glevo new product profile

8/13/2019 GLEVO New Product Profile

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Fluoroquinolones

1962 Nalidixic acid was the first quinolone

discovered.

Modified to enhance or limit the extent ofantimicrobial activity & improve various other

product attributes, such as pharmacokinetic

profile, tolerability, drug interaction & toxicity of

each new agent.


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Levofloxacin


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Spectrum of Activity of 4 generations of

Quinolones

1st Gen 2nd Gen 3rd Gen 4th Gen

Gram -ve Gram-ve Gram -ve Same as 3rd

Gram +ve Gram +ve generation wit

(Except S. Gram +ve extended

pneumoniae) (including anaerobicS. pneumoniae) coverage

Intracellular bacteria

Anaerobic bacteria

Moxifloxacin

Nalidixic Norfloxacin,

acid Lomefloxacin, Levofloxacin, TrovafloxacinOfloxacin, Sparfloxacin, (withdrawn du

Ciprofloxacin Gatifloxacin to toxicity)


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Spectrum of Activity

Levofloxacinis more active against Gram +ve

& Gram -ve organisms, intracellular pathogens

than earlier quinolones such as Ciprofloxacin. Has excellent activity against most commonly

encountered pathogens in RTIs such as Strep.

pneumoniae as well as H. influenzae, M.

catarrhalis & against intracellular organisms.


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Unique Chemical Structure (Levofloxacin)

A fluoroquinolone - optically active Levo - isomer ofOfloxacin with side effects.

It has 2-4 times >activity than Ofloxacin.

It is a L-isomer of the D, L - racemate Ofloxacin. Antibacterial activity is due to L - isomer (Levofloxacin)

that has >affinity for the target molecule DNA gyrase &

has 128 times affinity than the D-isomer.

Potency differences between these isomers is because

differences in their ability to inhibit DNA gyrase.


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Structure Activity Relationship

4-methyl piperazinyl group Oxazine ring

oral absorption activity against some gram-ve

bacilli

half life

activity against gram-vecoverage

half life


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Inhibits DNA gyrase to exert bactericidal effects

Broad spectrum antibacterial with bactericidal

activity

Binds & inhibits bacterial DNA-gyrase.

This enzyme (a type II topoisomerase) produces

negative super-coiling of cellular DNA, needed forbacterial DNA synthesis.

Bacterial DNA is approx. 1800 nm long, to fit inside

a cell (2 x1 nm) it is super coiled with the help of

DNA gyrase.

This prevents DNA replication & results in bacterial

cell death


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Safety :

Only inhibits bacterial DNA gyrase

At clinically achievable concentrations

Fluoroquinolones does not inhibit

human topoisomerase II & thereforethere is no disturbance to the human

cell structures.


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Unique Mode of Action


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Unique Mode of Action

Stabilize

(+)

(-)

Break

Back segment

(-)

(-)

(-)

Reseal Break

on front

Inhibits both the nicking & closing activityof gyrase resulting in +ve supercoiling & unstable

DNA

Formation of -ve DNA supercoils by DNA gyrase

GLEVO(Quinolones)

DNA

Stabilize


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Pharmacokinetics Profile

Offers nearly 100% bioavailability after oral

administration, making it possible to

administer the drug at the same dosageseither orally or intravenously. Hence ideal

for sequential therapy in CAP/AECB.


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Pharmacokinetics Profile


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Pharmacokinetics of Quinolones

Source : Drug Facts and Comparison 1994 pg

Parameter Ciprofloxacin

(I.V./Oral)

Levofloxacin

(I.V./Oral)

Norfloxacin Ofloxacin

(I.V./Oral)

Sparfloxaci

Bioavailability

(%)

70-80 99 30-40 98 92

Maximum

Serum

Concentrationmcg/ml (Dose)

1.2 (250 mg)

2.4 (500 mg)

4.3 (750 mg)

5.4 (1000mg)

2.8 (250 mg)

5.1 (500mg)

0.8 (200 mg)

1.5 (400mg)

1.5 (200

mg)

2.4 (300mg)

2.9 (400

mg)

1.1 (200 mg)

1.3 (400 mg)

Area under

curve (AUC)

mcgxhr/ml(Dose)

4.8 (250 mg)

11.6 (500 mg)

20.2 (750 mg)30.8 (1000mg)

