INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
LITARES (film-coated tablets)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

LITARES (film-coated tablets)

COMPOSITION
LITARES: Each film-coated tablet contains moxifloxacin hydrochloride equivalent to moxifloxacin 400 mg
Sugar free

PHARMACOLOGICAL CLASSIFICATION
A 20.1.1 Broad and medium spectrum antibiotics

PHARMACOLOGICAL ACTION
Moxifloxacin is a fluoroquinolone antibacterial with a broad spectrum of bactericidal action.
Moxifloxacin has been shown to be active in vitro against most of the following microorganisms listed below. In vitro sensitivity may not always have been confirmed in clinical infection (see INDICATIONS).
Microbiology
Moxifloxacin has in vitro activity against a wide range of Gram-positive and Gram-negative microorganisms.
The bactericidal action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV required for bacterial DNA replication, transcription, repair and recombination.
There is no known cross-resistance between moxifloxacin and other classes of antimicrobials.
Cross-resistance has been observed between moxifloxacin and other fluoroquinolones against Gram-negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones may, however, still be susceptible to moxifloxacin.
Moxifloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described under INDICATIONS AND DOSAGE AND DIRECTIONS FOR USE.
Aerobic Gram-positive microorganisms
Staphylococcus aureus (methicillin-susceptible strains only)
Streptococcus pneumoniae (penicillin-susceptible strains)
Aerobic Gram-negative microorganisms
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Other microorganisms
Chlamydia pneumoniae
Mycoplasma pneumoniae
The following in vitro data are available, but their clinical significance is unknown.
Moxifloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 2 micrograms/mL or less against most (> 90%) strains of the following microorganisms, however, the safety and effectiveness of moxifloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic Gram-positive microorganisms
Streptococcus agalactiae
Streptococcus viridans group
Aerobic Gram-negative microorganisms
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Legionella pneumophila
Proteus mirabilis
Anaerobic microorganisms
Fusobacterium species
Peptostreptococcus species
Prevotella species
In vitro sensitivity does not necessarily imply in vivo efficacy.

Pharmacokinetics
Following oral administration moxifloxacin is absorbed rapidly and almost completely. The absolute bioavailability amounts to approximately 90% after oral administration of a 400 mg dose. Pharmacokinetics are linear in the range of 50 to 1 200 mg single oral dose and up to 600 mg once daily dosing over 10 days. Steady state is reached within 3 days. Following a 400 mg oral dose, peak concentrations of 3,1 mg/L are reached within 0,5 to 4 hours post administration. Peak and trough plasma concentrations at steady state (400 mg once daily) were 3,2 and 0,6 mg/L, respectively.
Moxifloxacin undergoes Phase II biotransformation and is excreted via renal and biliary faecal pathways as unchanged drug as well as in form of a sulfo-compound (M1) and a glucuronide (M2). M1 and M2 are the only metabolites relevant in humans. Both are microbiologically inactive. The recovery from urine (approximately 19% for unchanged drug, approximately 2,5% for M1 and approximately 14% for M2) and faeces (approximately 25% of unchanged drug, approximately 36% for M1 and no recovery for M2) totalled to approximately 96,98% of the dose independent from the route of administration.
Moxifloxacin is eliminated from plasma and saliva with a mean terminal half life of approximately 12 hours. The mean apparent total body clearance following a 400 mg dose ranges from 179 to 246 mL/min. Renal clearance amounted to about 24 to 53 mL/min suggesting partial tubular reabsorption of the drug from the kidneys. Approximately 19% of the dose is excreted unchanged into the urine and approximately 25% in the faeces. Approximately 2,5% is recovered as M1 in the urine and 36% in the faeces respectively. About 14% is recovered as M2 in the urine.

