NEW DRUG DEVELOPMENTAL & APPROVAL PROCESS

LEVOMAX (Levofloxacin)

Submitted By:

Zohaib Ahmad(Roll#14)

Jalwaz Tihami(Roll#20)

Azeem Imam(Roll#25)

Rizwan Rashid(Roll#43)

Ali Tariq(Roll#136)

Submitted to:

Sir Ikram Ullah Khan B-Pharm, M.Phil,

COLLEGE OF PHARMACY

GC UNIVERSITY FAISALABAD

MS (TQM), R.Ph.

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CHAPTER#01 INTRODUCTION

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INTRODUCTION OF DRUG DISCOVERY AND

DEVELOPMENT INTRODUCTION:

Discovering and bringing one new drug to the public typically costs a pharmaceutical

or biotechnology company nearly $900 million and takes an average of 10 to 12

years. In special circumstances, such as the search for effective drugs to treat AIDS,

the U.S. Food and Drug Administration (FDA) has encouraged an abbreviated process

for drug testing and approval called fast-tracking. The drug discovery and drug

development process is designed to ensure that only those pharmaceutical products

that are both safe and effective are brought to market. PPD provides a broad array of

drug discovery and development services and products to pharmaceutical,

biotechnology and medical device companies to expedite drug development, from

drug discovery through clinical studies and post-approval support.

Drug development is a blanket term used to define the entire process of bringing a

new drug or device to the Market. It includes Drug discovery / product development,

pre-clinical research (microorganisms/animals) and Clinical trials (on humans). Few

people still refer to the drug development as mere preclinical development.

HOW ARE NEW DRUGS DISCOVERED?

New drugs begin in the laboratory with scientists, including chemists and

pharmacologists, who identify cellular and genetic factors that play a role in specific

diseases. They search for chemical and biological substances that target these

biological markers and are likely to have drug-like effects. Out of every 5,000 new

compounds identified during the discovery process, only five are considered safe for

testing in human volunteers after preclinical evaluations. After three to six years of

further clinical testing in patients, only one of these compounds is ultimately

approved as a marketed drug for treatment. The following sequence of research

activities begins the process that results in development of new medicines:

• Target Identification. Drugs usually act on either cellular or genetic

chemicals in the body, known as targets, which are believed to be associated

with disease. Scientists use a variety of techniques to identify and isolate

4

individual targets to learn more about their functions and how they influence

disease. Compounds are then identified that have various interactions with the

drug targets that might be helpful in treatment of a specific disease.

• Target Prioritization/Validation. To select targets most likely to be useful in

the development of new treatments for disease, researchers analyze and

compare each drug target to others based on their association with a specific

disease and their ability to regulate biological and chemical compounds in the

body. Tests are conducted to confirm that interactions with the drug target are

associated with a desired change in the behavior of diseased cells. Research

scientists can then identify compounds that have an effect on the target

selected.

• Lead Identification. A lead compound or substance is one that is believed to

have potential to treat disease. Laboratory scientists can compare known

substances with new compounds to determine their likelihood of success.

Leads are sometimes developed as collections, or libraries, of individual

molecules that possess properties needed in a new drug. Testing is then done

on each of these molecules to confirm its effect on the drug target.

• Lead Optimization. Lead optimization compares the properties of various

lead compounds and provides information to help biopharmaceutical

companies select the compound or compounds with the greatest potential to be

developed into safe and effective medicines. Often during this same stage of

development, lead prioritization studies are conducted in living organisms (in

vivo) and in cells in the test tube (in vitro) to compare various lead compounds

and how they are metabolized and affect the body.

WHAT IS REQUIRED BEFORE AN INVESTIGATIONAL DRUG CAN

BE TESTED IN HUMAN VOLUNTEERS?

In the preclinical stage of drug development, an investigational drug must be tested

extensively in the laboratory to ensure it will be safe to administer to humans. Testing

at this stage can take from one to five years and must provide information about the

pharmaceutical composition of the drug, its safety, how the drug will be formulated

and manufactured, and how it will be administered to the first human subjects.

5

• Preclinical Technology. During the preclinical development of a drug,

laboratory tests document the effect of the investigational drug in living

organisms (in vivo) and in cells in the test tube (in vitro).

• Chemistry Manufacturing and Controls (CMC)/Pharmaceutics. The

results of preclinical testing are used by experts in pharmaceutical methods to

determine how to best formulate the drug for its intended clinical use. For

example, a drug that is intended to act on the sinuses may be formulated as a

time-release capsule or as a nasal spray. Regulatory agencies require testing

that documents the characteristics -- chemical composition, purity, quality and

potency -- of the drug's active ingredient and of the formulated drug.

• Pharmacology/Toxicology. Pharmacological testing determines effects of the

candidate drug on the body. Toxicology studies are conducted to identify

potential risks to humans.

Results of all testing must be provided to the FDA in the United States and/or other

appropriate regulatory agencies in order to obtain permission to begin clinical testing

in humans. Regulatory agencies review the specific tests and documentation that are

required to proceed to the next stage of development.

HOW ARE INVESTIGATIONAL DRUGS TESTED IN HUMANS?

Testing of an investigational new drug begins with submission of information about

the drug and application for permission to begin administration to healthy volunteers

or patients.

Investigational New Drug (IND)/Clinical Trial Exception (CTX)/Clinical Trial

Authorization (CTA) Applications. INDs (in the U.S.), CTXs (in the U.K.) and

CTAs (in Australia) are examples of requests submitted to appropriate regulatory

authorities for permission to conduct investigational research. This research can

include testing of a new dosage form or new use of a drug already approved to be

marketed.

In addition to obtaining permission from appropriate regulatory authorities, an

institutional or independent review board (IRB) or ethical advisory board must

approve the protocol for testing as well as the informed consent documents that

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volunteers sign prior to participating in a clinical study. An IRB is an independent

committee of physicians, community advocates and others that ensures a clinical trial

is ethical and the rights of study participants are protected.

Clinical testing is usually described as consisting of Phase I, Phase II and Phase III

clinical studies. In each successive phase, increasing numbers of patients are tested.

• Phase I Clinical Studies. Phase I studies are designed to verify safety and

tolerability of the candidate drug in humans and typically take six to nine

months. These are the first studies conducted in humans. A small number of

subjects, usually from 20 to 100 healthy volunteers, take the investigational

drug for short periods of time. Testing includes observation and careful

documentation of how the drug acts in the body -- how it is absorbed,

distributed, metabolized and excreted.

• Phase II Clinical Studies. Phase II studies are designed to determine

effectiveness and further study the safety of the candidate drug in humans.

Depending upon the type of investigational drug and the condition it treats,

this phase of development generally takes from six months up to three years.

Testing is conducted with up to several hundred patients suffering from the

condition the investigational drug is designed to treat. This testing determines

safety and effectiveness of the drug in treating the condition and establishes

the minimum and maximum effective dose. Most Phase II clinical trials are

randomized, or randomly divided into groups, one of which receives the

investigational drug, one of which gets a placebo containing no medication

and sometimes a third group that receives a current standard treatment to

which the new investigational drug will be compared. In addition, most Phase

II studies are double-blinded, meaning that neither patients nor researchers

evaluating the compound know who is receiving the investigational drug or

placebo.

• Phase III Clinical Studies. Phase III studies provide expanded testing of

effectiveness and safety of an investigational drug, usually in randomized and

blinded clinical trials. Depending upon the type of drug candidate and the

condition it treats, this phase usually requires one to four years of testing. In

Phase III, safety and efficacy testing is conducted with several hundred to

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thousands of volunteer patients suffering from the condition the

investigational drug treats.

New Drug Application (NDA)/Marketing Authorization Application (MAA):

NDAs (in the U.S.) and MAAs (in the U.K.) are examples of applications to market a

new drug. Such applications document safety and efficacy of the investigational drug

and contain all the information collected during the drug development process. At the

conclusion of successful preclinical and clinical testing, this series of documents is

submitted to the FDA in the U.S. or to the applicable regulatory authorities in other

countries. The application must present substantial evidence that the drug will have

the effect it is represented to have when people use it or under the conditions for

which it is prescribed, recommended or suggested in the labeling. Obtaining approval

to market a new drug frequently takes between six months and two years.

DOES TESTING CONTINUE AFTER A NEW DRUG IS APPROVED?

After the FDA (or other regulatory agency for drugs marketed outside the U.S.)

approves a new drug, pharmaceutical companies may conduct additional studies,

including Phase IIIb and Phase IV studies. Late-stage drug development studies of

approved, marketed drugs may continue for several months to several years.

• Phase IIIb/IV Studies. Phase IIIb trials, which often begin before approval,

may supplement or complete earlier trials by providing additional safety data

or they may test the approved drug for additional conditions for which it may

prove useful. Phase IV studies expand testing of a proven drug to broader

patient populations and compare the long-term effectiveness and/or cost of the

drug to other marketed drugs available to treat the same condition.

• Post-Approval Studies. Post-approval studies test a marketed drug in new

age groups or patient types. Some studies focus on previously unknown side

effects or related risk factors. As with all stages of drug development testing,

the purpose is to ensure the safety and effectiveness of marketed drugs

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STEPS IN NEW DRUG DEVELOPMENT TILL NDA IS

FILED

9

Steps in New Drug Development till NDA is Filed

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CHAPTER#02 FLOW CHART FOR NEW DRUG

DEVELOPMENT

F L O W C H A R T

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NEW CHEMICAL ENTITY • Organic Synthesis • Molecular Modification• Isolation from Plants

PRECLINICAL STUDIES • Chemistry • Physical Properties • Biological Properties

ADME Toxicology

• Preformulation

INVESTIGATIONAL NEW DRUG APPLICATION (IND)

• Submission • FDA Review

CLINICAL TRIALS • Phase І • Phase І І • Phase І І І

PRECLINICAL STUDIES (Continued) • Long Term Animal Toxicity • Product Formulation • Manufacturing and Controls • Package and Label Design

NEW DRUG APPLICATION (NDA) • Submission • FDA Review • Preapproval Plant Inspection • FDA Action

POST MARKETING SURVEILLANCE • Phase 4 clinical studies • Additional Indications • Adverse Drug Reporting • Product Defect Reporting • Product Line Extention

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CHAPTER#03

SOURCE AND SYNTHESIS

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SYNTHESIS OF LEVOFLOXACIN Levofloxacin is a synthetic compound and is synthesized as follow;

Procedure:

1,2-Cyclic sulfamidates undergo efficient and regiospecific nucleophilic cleavage

with 2-bromophenols (and related anilines and thiophenols), followed by Pd(0)-

mediated amination to provide an entry to substituted and enantiomerically pure 1,4-

benzoxazines (and quinoxalines and 1,4-benzothiazines). This chemistry provides a

short and efficient entry to (3S)-3-methyl-1,4-benzoxazine 19, a late stage

intermediate in the synthesis of levofloxacin. This intermediate, through a series of

steps, is than converted into levofloxacin.

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CHAPTER#04 PRECLINICAL STUDIES

Chemistry

Physical Properties

Biological Properties

• Pharmacology

• Pharmacokinetics

• Toxicity

UNIT-1:

15

CHEMISTRY OF LEVOFLOXACIN

IUPAC-Name: (S)-7-fluoro-6-(4-methylpiperazin-1-yl)-10-oxo-4-thia-1-azatricyclo

[7.3.1.05,13] trideca-5(13),6,8,11-tetraene-11-carboxylic acid

Chemical Formula: (-) - (S)- 9 fluoro- 2, 3- dihydro -3- methyl- 10- (4- methyl- 1-

piperazinyl) –7 – oxo -7H – pyrido [1, 2, 3 -de]- 1, 4 benzoxazine- 6- carboxylic acid

hemihydrate.

Empirical Formula: C18H20FN3O4�½H2O

Routes: Oral, IV, ophthalmic

Molecular Weight: 370.38.

Stable Coordination Compounds:

Levofloxacin has the potential to form stable coordination compounds with many

metal ions. This in vitro chelation potential has the following formation order:

Al+3>Cu+2>Zn+2>Mg+2>Ca+2.

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Structural Formula of Levofloxacin

UNIT-2:

17

PHYSICAL PROPERTIES

Appearance: Levofloxacin is a light yellowish-white to yellow-white crystal or

crystalline powder.

Stability: Stable under ordinary conditions

Melting Point: 218 ºC (http://www.chemblink.com/products/100986-85-4.htm)

Solubility: Insoluble in water

The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin is

essentially constant (approximately 100 mg/mL). Levofloxacin is considered soluble

to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8, the

solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered

freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a

minimum value (about 50 mg/mL) at a pH of approximately 6.9.

Physical State: crystalline powder

Odour: Odourless

UNIT 3:

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BIOLOGICAL PROPERTIES

These biological properties are based on pre-clinical studies that are carried out in

animals.