27.2 (250 mg)

47.9 (500 mg)

5.4 (400 mg) 14.1 (200

mg)

21.2 (300

mg)

31.4 (400

mg)

18.7 (200 mg

20.6 (400 mg


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MIC breakpoints Breakpoints as per National Committee for

Clinical Laboratory Standards(NCCLS)

Categories MIC (g/ml)

Susceptible < 2

Intermediate 4

Resistant > 8


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In vitro activity against Gram-ve bacteria

Organisms Mean MIC90value (g / mL)

(Enterobacteriaceae)Escherichia coli 0.07

Klebsiella pneumoniae 0.18Enterobacter cloacae 0.28

Serratia marcescens 7.42

Proteus mirabilis 0.18

Citrobacter freundii 0.80Morganella morganii 0.13

Shigella spp. 0.05


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In vitro activity against Gram-ve bacteria

Organisms Mean MIC90value (g / mL)

(Enterobacteriaceae)

Salmonella spp. 0.09

Providencia rettgeri 2.26Providencia stuartii 0.22

Haemophilus influenzae 0.02

Moraxella catarrhalis 0.09

Neisseria gonorrhoeae 0.03Pseudomonas aeruginosa 3.70

Campylobacter jejuni 0.58


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In vitro activity against Intracellular pathogens &

Anaerobic bacteriaOrganisms Mean MIC90value (g / mL)

(Intracellular pathogens)

Chlamydia pneumoniae 0.5

Mycoplasma pneumoniae 0.5Legionella pneumophila 0.125

(Anaerobic bacteria)

Bacteroides fragilis 3.52

Clostridium difficile 5.00Clostridium perfringens 0.75

Peptostreptocooccus spp. 4.62


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Eradication rates of Common Respiratory Pathogens

Pathogens Levofloxacin 250-1000 mg/day% eradicated (Drug s 1998)

Gram-positive cocci

Staphylococci aureus 69.9

Streptococcus pneumoniae 89.1

Gram-negative cocci

Moraxella catarrhalis 93.0

Gram-negative bacilli

Escherichia coli 100

Haemophilus influenzae 94.4

H. parainfluenzae 94.3

Klebsiella pneumoniae 100

Pseudomonas aeruginosa 63.3Atypical pathogens

Chlamydia pneumoniae 95.9

Mycoplasma pneumoniae 100

Legionella pneumophila 90


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Steady State Plasma Level

Achieves plasma levels that are above (MIC) values

for 24 hours for most common pathogens after a

single 500 mg Oral or I.V. dose.

Clinical & microbiological outcomes can be predictedby site of infection & ratio of Cmax to MIC.

313 patients with respiratory, skin or UTI treated

showed the median Cmaxto MIC ratio of 12.1

Clinical cure or improvement was seen in 99% ofpatients with Cmax: ratio of > 12.2


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Distribution in relevant tissues & fluids

Body fluid Dose Plasma Conc. Tissue fluid Tissue/ fluior tissue (mg) (ug/ml) conc. (ug.ml) plasma

conc. ratio

Sputum 100 1.10 1.27 1.15

Maxillary sinus 100 0.45 0.67 1.15

Bronchial lavage fluid 200 2.52 0.12 0.06Alveolar Macrophage 500 4.1 27.7 6.8

Lung 500 2.93 11.28 5.02

Epithelial lining fluid 500 4.1 10.9 3.0

Skin 200 1.73 1.85 1.14

Blister fluid 500 5.0 4.7 0.94

Prostate gland 100 0.90 1.15 1.28Testis 200 2.85 4.73 1.66

Female genital tissues 200 0.73 0.94 1.29

Urine 200 1.01 286 283


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Distinguishing Characteristics of Quinolone