INDICATIONS
LITARES is indicated for the treatment of adults (> 18 years of age) with mild to moderately severe infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

*	Acute bacterial sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis.
*	Acute bacterial exacerbation of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Staphylococcus aureus or Moraxella catarrhalis.
*	Community acquired pneumonia (of mild to moderate severity) caused by Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae or Moraxella catarrhalis.
*	Skin and soft tissue infections caused by Staphylococcus aureus or Streptococcus pyogenes.

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to moxifloxacin.
Known hypersensitivity to any component of the tablets or other quinolones.

CONTRAINDICATIONS
Due to the lack of clinical data the use of LITARES is not recommended in patients with moderate or severe hepatic insufficiency.
Quinolones are known to distribute well into breast milk of lactating women. The use of LITARES in pregnancy and nursing mothers is contraindicated.

LITARES is contraindicated in children under 18 years and in growing adolescents (except where no other suitable antimicrobial agent can be used). Experimental evidence indicates that species variable reversible lesions of the cartilage of weight bearing joints has been seen in immature members of certain animal species.

WARNINGS
The safety and efficacy of LITARES in paediatric patients, adolescents (less than 18 years of age), pregnant and lactating women have not been established. LITARES has been shown to prolong the QT interval of the electrocardiogram in some patients.
LITARES should be avoided in patients with known prolongation QT interval, patientswith uncorrected hypokalaemia and patients receiving Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic agents, due to lack of clinical experience with LITARES in these patient populations.
Pharmacokinetic studies between moxifloxacin and other medicines that prolong the QT interval such as cisapride, erythromycin, antipsychotics and tricyclic antidepressants have not been performed.
An additive effect of LITARES and these medicines cannot be excluded; therefore LITARES should be used with caution when given concurrently with these medicines.
The effect of LITARES on patients with congenital prolongation of the QT interval has not been studied; however it is expected that these individuals may be more susceptible to drug-induced QT prolongation. Because of limited clinical experience, LITARES should be used with caution in patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia and acute myocardial ischemia.
The magnitude of QT prolongation may increase with increasing concentrations of LITARES therefore the recommended dose should not be exceeded. QT prolongation may lead to an increased risk for ventricular arrhythmias including torsade de pointes. The mean +SD effect of moxifloxacin 400 mg on the QTc interval was 6 + 26 ms.
The oral administration of moxifloxacin caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class medicines also produce erosions of cartilage of weight bearing joints and other signs of arthropathy in immature animals of various species.
Convulsions have been reported in patients receiving quinolones such as LITARES. Quinolones may also cause central nervous system (CNS) events including:
dizziness, confusion, tremors, hallucinations, depression and rarely, suicidal thoughts or acts.
These reactions may occur following the first dose. If these reactions occur in patients receiving moxifloxacin, LITARES should be discontinued and appropriate measures instituted.
LITARES should be used with caution in patients with known or suspected CNS disorders (e.g. severe cerebral arteriosclerosis and epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (see PRECAUTIONS AND SIDE-EFFECTS)
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy such as LITARES. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial oedema, dyspnoea, urticaria and itching.
Serious anaphylactic reactions require immediate emergency treatment with epinephrine (adrenaline). LITARES should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Oxygen, intravenous steroids and airway management, including intubation, may be administered as indicated.
Severe and sometimes fatal events, some due to hypersensitivity and some of uncertain etiology, have been reported in patients receiving therapy with LITARES. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: rash, fever, eosinophilia, jaundice and hepatic necrosis.
Pseudomembranous colitis has been reported with Moxifloxacin and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of LITARES.
Treatment with LITARES alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis".
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported with quinolones. LITARES should be discontinued if the patient experiences pain, inflammation or rupture of a tendon.
Quinolones such as LITARES may cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.