(A) PHARMACOLOGY:

Pharmacotherapeutic Group: Quinolone Antibacterials, Fluoroquinolones

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the

S (-) enantiomer of the racemic drug substance ofloxacin.

Mechanism of action:(Chemical Basis)

Levofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive

and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II

topoisomerase, and topoisomerase iv, which is an enzyme necessary to separate

replicated DNA, thereby inhibiting cell division.

The fluoroquinolones interfere with DNA replication by inhibiting an enzyme

complex called DNA gyrase. In particular, some congeners of this drug family display

high activity not only against bacterial topoisomerases but also against eukaryotic

topoisomerases, and are toxic to cultured cells and in vivo tumor models. Although

the quinolone is highly toxic to mammalian cells in culture, its mechanism of

cytotoxic action is not known. Quinolone-induced DNA damage was first reported in

1986.

Pharmacokinetics:

Absorption:

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Bioavailability

Approximately 99%.

Rapidly absorbed from GI tract.Peak plasma concentrations usually attained 1-2 hours

after an oral dose. Steady-state plasma concentrations attained within 48 hours with

once-daily regimen.

Distribution:

Extent

Widely distributed into body tissues and fluids, including skin, blister fluid, and lungs.

It is also distributed into CSF.

Plasma Protein Binding

24-38% bound to serum proteins.

Elimination:

Metabolism

Undergoes limited metabolism to inactive metabolites.

Elimination Route

Eliminated principally as unchanged drug in urine. Approximately 87% of an oral

dose eliminated in urine and <4% eliminated in feces.

Half-life

Terminal elimination half-life approximately 6-8 hours after oral administration.

(B) TOXICOLOGICAL STUDIES:

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Levofloxacin, when administered orally to rats at a dose of 20 mg/kg, was absorbed

primarily from the small intestine, and the maximum serum concentration (2.5 ug/ml)

was reached 0.5 hours after administration, except for the level, in the central nervous

system and fat, levofloxacin concentration in almost all tissues of the body were

higher than the serum level, demonstrating the good transference to tissues. Drug

concentrations in the main organs were high in the kidneys and liver and lowest in the

brain.

Repeated dose toxicity:

Studies of one and six month’s duration by gavage have been carried out in the rat and

monkey. Doses were 50, 200, 800 mg/kg/day and 20, 80, 320 mg/kg/day for 1 and 6

months in the rat and 10, 30, 100 mg/kg/day and 10, 25, 62.5 mg/kg/day for 1 and 6

months in the monkey.

Signs of reactions to treatment were minor in the rat with slight effects principally at

200 mg/kg/day and above in reducing food consumption and slightly altering

haematological and biochemical parameters. The “No Observed Adverse Effect

Levels” (NOEL) in these studies were concluded to be 200 and 20 mg/kg/day after

one-and six months, respectively.

Toxicity after oral dosing in the monkey was minimal with reduced body weight at

100 mg/kg/day together with salivation, diarrhoea and decreased urinary pH in some

animals at this dose. No toxicity was seen in the 6-months study. The NOELs were

concluded to be 30 and 62.5 mg/kg/day after 1 and 6 months respectively.

The “ No Observed Adverse Effect Levels” (NOEL) in the six-month studies were

concluded to be 20 and 62.5 mg/kg/day in the rat and monkey respectively.

Subacute Toxicity:

Following 4-weeks oral administration to rats, no toxicological changes in clinical

signs, hematology, blood chemistry urinalysis and histopathology were observed in

the 50 mg/kg and 200 mg/kg administered groups. At a dose of 800 mg/kg, however,

increased M/E ratio of bone marrow cells, decreased neutrophil count and slight

degeneration of the articular cartilage of limb joint were observed. Following 4 weeks

oral administration to cynomolgus monkeys, no toxicological changes were observed

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at doses of 10 and 30 mg/kg, but salivation, diarrhea, slight inhibition of body weight

gain and decrease in urine pH were observed at 100 mg/kg.

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CHAPTER#05 PREFORMULATION

Bulk Characterization

Solubility Analysis

Stability Analysis

UNIT-1:

23

BULK CHARACTERIZATION

Molecular Weight: 370.38.

Method: By Mass Spectroscopic Method

Particle Size: Large

Method: By sieving method particle size is determined. it is large in size

Melting Point: 218 ºC (http://www.chemblink.com/products/100986-85-4.htm)

Method: By Hot Stage Microscopy

The melting point of a drug can be measured using three techniques:

Capillary melting

Hot stage microscopy

Differential scanning calorimetry or thermal analysis.

Capillary Melting

Capillary melting (the observation of melting in a capillary tube in a heated metal

block) gives information about the melting range but it is difficult to assign an

accurate melting point.

Hot stage Microscopy

This is the visual observation of melting under a microscope equipped with a heated

and lagged sample stage. The heating rate is controllable and up to three transitions

can be registered. It is more precise as the phase transitions (first melt, 50% melt and

completion) can be registered on a recorder as the melting proceeds, and because of

the high magnification the values are more accurate.

Differential Scanning Calorimetry and Thermal Analysis:

Neither of the previous methods is as versatile as either differential thermal analysis

(DTA) or differential scanning calorimetry (DSC). An additional advantage is that the

sample size required is only 2-5 mg. DTA measures the temperature difference

between the sample and a reference as a function of temperature or time when heating

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at a constant rate. DSC is similar to DTA, except that the instrument measures the

amount of energy required to keep the sample at the same temperature as the

reference, i.e. it measures the enthalpy of transition. When no physical or chemical

change occurs

within the sample then there is neither a temperature change nor input energy to

maintain an isotherm. However, when phase changes occur then latent heat

suppresses a temperature change and the isothermal energy required registers as an

electrical signal generated by thermocouples. Crystalline transitions, fusion,

evaporation and sublimation are obvious changes in state which can be quantified

(Fig. 8.3). The major concern in preformulation is polymorphism, and the

measurement of melting point and other phase changes is the primary diagnostic tool.

Confirmation by IR spectroscopy and X-ray diffraction

is usually required.

Crystal Habit: Microcrystalline

Technique: By SEM, Crystal Habit is observed

Microscopy:

The microscope has two major applications in pharmaceutical preformulation:

Basic crystallography, to determine crystal morphology (structure and habit),

polymorphism and solvates

Particle size analysis

Most pharmaceutical powders have crystals in the range 0.5-300 /Jim. However, the

distributions are often smaller, typically 0.5-50 /mi, to ensure good blend

homogeneity and rapid dissolution. These are the major reasons for particle size

control. A lamp-illuminated mono-objective microscope fitted with polarizing filters

above and below the stage is more than adequate. For most preformulation work a 10

x eyepiece and a 10-x objective are ideal, although occasionally, with micronized

powders and when following solid-solid and liquid-liquid transitions in

polymorphism, 10 x 20 may be required.

Crystal Purity:

25

Thermal analysis has been widely used as a method of purity determination and the

USP includes an appendix describing the methods. This is particularly pertinent at the

preformulation stage, because early samples of a new drug are inevitably 'dirty' while

Improvements in synthetic route are made. Thermal analysis is rapid and will

discriminate 0.002% of impurity.

Hygroscopicity: Hygroscopic

A substance that absorbs sufficient moisture from the atmosphere to dissolve itself is

deliquescent is called hygroscopic. A substance that loses water to form a lower

hydrate or becomes anhydrous is termed efflorescent. These are extreme cases, and

most pharmaceutical compounds are usually either impassive to the water available in

the surrounding atmosphere or lose or gain water from the atmosphere, depending on

the relative humidity (RH). Materials unaffected by RH are termed non-hygroscopic,

whereas those in dynamic equilibrium with water in the atmosphere are hygro-scopic.

Ambient RH (0% poles and desert, 55% temperate and 87% tropics) can vary widely

and continually depending on the weather and air temperature, and these cyclic

changes lead to constant variations in the moisture content of unprotected bulk drug

and excipients. The constant sinusoidal change in day and night temperatures is the

major influence. For this reason pharmaceutical air conditioning is usually set below

50% RH, and very hygroscopic products, e.g. effervescents, which are particularly

moisture sensitive, are stored and made below 40% RH.

Crystal Morphology

Crystals are characterized by repetition of atoms or molecules in a regular three-

dimensional structure, which is absent in glasses and some polymers. There are six

crystal systems (cubic, tetragonal, orthorhombic, monoclinic, triclinic and hexagonal),

which have different internal structures and spatial arrangements. Although not

changing their internal structure, which occurs with polymorphism, crystals can adopt

different external structures. This is known as crystal habit, of which five types are

recognized:

Tabular: moderate expansion of two parallel faces

Platy: plates

Prismatic: columns

Acicular: needle-like

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Bladed: flat acicular.

These occur in all six-crystal systems.

Conditions during crystallization will contribute to changes in crystal habit and may

be encountered in early batches of a new drug substance until the synthetic route has

been optimized. Crystal habit can be modified by:

Excessive supersaturation, which tends to transform a prism or isodiametric

(granular) crystals to a needle shape.

Cooling rate and agitation, which changes habit as it changes the degree of

supersaturation. Naphthalene gives thin plates (platy) if rapidly recrystallized

in cold ethanol or methanol, whereas slow evaporation yields prisms.

The crystallizing solvent affects habit by preferential absorption on to certain

faces, inhibiting their growth. Resorcinol produces needles from benzene and

squat prisms from butyl acetate.

The addition of cosolvents or other solutes and ions which change habit by poisoning

crystal growth in one or more directions. Sodium chloride is usually cubic, but urea

produces an octahedral habit.

Powder Flow Properties:

Flow Ability: Good

Technique: Flow ability is determined by calculating angle of repose.

Angle of Repose: 22º

Explanation:

A static heap of powder, with only gravity acting upon it, will tend to form a conical

mound. One limitation exists: the angle to the horizontal cannot exceed a certain

value, and this is known as the angle of repose (0). If any particle temporarily lies

outside this limiting angle, it will slide down the adjacent surface under the influence

of gravity until the gravitational pull is balanced by the friction caused by

interparticulate forces. Accordingly, there is an empirical relationship between 6 and

the ability of the powder to flow. However, the exact value for angle of repose does

depend on the method of measurement. The angles of repose given in Table 8.14 may

be used as a guide to flow.

A simple relationship between angle of repose, Carr's index and the expected powder

flow is shown in Figure 8.6. When only small quantities of powder are available, an

alternative is to determine the 'angle of spatula' by picking up a quantity of powder on

27

a Table 8.14 Angle of repose as an indication of powder flow propertiesspatula and

estimating the angle of the triangular section of the powder heap viewed from the end

of the spatula. This is obviously crude but is useful during preformulation, when only

small quantities of drug are available.

Of primary importance when handling a drug powder is flow. When limited amounts

of drug are available this can be evaluated by measurements of bulk density and angle

of repose. These are extremely useful derived parameters to assess the impact of

changes in drug powder properties as new batches become available. Changes in

particle size and shape are generally very apparent; an increase in crystal size or a

more uniform shape will lead to a smaller angle of repose and a smaller Carr's index.

Bulk density

A simple test has been developed to evaluate the flowability of a powder by

comparing the poured (fluff) density (pBmin) and tapped density (psmax) of a powder

and the rate at which it packed down. A useful empirical guide is given by Carr's

compressibility index ('Compressibility' is a misnomer, as compression is not

involved):

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This is a simple index that can be determined on small quantities of powder and may

be interpreted as

A similar index has been defined by Hausner (1967):

Values less than 1.25 indicate good flow (= 20% Carr), whereas greater than 1.25

indicates poor flow (= 33% Carr). Between 1.25 and 1.5, added glidant normally

improves flow. Carr's index is a one-point determination and does not always reflect

the ease or speed with which the powder consolidates. Indeed, some materials have a

high index (suggesting poor flow) but may consolidate rapidly. Rapid consolidation is

essential for uniform filling on tablet machines, when the powder flows at pBmin into

29

the die and consolidates, approaching pBmaxJ at compression. An empirical linear

relationship exists between the change in bulk density and the log number of taps in a

jolting volumeter. Non-linearity occurs up to two taps and after 30 taps when the bed

consolidates more slowly. The slope is a measure of the speed of consolidation and is

useful for assessing powders or blends with similar Carr's indices and the benefit of

glidants.

Polymorphic Forms:

Three polymorphic forms (anhydrous α, β, γ) and two pseudopolymorphic forms

(hemihydrate and monohydrate) of levofloxacin are present. Hemihydrate and

monohydrate forms are mentioned in EP 0444 678 B1 and in U.S. Patent No.

5,545,737. These two patents are directed toward processes for the preparation of

hemihydrate form free of monohydrate and for the preparation of monohydrate free of

hemihydrate.

Transformation Kinetics:

Heating the hemihydrate form resulted in a removal of the hydrated water to give

anhydrous form γ. Further heating resulted in the formation of anhydrous form β, and

then the formation of anhydrous form α. Heating of the monohydrate form resulted in

a removal of the hydrated water to give anhydrous form α. Form γ and form α

adsorbed water vapor rapidly under ordinary relative humidity conditions and

transformed into the hemihydrate and monohydrate, respectively.

