INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
FACTIVE ®

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

FACTIVE ®
Film-Coated Tablets

COMPOSITION:
Each tablet contains gemifloxacin mesylate equivalent to 320 mg gemifloxacin.

PHARMACOLOGICAL CLASSIFICATION:
A. 20.1.1        Antimicrobial agents: Broad and medium spectrum antibiotics.

PHARMACOLOGICAL ACTION:
Microbiology
Gemifloxacin is a fluoroquinolone antibiotic. Gemifloxacin is bactericidal with minimum bactericidal concentrations generally within one dilution of the minimum inhibitory concentrations. Gemifloxacin acts by inhibiting DNA synthesis through inhibition of the bacterial type II topoisomerases, DNA gyrase, and/or topoisomerase IV (TOPO IV) which are both essential for bacterial growth. The primary target for gemifloxacin in pneumococci is TOPO IV and the strong affinity of gemifloxacin for this enzyme correlates well with the high potency demonstrated against pneumococci. Gemifloxacin has a higher affinity than other fluoroquinolones for TOPO IV enzymes of Streptococcus pneumoniae, including those with resistance mutations. Most strains of streptococci showing mutations in both DNA gyrase and TOPO IV are resistant to all fluoroquinolones in clinical use. However, gemifloxacin maintains activity against most of these double mutants. Gemifloxacin is highly selective for bacterial rather than human topoisomerase II.
There is generally no cross-resistance between gemifloxacin and other classes of antibiotics, such as beta-lactams, macrolides and aminoglycosides, due to the different mechanisms of action. Therefore, organisms resistant to these agents may be susceptible to gemifloxacin.
No antagonism has been observed in in vitro studies when gemifloxacinis combined with other antimicrobial agents such as beta-lactams, aminoglycosides or macrolides. Synergy has been reported, particularly with the combination of gemifloxacin and a beta-lactam.
Resistance to gemifloxacin develops slowly via multistage mutations and efflux in a manner similar to other fluoroquinolones. The frequency of spontaneous mutation is low (10^–7 to <10^-10).
The main mechanism of fluoroquinolone resistance is due to mutations in DNA gyrase and/or TOPO IV. Although cross-resistance has been observed between gemifloxacin and other fluoroquinolones,some microorganisms resistant to other fluoroquinolones may be susceptible to gemifloxacin.

PHARMAKOKINETIC PROPERTIES
Absorption and Bioavailability
Gemifloxacin is rapidly absorbed after oral administration. Peak plasma concentrations are observed between 0.5 and 2 hours post-dose and the absolute bioavailability is, approximately, 71%.
The pharmacokinetics of gemifloxacin are approximately linear over the dose range 20 to 800 mg. There was minimalaccumulation of gemifloxacin following multiple doses for 7 days (ca. 10% compared to single dose data). Steady-state is achieved by the third day of dosing. Food does not affect the absorption of gemifloxacin.
Distribution
The mean plasma protein bound fraction is approximately 70%, is concentration independent. Gemifloxacin is widely distributed throughout the body. The steady-state volume of distribution of approximately 3.5 L/kg exceeds total body water indicating high level distribution into various body tissues.
Penetration into tissues and body fluids:
Studies in healthy subjects showed that gemifloxacin is distributed rapidly into target tissues and body fluids such as the lung (epithelial lining fluid, alveolar macrophages, bronchial tissue) and nasal secretions.
Metabolism
Gemifloxacin is partly metabolised and the compound itself is the predominant drug-related component detected in plasma (ca 65%) up to 4 h after dosing. All metabolites formed are minor of which the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin.
Elimination
Following oral administration of gemifloxacin, approximately 36% and 61% of the dose is excreted in the urine and faeces, respectively, as unchanged drug and metabolites. Data obtained in animals suggest that some medicine-related material is excreted in the faeces via biliary and gut wall secretion. Approximately 25% (range 20-40%) and 42% (range 29-66%) of the administered dose is excreted in the urine and faeces, respectively, as unchanged gemifloxacin. Renal clearance of gemifloxacin (ca 160 mL/min) is slightly greater than the glomerular filtration rate of 120 mL/min, and indicates active renal secretion is involved in the elimination of gemifloxacin. The plasma and urinary elimination half-lives are approximately 8 and 15 hours, respectively.
Elderly
The pharmacokinetics of gemifloxacin are unaffected with age. Dose adjustment is not required.
Gender
AUC values were generally only slightly higher (approx. 10%) in women than in men. This small difference is not of any clinical relevance. No dose adjustment is required based on gender.
Renal Insufficiency
The plasma clearance of gemifloxacin is reduced by approximately 50% in patients with severe renal impairment (Creatinine clearance <40 mL/min) and patients undergoing dialysis or CAPD, when compared to subjects with normal renal function. Gemifloxacin is not notably removed by dialysis.
Dose adjustment is not required in patients with mild-moderate renal impairment (Creatinine clearance >40 mL/min). For severe renal impairment (Creatinine clearance <40 mL/min), haemodialysis patients and CAPD patients the dose should be reduced to 160 mg.
Hepatic Insufficiency
Hepatic impairment does not have a marked effect on gemifloxacin pharmacokinetics, and no dose adjustment is required.