INTERACTIONS
Food and dairy products
Absorption of moxifloxacin was not altered by food intake. Therefore, LITARES can be taken independent from food intake.
Ranitidine
The concomitant administration with ranitidine did not change the absorption characteristics of moxifloxacin significantly. Absorption parameters (Cmax, tmax, AUC) were very similar indicating absence of an influence of gastric pH on LITARES uptake from the gastrointestinal tract.
Antacids, minerals and multivitamins
Concomitant ingestion of LITARES together with antacids, minerals and multivitamins may result in impaired absorption of the drug due to formation of chelate complexes with the multivalent cations contained in these preparations. This may lead to plasma concentrations considerably lower than desired. Hence, antacids, anti-retroviral medicines and other preparations containing magnesium, aluminium and other minerals such as iron should be administered at least 4 hours before or 2 hours after ingestion of an oral moxifloxacin dose.
Warfarin
No interaction during concomitant treatment with warfarin on prothrombin time and other coagulation parameters has been observed.
Digoxin
The pharmacokinetics of digoxin are not significantly influenced by LITARES (and vice versa).
Itraconazole
The pharmacokinetics of moxifloxacin are not significantly altered by itraconazole. No dose adjustment is necessary for itraconazole when given with LITARES and vice versa.
Theophylline
No influence of LITARES on theophylline pharmacokinetics (and vice versa) at steady state was detected. Hence, no recommendations with respect to theophylline dosing need to be given.
Probenecid
No significant effect on apparent total body clearance and renal clearance of moxifloxacin was found in a clinical study investigating the impact of probenecid on renal excretion. Therefore, dosing adjustments need not be made when both drugs are administered concomitantly.
Antidiabetics
Concomitant administration of LITARES with glibenclamide may result in a decrease of approximately 21% in the peak plasma concentrations of glibenclamide.
Oral contraceptives
No interaction has occurred following concomitant oral administration of moxifloxacin with oral contraceptives.
Medicines metabolized by Cytochrome P450 enzymes
In vitro studies with cytochrome P450 isoenzyrnes (CYP) indicate that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19 or CYP1A2, suggesting that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes (e.g. midazolam, cycIosporine, warfarin, theophylline).
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Although not observed with moxifloxacin in preclinical and clinical trials, the concomitant administration of NSAIDs with LITARES may increase the risk of CNS stimulation and convulsions (see WARNINGS).
Charcoal
Concomitant administration of charcoal with a dose of 400 mg LITARES will reduce systemic availability of the drug by more than 80%.

PREGNANCY AND LACTATION
Quinolones pass into and are present in breast milk of lactating women. The use of LITARES in pregnancy and nursing mothers is contraindicated.

DOSAGE AND DIRECTIONS FOR USE
Adults: The recommended dose for LITARES is 400 mg once-daily for all indications.
Swallow the tablet whole with a glass of water. LITARES can be taken independent of food intake.
The duration of treatment should be determined by the severity of the indication or clinical response.
The following general recommendations for the treatment of upper and lower respiratory tract infections are made:

Acute exacerbation of chronic bronchitis	5 days
Community acquired pneumonia	10 days
Acute sinusitis	10 days