Method: Transformation Kinetics are checked by differential scanning calorimetry

(DSC).

30

Unit-2:

SOLUBILITY ANALYSIS

Solubility in water:Insoluble

The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin is

essentially constant (approximately 100 mg/ mL). Levofloxacin is considered soluble

to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8,

the solubility increases rapidly to its maximum at pH 6.7 (272 mg/ mL) and is

considered freely soluble in this range. Above pH 6.7, the solubility decreases and

reaches a minimum value (about 50 mg/ mL) at a pH of approximately 6.9.

Partion Coefficient: Pka value is 6.8 ± 0.3 Method: Shake flask method is used to determine Pka

Membrane Permeabiliy: High permeability drug

Permeability classification of representative fluoroquinolones by a cell culture

method: This study was undertaken to categorize representative fluoroquinolone drug

substance permeability based on the methods outlined in the Food and Drug

Administration's biopharmaceutic classification system (BCS) Guidance for Industry.

The permeability of ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin was

measured in an in vitro Caco-2 assay with previously demonstrated method suitability. The permeability class

and efflux potential were ascertained by comparing test drug results with standard

compounds (metoprolol, atenolol, labetalol, and rhodamine-123). All 4 quinolones

drugs demonstrated concentration-dependent permeability, indicating active drug

transport. In comparing absorptive versus secretive in vitro transport, the tested

fluoroquinolones were found to be subject to efflux in varying degrees (ciprofloxacin

> lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). Based on comparison to

31

labetalol, the high permeability internal standard, ciprofloxacin was classified as a

low permeability drug, whereas lomefloxacin, levofloxacin, and ofloxacin were

classified as high permeability drugs. The in vitro permeability results matched

human in vivo data based on absolute bioavailabilities. This laboratory exercise

demonstrated the applicability of an in vitro permeability method for classifying drugs

as outlined in the BCS Guidance.

Dissolution: Drug exhibit good dissolution properties.

Method and Equipment: Rotating Basket Apparatus is used.

Drug is placed in the Rotating Basket Apparatus and the dissolution of compound is

determined

32

UNIT-3:

STABILITY ANALYSIS

Hydrolysis: There is no effect of moisture.

Stability-indicating RP-HPLC method for levofloxacin in the presence of

degradation products, its process related impurities and identification of

oxidative degradant

The objective of current study was to develop a validated specific stability indicating

reversed-phase liquid chromatographic method for the quantitative determination of

levofloxacin as well as its related substances determination in bulk samples,

pharmaceutical dosage forms in the presence of degradation products and its process

related impurities. Forced degradation studies were performed on bulk sample of

levofloxacin as per ICH prescribed stress conditions using acid, base, oxidative, water

hydrolysis, thermal stress and photolytic degradation to show the stability indicating

power of the method.

RESULT:

Significant degradation was observed during oxidative stress and the degradation

product formed was identified by LCMS/MS, slight degradation in acidic stress and

no degradation was observed in other stress conditions. The chromatographic method

was optimized using the samples generated from forced degradation studies and the

impurity spiked solution. Good resolution between the peaks corresponds to process

related impurities and degradation products from the analyte were achieved on ACE

C18 column using the mobile phase consists a mixture of 0.5% (v/v) triethyl amine in

sodium dihydrogen orthophosphate dihydrate (25 mM; pH 6.0) and methanol using a

simple linear gradient. The detection was carried out at 294 nm. The limit of detection

and the limit of quantitation for the levofloxacin and its process related impurities

were established. The stressed test solutions were assayed against the qualified

working standard of levofloxacin and the mass balance in each case was in between

99.4 and 99.8% indicating that the developed LC method was stability indicating.

Validation of the developed LC method was carried out as per ICH requirements. The

developed LC method was found to be suitable to check the quality of bulk samples

33

of levofloxacin at the time of batch release and also during its stability studies (long

term and accelerated stability).

34

CHAPTER#06

INVESTIGATIONAL NEW DRUG

APPLICTION

35

Documents required by Ministry of Health for the approval of Clinical Trials in

Pakistan

Documents

Investigator Brochure.

Final protocol.

Informed Consent (English and Urdu )Form

Fees 5000.

(Head of Account)

C-Non Tax Revenue

C02- Receipts from Civil Administration and other Functions.

C028-Social Services.

C02841-Health-Other Receipts

List of participating countries.

Phase of Trial

Quantity of drug to be imported on Form 4 of Drugs Import & Export Rules 1976

along with the sites where trial is to be conducted.

CV’s of Investigators.

Ethics committee approval of sites, with complete composition of committee i.e names

and designation of members.

GMP Certificate along with CPP/Free Sale Certificate of Country of Origin.

Pre- clinical/ Clinical data/ Safety studies.

Summary of the Protocol

Summary of the IB ( for quick review on drug).

Adverse Event Reporting Form .

Number patients to be enrolled in each center

Name of Monitors/ Clinical Research Associate

Evidence of registration in country of origin

Copy of registration letter if drug is registered in Pakistan

Sample of label of drug

Duration of Trial

36

CHAPTER#07 CLINICAL TRIALS

37

CLINICAL TRIALS

Our product is converted into a suitable dosage form. Than we submitted

investigational to FDA. All preclinical studies mentioned and took permission for

clinical trials.

PHASE-1 CLINICAL TRIALS:

Aims:

To study the safety of the drug in healthy volunteers

No. of Patients:

We selected 20-100 healthy voluntaries for phase 1 trials.

Procedure:

We administered 1/10 of no effect dose of animals. This purloins gets stable so we

increased the dose gradually and checked the response. In this phase, Parmacokinetics

and Pharmacodynamic studies of a drug are undertaken to determine its toxicity,

metabolism, absorption, distribution and elimination and pharmacological action

preferred route of administration and safe dosage.

Duration:

Phase-1 survives usually for 1-2 years.

Results:

We conducted study under careful circumstances by personals trained in clinical

pharmacology. The clinical research on ranitidine is preceded to phase-2 because

phase 1 studies showed promise and no drug reaction, which became evident.

PHASE-2 CLINICAL TRIALS:

Phase II studies are sometimes divided into Phase IIA and Phase IIB.

Phase IIA is specifically designed to assess dosing requirements (how much

drug should be given).

38

Phase IIB is specifically designed to study efficacy (how well the drug works

at the prescribed dose(s)).

Aims:

This trial aims to demonstrate conclusively efficacy of drug in relation to its

safety.

Pharmacokinetics of a drug should be investigated in patients because they

may handle it differently from healthy people. Variation may occur due to the

following reasons:

• Effect of disease

• Age as compared with that of the volunteers studies that

in phase-1 trials.

No. of Patients:

We recruited hundred of patients for the conformation of phase-1 trials.

Duration:

It took 1-2 years for its completion.

A STUDY TO EVALUATE THE PHARMACOKINETICS AND SAFETY OF

LEVOFLOXACIN IN PATIENTS WITH VARYING DEGREES OF RENAL

FUNCTION

PURPOSE:

The primary objective was to evaluate the pharmacokinetics and safety of two dosing

regimens of Levofloxacin in patients with varying degrees of renal function.

Condition Intervention Phase

Renal Diseases Drug: Levofloxacin Phase 2

Study Type Interventional

Study Design Treatment, Randomized, Open Label, Parallel Assignment, Pharmacokinetics Study

Official Title An Open-Label Randomized Multiple-Dose Study to Evaluate Levofloxacin Steady-State Pharmacokinetics and Safety in Subjects With Varying Degrees of Renal Function

39

FURTHER STUDY DETAILS AS PROVIDED Primary Outcome Measures:

Evaluation of the pharmacokinetics of two dosing regimens of Levofloxacin in

renally impaired and dialysis patients.

Secondary Outcome Measures:

Safety of two dosing regimens of Levofloxacin in renally impaired and dialysis

patients.

Estimated Enrollment: 60

Study Start Date: October 2007

Study Completion Date: April 2009

Detailed Description:

In this multiple-dose study conducted at 4 centers, the pharmacokinetics of two dosing

regimens of levofloxacin were assessed in medically stable men and women with

varying degree of renal function. The study consisted of a 21 day pretreatment

screening phase, a 7-day open label treatment phase, and a 7 day posttreatment phase

(or a follow-up phase for subjects with early study withdrawal). Patients were

randomized into 1 of 10 treatment groups, for a total of 6 patients per group, based on

degree of renal function to ensure that creatinine clearance values within each group

represented the full range of values defined in the Food and Drug Administration's

(FDA) 1998 guideline for pharmacokinetic studies in patients with impaired renal

function. Fifty-nine patients were enrolled in the study. All patients received a single

750-mg dose of levofloxacin on Day 1; subsequent doses of either 250, 500, or 750

mg of levofloxacin (q24h or q48h) were based on renal function. Blood samples were

collected from each patient from Day 1 to Day 14 for pharmacokinetic evaluation.

Urine was collected on Days 1 and 7 before dosing and over specific time intervals up

to 24 or 48 hours postdosing depending on the patient's dosing regimen. Dialysate

samples were collected on Day 7 from HD patients immediately before dosing (as

40

dialysis began) and at the end of the dialysis treatment. Patients were confined

overnight at the study unit on Days 0, 1, 6, and 7, and remained confined until the 24

hour blood samples were collected on Days 2 and 8. Safety was based on the

incidence, relationship to therapy, and severity of treatment-emergent adverse events

and on changes in clinical laboratory values (hematology, chemistry, and urinalysis),

vital sign measurements, electrocardiograms (ECGs), and physical examination

findings.

Single 750-mg dose of levofloxacin on Day 1; subsequent doses of Levofloxacin 250

milligram (mg), 500 mg, and 750 mg tablets administered every 24 hours for 7 days or

every 48 hours for 7 days

Eligibility Criteria:

Ages Eligible for Study: 18 Years to 65 YearsGenders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

BMI between 18 and 35 kg/m2

No prescription or over-the-counter medications for previous 7 days

Negative tests for drug and alcohol abuse, HIV, hepatitis B and hepatitis C

Medically stable based on medical history, physical examination, 12-lead

electrocardiograms, toxicology, antigen, and antibody screens, and clinical

laboratory evaluations

Stable renal function based on calculated creatine clearance for non-dialysis

patients and the same dialysis treatment for at least 6 months prior to screening

for dialysis patients

Patients with creatinine clearance ≤80 mL/min who require treatment for renal

impairment or other chronic disease (e.g., well-controlled diabetes,

hypertension) must be on a stable treatment plan (medicines, doses, and

regimens) for at least 2 months prior to Day 1 and during the entire study

Hematocrit (hct) within the normal range based on patients' renal function at

screening.

41

Exclusion Criteria:

Allergic reaction to quinolones

Known or suspected allergy to heparin

Clinically significant ECG or clinical laboratory abnormalities

Creatinine clearance <80 mL/min whose medical condition was unstable

Creatinine clearance >= 80 mL/min who required concomitant medication

during the study

Poorly controlled type 1 or type 2 diabetes

Patients with creatinine clearance >= 50 mL/min with screening blood

pressure outside the normal range (sitting systolic blood pressure <90 or >140

mm mercury [Hg] or diastolic blood pressure <60 or >90 mm Hg)

Patients with CLCR <50 mL/min who had sitting systolic blood pressure <90

or >160 mm Hg, or diastolic blood pressure <60 or >90 mm Hg

Required immunosuppressive medications for treatment of immune-mediated

renal disease or kidney transplant

Pregnant or breastfeeding

Results:

We conducted study under careful circumstances by personals trained in clinical

pharmacology. The clinical research on ranitidine is preceded to phase-3 because

phase-2 studies showed promise and no drug reaction, which became evident.

Phase-3 Clinical Trials:

The phase-3 studies are intended to assess the drug-s safety, effectiveness and most

desirable dosage in treating a specific disease in a large group of subjects. Basically

phase-3 involves the comparison between the existing therapies of a particular disease

and the new drug.

We conducted following phase-3 clinical studies

42

A Study of the Safety and Effectiveness of Levofloxacin Compared With

Ceftriaxone Sodium or Cefuroxime Axetil in the Treatment of Adults With

Pneumonia

Purpose:

The purpose of this study is evaluation of the safety and effectiveness of levofloxacin,

an antibiotic, compared with ceftriaxone sodium or cefuroxime axetil in the treatment

of adults with pneumonia.

Condition Intervention Phase

Pneumonia Drug: levofloxacin Phase II Phase III

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Official Title: A Multicenter, Active-Controlled, Randomized Study To Evaluate The Safety And Efficacy Of Levofloxacin Versus Ceftriaxone

Sodium Or Cefuroxime Axetil In The Treatment Of Community-Acquired Pneumonia In Adults

Further study details as provided

Primary Outcome Measures:

Clinical response rate (reduction in signs and symptoms, improvement in x-ray

findings) at post-therapy (5 - 7 days after the last dose of study drug).