Class & agent Half-life Route of Dosage Significant Significant drug

administration adjustment adverse interactions

required effects

1st generation

Nalidixic acid 60 to 90 Oral Renal Not used in poor Warfarin

mins impairment renal function

2nd generation

Norfloxacin 2.3 to 5.5 Oral Renal Warfarin,

hours impairment Cyclosporine

Lomefloxacin 7 to 8.5 Oral Renal Phototoxicity,

hours impairment headache 3 -44 %, abdo-

minal pain 11 %

nausea 5.6%


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Distinguishing Characteristicsof QuinolonesClass & agent Half-life Route of Dosage Significant Significant drug

administration adjustment adverse interactions

required effects

Ofloxacin 5 to 8 hrs Oral / IV Renal or Insomnia 13% Warfarin

hepatic

impairment

Ciprofloxacin 3 to 5.4 Oral / IV Renal Nausea, Warfarin,

hours imparment vomiting, theophylline,

abdominal pain caffeine,

cyclosporine,glyburide


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Distinguishing Characteristicsof QuinolonesClass & agent Half-life Route of Dosage Significant Significant drugadministration adjustment adverse interactions

required effects

3rd GenerationLevofloxacin 6 hrs Oral, Renal Headache, Drug interactions

intravenous impairment nausea 6.6 % , are clinicallydiarrhea, Pho- insignificanttotoxicity 1%

Sparfloxacin 21 hrs Oral Renal Phototoxicty Drugs that prolongimpairment 8% QT interval QT interval,

prolongation , including class Itorsades des antiarrhythmics,pointes tricyclic anti-

depressants,phenothiazines,cisapride, penta-midine &erythromycin


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Lower phototoxicity compared to

Sparfloxacin Photosensitivity is infrequent (


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Dosage in Normal Renal Function:

Indication Daily dose regimen Duration of

treatmentAcute sinusitis 500mg once daily 10-14 days

Acute Exacerbation of 250 to 500mg once daily or 7-10 days

Chronic Bronchitis(AECB) 750 mg once daily 5 days

CAP / Nosocomial Pneumonia 500 mg / 750 mg once daily 7-14 days/ 5 days

Complicated urinary tract infections 250 mg/500 mg once daily 7-10 days

including Pyelonephritis /

Bacterial Prostatitis 500 mg once daily 28 days

Skin & Soft tissue infection 500 mg once daily 7 days

Gonorrhoea 750 mg Single dose

Impaired renal clearance (creatinine clearance < 3 L / h or


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Dosage in Normal Renal Function:

Indication Daily dose regimen Duration oftreatment

Bone related Infections 750mg once daily 4weeks or more

Meningitis 500mg IV/Oral once daily Titrated to symptoms

Opportunistic Infections

(Pseudomonas aeruginosa) 750 mg once daily as per need

Bacterial Diarrhoea 500 mg once daily 5 days

Enteric Fever (Typhoid fever) 500 mg once daily 14 days

Clostridium difficle associated

diarrhoea/CDAD 750 mg once daily 5 daysMDR-TB cases 500 -750 mg OD Till Negative SputumCulture

Impaired renal clearance (creatinine clearance < 3 L / h or


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Acute Maxillary Sinusitis

Dosage (mg) Clinical success Bacteriological

rate (%) eradication rate (%)

Comparative studies

LVFX 500 od 88.4 NAAMC 500/125 tid 87.3 NA

LVFX500 od 96.0 NA

CLR 500 bid 93.3 NA

Non-Comparative studies

LVFX500 od 88.3 92

AMC =Amoxicillin / Clavulanic acid ;LVFX =Levofloxacin; CLR=

ClarithromycinDru gs 1998, 56 (3) pg 487-515


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Community Acquired Pneumonia



Comparative studies

LVFX 500 od 96 NACXM500 bid 90 NA

LVFX500 od 87 87

CRO4000 od IV 86 87

Non-Comparative studies

LVFX500 od IV or PO 94.7 95.1

LVFX =Levofloxacin; CXM =Cefuroxime; CRO = Ceftriaxone; PO =

Oral Drugs 1998, 56 (3) pg 487-51


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Urinary tract infection



Comparative studiesLVFX250 od 92 93.6

CIP250 bid 88 97.5

LVFX =Levofloxacin;CIP =Ciprofloxacin

Dru gs 1998, 56 (3) pg 487-51


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Skin & Soft tissue infection



Comparative studies

LVFX500 od 97.8 97.5CIP500 bid 94.3 88.8

LVFX500 od 96.1 93.2

CIP500 tid 93.5 91.7

LVFX =Levofloxacin; CIP =Ciprofloxacin

Drug s 1998, 56 (3) pg 487-51


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Jo urn al of An tim icro bial Chemoth erapy (1999) 43, Suppl. C, 67

Aim :To assess serum bactericidal activity (SBA) ofLevofloxacincompared to Ofloxacinagainst

Methicillin-resistant Staphylococcus aureus.

