WINTHROX LABORAORIES (Pvt.) Ltd.

DESCRIPTION

LYST is a Mucolytic for oral and intravenous administration. Chemically, in, a chiral fluorinated
carboxyquinolone, is the pure (-)(S)-enantiomer of the racemic drug substance ofloxacin. The
chemical name is (-)-(S)-9-fluoro- 2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-
pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate.

The Chemical Structure of Acetylcystenine

NHCOCH3

HSCH2----C----COOH

The empirical formula is C5H9NO3S and the molecular weight is 163.00

COMPOSITION
Each SACHET contains
Acetylcystenine………… 200mg

PHARMACODYNAMICS

Pharmacotherapeutic group: Antidot,Mucolytic agent

Mechanism of action

As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA-gyrase complex

and topoisomerase IV.

PK/PD relationship

The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum
concentration in serum (Cmax) or the area under the curve (AUC) and the minimal inhibitory
concentration (MIC).

Mechanism(s) of resisance

Resistance to levofloxacin is acquired through a stepwise process by target site mutations in both
type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms such as
permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may also
affect susceptibility to levofloxacin.
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Cross-resistance between levofloxacin and other fluoroquinolones is observed. Due to the

mechanism of action, there is generally no cross-resistance between levofloxacin and other
classes of antibacterial agents.

Breakpoints

The WINFLOX recommended MIC breakpoints for levofloxacin, separating susceptible from
intermediately susceptible organisms and intermediately susceptible from resistant organisms are
presented in the below table for MIC testing (mg/L).

WINFLOX clinical MIC breakpoints for levofloxacin

Pathogen Susceptible Resistant

Enterobacteriacae ≤1 mg/L >2 mg/L
Pseudomonas spp. ≤1 mg/L >2 mg/L
Acinetobacter spp. ≤1 mg/L >2 mg/L
Staphylococcus spp. ≤1 mg/L >2 mg/L
1
S.pneumoniae ≤2 mg/L >2 mg/L
Streptococcus A,B,C,G ≤1 mg/L >2 mg/L
2, 3 3
H.influenzae M.catarrhalis ≤1 mg/L >1 mg/L
Non-species related breakpoints 4 ≤1 mg/L >2 mg/L

1
. The breakpoints for levofloxacin relate to high dose therapy.

2. Low-level fluoroquinolone resistance (ciprofloxacin MICs of 0.12-0.5 mg/l) may occur but
there is no evidence that this resistance is of clinical importance in respiratory tract infections
with H. influenzae.

3. Strains with MIC values above the susceptible breakpoint are very rare or not yet reported.
The identification and antimicrobial susceptibility tests on any such isolate must be repeated and
if the result is confirmed the isolate must be sent to a reference laboratory. Until there is evidence
regarding clinical response for confirmed isolates with MIC above the current resistant
breakpoint they should be reported resistant.

4. Breakpoints apply to an oral dose of 500 mg x 1 to 500 mg x 2 and an intravenous dose of 500
mg x 1 to 500 mg x 2.

The prevalence of resistance may vary geographically and with time for selected species and
local information on resistance is desirable, particularly when treating severe infections. As
necessary expert advice should be sought when the local prevalence of resistance is such that the
utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

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Aerobic Gram-positive bacteria

Bacillus anthracis

Staphylococcus aureus methicillin-susceptible

Staphylococcus saprophyticus

Streptococci, group C and G

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes
Aerobic Gram- negative bacteria
Eikenella corrodens

Haemophilus influenzae

Haemophilus para-influenzae

Klebsiella oxytoca

Moraxella catarrhalis

Pasteurella multocida

Proteus vulgaris

Providencia rettgeri
Anaerobic bacteria
Peptostreptococcus
Other
Chlamydophila pneumoniae

Chlamydophila psittaci

Chlamydia trachomatis

Legionella pneumophila

Mycoplasma pneumoniae
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Mycoplasma hominis

Ureaplasma urealyticum
Species for which acquired resistance may be a problem
Aerobic Gram-positive bacteria
Enterococcus faecalis

Staphylococcus aureus methicillin-resistant#

Coagulase negative Staphylococcus spp

Aerobic Gram- negative bacteria
Acinetobacter baumannii

Citrobacter freundii

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Klebsiella pneumoniae

Morganella morganii

Proteus mirabilis

Providencia stuartii

Pseudomonas aeruginosa

Serratia marcescens
Anaerobic bacteria
Bacteroides fragilis
Inherently resistant Strains
Aerobic Gram-positive bacteria
Enterococcus faecium

# Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones,

including levofloxacin.

PHARMACOKINETICS
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Absorption

Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma
concentrations being obtained within 1- 2 h. The absolute bioavailability is 99- 100 %.