Secondary Outcome Measures:

Rate of elimination of disease-causing bacteria, by patient, and by type of bacteria;

incidence of adverse events; changes in physical examination and laboratory tests

after treatment with study drug

43

Estimated Enrollment: 528

Study Start Date: September 2005

Estimated Study Completion Date: January 2007

Detailed Description:

This is a randomized, open-label, parallel group, multicenter study to determine the

safety and effectiveness of levofloxacin (500 mg once daily by mouth) compared with

ceftriaxone sodium (1 - 2 grams administered into a vein or muscle once daily or in

divided doses twice daily for 7 - 14 days) or cefuroxime axetil (500 mg by mouth

twice daily for 7 - 14 days) in adults with community-acquired pneumonia. The study

consists of 4 visits: one visit for screening and enrollment, and 3 visits for assessment

of safety and effectiveness (one visit on Day 2 - 4 [on-therapy], one visit [post-

therapy] 5 - 7 days after the last dose of the study drug, and one visit [post-study] 21 -

28 days after the last dose of the study drug). The total duration of patient

participation in the study is approximately 6 weeks. Levofloxacin is an antibacterial

agent used for the treatment of many types of infections in adults. The purpose of this

study is to compare the safety and effectiveness of levofloxacin with other frequently

used antibiotics (ceftriaxone sodium or cefuroxime axetil) in the treatment of adults

with pneumonia acquired in the community. The primary efficacy assessment is the

clinical response 5 - 7 days after the last dose of study drug, (categorized as cured,

improved, or failed) based upon changes in signs and symptoms, and changes in x-ray

findings, Safety evaluations (incidence of adverse events, physical examination, and

laboratory tests) are performed throughout the study. Cost-effectiveness is also

assessed for the study drugs. The study hypothesis is that treatment with levofloxacin

will be at least as effective as ceftriaxone sodium or cefuroxime axetil in treating

patients with pneumonia acquired in the community, and that it will be well tolerated.

Levofloxacin 500 mg by mouth once daily; ceftriaxone sodium (1 - 2 grams

administered into a vein or muscle once daily or in divided doses twice daily); or

cefuroxime axetil (500 mg by mouth twice daily). Treatment duration is 7 - 14 days.

44

Eligibility Criteria:

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

Diagnosis of pneumonia based upon clinical signs and symptoms of a lower

respiratory tract infection including at least 2 of the following: fever, cough,

greenish-yellow mucus produced on coughing, chest pain, shortness of breath,

or evidence of decreased lung function during the physical examination

Has chest x-ray findings consistent with acute pneumonia

Previously received antibiotics for pneumonia if the duration of therapy was

<= 24 hours, or if greater than 24 hours, but without improvement or

stabilization with that therapy

Exclusion Criteria:

Previous allergic or serious adverse reaction to any antibiotic similar to those

used in this study or to penicillin

Collection of pus in the cavity between the lung and the membrane that

surrounds it

Has cystic fibrosis

Has a lung infection due to fungus, bacteria, or virus known prior to the start

of the study to be resistant to any of the study drugs

Has severe kidney failure, decrease in white blood cell count, seizure disorder,

or an unstable psychiatric condition.

Results:

Levofloxacin 500 mg by mouth once daily is more efficacious as compared to

ceftriaxone sodium (1 - 2 grams administered into a vein or muscle once daily or in

divided doses twice daily); or cefuroxime axetil (500 mg by mouth twice daily)

45

A Study to Compare the Safety and Effectiveness of 2 Doses of Levofloxacin

Given for Different Time Periods in Patients With Pneumonia

Purpose:

The purpose of this study is to evaluate the effectiveness and safety of two antibiotic

regimens in the treatment of community-acquired pneumonia in non-hospitalized

adult patients. A 5-day course of 750 milligrams of levofloxacin given once daily will

be compared to a 10-day course 500 milligrams of levofloxacin given once daily.

Condition Intervention Phase

Pneumonia Drug: levofloxacin Phase III

Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Parallel Assignment, Safety/Efficacy Study

Official Title: Multicenter, Double-Blind Randomized Study to Compare the Safety and Efficacy of Levofloxacin 750 mg Once Daily for Five

Days vs. Levofloxacin 500 mg Once Daily for 10 Days in the Treatment of Mild to Severe Community-Acquired Pneumonia in

Adults

Further study details as provided

Primary Outcome Measures:

Clinical response rates based on signs and symptoms at posttherapy visit.

Secondary Outcome Measures:

Microbiologic eradication rates at posttherapy visit; Clinical response rates (chest x-

ray findings and signs/symptoms) and microbiologic eradication rates at poststudy;

Incidence of adverse events.

46

Enrollment: 530

Study Start Date: March 2007

Study Completion Date: June 2009

Detailed Description:

Levofloxacin is an antibiotic that is approved by the FDA for the treatment of

sinusitis, chronic bronchitis, skin infections, urinary tract infections, and community-

acquired pneumonia. This multicenter, double-blind (neither the patient nor the study

doctor will know the dose of levofloxacin being administered) study evaluates the

effectiveness and safety of two antibiotic regimens in the treatment of community-

acquired pneumonia in adult patients. A 5-day course of 750 milligrams of

levofloxacin given once daily will be compared to a 10-day course 500 milligrams of

levofloxacin given once daily. Patients receive levofloxacin by mouth or through a

vein depending on the severity of their pneumonia. Patients are assessed after 3 days

of treatment; treatment is discontinued if no significant improvement is noted.

Patients showing signs of improvement continue in the study, with assessments on

study days 12-16, and 17-21 (posttherapy visits), and 31-38 (poststudy visit).

Effectiveness is assessed by measuring the ability of the study drug to eliminate

bacteria causing pneumonia and to reduce the signs and symptoms of pneumonia.

Chest x-rays and laboratory tests for presence of bacteria are performed during the

study. Safety evaluations (incidence of adverse events, physical examinations,

laboratory tests) are performed throughout the study. The study hypothesis is that

levofloxacin administered at a higher dose for a shorter duration is at least as effective

as levofloxacin administered at a lower dose for a longer duration in the treatment of

community-acquired pneumonia and is generally well-tolerated.

Levofloxacin, 500 milligrams (mg) by mouth or through vein daily for 10 days or 750

mg by mouth or slowly through a vein daily for 5 days

47

Eligibility Criteria:

Ages Eligible for Study: 18 Years and olderGenders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

Diagnosis of community-acquired pneumonia as follows: clinical signs and

symptoms of a lower respiratory tract infection and chest-x-ray findings

consistent with pneumonia within 24 hours before entry into the study

At least one of the following: abnormal temperature (high or low) or abnormal

white blood cell count

Previous antibiotic treatment <= 24 hours or, if the duration of treatment was

>= 72 hours and that therapy failed based on at least 2 of the following: fever

within 12 hours of entry into the study, chest x-ray findings have worsened

compared to the initial chest-x-ray, white blood cell count is significantly

increased, respiratory rate higher than at the start of treatment and >= 20

breaths per minute or need for supplemental oxygen if not previously needed

Patients whose infection is acquired in the community or, if in a nursing home,

who had been living there < 14 days

Fine Class (rating scale used to assess patients' overall condition which

includes information such as age, gender, other diseases, physical examination

and laboratory findings) score <= 130 upon admission (patients with Fine

Class scores > 70 but < = 130 must initially be hospitalized

Patients with scores of <= 70 may be treated as outpatients or hospitalized at

the discretion of the investigator)

Exclusion Criteria:

Pneumonia known or suspected to be due to a bacteria resistant to levofloxacin

Previous allergic or serious reaction to or failed therapy with levofloxacin or

similar drugs

Life expectancy < 72 hours

48

Hospitalized within 2 weeks before entry in the study or within 1 month

before entry in the study if treated with antibiotics

Pneumonia acquired in a hospital

Cystic fibrosis or other lung disorders

Receiving chronic steroid treatment

Received assistance from a machine to breathe within the previous month

Results:

Levofloxacin, 500 milligrams (mg) by mouth or through vein daily for 10 days show

better results than 750 mg by mouth or slowly through a vein daily for 5 days.

WE GIVE CONSTANT REPORTS ON PROGRESS OF EACH

PHASE TO THE AUTHORITY.

49

CHAPTER#08 LONG TERM ANIMAL TOXICITY

STUDIES

LONG TERM ANIMAL TOXICITY STUDIES

Levofloxacin, when administered orally to rats at a dose of 20 mg/kg, was absorbed

primarily from the small intestine, and the maximum serum concentration (2.5 ug/ml)

50

was reached 0.5 hours after administration, except for the level, in the central nervous

system and fat, levofloxacin concentration in almost all tissues of the body were

higher than the serum level, demonstrating the good transference to tissues. Drug

concentrations in the main organs were high in the kidneys and liver and lowest in the

brain

Long term toxicity studies show following results;

Repeated dose toxicity:

Studies of one and six month’s duration by gavage have been carried out in the rat and

monkey. Doses were 50, 200, 800 mg/kg/day and 20, 80, 320 mg/kg/day for 1 and 6

months in the rat and 10, 30, 100 mg/kg/day and 10, 25, 62.5 mg/kg/day for 1 and 6

months in the monkey.

Signs of reactions to treatment were minor in the rat with slight effects principally at

200 mg/kg/day and above in reducing food consumption and slightly altering

haematological and biochemical parameters. The “No Observed Adverse Effect

Levels” (NOEL) in these studies were concluded to be 200 and 20 mg/kg/day after

one-and six months, respectively.

Toxicity after oral dosing in the monkey was minimal with reduced body weight at

100 mg/kg/day together with salivation, diarrhoea and decreased urinary pH in some

animals at this dose. No toxicity was seen in the 6-months study. The NOELs were

concluded to be 30 and 62.5 mg/kg/day after 1 and 6 months respectively.

The “ No Observed Adverse Effect Levels” (NOEL) in the six-month studies were

concluded to be 20 and 62.5 mg/kg/day in the rat and monkey respectively.

Subacute Toxicity:

Following 4-weeks oral administration to rats, no toxicological changes in clinical

signs, hematology, blood chemistry urinalysis and histopathology were observed in

the 50 mg/kg and 200 mg/kg administered groups. At a dose of 800 mg/kg, however,

increased M/E ratio of bone marrow cells, decreased neutrophil count and slight

degeneration of the articular cartilage of limb joint were observed. Following 4 weeks

oral administration to cynomolgus monkeys, no toxicological changes were observed

at doses of 10 and 30 mg/kg, but salivation, diarrhea, slight inhibition of body weight

gain and decrease in urine pH were observed at 100 mg/kg.

51

Chronic Toxicity:

Following 26 weeks oral administration to rats, no toxicological changes were

observed at a dose of 20 mg/kg, but salivation and high urinary pH were observed at

doses of 80 and 320 mg/kg. In addition, at a dose of 320 mg/kg, increased feces and

enlargement of goblet cells in cecal mucosa were seen. Following 26-weeks oral

administration to cynomolgus monkeys, no toxicological changes were observed at

doses of 10, 25 and 62.5 mg/kg

Genotoxicity:

Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did

induce chromosome aberrations in Chinese hamster lung (CHL) cells in vitro at or

above 100 μg/ml, in the absence of metabolic activation.

In-vivo tests (micronucleus, sister chromatid exchange, unscheduled DNA synthesis,

dominant lethal tests) did not show any genotoxic potential.

Reproductive studies:

Fertility study : No effects were observed on fertility in either sex or on

fetuses after oral administration to rats at upto 360 mg/kg.

Teratogenic study: No effects were observed on fetuses or neonates after oral

administration to rats upto 90 mg/kg. Moreover lethal effect to

embryos and fetuses, growth retardation in fetuses and neonates or

teratogenesis were not observed in rabbits after oral administration at 50

mg/kg.

Prenatal & postnatal study: No effects Were observed on maternal

parturition and nursing or on neonates in rats after oral administration of upto

360 mg/kg.

Antigenicity:

No specific antibody to levofloxacin was produced in mice, guinea pigs, and rabbits

concurrently treated with adjuvants. In PCA test

using serum of experimentally sensitized animals, mice showed positive reaction, but

52

guinea pigs and rabbits were negative, and systemic anaphylactic reactions were not

observed in guinea pigs.

Mutagenicity:

Chromosomal aberration test and sister chromatid exchange test using cultured

Chinese hamster cell showed positive results.

However, in vivo studies for the same items, mouse bone marrow micronucleus test

and sister chromatid exchange test results were

negative. Moreover, the reverse mutation test, induced mutation frequency test,

HGPRT test, in vivo unscheduled DNA synthesis

test, and dominant lethal test were negative.

Effect on kidneys:

Following oral administration of upto 120 mg/kg to rabbits for 10 days, no

abnormalities were observed in renal function and morphology.

