interference with serological testing: Interference with Coombs tests may occur, as Zoxon® may lead to false-positive test results. Zoxon® can also lead to false-positive test results for galactosaemia (see section 4.8).

Non-enzymatic methods for the glucose determination in urine may give false-positive results. Urine glucose determination during therapy with Zoxon® should be done enzymatically (see section 4.8).
The presence of ceftriaxone may falsely lower estimated blood glucose values obtained with some blood glucose monitoring systems. Please refer to instructions for use for each system. Alternative testing methods should be used if necessary.

Sodium

Each gram of Zoxon® contains 3.6 mmol sodium. This should be taken into consideration in patients on a controlled sodium diet.

Antibacterial spectrum

Ceftriaxone has a limited spectrum of antibacterial activity and may not be suitable for use as a single agent for the treatment of some types of infections unless the pathogen has already been confirmed (see section 4.2). In polymicrobial infections, where suspected pathogens include organisms resistant to ceftriaxone, administration of an additional antibiotic should be considered.

Use of lidocaine

In case a lidocaine solution is used as a solvent, ceftriaxone solutions must only be used for intramuscular injection. Contraindications to lidocaine, warnings and other relevant information as detailed in the Summary of Product Characteristics of lidocaine must be considered before use (see section 4.3). The lidocaine solution should never be administered intravenously.

Biliary lithiasis

When shadows are observed on sonograms, consideration should be given to the possibility of precipitates of calcium ceftriaxone. Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder and have been observed more frequently at ceftriaxone doses of 1 g per day and above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of ceftriaxone therapy. Rarely precipitates of calcium ceftriaxone have been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended and discontinuation of ceftriaxone treatment should be considered by the physician based on specific benefit risk assessment (see section 4.8).

Biliary stasis

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in patients treated with Zoxon® (see section 4.8). Most patients presented with risk factors for biliary stasis and biliary sludge e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or co-factor of Zoxon® related biliary precipitation cannot be ruled out.

Renal lithiasis

Cases of renal lithiasis have been reported, which is reversible upon discontinuation of ceftriaxone (see section 4.8). In symptomatic cases, sonography should be performed. Use in patients with history of renal lithiasis or with hypercalciuria should be considered by the physician based on specific benefit risk assessment.

INTERACTIONS

Calcium-containing diluents, such as Ringer’s solution or Hartmann’s solution, should not be used to reconstitute Zoxon® vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium (see sections 4.2, 4.3, 4.4, 4.8 and 6.2).

Concomitant use with oral anticoagulants may increase the anti-vitamin K effect and the risk of bleeding. It is recommended that the International Normalised Ratio (INR is monitored frequently and the posology of the anti-vitamin K drug adjusted accordingly, both during and after treatment with ceftriaxone (see section 4.8).

There is conflicting evidence regarding a potential increase in renal toxicity of aminoglycosides when used with cephalosporins. The recommended monitoring of aminoglycoside levels (and renal function) in clinical practice should be closely adhered to in such cases.
In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone. The clinical relevance of this finding is unknown.

There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (intravenous or oral).

In patients treated with ceftriaxone, the Coombs' test may lead to false-positive test results.
Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia.

Likewise, non-enzymatic methods for glucose determination in urine may yield false-positive results. For this reason, glucose level determination in urine during therapy with ceftriaxone should be carried out enzymatically.

No impairment of renal function has been observed after concurrent administration of large doses of ceftriaxone and potent diuretics (e.g. furosemide).

Simultaneous administration of probenecid does not reduce the elimination of ceftriaxone.

PREGNANCY AND LACTATION

Pregnancy

Ceftriaxone crosses the placental barrier. There are limited amounts of data from the use of ceftriaxone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal, perinatal and postnatal development (see section 5.3). Ceftriaxone should only be administered during pregnancy and in particular in the first trimester of pregnancy if the benefit outweighs the risk.

Lactation

Ceftriaxone is excreted into human milk in low concentrations but at therapeutic doses of ceftriaxone no effects on the breastfed infants are anticipated. However, a risk of diarrhoea and fungal infection of the mucous membranes cannot be excluded.The possibility of sensitisation should be taken into account. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

UNDESIRABLE EFFECTS

The most frequently reported adverse reactions for ceftriaxone are eosinophilia, leucopenia, thrombocytopenia, diarrhoea, rash, and hepatic enzymes increased.

For uncommon, rare and very rare side effects see full prescribing information.

OVERDOSE

In overdose, the symptoms of nausea, vomiting and diarrhoea can occur. Ceftriaxone concentrations cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdose should be symptomatic.