INDICATIONS:
FACTIVE is indicated for the treatment of the following bacterial infections in adults caused by sensitive organisms as follows:
Respiratory Tract Infections:

-	Community acquired pneumonia (CAP) caused by S. pneumoniae, C. pneumoniae, M. pneumoniae, H. influenzae, M. catarrhalis, L. pneumophila
-	Acute exacerbations of chronic bronchitis (AECB) caused by H. influenzae, M. catarrhalis, S. pneumoniae
-	Acute bacterial sinusitis caused by S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus

Urinary Tract Infections:

-	Acute uncomplicated pyelonephritis caused by E. coli, K. pneumoniae
-	Uncomplicated urinary tract infections (uUTI) in females caused by E. coli, K. pneumoniae

CONTRA-INDICATIONS:
Known hypersensitivity to gemifloxacin, other quinolones, or any of the excipients.
Patients who have previously suffered tendon damage with fluoroquinolones.
Factive should not be used in children under 18 years of age.
Factive should not be used in pregnant or lactating woman.

WARNINGS:

	Safety and efficacy in children and adolescents <18 years have not been studied. Quinolones as a class have been shown to cause arthropathy in immature animals.
	Pseudomembranous colitis has been reported with the use of broad spectrum antibiotics. Hence it is important to consider this diagnosis in patients who develop diarrhoea during or after treatment with antibiotics, including Factive, particularly if the diarrhoea is severe.
	Tendinitis and tendon ruptures may occur in any age group during treatment with quinolones, including Factive, but particularly in elderly patients or when corticosteroids are being co-administered. Factive should be discontinued if tendinitis is suspected or at the first sign of pain or inflammation and the affected limb should be rested.
	In clinical studies with gemifloxacin a small mean increase in QTc interval was observed. Gemifloxacin should be used with caution in patients predisposed to QT intervalprolongation or in patients taking other medications that are known to prolong the QT interval.
	Factive should be used with caution in patients with epilepsy or with other factors that predispose for seizures.
	Quinolones should be used with caution in patients with existing or family history of glucose-6-phosphate dehydrogenase deficiency as haemolytic reactions may develop during therapy.
	Photosensitisation has been reported with the use of quinolones. Patients taking Factive should avoid unnecessary exposure to strong sunlight or artificial UV rays eg. sunray lamp, solarium.