Effect on eyes:

Eye toxicity tests in pigmented rats orally administered 100 mg/kg/day for 14 days

showed no changes in electroretiongram, ophthalmological examination and

histopathology.

Effect on articular cartilage:

When levofloxacin was orally administered to juvenile rats (3 to 4 weeks of age) and

beagle dogs (4 months) for 7 days, lesions were seen in the articular cartilage in rats at

300 mg/kg or more and in dogs at 10 mg/kg or more. Juvenile dogs were more

susceptible to the chondrotoxicity. When levofloxacin was orally administered to

young adult dogs (13 months of age) for 7 days, very mild toxicity was observed at 40

mg/kg. However, in adult dogs aged 18 months in which the drug was administered

for 14 days, no toxicity was observed at a high dose of 30 mg/kg.

Phototoxicity test:

53

Albino mice were orally given levofloxacin and subsequently irradiated with UVA

(wave length 320-400nm), and auricular thickness was measured. Phototoxicity

(increase in thickness) was not shown at 200 mg/kg.

54

CHAPTER#09 PRODUCT FORMULATION

55

PRODUCT FORMULATION

Levomax 500mg tablets: Each film-coated tablet of Levomax contains 500mg of levofloxacin as active

ingredient corresponding to 512.46mg of levofloxacin hemihydrate.

List of excipients: Levomax 500mg film-coated tablets contain the following excipients for a weight of

630mg respectively.

Tablet core

Crospovidone

Methylhydroxypropylcellulose

Microcristalline cellulose

Sodium stearyl fumarate

Tablet coating

Methylhydroxypropylcellulose

Titanium dioxide

Talc

Polyethylene glycol (E 171)

Yellow ferric oxide (E 172)

Red ferricoxide (E 172).

56

Machinery and Equipments:

Weighing Balance

Glen Mixer

Fitzpatrick Mill

Stainless Steel Spatula

Multiple Punching Machine

Fluidized Bed Dryer

Trolleys

57

CHAPTER#10 MANUFACTURING PROCESS

QUALITY CONTROLS

58

MANUFACTURING PROCESS

Levomax tablets of the same dosage amount are manufactured in batches. After

careful weighing, the necessary ingredients are mixed and compressed into units of

granular mixture called slugs. The slugs are than filtered to remove air and lumps, and

are compressed again into numerous individual tablets. Documentation on each batch

is kept throughout the manufacturing process and finished tablets undergo several

tests before they are bottled and packaged for distribution.

The procedure for manufacturing levomax tablets, known as dry granulation or

slugging, is as follows:

Weighing:

The active ingredient-levofloxacin, the lubricant-sodium steryl fumerate and other

excepients are weighed separately in sterile canisters to determine if the ingredients

meet pre-determined specifications for the batch size and dosage amount.

Mixing:

Sodium steryl fumerate is dispensed into cold purified water, than heated and stirred

until a translucent paste forms. The active ingredient, the microcrystalline cellulose, a

part of binder-methyl hydroxypropyl cellulose and a part of lubricant -sodium steryl

fumerate are next poured into one sterile canister, and the canister is wheeled to a

mixing machine called Glen Mixer. Mixing blends the ingredients as well as expels

air from the mixture.

Slugging:

The mixture is than mechanically separated into units, which are generally from 7/8 to

1 inches (2.22 to 2.54 cm) in size. These units are called slugs.

Dry Screening:

Next, small batches of slugs are forced through a mesh screen by a handle-held

stainless steel spatula. Large batches in sizable manufacturing outlets are filtered

59

through machine called Fitzpatrick mill. The remaining lubricant is added to the

mixture, which is blended gently in a rotary granulator and sifter. The lubricant keeps

the mixture from sticking to the tablet machine during the compression process.

Compression:

The mixture is compressed into tablets either by a single punch machine (for small

batches) or by a rotary tablet machine (for large scale production).

On single punch machines, the mixture is fed into one tablet mold (called a die cavity)

by a feed shoe. After this, the powder is compressed into tablet with the help of a

punch. This punch descends into the die compressing the mixture into a tablet.

On a rotary tablet machine, the mixture runs through a feed line into a number of die

cavities that are situated on a large steel plate. The plate revolves as the mixture is

dispensed through the feed line, rapidly filling each die cavity. Punches, both above

and below the die cavities, rotate in sequence with the rotation of the die cavities.

Rollers on top of upper punches press the punches down onto the die cavities,

compressing the mixture into tablets, while roller-activated punches beneath the die

cavities lift up and eject the tablets from the die platform.

Coating:

Film coating;

The optimization of film coating may be necessary to improve adhesion of the coating

to the core, to decrease bridging of intagliations, to increase coating hardness or to

improve any other property that the formulator deems deficient. The development

scientist has to consider three major factor which affect the film quality –tensile

strength of the film coating formulation, elasticity of the resultant film and the film

tablet surface interaction. Due to these considerations, it becomes very important to

use the most optimized coating formulation in order to get the best results. Film coating involves the deposition, usually by a spray method, of a thin film of

polymer formulation around each tablet core. It is possible to use conventional

panning equipment but usually specialized equipment is employed to take advantage

of the fast coating times and higher degree of automation possible.

The coating liquid contains a polymer in suitable liquid medium together with other

ingredient such as pigments and plastesizers. This solution is sprayed on a rotating,

60

mixed tablet bed. The drying condition results in the removal of the solvent leaving a

thin deposit of a coating material around each tablet core.

Film Coating Parameters:

Inlet Air Temperature 50°C

Exhaust Air Temperature 60°C

Air Flow 245 CMH

Spray Rate 06 g/min

Atomization Air 2.0 bar

Pan Speed 20 RPM

Pattern Air 2.0 bar

61

QUALITY CONTROL TESTS

Disintegration Test

Dissolution Test

Tablet Hardness and Friability

Tablet Weight and Weight Variation Test

Content Uniformity Test

Tablet Thickness

Disintegration Test: Disintegration test determines whether tablet disintegrate within the prescribed time

when placed in a liquid medium. Disintegration is considered to be achieved when;

No residue remain on screen

If there is a residue, it consist of a soft mass having no palpably firm,

unmoisture core sieve only fragments of coating remain on screen.

Test:

a) A riged basket rack assembly supporting six cylindrical transperant tubes 75-

80 mm long, 21.5 mm in internal diameter. Wall thickness is about 2mm.

b) A cylindrical disk for each tube, each 20.55-20.85 mm in diameter and 9.35-

9.65 mm thick, made for transparent plastic with a related density of 1.18-

1.20, weighing 2.8-3.2g pierced with 5 holes, one in the center and other four

spaced equally on the circle of radius 6 mm from the center of the disc.

c) The tubes are held vertically by two separate and superimposed rigid plastic

plates 90mm in diameter and 6 mm thick.

d) The plates are held rigidly in position and 77.5mm apart by vertical metal rod

at the periphery and metal rod is also fixed to center of upper plate to enable

the assembly to be attached to a mechanical device capable of raising and

lowering it smoothly through a distance of 50-60 mm at a constant frequency

of between 25-30 cpm.

e) The assembly is suspended in a specific liquid medium. The volume of liquid

is such that when the assembly is in highest position, the wire mesh is atleast

15mm below the surface liquid and when the assembly is in lowest position,

62

wire mesh is at least 25mm above the bottom of the beaker and the upper open

ends of the tubes remain above the surface of the liquid.

Method:

Unless otherwise stated in the individual monograph, introduce one tablet into each of

the 6 tubes and, if prescribed, add the disc to each tube. Suspend the assembly in the

beaker containing the specified liquid and operate the apparatus for the specified

time. Remove the assembly from the liquid. The tablet has passed the tst if all 6 have

disintegrated.

Disintegration Test: Apparatus:

Basket Rack Assembly

Description:

The basket rack assembly consist of six open glass tubes each 7.75±0.25cm long

having inside diameter of approximately 21.5mm and wall approximately 2mm thick.

The tubes are held in vertical position by two plastic plates, each about 9mm in

diameter and 6mm in thickness, with 6 holes each about 24mm in diameter

equidistant from the center of the plates and equally spaced from one another.

Procedure:

1. Replace the 10 mesh stainless steel cloth in the basket rake assembly with 40

mesh and also to the top of the assembly to provide for the insertion in the

dissolution medium.

2. Adjust the apparatus so that it descends to 1±0.1cm from the bottom of the

vessel on the downward stroke.

3. Use the medium as specified and proceed as directed in the individual

monograph.

Tablet Hardness and Friability: It is fairly common for a tablet press to exert as little as 3000 and as much as 4000 lb

of force in production of tablet. Generally the greater the pressure applies, the harder

the tablet is. Although the granulation also have a baring on hardness. In general

tablets should be sufficiently hard to resist breaking during normal handling and yet

soft enough to disintegrate properly after swallowing. Special dedicated hardness

63

tester or multifunctional systems are used to measure the degree of force required to

break the tablet. Multifunctional automated equipments can determine weight,

thickness, hardness and diameter of the tablet.

Tablet Weight and USP Weight Variation Test: The quantity of fill in a die of a tablet press determines the weight of the tablet. The

volume fill is adjusted with the first few tablets to yield the desired weight and

content. During production, sample tablets are periodically removed for visual

inspection and automated physical measurement.

The USP contain a test for determination of dosage form uniformity by weight

variation for uncoated tablets. In this test, 10 tablets are weighed individually and the

average weight calculated. The tablets are assayed and the contents of active

ingredient in each of the 10 tablets are calculated assuming homogeneous drug

distribution.

Content Uniformity: By the USP method, 10 dosage units are individually assayed for their content

according to the method described in the individual monograph. Unless otherwise

stated in the monograph, the requirements for content uniformity are met if the

amount of active ingredient in each dosage units lies within range of 85%-115% of

the label claim and the standard deviation is less than 6%. If one or more units don’t

meet these criteria, additional tests as prescribed in the USP are required.

Tablet Thickness: The thickness of a tablet is determined by

The diameter of the die,

The amount of fill permitted to enter the die,

The compaction characteristics of the fill material and

The force or pressure applied during compression

To produce tablets of uniform thickness during and between batch productions for the

same formulation, care must be exercised to employ the same factors ogf fill, die and

pressure. The degree of pressure affects not only thickness but also hardness of the

tablets; hardness is perhaps the more important criteria, since it can affect

64

disintegration and dissolution. Thus, for tablets of uniform thickness and hardness, it

is doubly important to control pressure. Tablet thickness can be measured by hand

gauge during production or by automated equipment

65

CHAPTER#11

PACKAGE AND LABEL DESIGN

66

PACKAGE AND LABEL DESIGN

PACKAGE DESIGN

PRIMARY PACKAGING: Tablets after manufacturing was packed into aluminum foil. Other

specifications are given below;

Packaging Material Aluminium Foil

Length 10.4cm

Width 6.5cm

No. of Tablets per Blister 10

Tablet Strength 500 mg

Batch No. 271186

Registration No. 51536

Manufacturing Date 11-12-2009

Expiry Date 11-12-2011

Manufactured by Kenstars Pharmaceuticals

Secondary Packaging:

Folding Cartons:

Provide excellent secondary protection for individually packaged multiple unit

packs. For multiple unit packs, the carton can be designed as a dispenser carton by

including a perforated area into the carton. The user exposes the product for easy

removal by their customer using the perforated section.

There are a great many styles of folding cartons available at numerous

specialized features that can be added to these designs styles. Although some simple

styles dcan be ordered as of –the- shelf items, the vast majority of folding cartons

used for medical products are custom designed to fit the product and to incorporate

the specialized features which enhance the product presentation.

67

Packaging Specifications for Unit Carton

Dimensions:

Dimensions are described based on the opening of an assembled box. The opening

can be located on the top or the side, depending on how the product will load into the

box.

