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MAXAQUIN® Tablets

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

MAXAQUIN^® Tablets

COMPOSITION:
Each tablet contains lomefloxacin hydrochloride equivalent to 400 mg lomefloxacin base.

PHARMACOLOGICAL CLASSIFICATION:
A 20.1.1 Broad and medium spectrum antibiotics.

PHARMACOLOGICAL ACTION:
MAXAQUIN^®, a difluoroquinolone, is a synthetic broad spectrum antibacterial agent.

Clinical Pharmacology
Lomefloxacin is rapidly and well absorbed from the gastrointestinal tract after oral administration. Lomefloxacin is 95 - 98% bioavailable. There is no first-pass metabolism. Plasma concentrations increase proportionately between 100 mg and 400 mg.

Maximum plasma concentrations are attained 1 to 1,5 hours after oral dosing and are usually between 2,0 to 3,0 /mcg/mL following a 400 mg dose. The elimination half-life in subjects with normal renal function is approximately 8 hours. At 24 hours post-dose, subjects with normal renal function receiving single doses of 200, 400 or 800 mg had mean plasma lomefloxacin concentrations of 0,10; 0,24 and 0,61 mcg/mL respectively. Steady-state concentrations are achieved within 48 hours of initiating therapy with once-a-day dosing. There is no accumulation with single daily dosing in patients with normal renal function.

In healthy, elderly volunteers (61 to 76 years of age) with normal renal function for their age lomefloxacin half-life (mean of 8 hours) and peak plasma concentration (mean of 4,2 mcg/mL) following a 400 mg dose were similar to those seen in younger subjects.

Following oral administration, lomefloxacin is widely distributed throughout the body. Studies have not been conducted to assess the penetration into human cerebrospinal fluid.

Lomefloxacin is minimally metabolized although five metabolites have been identified in human urine. The glucuronide metabolite is found in the highest concentration and accounts for approximately 10% of the administered dose. The other four metabolites together account for less than 0,5% of the dose.

Approximately 65% of an orally administered dose is excreted as unchanged drug in the urine of patients with normal renal function. Following a single dose or multiple daily doses of 400 mg lomefloxacin urine concentrations are in excess of 400 mcg/mL by 4 hours post dose and remain above 35 mcg/mL for at least 24 hours after dosing. Urinary excretion is virtually complete within 72 hours after cessation of dosing, with approximately 75% of the dose being recovered as parent drug or its glucuronide metabolite. The renal clearance exceeds the normal glomerular filtration rate, averaging about 200 mL/min in subjects with renal function (GFR=120 mL/min), indicating tubular secretion. Approximately 10% of an oral dose is recovered as unchanged drug in the faeces.

The elimination of lomefloxacin is modified in patients with renal insufficiency (see Dosage and Directions for Use for dosing recommendations).

The plasma protein binding of lomefloxacin is about 10%, which is not sufficient to produce significant drug-drug interactions arising from displacement of bound drug.

Microbiology
Lomefloxacin is a bactericidal agent with in vitro activity against gram-negative and gram-positive organisms. The bactericidal action of lomefloxacin results from interference with the activity of the bacterial enzyme DNA gyrase, needed for the transcription and replication of bacterial DNA. The minimum bactericidal concentration (MBC) generally does not exceed the minimum inhibitory concentration (MIC) by more than a factor of two.

Lomefloxacin is slightly less active when tested at acidic pH. An increase in inoculum size has little effect on in vitro activity of lomefloxacin. In vitro resistance to lomefloxacin develops slowly (multiple-step mutation). Rapid one-step development of resistance occurs only rarely (<10 ^-9) in vitro.

INDICATIONS
Treatment:
MAXAQUIN^®is indicated for the treatment of mild to moderate infections caused by susceptible strains in the conditions listed below:

Uncomplicated urinary tract infections (cystitis) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Staphylococcus saprophyticus.

Complicated, including recurrent, urinary tract infections caused by Citrobacter diversus, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa.

Acute exacerbation of chronic bronchitis caused by Branhamella catarrhalis [beta lactamase (+) and (-)], Haemophilus influenzae [beta lactamase (+) and (-)].

Note:
MAXAQUIN^® is not indicated for the empiric treatment of acute bacterial exacerbation of chronic bronchitis when it is probable that S. pneumoniae is a causative pathogen. S. pneumoniae exhibits in vitro resistance in lomefloxacin. Safety and efficacy of lomefloxacin in the treatment of patients with acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae have not been demonstrated. If lomefloxacin is to be prescribed for Gram-stain guided empiric therapy of acute bacterial exacerbation of chronic bronchitis, it should be used only if sputum gram stain demonstrates an adequate quality of specimen (>25 polymorphonucleocytes/low power field) and there is both a predominance of gram negative organisms and not a predominance of gram positive organisms.

Prevention:
The administration of MAXAQUIN^® is indicated preoperatively to reduce the incidence of postoperative urinary tract infections in patients undergoing transurethral surgical procedures.