PHARMACODYNAMIC PROPERTIES

Date of SmPC approval: January 2018;
Date of abbreviated prescribing information: November 2019;
More detailed Information on request: Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, Volta Place,
35 Patrice Lumumba Road, Airport Residential Area, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.

Therapeutic indications

Its use is limited to the treatment of infections caused by microorganisms which have been shown to be susceptible to the drug: all forms of amebiasis, urogenital trichomoniasis, non- specific vaginitis, giardiasis, acute ulcerative gingivitis (Vincent's), acute pericoronitis, curative treatment of medical and surgical infections caused by susceptible anaerobes, replacement therapy after curative treatments given by injection of infections caused by susceptible anaerobes; Treatment of infections in which anaerobic bacteria have been identified or are suspected as pathogens, particularly Bacteroides fragilis and other species of Bacteroides and including other species for which metronidazole is bactericidal, such as fusobacteria, clostridia, eubacteria and anaerobic streptococci. FLAGYL has been used successfully for anaerobic infections in the following conditions: pelvic inflammatory disease and postoperative wound infections. Combined therapy is often indicated as there are usually mixed infections.
Prevention of postoperative infections due to anaerobic bacteria: Given before and after gynaecological surgery; Given before and after appendectomy; Given before and after colonic surgery.
Treatment of Helicobacter pylori-associated gastritis and duodenal ulcer. FLAGYL is used in combination with bismuth subsalicylate or colloidal bismuth subcitrate and appropriate antibiotic therapy.

POSOLOGY AND METHOD OF ADMINISTRATION

CONTRA-INDICATIONS

Hypersensitivity to metronidazole or to imidazoles or to any of the excipients.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Hypersensitivity / Skin and appendages

Allergic reactions, including anaphylactic shock, can occur and be life-threatening. In this case, treatment with metronidazole must be discontinued and appropriate medical treatment initiated. If, at the start of treatment, patients experience generalized erythema with fever and pustules, acute generalized exanthematous pustulosis should be suspected (see Section 4.8). If this occurs, treatment must be discontinued and any further administration of metronidazole alone or in combination with other agents is contraindicated. Severe skin reactions have been reported with metronidazole, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or Lyell syndrome) and acute generalized exanthematous pustulosis. Patients must be informed of the signs and symptoms of these conditions and the skin should be closely monitored. If any signs or symptoms of Stevens-Johnson syndrome, toxic epidermal necrolysis (e.g. progressive skin rash often with blisters or mucosal lesions) or acute generalized exanthematous pustulosis occur, treatment must be discontinued and any further administration of metronidazole alone or in combination with other agents is contraindicated.

Central nervous system

If symptoms indicative of encephalopathy or cerebellar syndrome appear, patient management should be immediately reassessed and metronidazole treatment discontinued. Patients should be monitored for warning signs of encephalopathy, and exacerbation of symptoms in patients with CNS disorders. If aseptic meningitis occurs during treatment, rechallenge with metronidazole is not recommended, and an assessment of the benefit/risk ratio should be done for patients with serious infection.

Peripheral nervous system

Patients should be monitored for warning signs of peripheral neuropathy, particularly in long-term treatment or in patients with severe, chronic or progressive peripheral neurological disorders.

Psychiatric disorders

From administration of the first doses, patients may experience psychotic reactions, including self-endangering behavior, particularly if they have a history of psychiatric disorders. If this happens, metronidazole must be discontinued, the physician informed and appropriate therapeutic measures instituted immediately.

Hematological effects

In patients who have a history of hematological disorders or who are receiving high-dose and/or long-term treatment, regular blood tests, and particularly leukocyte counts, should be performed. In patients with leukopenia, continued treatment will depend on how serious the infection is.

Excipients with known effect

This medicinal product contains sucrose. Patients with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase insufficiency should not take this medicinal product. This medicinal product contains 3 g of sucrose per measuring-spoon. This should be taken into account in the daily allowance in patients on a low-sugar diet or with diabetes. This medicinal product contains 1% V/V ethanol (alcohol), i.e. up to 40 mg ethanol per measuring-spoon, equivalent to 12 mL of beer or 5 mL of wine per dose. Use of this medicinal product is harmful for those suffering from alcoholism. This should be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy.
This medicinal product contains sodium. The sodium content is less than 1 mmol per dose, i.e. it is essentially “sodium-free”. This medicinal product contains “parahydroxybenzoate” and may cause allergic reactions (possibly delayed).