Food has little effect on the absorption of levofloxacin.

Steady state conditions are reached within 48 hours following a 500 mg once or twice daily
dosage regimen.

Distribution

Approximately 30 - 40 % of levofloxacin is bound to serum protein. The mean volume of

distribution of levofloxacin is approximately 100 l after single and repeated 500 mg doses,
indicating widespread distribution into body tissues.

Penetration into tissues and body fluids:

Levofloxacin has been shown to penetrate into bronchial mucosa, epithelial lining fluid, alveolar
macrophages, lung tissue, skin (blister fluid), prostatic tissue and urine. However, levofloxacin
has poor penetration intro cerebro-spinal fluid.

Biotransformation

Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin

and levofloxacin N-oxide. These metabolites account for < 5 % of the dose excreted in urine.
Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

Following oral and intravenous administration of levofloxacin, it is eliminated relatively slowly

from the plasma (t½: 6 - 8 h). Excretion is primarily by the renal route > 85 % of the administered
dose).

The mean apparent total body clearance of levofloxacin following a 500 mg single dose was 175
+/-29.2 ml/min.

There are no major differences in the pharmacokinetics of levofloxacin following intravenous

and oral administration, suggesting that the oral and intravenous routes are interchangeable.

Linearity

Levofloxacin obeys linear pharmacokinetics over a range of 50 to 1000 mg.

INDICATIONS
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WINFLOX is a fluoroquinolone antibacterial indicated in adults (≥18 years of age) with

infections caused by designated, susceptible bacteria

 Pneumonia: nosocomial and community acquired

 Acute bacterial sinusitis
 Acute bacterial exacerbation of chronic bronchitis
 Skin and skin structure infections: complicated and uncomplicated
 Chronic bacterial prostatitis
 Urinary tract infections: complicated and uncomplicated
 Acute pyelonephritis
 Inhalational anthrax, post-exposure
 Plague

DOSAGE AND ADMINISTRATION

 Dosage in patients with normal renal function

Type of Infection Dose Every 24 hours Duration

(days)

Nosocomial Pneumonia 750 mg 7–14

Community Acquired Pneumonia 500 mg 7–14

Community Acquired Pneumonia 750 mg 5

Acute Bacterial Sinusitis 750 mg 5

500 mg 10–14

Acute Bacterial Exacerbation of Chronic

500 mg 7
Bronchitis

Complicated Skin and Skin Structure Infections

750 mg 7–14
(SSSI)

Uncomplicated SSSI 500 mg 7–10

Chronic Bacterial Prostatitis 500 mg 28

Complicated Urinary Tract Infection or Acute

750 mg 5
Pyelonephritis

Complicated Urinary Tract Infection or Acute

250 mg 10
Pyelonephritis

Uncomplicated Urinary Tract Infection 250 mg 3

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Type of Infection Dose Every 24 hours Duration

(days)

Inhalational Anthrax (Post-Exposure)

Adults and Pediatric Patients > 50 kg 500 mg 60

8 mg/kg BID (not to exceed 250

Pediatric Patients < 50 kg and ≥ 6 months of age 60
mg/dose)

Plague

Adults and Pediatric Patients > 50 kg 500 mg 10 to 14

8 mg/kg BID (not to exceed 250

Pediatric Patients < 50 kg and ≥ 6 months of age 10 to 14
mg/dose)

 Adjust dose for creatinine clearance < 50 mL/min

 IV Injection Premix: Slow IV infusion only, over 60 or 90 minutes depending on dose. Avoid
rapid or bolus IV
 Do not mix with other medications in IV line

WARNINGS AND PRECAUTIONS FOR USE

 Risk of tendinitis and tendon rupture is increased. This risk is further increased in older patients
usually over 60 years of age, in patients taking corticosteroids, and in patients with kidney, heart
or lung transplants. Discontinue if pain or inflammation in a tendon occurs
 May exacerbate muscle weakness in persons with myasthenia gravis. Avoid use in patients with a
known history of myasthenia gravis
 Anaphylactic reactions and allergic skin reactions, serious, occasionally fatal, may occur after
first dose
 Hematologic (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after
multiple doses
 Hepatotoxicity: Severe, and sometimes fatal, hepatoxicity has been reported. Discontinue
immediately if signs and symptoms of hepatitis occur
 Central nervous system effects, including convulsions, anxiety, confusion, depression, and
insomnia may occur after the first dose. Use with caution in patients with known or suspected
disorders that may predispose them to seizures or lower the seizure threshold. Increased
intracranial pressure (pseudotumor cerebri) has been reported
 Clostridium difficile-associated colitis: evaluate if diarrhea occurs
 Peripheral neuropathy: discontinue immediately if symptoms occur in order to prevent
irreversibility
 Prolongation of the QT interval and isolated cases of torsade de pointes have been reported.
Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs
that prolong the QT interval
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SPECIFIC POPULATIONS