CONTRA-INDICATIONS:
Severe renal impairment (creatinine clearance below 40 mL/min). A history of hypersensitivity to MAXAQUIN^® is a contra-indication to its use. A history of hypersensitivity to other quinolones may also contra-indicate the use of MAXAQUIN^®.

Pregnancy and Lactation.

Should not be used in children and growing adolescents.

DOSAGE AND DIRECTIONS FOR USE:
Treatment:
For the treatment of uncomplicated urinary tract infection, complicated, including recurrent. urinary tract infection, and acute exacerbation of chronic bronchitis, the usual dosage is one 400 mg tablet daily with or without food. The duration of therapy depends on the severity of infection. Generally MAXAQUIN^® should be continued for at least 3 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 7 - 10 days.

Prevention:
For the prevention of postoperative urinary tract infections in patients undergoing transurethral surgery, a single dose of 400 mg should be given 2 to 6 hours prior to surgery to achieve effective tissue and urinary concentrations.

Elderly: No dosage adjustment is required for elderly patients if renal function is normal (a creatinine clearance of > 30 mL/min/1.73 m²).

Mild to moderate impaired renal function: MAXAQUIN^® may be used in patients with mild to moderate renal insufficiency.

Impaired hepatic function: Impaired hepatic function does not reduce the non-renal clearance of lomefloxacin. The need for a dosage reduction should be based on the degree of renal function of the patient (see above).

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects
The most common side effects seen are nausea, dizziness, headache, diarrhoea and photosensitivity.

Less frequently occurring side effects are:
Autonomic: sweating, flushing, dry mouth.

Body as a whole: fatigue, back pain, weakness, malaise, allergic reaction, chills, oedema of the face or hands.

Cardiovascular: oedema, hypertension, syncope, tachycardia, bradycardia, arrhythmia, angina pectoris, extrasystoles, phlebitis.

Central nervous system: tremor, paraesthesia, twitching, vertigo.

Gastro-intestinal: dyspepsia, vomiting, constipation, dry mouth, flatulence, enanthema, gastro-intestinal inflammation, oral candidiasis.

Hearing: tinnitus

Haematologic: thrombocytopaenia

Metabolic: gout, thirst

Musculoskeletal: leg cramps, arthralgia

Psychiatric: nervousness, somnolence, agitation, insomnia, changes in appetite, confusion, depersonalization, depression.

Reproductive Disorders: Female: vaginitis, leukorrhoea, inter menstrual bleeding, vaginal candidiasis. Male: orchitis.

Respiratory: dyspnoea, respiratory infection, epistaxis, flu, respiratory disorder.

Skin: pruritus, rash, urticaria, skin disorder

Special senses: bad taste

Vision disorders: blurred vision

Precautions
Lomefloxacin may cause central nervous system (CNS) stimulation which may lead to tremor, restlessness, lightheadedness, confusion, and, very rarely, to convulsive seizures. Therefore MAXAQUIN^® should be used with caution in patients with known or suspected CNS disorders such as epilepsy or other factors which predispose to seizures.

MAXAQUIN^® has been shown to cause photo-sensitivity. Patients should be advised to avoid prolonged exposure to ultraviolet light while taking MAXAQUIN^®.

When MAXAQUIN^® is given concomitantly with food, absorption is delayed, but the extent of absorption is not substantially affected. Concomitant administration of magnesium- and aluminium-containing antacids significantly decreases the bioavailability of lomefloxacin. Separating the doses of antacid and MAXAQUIN^® by 2 or more hours minimizes this decrease in bio-availability.

Drug interactions:
In comparative clinical studies MAXAQUIN^® has not been shown to have any interaction with theophylline.

Sucralfate and antacids containing magnesium or aluminium form chelation complexes with lomefloxacin and interfere with its bio-availability. Administration of these agents should precede or follow lomefloxacin HCl dosing by at least 2 hours.

Co-administration with probenecid slows the elimination of lomefloxacin.

Although there is no clinical evidence for an interaction between fenbufen and lomefloxacin, concurrent use should be avoided.

Paediatric Use: MAXAQUIN^® should not used in children or growing adolescents (see Contra-indications).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Information on overdosage in humans is limited. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient care fully observed and given supportive treatment. Adequate hydration should be maintained. Haemodialysis or peritoneal dialysis in unlikely to aid in the removal of lomefloxacin from the body. Treatment is supportive and symptomatic.

IDENTIFICATION:
MAXAQUIN^® is available in 400 mg white to off-white, oval, biconvex, film-coated tablets, scored on one side and debossed Maxaquin 400 on the other.

PRESENTATION:
Blister pack (5 tablets).

STORAGE INSTRUCTIONS:
Protect from light. Store below 30°C.
Keep out of reach of children.

REGISTRATION NUMBER:
Z/20.1.1/74

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
G.D. Searle (South Africa) (Pty) Ltd.
14 Mandy Road
Reuven
Johannesburg

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
28 August 1992.

Code 4243 [ICR 8220 (R7)]-1-9/92
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