Levofloxacinwas significantly more bacericidal than

Ofloxacinagainst all strains of S. aureus tested. WithOfloxacinSBA was recorded for only a short period

and thereafter only bacteriostatic activity remained.

This study, therefore, confirms the superior activity of

Levofloxacinover that of Ofloxacin against MSSA &

MRSA.

Comparative Clinical Trials


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Journ al of An tim icro bial Chemotherapy (1999) 43, Supp l. C, 77-8

Aim :To compare bactericidal efficacy of

Levofloxacinand Ofloxacinagainst

Streptococcus pneumoniae. Conclusion :The

data, together with the two-fold higher activityof Levofloxacin in comparison with Ofloxacin,

indicate good therapeutic perspectives for

Levofloxacin over Ofloxacinin the treatment of

S. pneumoniae infections.



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Oto laryn go l Head Neck Surg 1999,120:320-7

Aim :To compare effectiveness of Levofloxacin (500mg OD) andAmoxicillin-clavulanate(500/125 mg tid)

for the treatment of acute sinusitis in adults

Success rate : Levofloxacin88.4%

Amoxicillin-clavulanate :87.3%

Adverse effect : Levofloxacin7.4%

Amoxicillin-clavulanate :21.2%

Conclusion :Once daily Levofloxacinis as effective &better tolerated thanAmoxicillin-clavulanatetid.



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Chemotherapy 2000; 4(supp l 1):6-14

Pharmacodynamics & Pharmacokinetics :

Pharmacodynamic analysis of the activity of Levofloxacin

against Streptococcus pneumoniae revealed that, 99% of

the time, actual hospitalized patients achieve an AUC /

MIC of > 30. This indicates that Levofloxacinwill be very

effective in treating S. pneumoniae infections in majority of

patients. (AUC/MIC of greater than 30 required for

effective eradication of bacterial & good clinical outcome).

Clinical Trials


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Jou rnal o f An t imic rob ial Chemo therapy (1997) 39, 719-723

Aim :To compare bactericidal activity of Levofloxacin, Ofloxacin,D-Ofloxacin, Ciprofloxacin, Sparfloxacin & Cefotaximeagainst

Streptococcus pneumoniae

Observation :Levofloxacinwas found to be the most bactericidal

followed by Ofloxacin, Ciprofloxacin, Sparfloxacin and D-

Ofloxacin.Against penicillin-resistant pneumococcus, Levofloxacinwas more

potent than CefotaximeLevofloxacinhas enhanced activity

against pneumococci compared with clinically available quinolones.

In addition, Levofloxacin may be the future quinolone of choice in

the treatment of penicillin-resistant pneumococci



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Comparative Clinical trials

% Clinical % Bacterial

Infection Regimens Cure Cure

CAP Levofloxacin200 mg bid po 94.4 93.3

(17/18)

Ofloxacin 200 mg tid po 90 89.5(18/20)

AECB Levofloxacin200 mg bid po 95.2 93.3

(20/21)

Ofloxacin 200 mg tid po 95.8 89.5

Sinusitis Levofloxacin 500 mg qd po 91.8 100

(98/107)


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Comparative Clinical trials

% %Clinical Bacterial

Infection Regimens Cure Cure Comments

Sinusitis Levofloxacin

500 mg qd po 88.4 NA 2.1% relapse at latefollow-up

(236/267)

Amoxicillin/Clavulanate 87.3 NA 3.8% relapse at late

500/125mg tid po (234/268) follow-up

Acute

pyelo- Levofloxacin 93 95Nephritis 250 mg qd po (83/90)


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Salient Features

Nearly 100% bioavailability making it equivalent to IV

administration & for sequential use in CAP.

Effective as monotherapy in serious CAP when

compared with standard regimens

High tissue penetration

Higher t making it OD dosage

Fewer side effects compared to 1st & 2nd generationquinolones


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Salient Features Broad spectrum of activity covering gram +ve,

gram-ve, intracellular pathogens & anaerobic

bacteria.