Length of Carton 14.5 cm

Width of Carton 7.7 cm

Length of Front Flap 7.6 cm

Width of Front Flap 2.2 cm

Width of Folding Flap (top) 0.7cm

Width of Folding Flap (bottom) 0.7cm

Length of Folding Flap 7.6cm

Cut of Lock 1 cm

Length of Side Flap 11cm

Width of side Flap (top) 1.5 cm

Width of side Flap (bottom) 1cm

Text:

AS PER REFERENCE

68

69

70

LLAABBEELL DDEESSIIGGNN

LLeevvoommaaxx ((LLeevvooffllooxxaacciinn)) 550000mmgg TTaabblleett DDEESSCCRRIIPPTTIIOONN:: LLeevvoommaaxx ((lleevvooffllooxxaacciinn)) iiss aa ssyynntthheettiicc bbrrooaadd ssppeeccttrruumm aannttii--bbaacctteerriiaall aaggeenntt.. CChheemmiiccaallllyy,, lleevvooffllooxxaacciinn,, aa cchhiirraall fflluuoorriinnaatteedd ccaarrbbooxxyyqquuiinnoolloonnee,, iiss tthhee ppuurree (( --))--((SS))--eennaanncciioommeerr ooff tthhee rraaccmmiicc ddrruugg ssuubbssttaannccee ooffllooxxaacciinn.. Qualitative and quantitative composition: LLeevvoommaaxx((lleevvooffllooxxaacciinn)) iiss aavvaaiillaabbllee ffoorr oorraall aaddmmiinniissttrraattiioonn iinn ffiillmm ccooaatteedd ttaabblleettss aass:: LLeevvooffllooxxaacciinn……………………………………………………..550000mmgg CCLLIINNIICCAALL PPHHAARRMMAACCOOLLOOGGYY:: MaMMaaccchhhaaannniiisssmmm OOOfff AAAccctttiiiooonnn::: IItt iinnvvoollvveess tthhee iinnhhiibbiittiioonn ooff DDNNAA GGyyrraassee,, wwhhiicchh iiss eesssseennttiiaall iinn tthhee rreepprroodduuccttiioonn ooff bbaacctteerriiaall DDNNAA.. IItt iiss oofftteenn bbaacctteerriicciiddaall aatt ccoonncceennttrraattiioonn eeqquuaall ttoo oorr sslliigghhttllyy ggrreeaatteerr tthhaann iinnhhiibbiittoorryy ccoonncceennttrraattiioonn.. PPPhhhaaarrrmmmaaacccoookkkiiinnneeetttiiicccsss::: Absorption: IItt iiss rraappiiddllyy aanndd eesssseennttiiaallllyy ccoommpplleetteellyy aabbssoorrbbeedd aafftteerr oorraall aaddmmiinniissttrraaiioonn.. PPeeaakk ppllaassmmaa ccoonncceennttrraattiioonn iiss aattttaaiinneedd 11--22 hhoouurrss aafftteerr oorraall ddoossiinngg.. Distribution: MMeeaann vvoolluummee ooff ddiissttrriibbuuttiioonn rraannggeess ffrroomm 7744--111122 lliittrreess aafftteerr ssiinnggllee aanndd mmuullttiippllee ddoossiinngg.. Metabolism and Elimination: IItt uunnddeerrggoo lliimmiitteedd mmeettaabboolliissmm iinn bbooddyy aanndd mmaaiinnllyy eelliimmiinnaatteedd ffrroomm bbooddyy iinn uunncchhaannggeedd ddrruugg iinn uurriinnee.. TTHHEERRAAPPUUTTIICC IINNDDIICCAATTIIOONN:: LeLevvoommaaxx ((lleevvooffllooxxaacciinn)) taabblleettss aarree iinnddiiccaatteedd ffoorr tthhee ttrreeaattmmeenntt ooff ccoommmmuunniittyy aaccqquuiirreedd tPPnneeuummoonniiaa aanndd nnoossooccoommiiaall PPnneeuummoonniiaa.. DDOOSSAAGGEE A ANNDD A ADDMMIINNIISSTTRRAATTIIOONN:: LeLevvoommaaxx ((lleevvooffllooxxaacciinn)) 550000mmgg ttaabblleettss aarree aaddmmiinniisstteerreedd oonnccee ddaaiillyy.. TThhee dduurraattiioonn ooff ttrreeaattmmeenntt ddeeppeennddss oonn tthhee ttyyppee aanndd sseevveerriittyy ooff tthhee iinnffeeccttiioonn aanndd tthhee sseennssiittiivviittyy ooff tthhee ppaatthhooggeenn.. IInn ccaassee ooff ccoommmmuunniittyy aaccqquuiirreedd PPnneeuummoonniiaa aanndd nnoossooccoommiiaall PPnneeuummoonniiaa,, lleevvoommaaxx ttaabblelett iiss adadmmiinniisstteerreedd oonnccee ddaaiillyy ffoorr 0077--1144 ddaayyss.. AADDVVEERRSSEE RREEAACCTTIIOONNSS:: AAlllleerrggiicc rreeaaccttiioonn mmaayy iinncclluuddee:: RRaasshh,, SSwwaalllloowwiinngg,, BBrreeaatthhiinngg PPrroobblleemmss,, SSwweelllliinngg ooff

71

YYoouurr LLiippss,, FFaaccee,, TThhrrooaatt,, oorr TToonngguuee;; FFeeeelliinngg SSiicckk ((nnaauusseeaa)) aanndd DDiiaarrrrhheeaa;; SSkkiinn rraasshh aanndd IIttcchhiinngg;; DDrroowwsseenneessss;; SSlleeeeppiinngg PPrroobblleemmss;; PPaarreesstthheessiiaa;; AArrtthhrraallggiiaa;; NNaauusseeaa aanndd DDiiaarrrrhheeaa.. CCOONNTTRRAAIINNDDIICCAATTIIOONNSS:: LLeevvoommaaxx iiss ccoonnttrraaiinnddiiccaatteedd iinn cchhiillddrreenn,, aaddoolleesscceennttss aanndd iinn ppaattiieennttss wwiitthh aa hhiissttoorryy ooff hhyyppeerrsseennssiittiivviittyy ttoo tthhiiss ddrruugg..

PPRREEGGNNEENNCCYY:: TThheerree aarree nnoo aaddeeqquuaattee aanndd wweellll--ccoonnttrroolllleedd ssttuuddiieess iinn pprreeggnnaanntt wwoommeenn.. NNUURRSSIINNGG MMOOTTHHEERRSS:: NNoo aaddeeqquuaattee aanndd wweellll--ccoonnttrroolllleedd ssttuuddiieess.. PPRREECCAAUUTTIIOONNSS:: TTaabblleett sshhoouulldd bbee sswwaalllloowweedd wwiitthhoouutt ccrruusshhiinngg.. IItt sshhoouulldd bbee ttaakkeenn ttaakkeenn wwiitthh ssuuffffiicciieenntt aammoouunntt ooff wwaatteerr.. IItt mmaayy bbee ttaakkeenn dduurriinngg mmeeaall aanndd bbeettwweeeenn mmeeaallss.. IItt sshhoouulldd nnoott bbee aaddmmiinniisstteerreedd wwiitthh aannttaacciiddss.. SShhoouulldd bbee ttaakkeenn ttwwoo hhoouurrss bbeeffoorree oorr aafftteerr aannttaacciiddss.. IItt sshhoouulldd bbee ddiissccoonnttiinnuuee iiff tthhee ppaattiieenntt eexxppeerriieenncceess ppaaiinn,, iinnffllaammmmaattiioonn oorr rruuppttuurree ooff aa tteennddoonn dduurriinngg tthheerraappyy.. SSTTOORRAAGGEE:: SSttoorree bbeellooww 3300ººCC.. PPrrootteecctt ffrroomm ssuunnlliigghhtt aanndd mmooiissttuurree.. KKeeeepp oouutt ooff tthhee rreeaacchh ooff cchhiillddrreenn.. PPLLEEAASSEE RREEAADD TTHHEE CCOONNTTEENNTTSS CCAARREEFFUULLLLYY BBEEFFOORREE UUSSEE.. MMAANNUUFFAACCTTUURREEDD BBYY::

KKeennssttaarrss PPhhaarrmmaacceeuuttiiccaallss IInndduussttrriiaall aarreeaa,, FFssdd..

LOGO:

NEW DRUG APPLICATION (NDA)

CHAPTER#12

72

The Secretory,

on Board,

ubject: Application for Registration of a Drug for Local Manufacturer

ear Sir,

e, Kenstars Pharmaceuticals (Pvt) Ltd., Lahore, hereby apply for registration of

enclosed.

hanking You.

ours Truly,

aceuticals (Pvt) Ltd., Lahore,

irector

Drug Registrati

Government of Pakistan,

Islamabad.

S

D

W

drug namely LEVOMAX, details of which are enclosed.

Treasury Challan of Rs. 8000/- being fee of registration is

T

Y

Kenstar Pharm

D

73

UNDERTAKING

We, Kenstars Pharmaceutical do hereby declare that the

abel/Carton/Color Scheme and printed Matter of LEVOMAX is not a

Director

armaceuticals (Pvt) Ltd., Lahore,

s (Pvt) Ltd., Lahore,

L

copy/counterfeit of any other registered drug in Pakistan. We also declare that the

name of LEVOMAX bears no resemblance to any other registered drug in Pakistan.

Kenstar Ph

74

FORM 5-D [See rule 26 (1)]

APPLICATION FORM FOR REGISTRATION OF A DOSAGE FORM

CONTAINING A NEW DRUG MOLECULE OR A NEW COMBINATION /

DOSAGE FORM, FOR LOCAL MANUFACTURE.

I / We Kenstars Pharmaceuticals (Pvt) Ltd., Lahore hereby apply for registration

of the drug, namely Levomax Tablet containing a new drug molecule for a local

manufacturer.

Details of which are enclosed.

Date: 27.11.2009 Signed:

Place: Lahore

ENCLOSURES OF THE APPLICATION FOR REGISTRATION OF A NEW

DRUG OR A NEW COMBINATION / DOSAGE FORM

Dosage Form:Tablet

1. Name and address of the manufacturer: Kenstar Pharmaceuticals (Pvt) Ltd., Lahore,

2. Brand (Proprietary) name of the drug: Levomax

3. The chemical name(s) and, as appropriate and available, the

established (generic) and synonyms of the drug: Levofloxacin

4. Strength of active ingredient(s) per unit, e.g. each tablet or

5 ml, etc. contains:

75

Each film-coated tablet of Levomax contains 500mg of levofloxacin as active

ingredient corresponding to 512.46mg of levofloxacin hemihydrate.

5. Pharmacological group: Flouroquinolone Antibiotic

6. Proposed route of administration: Oral

7. Composition (actives & excepients) including statement of

the quantitative composition, giving the weight or measure

for each active substance used in the manufacture of the

dosage form.

Formulation:

As given on page#56 of chapter-09

Manufacturing:

As given on page#58 of chapter-10

8. Recommended clinical use. For the treatment of Pneumonia in adult patients.

9. Full description of the specifications and analytical

methods necessary to assure the identity, strength, quality,

purity and homogeneity through out the shelf life of the

drug product. RAW MATERIAL SPECIFICATIONS

Quality Control Laboratory

General Profile

Name Levofloxacin

Category Flouroquinolone Antibiotic

Formula C18H20FN3O4�½H2O

Molecular Weight 370.38

76

Characteristics/Parameters Description/Limits

Physical state Light yellowish-white to yellow-white crystal or crystalline powder, Insoluble in water

Identification Positive

Acidity and Alkalinity Complies to B.P

Halogenated Compounds Complies to B.P

Heavy Metals 20ppm

Storage Stable under ordinary conditions, Store in air tight contained, Protect from light

FINISHED GOODS SPECIFICATIONS

Quality Control Laboratory

Brand Name Levomax

Generic Name Levofloxacin

Dasage Form Tablet

Shelf Life 2 years

Characteristics/Parameters Description/Limits

Physical inspection Light yellowish-white to yellow-white in colour

Identification Positive for levofloxacin

Strength 500 mg

10. Labeling and prescribing information (to be mentioned

on the pack/leaflet) specimen or draft shall be submitted. LEAFLET

Levomax® 500 mg tablets

Levofloxacin

Read all of this leaflet carefully before you start taking this medicine.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or your pharmacist.

This medicine has been prescribed for you.

77

Do not pass it on to others. It may harmthem, even if their symptoms are the

same as yours.

If any of the side effects gets serious, or if you notice any side effects not

listed in this leaflet, please tell your doctor or pharmacist.

What Tavanic tablets are and what they are used for:

The name of your medicine is Levomax tablets. Levomax tablets contain a medicine

called levofloxacin. This belongs to a group of medicines called antibiotics.

Levofloxacin is a ‘quinolone’ antibiotic. It works by killing the bacteria that cause

infections in your body.

Tavanic tablets can be used to treat infections of the:

Sinuses

Lungs, in people with long-term breathing problems or pneumonia

Urinary tract, including your kidneys or bladder

Prostate gland, where you have a long lasting infection

Skin and underneath the skin, including muscles. This is sometimes called

‘soft tissue’

Before you take Levomax tablets

Do not take this medicine and tell yourdoctor if:

You are allergic to levofloxacin, any other quinolone antibiotic such as

moxifloxacin, ciprofloxacin or ofloxacin or any of the other ingredients of

Levomax tablets (listed in Section 6 below) Signs of an allergic reaction

include: a rash, swallowing or breathing problems, swelling of your lips, face,

throat or tongue

You have ever had epilepsy

You have ever had a problem with your tendons such as tendonitis that was

related to treatment with a ‘quinolone antibiotic'. A tendon is the cord that

joins your muscle to your skeleton

You are a child or a growing teenager

You are pregnant, might become pregnant or think you may be pregnant

You are breast-feeding

Do not take this medicine if any of the above apply to you. If you are not sure,

talk to your doctor or pharmacist before taking Levomax tablets.