The recommended duration of treatment in skin and soft tissue infections is 10 days.
Special Populations
Elderly
No adjustment of dosage is required in the elderly.
Children
The use of LITARES in children and adolescents under 18 years in the growth phase is contraindicated.
Hepatic impairment
No dosage adjustment is required in patients with slightly impaired liver function (Child-Pugh A). No pharmacokinetic data are available for patients with moderate to severely impaired liver function (Child-Pugh B, C). Due to the lack of data LITARES is contraindicated in patients with moderate or SBY9I9 hepatic impairment.
Renal impairment
No dose adjustment is required in patients with any degree of renal impairment (including creatinine clearance < 30 mL/min/1,73 m²).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
Infections and infestations
Frequent: Oral and vaginal candidiasis
Blood and lymphatic system disorders
Less frequent: Anaemia, leukopenia, thrombocytopenia, blood eosinophilia, thrombocytemia, prothrombin time prolonged/INR increased, thromboplastin decrease, prothrombin level increased/ INR decreased
Immune system disorders
Less frequent: Allergic reaction, anaphylactic reaction, anaphylactic shock
Metabolic and nutritional disorders
Less frequent: Hyperlipidaemia, hyperglycaemia, hyperuricaemia
Psychiatric disorders
Less frequent: Anxiety, confusion, depression, hallucinations, emotional lability, agitation, abnormal thinking, depersonalisation
Nervous system disorders
Less frequent: Headache, dizziness, malaise, insomnia, vertigo, somnolence, tremor, parasthesia, nervousness, incoordination, amnesia, speech disorder or aphasia, abnormal dreams, convulsions, hypesthesia, hypertonia
Eye disorders
Less frequent : Amblyopia, abnormal vision
Ear and labyrinth disorders
Less frequent: Tinnitus
Cardiac disorders
Frequent: QT prolongation
Less frequent: Palpitations, tachycardia, chest pain
Vascular disorders
Less frequent: Peripheral oedema, hypertension, hypotension, vasodilation
Respiratory, thoracic and mediastinal disorders
Less frequent: Dyspnoea, asthma
Gastrointestinal disorders
Frequent: Abdominal pain, nausea, diarrhoea, vomiting, dyspepsia
Less frequent: Taste perversion, dry mouth, flatulence, constipation, anorexia, stomatitis, glossitis, increased amylase, gastritis, tongue discolouration, dysphagia, pseudomembranous colitis
Hepato-biliary disorders
Frequent: Increase in transaminases
Less frequent: Increase in gamma-glutamyl-transferase (gGT), hepatic impairment including LDH increase, increased bilirubin, increase in alkaline phosphatase, jaundice
Skin and subcutaneous tissue disorders
Less frequent: Pruritus, urticaria, sweating, rash (maculopapular, purpuric, pustular)
Musculoskeletal, connective tissue and bone disorders
Less frequent: Asthenia, back pain, leg pain, arthralgia, myalgia, tendonitis, arthritis, tendon rupture
Renal and urinary disorders
Less frequent: Renal impairment
Reproductive system and breast disorders
Less frequent: Vaginitis
General disorders and administration site conditions
Less frequent: Pain (including pain in back, chest, pelvis and extremities), face oedema

Investigations
The most common changes in laboratory parameters not listed above include increased and decreased haematocrit, increased WBC, increased and decreased RBC, hypoglycaemia, decreased haemaglobin, increased SGOT/AST, increased SGPT/ALT, increased urea, increased creatinine. It is not known whether these laboratory alterations are caused by LITARES or by the underlying condition being treated.

Special precautions
Suspicion of pseudomembranous colitis requires immediate cessation of treatment.
Psychotic reactions have been reported to occur already after the first dose. In the event of such adverse reactions, LITARES must be discontinued immediately and a medical practitioner be informed.
In the event of allergic manifestations LITARES must be discontinued immediately. Medical treatment therapy for shock is imperative.
If tendonitis is suspected treatment with LITARES must be discontinued immediately and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon. Tendon rupture may occur within 48 hours after starting treatment with LITARES and may be bilateral.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
No specific countermeasures after accidental over dosage are recommended. General symptomatic therapy should be initiated. Concomitant administration of charcoal with a dose of 400 mg oral LITARES will reduce systemic availability of the medicine by more than 80%.

IDENTIFICATION
Beige coloured, modified capsule shaped, biconvex, film-coated tablets embossed 'RDY' one side and '112' on other side.

PRESENTATION
5 and 10 film-coated tablets in Alu/Alu blisters.

STORAGE INSTRUCTIONS
Store below 25ºC.
Keep the blisters in the carton until required for use.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
42/20.1.1/0142

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Dr. Reddy's Laboratories (Pty) Limited
381 Rossouw Street
Murrayfield
Pretoria

DATE OF PUBLICATION OF THE PACKAGE INSERT
December 2009

LITARES South Africa 150021876

Updated on this site: June 2010
Source: Pharmaceutical Industry

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