Impaired renal function (creatinine clearance ≤ 50 ml/min)

Creatinine clearance Dosage regimen

250 mg/24 h 500 mg/24 h 500 mg/12 h
First dose: 250 mg First dose: 500 mg First dose: 500 mg
50-20 ml/min Then:125 mg/24h Then: 250 mg/24 h Then:250 mg/12 h
19-10 ml/min Then: 125 mg/48 h Then: 125 mg/24 h Then:125 mg/12 h
< 10 ml/min (including Then: 125 mg/48 h Then: 125 mg/24 h Then:125 mg/24 h
haemodialysis and
CAPD)1

1
No additional doses are required after haemodialysis or continuous ambulatory peritoneal
dialysis (CAPD).

Impaired liver function

No adjustment of dosage is required since levofloxacin is not metabolised to any relevant extent
by the liver and is mainly excreted by the kidneys.

Elderly population

No adjustment of dosage is required in the elderly, other than that imposed by consideration of
renal function (see section 4.4 “Tendinitis and tendon rupture” and “QT interval prolongation”).

Paediatric population

Levofloxacin is contraindicated in children and growing adolescents (see section 4.3).

Method of administration

Levofloxacin Tablets should be swallowed without crushing and with sufficient amount of
liquid. They may be divided at the score line to adapt the dose. The tablets may be taken during
meals or between meals. Levofloxacin Tablets should be taken at least two hours before or after
iron salts, zinc salts, magnesium- or aluminium-containing antacids, or didanosine (only
didanosine formulations with aluminium or magnesium containing buffering agents), and
sucralfate administration since reduction of absorption can occur (see section 4.5).

FERTILITY, PREGNANCY AND LACTATION

Pregnancy

There are limited amount of data with respect to the use of levofloxacin in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive
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toxicity (see section 5.3). However in the absence of human data and due to that experimental
data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing
organism, levofloxacin must not be used in pregnant women (see sections 4.3 and 5.3).

Breast-feeding

Levofloxacin tablets are contraindicated in breast-feeding women. There is insufficient

information on the excretion of levofloxacin in human milk; however other fluoroquinolones are
excreted in breast milk. In the absence of human data and due to that experimental data suggest a
risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism,
levofloxacin must not be used in breast-feeding women (see sections 4.3 and 5.3).

Fertility

Levofloxacin caused no impairment of fertility or reproductive performance in rats.

Drug Interactions

Interacting Drug Interaction

Absorption of levofloxacin is decreased when the

Multivalent cation-
tablet or oral solution formulation is taken within 2
containing products
hours of these products. Do not co-administer the
including antacids, metal
intravenous formulation in the same IV line with a
cations or didanosine
multivalent cation, e.g., magnesium

Effect may be enhanced. Monitor prothrombin time,

Warfarin
INR, watch for bleeding

Antidiabetic agents Carefully monitor blood glucose

CONTRAINDICATIONS

WINFLOX tablets are contraindicated in patients with a hypersensitivity to levofloxacin or any

of the inactive ingredients in WINFLOX tablets.

SIDE EFFECTS

The following serious and otherwise important adverse drug reactions are discussed in greater
detail in other sections of labeling:

 Tendon Effects
 Exacerbation of Myasthenia Gravis
 Hypersensitivity Reactions
 Other Serious and Sometimes Fatal Reactions
 Hepatotoxicity
 Central Nervous System Effects
 Clostridium difficile-Associated Diarrhea
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 Peripheral Neuropathy that may be irreversible

 Prolongation of the QT Interval
 Musculoskeletal Disorders in Pediatric Patients
 Blood Glucose Disturbances
 Photosensitivity/Phototoxicity
 Development of Drug Resistant Bacteria

Hypotension has been associated with rapid or bolus intravenous infusion of WINFLOX.
WINFLOX should be infused slowly over 60 to 90 minutes, depending on dosage

Crystalluria and cylindruria have been reported with quinolones, including WINFLOX.
Therefore, adequate hydration of patients receiving WINFLOX should be maintained to prevent
the formation of a highly concentrated urine

OVERDOSAGE:
In the event of an acute overdosage, the stomach should be emptied. The patient should be
observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by
hemodialysis or peritoneal dialysis.

STORAGE:
Store at room temperature below 30°C
Protect from sunlight & moisture
Keep away from children's reach

PRESENTATION:

PARLEY Tablet: available in Alu-PVC blister of 1x10’s

Manufactured by:
Pakistan Pharmaceutical Products (Pvt) Ltd
D-122, S.I.T.E, Karachi
In association with
Arco Pharma S.A, Switzerland