78

Take special care with Levomax tablets. Check with your doctor or

pharmacistbefore taking your medicine if:

You are 65 years of age or older

You are using corticosteroids, sometimes called steroids (see “Taking other

medicines” below)

You have ever had a fit (seizure)

You have had damage to your brain due to a stroke or other brain injury

You have kidney problems

You have something known as ‘glucose – 6 – phosphate dehydrogenase

deficiency’. You are more likely to have serious problems with your blood

when taking this medicine

You have ever had mental health problems

You have ever had heart problems

You are diabetic

You have ever had liver problems

If you are not sure if any of the above applies to you, talk to your doctor or

pharmacist before taking Levomax tablets.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any

other medicines.

This includes medicines you buy without a prescription, including herbal medicines.

This is because Levomax tablets can affect the way some other medicines work. Also

some medicines can affect the way Levomax tablets work.

In particular, tell your doctor if you are taking any of the following medicines.

This is because it can increase the chance of you getting side effects, when taken

with Levomax tablets:

Corticosteroids, sometimes called steroids – used for inflammation. You may

be more likely to have inflammation and/or breakage of your tendons.

Warfarin - used to thin the blood. You may be more likely to have a bleed.

Your doctor may need to take regular blood tests to check how well your

blood clot.

Theophylline - used for breathing problems. You are more likely to have afit

(seizure) if taken with Levomax tablets

79

Non-steroidal anti-inflammatory drugs (NSAIDS) - used for pain and

inflammation such as aspirin, ibuprofen, fenbufen, ketoprofen and

indomethacin. You are more likely to have a fit (seizure) if taken with

Levomax tablets

Ciclosporin - used after organ transplants. You may be more likely to get the

side effects of Ciclosporin

Medicines known to affect the way your heart beats. This includes medicines

used for abnormal heart rhythm (antiarrhythmics such as quinidine and

amiodarone), for depression (tricyclic antidepressants such as amitriptylineand

imipramine) and for bacterial infections (‘macrolide’ antibiotics such as

erythromucin, azithromycin and Clarithromycin).

Probenecid - used for gout, and cimetidine - used for ulcers and heartburn.

Special care should be taken when taking either of these medicines with

Levomax. If you have kidney problems, your doctor may want to give you a

lower dose.

Do not take Levomax tablets at the same time as the following medicines. This is

because it can affect the way Levomax tablets work:

Iron tablets (for anemia), magnesium or aluminum-containing antacids (for acid or

heartburn) or sulcralfate (for stomach ulcers).

Urine tests for opiates

Urine tests may show ‘false-positive’ results for strong painkillers called ‘opiates’ in

people taking Levomax tablets. If your doctor is due to take a urine test, tell them you

are taking Levomax tablets.

Pregnancy and breast-feeding

Do not take this medicine if:

You are pregnant, might become pregnant or think you may be pregnant

You are breast-feeding or planning to breast-feed Ask your doctor or

pharmacist for advice before taking any medicine if you are pregnant or

breast-feeding.

Driving and using machines

You may get side effects after taking this medicine, including feeling dizzy, sleepy, a

spinning feeling (vertigo) or changes to your eyesight. Some of these side effects can

affect you being able to concentrate and your reaction speed. If this happens, do not

drive or carry out any work that requires a high level of attention

80

How to take Levomax tablets

Always take Levomax tablets exactly as your doctor has told you. You should check

with your doctor or pharmacist if you are not sure.

Taking this medicine

Take this medicine by mouth

Swallow the tablets whole with a drink of water

The tablets may be taken during meals or at any time between meals

Protect your skin from sunlight

Keep out of direct sunlight while taking this medicine. This is because your skin will

become much more sensitive to the sun and may burn, tingle or severely blister if you

do not take the following precautions:

Make sure you use high factor sun cream

Always wear a hat and clothes which cover your arms and legs

Avoid sun beds

If you are already taking iron tablets, antacids or sulcralfate

Do not take these medicines at the same time as Levomax. Take your dose at

least 2 hours before or after Levomax tablets

How much to take

Your doctor will decide on how many

Levomax tablets you should take

The dose will depend on the type of infection you have and where the

infection is in your body

The length of your treatment will depend on how serious your infection is

If you feel the effect of your medicine is too weak or strong, do not change the

dose yourself, but ask your doctor

Adults and the elderly

Sinuses

One tablet of Levomax 500 mg, once each day

Lungs, in people with long-term breathing problems

1/2 tablet or one tablet of Levomax 500 mg, once each day

Pneumonia

One tablet of Levomax 500 mg, once or twice each day

Urinary tract, including your kidneys or bladder

81

1/2 tablet of Levomax 500 mg, each day

Prostate gland

One tablet of Levomax 500 mg, once each day

Skin and underneath the skin, including muscles

½ tablet or one tablet of Levomax 500 mg, once or twice each day

Adults with kidney problems

Your doctor may need to give you a lower dose.

Children and Teenagers

This medicine must not be given to children or teenagers.

If you take more Levomax tablets than you should

If you accidentally take more tablets thanyou should, tell a doctor or get other medical

advice straight away. Take the medicine pack with you.

This is so the doctor knows what you have taken. The following effects may happen:

convulsive fits (seizures), feeling confused, dizzy, less conscious and heart problems -

leading to uneven heart beats as well as feeling sick (nausea).

If you forget to take Levomax tablets

If you forgot to take a dose, take it as soon as you remember unless it is nearly time

for your next dose. Do not double-up the next dose to make up for the missed dose.

If you stop taking Levomax tablets

Do not stop taking Levomax tablets just because you feel better. It is important that

you complete the course of tablets that your doctor has prescribed for you. If you stop

taking the tablets too soon, the infection may return, your condition may get worse or

the bacteria may become resistant to the medicine.

If you have any further questions on the use of this medicine, ask your doctor or

pharmacist.

Possible side effects

Like all medicines, Levomax can cause side effects, although not everybody gets

them. These effects are normally mild or moderate and often disappear after a short

time.

Stop taking Levomax tablets and see a doctor or go to a hospital straight away if

you notice the following side effect:

Very rare (affects less than 1 person in 10,000)

You have an allergic reaction. The signs may include: a rash, swallowing or

breathing problems, swelling of your lips, face, throat, or tongue

82

Stop taking Levomax tablets and see a doctor straight away if you notice any of

the following serious side effects – you may need urgent medical treatment:

Rare (affects less than 1 person in 1000)

Watery diarrhoea which may have blood in it, possibly with stomach cramps

and a high temperature. These could be signs of a severe bowel problem

Pain and inflammation in your tendons.

The Achilles tendon is affected most often and in some cases, the tendon could

break

Fits (convulsions)

Very rare (affects less than 1 person in 10,000)

Burning, tingling, pain or numbness. These may be signs of something called

‘neuropathy’

Other :

Severe skin rashes which may include blistering or peeling of the skin around

your lips, eyes, mouth, nose and genital• Loss of appetite, skin and eyes

becoming yellow in colour, dark-coloured urine, itching, or tender stomach

(abdomen).

These may be signs of liver problems

Tell your doctor if any of the following side effects gets serious or lasts longer

than a few days:

Common (affects less than 1 person in 10)

Feeling sick (nausea) and diarrhoea

Increase in the level of some liver enzymes in your blood

Uncommon (affects less than 1 person in 100)

Itching and skin rash

Loss of appetite, stomach upset or in digestion (dyspepsia), being sick

(vomiting) or pain in your stomach area, feeling bloated (flatulence) or

constipation

Headache, feeling dizzy, a spinning feeling (vertigo), feeling sleepy, sleeping

problems or feeling nervous

Blood tests may show unusual results due to liver or kidney problems

Changes in the number of white blood cells shown up in the results of some

blood tests

83

General weakness

Changes in the number of other bacteria or fungi may increase, which may

need to be treated

Rare (affects less than 1 person in 1,000)

Tingly feeling in your hands and feet (paraesthesia) or trembling

Feeling stressed (anxiety), depressed, mental problems, feeling restless

(agitation) or feeling confused

Unusual fast beating of your heart or low blood pressure

Joint pain or muscle pain

Bruising and bleeding easily due to a lowering in the number of blood

platelets

Low number of white blood cells (called neutropenia)

Difficulty breathing or wheezing (bronchospasm)

Shortness of breath (dyspnoea)

Severe itching or hives (called urticaria)

Very rare (affects less than 1 person in 10,000)

Increased sensitivity of your skin to sun and ultraviolet light

Lowering of your blood sugar levels (hypoglycaemia). This is important for

people that have diabetes

Problems with your hearing or eyesight or changes in the way things taste and

smell

Seeing or hearing things that are not there (hallucinations), change in your

opinion and thoughts (psychotic reactions) with a chance of having suicidal

thoughts or actions

Loss of circulation (anaphylactic like shock)

Muscle weakness. This is important in people with myasthenia gravis (a rare

disease of the nervous system)

Inflammation of the liver, changes in the way your kidney works and

occasional kidney failure which may be due to an allergic kidney reaction

called interstitial nephritis

Fever, sore throat and a general feeling of being unwell that does not go away.

This may be due to a lowering in the number of white blood cells

Fever and allergic lung reactions

84

Other side effects include:

Lowering in red blood cells (anemia). This can make the skin pale or yellow

due to damage of the red blood cells and lowering in the number of all types of

blood cells

Exaggerated immune response (hypersensitivity)

Sweating too much (hyperhidrosis)

Pain, including pain in the back, chest and extremities

Problems moving and walking

Attacks of porphyria in people who already have porphyria (a very rare

metabolic disease)

Inflammation of your tubes that carry blood around your body (vessels) due to

an allergic reaction

If any of the side effects gets serious, or if you notice any side effects not listed in

this leaflet, please tell your doctor or pharmacist.

How to store Levomax tablets

Keep out of the reach and sight of children.

This medicine does not require any special storage conditions but it is best to

keep Levomax tablets in the original strips and box in a dry place.

Do not use Levomax tablets after the expiry date (EXP) which is stated on the

carton and foil.

Medicines should not be disposed of via wastewater or household waste. Ask

your pharmacist how to dispose of medicines no longer required. These

measures will help to protect the environment

Further information

What Levomax tablets contain

The active ingredient is levofloxacin. Each tablet of Levomax 500 mg tablets contains

500 mg of levofloxacin.

The other ingredients are:

For the tablet core: crospovidone, hypromellose, microcrystalline cellulose

and sodium stearyl fumarate

For the tablet coating: hypromellose, titanium dioxide, talc, macrogol, yellow

ferric oxide and red ferric oxide

85

What Levomax tablets look like and contents of the pack

Levomax tablets are film-coated tablets for oral use.

For Levomax 500 mg, the tablets are provided in pack sizes of 10 tablets.

This leaflet does not contain all the information about your medicine. If you have

any questions or are not sure about anything, ask your doctor or pharmacist.

11. Proposed dosage: Oral route

500mg OD for pneumonia

12. Proposed shelf life of the drug: 01 years

13. Unit price of the drug, e.g. per tablet, per capsule, per

5ml, etc. Price of 500 mg tablet= 19 Rs

14. Proposed storage conditions of finished product. Store in dry cool place

Protect from sun, light and heat

Store away from children

15. Persons under whose direct supervision and control

the drug applied for registration shall be manufactured with

the following details, namely:-

a. Total number of technical staff

08 personnals

b. Name, qualification and designation of the persons

directly supervising the manufacture of the drug applied

for registration, and any change shall be properly

documented and record maintained by the manufacturer.

86

Zohaib Ahmad

17- Name of equipments that will be used in the

manufacture of the applied drug: LIST OF EQUIPMENTS

Oral Tablet Manufacturing Section

Sr. No. Name of Machinery and Equipments Quantity

1 Weighing Balance 1

2 Glen Mixer 1

3 Fitzpatrick Mill 1

4 Stainless Steel Spatula 1

5 Multiple Punching Machine 4

6 Fluidized Bed Dryer 4

7 Trolleys 2

Oral Tablet Packaging Section

Sr. No. Name of Machinery and Equipments Quantity

1 Turn Table (after air blowing) 1

2 Air Blower 1

3 Conveyer (before filling and after filling) 1

4 Turn Table (after filling and sealing) 1

5 Labeling Machine 1

6 Conveyer (packing) 1

Over Printing Section

Sr. No. Name of Machinery and Equipments Quantity

1 Printing Machine (Local) 1

2 Printing Machine (Manual) 2

3 Printing Machine (Automatic) K 420 1

4 Printing Machine (Automatic) K 550 2

87

18- Name, qualification and designation of the persons

who will be responsible for the quality control of the

drug. Following will be responsible for the completion of various steps,

under their supervision.

a) Q.A Incharge

Zohaib Ahmad (Senior Q.A officer)

b) Q.C Incharge

Jalwaz Tihami (Senior Q.C officer)

c) Person for physical testing

Rizwan Rashid (Analyst)

d) Person for chemical testing

Azeem Imam (Analyst)

e) Person for microbiological and pharmacological testing

Ali Tariq (Microbiologist)

19-Description of the equipment to be used for the

quality control of the active raw material and the

finished products.