Patients should be advised not to take alcohol during FLAGYL therapy and for at least one to three days afterwards because of the possibility of a disulfiram-like reaction. Co-administration with busulfan: As plasma levels of busulfan may be increased significantly, it may lead to severe busulfan toxicity and death.
Pseudomembranous colitis has been reported with the use of FLAGYL.
Studies have shown FLAGYL to be mutagenic in bacteria and carcinogenic in some animals. FLAGYL should be administered with caution to patients with hepatic encephalopathy.
FLAGYL should be used with great care in patients with blood dyscrasias or with active or chronic disease of the central and peripheral nervous system. All patients receiving FLAGYL for more than 10 days should be monitored and treatment discontinued if signs of peripheral neuropathy or central nervous system toxicity develop. Doses should be reduced in patients with severe liver disease.
FLAGYL has anti-treponemal activity and may mask the immunological response seen in untreated early syphilis; contacts of syphilis receiving FLAGYL should probably be screened for an additional 4 to 8 weeks.
Patients should be warned that FLAGYL may darken urine (due to metronidazole metabolite). Driving a vehicle or performing hazardous tasks: Patients should be warned about the potential for confusion, dizziness, hallucinations, convulsions or eye disorders (see SIDE EFFECTS), and advised not to drive or operate machinery if these symptoms occur.
FLAGYL 400mg tablets contain tartrazine which may cause allergic-type reactions (including bronchial asthma) in certain individuals. Although the overall incidence of tartrazine sensitivity in the general population is currently thought to be low, it is frequently seen in patients who also have aspirin sensitivity.

INTERACTIONS

Concomitant use of metronidazole and alcohol is not recommended; Concomitant use of metronidazole and busulfan is not recommended; Concomitant use of metronidazole and disulfiram is not recommended.
Oral anticoagulant therapy (warfarin type), Lithium, Ciclosporin, Phenytoin or phenobarbital, 5-Fluorouracil, Cimetidine.

PREGNANCY AND LACTATION

Pregnancy

There is no evidence from animal studies that metronidazole is teratogenic.
Safety in pregnancy and lactation has not been established.

Metronidazole may be prescribed during pregnancy if necessary.

Lactation

Since metronidazole is excreted in breast milk, administration should be avoided in breast-feeding women.

UNDESIRABLE EFFECTS

Blood and lymphatic system disorders

Neutropenia, agranulocytosis, thrombocytopenia.

Psychiatric disorders

Hallucinations, psychotic reactions with paranoia and/or delirium possibly accompanied by suicidal ideation or suicide attempts in some isolated cases, depressed mood.

Nervous system disorders

Peripheral sensory neuropathy, headache, dizziness, confusion, seizures, encephalopathy that may be associated with MRI changes, generally reversible upon treatment discontinuation. Very rare cases of fatal outcome have been reported, sub-acute cerebellar syndrome (ataxia, dysarthria, gait disorders, nystagmus, tremor), aseptic meningitis.

Eye disorders

Transient vision disorders such as blurred vision, diplopia, myopia, reduced visual acuity, impaired color vision, neuropathy / optic neuritis.

Gastrointestinal disorders

Minor gastrointestinal disorders (epigastric pain, nausea, vomiting, diarrhea), glossitis with dry mouth, stomatitis, taste disorders, anorexia, pancreatitis, reversible on treatment discontinuation, discoloration or change in the appearance of the tongue (mycosis).

Hepatobiliary disorders

Elevated liver enzyme levels (AST, ALT, alkaline phosphatase), very rare cases of acute cholestatic or mixed hepatitis and hepatocellular liver injury, sometimes with jaundice, have been reported. Isolated cases of hepatocellular insufficiency possibly requiring liver transplantation have been reported.

Skin and subcutaneous tissue disorders

Hot flushes, pruritus, skin rash occasionally with fever, urticaria, angioedema, anaphylactic shock, very rare cases of acute generalized exanthematous pustulosis, toxic epidermal necrolysis, Stevens-Johnson syndrome, fixed drug eruption.

Other effects

Urine can appear reddish-brown as water-soluble pigments may be found due to metabolism of the drug.
For uncommon, rare and very rare side effects see full prescribing information

OVERDOSE

Administration of up to 12g as a single dose has been reported in cases of attempted suicide and accidental overdose.
The symptoms were limited to vomiting, ataxia and mild disorientation. There is no specific antidote to metronidazole overdose. If massive overdose occurs, symptomatic treatment should be instituted.

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: antibacterial, antiparasitic antibiotics belonging to the 5- nitroimidazole group, ATC code: J01XD01 — P01AB01 (J: Antiinfectives for systemic use, other antibacterials - imidazole derivatives - P: Antiprotozoals, agents against amebiasis and other protozoal diseases - nitroimidazole derivatives).

Date of SmPC text revision: November 2017; March 2018;
Date of abbreviated prescribing information: August 2020.
More detailed Information on request:
Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, Sanofi Ghana Representative Office, 1st Floor Volta Place,
35 Patrice Lumumba Road, Airport Residential Area – Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.