DOSAGE AND DIRECTIONS FOR USE:
Factivecan be taken with or without food and should be swallowed with a liberal amount of liquid. The recommended dose of Factive is 320 mg daily, according to the following table:

INDICATION	DOSE	DURATION
Acute bacterial exacerbations of chronic bronchitis	One 320 mg tablet daily	5 days
Acute sinusitis	One 320 mg tablet daily	5 days
Community-acquired pneumonia	One 320 mg tablet daily	7 days*
Uncomplicated urinary tract infections	One 320 mg tablet daily	3 days
Acute pyelonephritis	One 320 mg tablet daily	10 days

* Therapy may be extended to 14 days of therapy in cases of serious pneumonia.
Renally Impaired Patients: Dose adjustment in patients with mild/moderate renal impairment is not required. Some modification of dosage is recommended for patients with severe renal dysfunction. The following table provides dosage guidelines for use in patients with renal impairment:

Creatinine Clearance         (mL/min)	Dose
>40	See Usual Dosage
<40	160 mg q24h

Patients on haemodialysis or continuous ambulatory peritoneal dialysis therapy should receive 160 mg q24h.
Hepatic impairment: FACTIVE may be given to patients with hepatic impairment, with no requirement for dose adjustment.
Elderly patients: Dose adjustment is not required.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
The most frequently reported adverse events include abdominal pain, diarrhoea, headache, nausea, rash and vomiting. The following side effects have been infrequently reported:-
Body as a whole:        Fungal overgrowth
Central nervous system/Psychiatric:        Dizziness and insomnia
Laboratory abnormalities:        Asymptomatic transient elevation in liver enzymes.
Skin:        Urticaria, pruritis and a maculopapular erythmatous skin rash. A diffuse maculopapular or erythematous skin rash was reported in some patients in the clinical trials. The rash occurred after one week, was generally mild to moderate and appeared to be a type IV hypersensitivity reaction. It is recommended that treatment with Factive should be discontinued if a patient experiences rash.
In clinical studies, elevated bilirubin was reported in <0.3% of patients and tendinitis, thrombocytopenia and photosensitivity reactions were reported in <0.1%.
Pregnancy and lactation: - see contra-indications
FACTIVE should not be used in pregnant or lactating women. The safety and efficacy of FACTIVE in pregnant or lactating women have not been established. Animal studies have shown adverse effects on embryo-foetal development and gemifloxacin-related material is excreted in the milk of lactating rats.

SPECIAL PRECAUTIONS:
For patients with severe impairment of renal function, alteration of the dosage regimen to 160 mg q24h is necessary (see DOSAGE AND DIRECTIONS FOR USE).
Adequate hydration of patients receiving Factive should be maintained to prevent the formation of a highly concentrated urine and crystalluria.
The photosensitivity potential of Factive is low, with <0.1% cases reported in clinical studies. However, it is recommended that patients should avoid unnecessary exposure to strong sunlight or to artificial UV rays (e.g., sunlamps, solariums), and should be advised of the appropriate use of broad spectrum sun block if in bright sunlight. Treatment should be discontinued if a photosensitivity reaction is suspected.
Factive may cause dizziness; if this occurs, patients should not operate an automobile or machinery or engage in activities requiring mental alertness or co-ordination.

INTERACTIONS:
Gemifloxacin absorption is significantly reduced when aluminium- or magnesium-containing antacids and iron salts are concomitantly administered. Factive should be taken at least 2 hours before or 3 hours after these agents. Factive should be taken at least 2 hours before sucralfate administration.
Results of in vitro CYP450 inhibition studies indicate that cytochrome P450 enzymes do not play an important role in gemifloxacin metabolism. Therefore gemifloxacin should not cause drug interactions with compounds mediated by CYP450 enzymes.
No clinically significant interactions have been observed when gemifloxacin was co-administered with omeprazole, theophylline, digoxin, warfarin and oral contraceptives.
Gemifloxacin AUC increased (average 45%) when co-administered with probenecid.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
No specific antidote is known. Dialysis does not remove gemifloxacin sufficiently to be useful in overdose. In the event of acute oral overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage; the patient should be carefully observed, treated symptomatically and adequate hydration should be maintained.

IDENTIFICATION:
A white to off-white tablet with break-lines on both faces.

PRESENTATION:
Factive tablets are available in blister packs of 3, 5 and 7 tablets in a carton.

STORAGE INSTRUCTIONS:
Store in a dry place below 30°C.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER:
35/20.1.1/0058

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacare Limited
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Johannesburg

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
12 November 2004

New addition to this site: May 2005
Source: Pharmaceutical Industry
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