Sr. No. Name of Equipments

01. H.P.L.C (Spectra physics U.S.A)

02. Infrared Spectrophotometer(FTIR)

03. Melting Point Apparatus (Gallenkamp U.K)

04. Moisture Analyzer (Mitsubishi Japan)

05. Precision Balance (Sartorioue)

06. Drying Oven (Mamart)

07. Fludized Bed Dryer (China)

08. pH Meter (Micro processor)

88

09. Glass Apparatus

10. Autoclave

11. Incubator

12. Sterile Filtration System

13. U-2800 Double Beam Spectrophotometer (Hitachi

Japan)

14. Moisture Balance MB-45 (Ohaus U.S.A)

15. Automatic Titrator GT-100 (Mitsubishi Japan)

16. Conductivity / TDS Meter (Jenway 4510 England)

20- Facility of the water processing with specifications. We donnot use water in our preparation because it is insoluble in water.

21-Environment control processing with details. Floor Polishing:

After washing allow the floor to air dry.

Apply the polish/cream properly on floor with clean cloth.

Use the polishing machine to polish the floor.

Floor Moping:

Squeezed the clean mop and moist it with potable water.

Use this moist mop accordingly to clean the floor.

If required use the detergent to remove the spots on the floor for

proper cleaning.

Clean the mod after use with potable water.

Insecticide Spray:

Acoording to the sop for pest control and disinfection.

Drainage and Sewerage:

Clean the inside and outsidethe plant drainage and sewerage

points by using germicidal agents.

89

Following points of outer sewerage are cleaned.

• In the washing area of tablet section.

• Outside the raw material in corridor.

• Inside syrup manufacturing area.

• Inside base preparation room.

22-Attach the last Inspection Report conducted by the

Ministry of Health. N/A

23-Clinical data (along with data of clinical trials

conducted and safety data of the drug, with reported

side effects and adverse drug reactions in the

indigenous community). As given in Chapter-07

24. Clinical justification. Clinically it is a better option because it is more efficacious and less

hazards.

25. Dosage form stability profile: Levofloxacin is film-coated and packed in aluminium foil to protect it

from heat light and moisture.

26-Any other relevant information that may be required

by the Board. N/A

90

UNDERTAKING

I / We hereby undertake that the above given information is true and correct to the

best of my / our knowledge and belief.

Zohaib Ahmad Jalwaz Tihami

Production Manager Quality Control Manager.

91

CHAPTER#13

POST MARKETING SURVEILLANCE

92

POST MARKETING SURVEILLANCE

Phase 4 clinical trials:

The data from phase 3 clinical trials may lead to a conditional approval of the drug

and require further monitoring of drug in phase 4 clinical trials.

No. of Patients:

These trials are undertaken in larger population, may exceeding 10,000 patients.

Phase 4 trials should be constructed to demonstrate;

Drug efficacy in prolonged use where perhaps the natural course of disease

may be modified over a period of several months or year

Adverse reactions which may only occur with long term use

Detailed examination of non-responders

Assessment of overdose and misuse or abuse liability

New dosage forms

New indications

Drug interactions

INTERACTIONS WITH OTHER MEDICAMENTS AND OTHER FORMS OF

INTERACTION

Levofloxacin interact with many other drugs through different machanisims such as

Inhibition or activation of cytochrome P450 enzymes

Complexation with other drugs

Alteration of gartric pH and

Compitition for renal tubular secretion

Following interactions have been reported during post marketing surveillance;

Iron salts, Magnesium-or Aluminum-containing Antacids:

Levofloxacin absorption is significantly reduced when iron salts, or magnesium-or

aluminum-containing antacids are administered concomitantly with Levomax tablets.

It is recommended that preparations containing divalent cations such as iron salts, or

magnesium-or aluminum-containing antacids should not be taken 2 hours before or

93

after Levomax tablet administration. No interaction was found with calcium

carbonate.

Sucralfate:

The bioavailability of Levomax tabltes is significantly reduced when administered

together with sucralfate. If the patient is to receive both sucralfate and Levomax, it is

best to administer sucralfate 2 hours after the Levomax tablet administration.

Theophylline, Fenbufen or Similar Non-Steroidal Anti-Inflammatory Drugs:

No pharmacokinetic interactions of levofloxacin were found with theophylline in a

clinical study. However a pronounced lowering of the cerebral seizure threshold may

occur when quinolones are given concurrently with theophylline, nonsteroidal anti-

inflammatory drugs, or other agents that lower the seizure threshold.

Levofloxacin concentrations were about 13% higher in the presence of fenbufen than

when administered alone.

Probenecid and Cimetidine:

Probenecid and cimetidine had a statistically significant effect on the elimination of

levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%)

and probenecid (34%). This is because both drugs are capable of blocking the renal

tubular secretion of levofloxacin. However, at the tested doses in the study, the

statistically significant kinetic differences are unlikely to be of clinical relevance.

Caution should be exercised when levofloxacin is coadministered with drugs that

affect the tubular renal secretion such as probenecid and cimetidine, especially in

renally impaired patients.

Cyclosporin:

The half life of cyclosporin was increased by 33% when coadministered with

levofloxacin.

Vitamin K antagonist:

Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have

been reported in patients treated with levofloxacin in combination with a vitamin K

94

antagonist (e.g. warfarin). Coagulation tests, therefore, should be monitored in

patients treated with vitamin K antagonists.

Meals:

There is no clinically relevant interaction with food. Levomax tablets may therefore

be administered regardless of food intake.

Other relevant information:

Clinical pharmacology studies were carried out to investigate possible

pharmacokinetic interactions between levofloxacin and some commonly prescribed

drugs. The pharmacokinetics of levofloxacin were not affected to any clinically

relevant extent when levofloxacin was administered together with the following

drugs: calcium carbonate, digoxin, glibenclamide, ranitidine, warfarin.

PATIENT MONITORING

Following parameters should be monitored during therapy;

Obtain patient history, including drug history and any known allergies.

Obtain baseline CBC, renal, and liver function tests, and electrolytes.

Obtain baseline vital signs. Monitor vital signs at least bid while administering

medication.

Assess for any skin rashes. Notify physician if skin rash occurs.

Monitor for signs of anaphylaxis (eg, pharyngeal or facial edema, dyspnea,

urticaria, itching).

Monitor patterns of elimination and stool consistency.

Monitor for signs of superinfection.

Encourage fluid intake.

Frequently assess patency of IV site and observe for signs of phlebitis during

therapy.

Notify physician if vomiting, fatigue, lymphocytopenia, increased liver

function test results, seizures, or vital disturbances occur.

Notify physician if symptoms of pseudomembranous colitis occur (eg, loose

or foul-smelling stools) or if symptoms of CNS stimulation occur (eg, tremor,

restlessness, confusion).

95

SIDE-EFFECTS/UNDESIRABLE EFFECTS

The information given below is based on data from clinical studies in more than 5000

patients and on extensive post marketing experience. The following frequency rating

has been used:

Very common - more than 10%

Common - 1 to 10%

Uncommon - 0.1 to 1%

Rare - 0.01 to 0.1%

Very rare - less than 0.01%

Isolated cases

Allergic Reactions:

Uncommon: pruritus, rash,

Rare: urticaria, bronchospasm/dyspnoea,

Very rare: angio-oedema, hypotension, anaphylactic-like shock;

photosensitisation

Isolated cases: severe bullous eruptions such as Stevens Johnson syndrome,

toxic epidermal necrolysis (Lyell’s syndrome) and erythema exsudativum

multiforme. Muco-cutaneous, anaphylactic/-oid reactions may sometimes

occur even after the first dose.

Gastro-Intestinal, Metabolism:

Common: nausea, diarrhoea,

Uncommon: anorexia, vomiting, abdominal pain, dyspepsia,

Rare: bloody diarrhoea which in very rare cases may be indicative of

enterocolitis, including pseudomembranous colitis,

Very rare: hypoglycaemia,particularly in diabetic patients.

Neurological:

Uncommon: headache,dizziness/vertigo, drowsiness, insomnia,

Rare: depression, psychotic reactions (with e.g. hallucinations), paraesthesia,

tremor, anxiety, agitation, confusion, convulsions,

96

Very rare: hypoaesthesia, visual and auditory disturbances, disturbances of

taste and smell,

Isolated cases: Psychotic reactions with self endangering behaviour including

suicidal ideation or acts.

Cardiovascular:

Rare: tachycardia, hypotension

Very rare: shock (anaphylactic)

Isolated cases: QT-interval prolongation

Musculo-Skeletal:

Rare: arthralgia, myalgia, tendon disorders including tendinitis (e.g. Achilles

tendon),

Very rare: tendon rupture (e.g. Achilles tendon), as with other

fluoroquinolones this undesirable effect may occur within 48 hours of starting

treatment and may be bilateral ; Muscular weakness, which may be of special

importance in patients with myasthenia gravis,

Isolated cases: rhabdomyolysis.

Liver, Kidney:

Common: increased liver enzyme levels (e.g. ALT, AST),

Uncommon: increase in bilirubin, increase in serum creatinine,

Very rare: liver reactions such as hepatitis ; acute kidney failure (e.g. due to

interstitial nephritis)

Blood

Uncommon: eosinophilia, leukopenia,

Rare: neutropenia, thrombocytopenia,

Very rare: agranulocytosis,

Isolated cases: haemolytic anaemia, pancytopenia

Others

Uncommon: asthenia, fungal overgrowth and proliferation of other resistant

microorganisms,

97

Very rare: allergic pneumonitis, fever.

Psychotic reactions such as acute confusional states and depressive mood

changes (these reactions may occur even after the first dose),

Extrapyramidal symptoms and other disorders of muscular coordination,

hypersensitivity vasculitis,

Attacks of porphyria in patients with porphyria

PRECAUTIONS

Pregnancy:

Reproductive studies in animals did not raise specific concerns. However in

the absence of human data and due to the experimental risk of damage by

fluoroquinolones to the weight-bearing cartilage of the growing organism, Levomax

tablets must not be used in pregnant women.

Lactation:

In the absence of human data and due to the experimental risk of damage by

fluoroquinolones to the weight-bearing cartilage of the growing organism, Levomax

tablets must not be used in breast-feeding women.

Effects on ability to drive and use machines:

Some undesirable effects (e.g. dizziness/vertigo, drowsiness, visual disturbances) may

impair the patient’s ability to concentrate and react, and therefore may constitute a

risk in situations where these abilities are of special importance (e.g. driving a car or

operating machinery).

CONTRAINDICATIONS

Hypersensitivity to Fluoroquinolones, Quinolone antibiotics, or any product

component; tendonitis or tendon rupture associated with Quinolone use.

CLINICAL PHARMACOLOGY/ TOXICOLOGY

Not Reported

PRODUCT DEFECT REPORTING

Not Reported

98

CHAPTER#14

PRODUCT LINE EXTENTION

99

PRODUCT LINE EXTENTION

Levomax Infusion:

Levomax infusion will available in 100ml unit dose colorless glass bottle.

Each ml contains 5 mg of levofloxacin.

100

RREEFFEERREENNCCEESS

Pharmaceutical Manufacturing Encyclopedia; 3rd Edition; Wlliam Andrew

Publishing ; Norwich, NY, USA

Handbook of Pharmaceutical Manufacturing Formulations; Compressed Solid

Products;

Volker Buhler; Generic Drug Formulations; 2nd edition

Pharmaceutical Preformulations and Formuation; A practical guide for

candidate drug selection to commercail dosage form: Editor: Mark Gibson;

IHS, Health Group

Handbook of Pharmaceutical Excipients, 5th Edition; Editors: Raymond C

Rowe, Paul J Sheskey & Sian C Owen; PhP Pharmaceutical Press

Reynolds JEF, editor; Martindale, The Extra Pharmacopoeia; 29th Edition; PhP

Pharmaceutical Press

AMA Drug Evaluation; 6th Edition; Chicago; American Medical Association.

Product Package

http://www.clinicaltrail.gov/

http://www.clinicaltrail.gov/ct2/show/NCT00645437?term=levefloxacin&rank

=5

http://www.clinicaltrail.gov/ct2/show/NCT00236821?term=levefloxacin&rank

=10

http://www.clinicaltrail.gov/ct2/show/NCT00257049?term=levefloxacin&rank

=26

http://emc.medicines.org.uk

101

http://emc.medicines.org.uk/medicine/12796/SPC/Tavanic+500mg+tablets/

http://emc.medicines.org.uk/medicine/3090/XPIL/Tavanic+250mg%2c+500m

g+tablets/

http://www.chemblink.com/products/100986-85-4.htm

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102