Extended activity against respiratory pathogens

such as Strep. pneumoniae, H. influenzae, M.

catarrhalis & intracellular pathogens


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Salient Features

2-4 times greater antibacterial activity than

Ofloxacinwith fewer side effects

Increased sensitivity to DNA gyrase compared to

other quinolone (Ciprofloxacin) hence better

activity against gram +ve & gram-ve organisms.

MICequals bactericidal concentrations (MBC).


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Salient Features Widely distributed in various tissues & fluids

including inflammatory exudates.

First quinolone to be approved for the treatment of

acute sinusitis.

Phototoxicity is infrequent & is


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Glevo v/s Other Levofloxacin Brands

Advantage of having a Complete Rangein

Oral & I.V. form

Firstto introduce 750 mg in Oral & I.V. form

Firstto provide an Economical price after

Tavanic

Firstto introduce Glevo Eye / Ear Drops


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Glevo v/s Gatifloxacin

Bioavailability is 99% v/s Gatifloxacin 96%

Higher Cmax & AUC (GLEVO500 mg 5.08mcg/ml &

48mcg/ml v/s Gatifloxacin 3.86mcg/ml & 33.8mcg/ml)

Unlike GLEVO, Gatifloxacin is not approved for 5 dayshort course treatment for CAP,CAP due to PRSP and

MDRSP and even in Nosocomial Pneumonia

Gatifloxacin causes Cardiac toxicity through changes i

electrical conduction, GLEVOis least likely to cause thproblem


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Glevo v/s Gatifloxacin (Contd.)

Gatifloxacin patients had 17 times greater risk of

hyperglycemia compared to control (Macrolides &

Cephalosporins)

Gatifloxacin promotes insulin release & hypoglycemia blocking the ATP-sensitive potassium channels of

pancreatic islet cell to cause hypoglycemia

Gatifloxacin triggers vacuolation (formation of small

cavity in the cytoplasm or tissue) of pancreatic beta celeading to reduced insulin levels & causes

hyperg lycemia


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Overall success rate in CAP - 98 % v/s 95%

In MDR-TB Levofloxacin was used upto 1000mg in

clinical trials with high safety whereas increasing the

dosage of Gatifloxacin > 400 mg leads to severeadverse effects & treatment withdrawals

Among fluoroquinolones, pseudomonal coverage is

highest with GLEVO, hence ideal for Nosocomial

Pneumonia


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Has lower incidence of adverse effects unlike

Gatifloxacin

Nausea = 1.2 % v/s 8 %

Diarrhea = 1.2 % v/s 4 %

Headache= 0.1 % v/s 4%


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Glevo v/s Cefadroxil

Offers wider spectrum of coverage against gram+ve

& gramve & atypical pathogens unlike Cefadroxil

(mainly has action against gram +ve pathogens)

Cefadroxil requires BID dosage, while GLEVOrequires OD dosage

Half the cost of therapy v/s Cefadroxil in URTIs

Offers high success rates as compared to

Cefadroxil in Sinusitis


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Glevo v/s Ciprofloxacin Achieves double the AUC than twice dailydose of

Ciprofloxacin Urinary excretion is 87 %as unchanged drug,unlike with

Ciprofloxacin it is only 25-35%

Clinical success rates in complicated UTI : 92 % v/s 79 %

Achieves 5 fold concentration in prostatic tissue thanCiprofloxacin, hence dosage is 500mg OD for 28 days v/s

500 mg BID for 28 days

Convenience of ODdosage unlike Ciprofloxacin is BID

Was associated with significantly greater pathogensusceptibility than Ciprofloxacin i.e.94.7 % v/s 90.6 %


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Glevo v/s Ciprofloxacin (Contd.)

Only fluoroquinolone for both gram+ve & gram-ve

pathogens in Chronic Bacterial Prostatitis

Has excellent activity against atypical pathogens,

including Chlamydia trachomatis, Ureaplasmaurealyticum & Mycoplasma hominis, unlike Ciprofloxac

Provides broad coverage of key pathogens in urogenit

tract infection as compared to Ciprofloxacin

Safety confirmed by > 10 years of Clinical experience &300 million prescriptions


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Glevo v/s Norfloxacin

Excretion of drug as unchanged in urine with

Norfloxacin is 26-32 %,while with GLEVO is 87 %

Hence, ideal for UTI

Convenience of ODdosage, unlike Norfloxacin

requires a BIDdosing

glevo new product profile

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