FINAL PROJECT LEVOFLOXACIN

NEW DRUG DEVELOPMENTAL & APPROVAL PROCESSLEVOMAX (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, MS (TQM), R.Ph. COLLEGE OF PHARMACY GC UNIVERSITY FAISALABAD CONTENTS CHAPTER.NO.01: INTRODUCTION CHAPTER.NO.02: FLOW CHART OF NEW DRUG DEVELOPMENT CHAPTER.NO.03: SOURCE AND SYNTHESIS CHAPTER.NO.04: PRECLINICAL STUDIES CHAPTER.NO.05: PREFORMULATION CHAPTER.NO.06: INVESTIGATION NEW DRUG APPLICATION CHAPTER.NO.07: CLINICAL TRIALS CHAPTER.NO.08: LONG TERM ANIMAL TOXICITY STUDIES CHAPTER.NO.09: PRODUCT FORMULATION CHAPTER.NO.10: MANUFACTURING AND CONTROL CHAPTER.NO.11: PACKAGE AND LABEL DESIGN CHAPTER.NO.12: NEW DRUG APPLICATION CHAPTER.NO.13: POST MARKETING SURVIELLANCE CHAPTER.NO.14: PRODUCT LINE EXTENTION 2 CHAPTER#01 INTRODUCTION 3 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 6 • Phase III Clinical Studies.how it is absorbed. In addition.volunteers sign prior to participating in a clinical study. safety and efficacy testing is conducted with several hundred to 7 . Testing is conducted with up to several hundred patients suffering from the condition the investigational drug is designed to treat. Phase II studies are designed to determine effectiveness and further study the safety of the candidate drug in humans. this phase of development generally takes from six months up to three years. increasing numbers of patients are tested. take the investigational drug for short periods of time. community advocates and others that ensures a clinical trial is ethical and the rights of study participants are protected. distributed. Phase III studies provide expanded testing of effectiveness and safety of an investigational drug. A small number of subjects. An IRB is an independent committee of physicians. most Phase II studies are double-blinded. or randomly divided into groups. • Phase II Clinical Studies. usually from 20 to 100 healthy volunteers. meaning that neither patients nor researchers evaluating the compound know who is receiving the investigational drug or placebo. These are the first studies conducted in humans. This testing determines safety and effectiveness of the drug in treating the condition and establishes the minimum and maximum effective dose. Depending upon the type of investigational drug and the condition it treats. Most Phase II clinical trials are randomized. this phase usually requires one to four years of testing. metabolized and excreted. In each successive phase. Phase I studies are designed to verify safety and tolerability of the candidate drug in humans and typically take six to nine months. Phase II and Phase III clinical studies. Depending upon the type of drug candidate and the condition it treats. 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. Testing includes observation and careful documentation of how the drug acts in the body -. one of which receives the investigational drug. Clinical testing is usually described as consisting of Phase I. • Phase I Clinical Studies. In Phase III. usually in randomized and blinded clinical trials. 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. Late-stage drug development studies of approved. • Phase IIIb/IV Studies. DOES TESTING CONTINUE AFTER A NEW DRUG IS APPROVED? After the FDA (or other regulatory agency for drugs marketed outside the U. Obtaining approval to market a new drug frequently takes between six months and two years. • Post-Approval Studies. Phase IIIb trials. Some studies focus on previously unknown side effects or related risk factors. marketed drugs may continue for several months to several years. this series of documents is submitted to the FDA in the U. New Drug Application (NDA)/Marketing Authorization Application (MAA): NDAs (in the U. At the conclusion of successful preclinical and clinical testing. recommended or suggested in the labeling.S. 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.) are examples of applications to market a new drug. including Phase IIIb and Phase IV studies.K. or to the applicable regulatory authorities in other countries. pharmaceutical companies may conduct additional studies.) approves a new drug.S. As with all stages of drug development testing.thousands of volunteer patients suffering from the condition the investigational drug treats. which often begin before approval. Post-approval studies test a marketed drug in new age groups or patient types. the purpose is to ensure the safety and effectiveness of marketed drugs 8 .S. 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. Such applications document safety and efficacy of the investigational drug and contain all the information collected during the drug development process.) and MAAs (in the U. STEPS IN NEW DRUG DEVELOPMENT TILL NDA IS FILED 9 . Steps in New Drug Development till NDA is Filed 10 . CHAPTER#02 FLOW CHART FOR NEW DRUG DEVELOPMENT FLOW CHART 11 . 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 PRECLINICAL STUDIES (Continued) • • • Phase І Phase І І Phase І І І • • • • 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 12 . CHAPTER#03 SOURCE AND SYNTHESIS 13 . followed by Pd(0)mediated amination to provide an entry to substituted and enantiomerically pure 1. a late stage intermediate in the synthesis of levofloxacin. Procedure: 1. is than converted into levofloxacin. This intermediate.4-benzoxazine 19. This chemistry provides a short and efficient entry to (3S)-3-methyl-1.2-Cyclic sulfamidates undergo efficient and regiospecific nucleophilic cleavage with 2-bromophenols (and related anilines and thiophenols).4benzoxazines (and quinoxalines and 1. 14 .4-benzothiazines).SYNTHESIS OF LEVOFLOXACIN Levofloxacin is a synthetic compound and is synthesized as follow. through a series of steps. CHAPTER#04 PRECLINICAL STUDIES Chemistry Physical Properties Biological Properties • Pharmacology • Pharmacokinetics • Toxicity UNIT-1: 15 . 6.(4.methyl.9 fluoro.8.6. 2. 16 . IV.1.05. 3 -de].10. ophthalmic Molecular Weight: 370.11-tetraene-11-carboxylic acid Chemical Formula: (-) .1.1piperazinyl) –7 – oxo -7H – pyrido [1.dihydro -3. 4 benzoxazine.38.methyl. Empirical Formula: C18H20FN3O4 ½H2O Routes: Oral. This in vitro chelation potential has the following formation order: Al+3>Cu+2>Zn+2>Mg+2>Ca+2. Stable Coordination Compounds: Levofloxacin has the potential to form stable coordination compounds with many metal ions.2.3. 3.13] trideca-5(13).CHEMISTRY OF LEVOFLOXACIN IUPAC-Name: (S)-7-fluoro-6-(4-methylpiperazin-1-yl)-10-oxo-4-thia-1-azatricyclo [7.carboxylic acid hemihydrate.(S). Structural Formula of Levofloxacin UNIT-2: 17 . 8. the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.7. Physical State: crystalline powder Odour: Odourless UNIT 3: 18 . the solubility increases rapidly to its maximum at pH 6.PHYSICAL PROPERTIES Appearance: Levofloxacin is a light yellowish-white to yellow-white crystal or crystalline powder. the solubility of levofloxacin is essentially constant (approximately 100 mg/mL). Levofloxacin is considered soluble to freely soluble in this pH range. Stability: Stable under ordinary conditions Melting Point: 218 ºC (http://www.8. Above pH 5.6 to 5.9.com/products/100986-85-4. Above pH 6.htm) Solubility: Insoluble in water The data demonstrate that from pH 0. as defined by USP nomenclature.7 (272 mg/mL) and is considered freely soluble in this range.chemblink. its mechanism of cytotoxic action is not known. some congeners of this drug family display high activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases. Quinolone-induced DNA damage was first reported in 1986. thereby inhibiting cell division. In particular. It functions by inhibiting DNA gyrase. Pharmacokinetics: Absorption: 19 . and topoisomerase iv.BIOLOGICAL PROPERTIES These biological properties are based on pre-clinical studies that are carried out in animals. (A) PHARMACOLOGY: Pharmacotherapeutic Group: Quinolone Antibacterials. The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. a type II topoisomerase. and are toxic to cultured cells and in vivo tumor models. which is an enzyme necessary to separate replicated DNA. Although the quinolone is highly toxic to mammalian cells in culture. 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. Approximately 87% of an oral dose eliminated in urine and <4% eliminated in feces.Bioavailability Approximately 99%. Half-life Terminal elimination half-life approximately 6-8 hours after oral administration. Steady-state plasma concentrations attained within 48 hours with once-daily regimen.Peak plasma concentrations usually attained 1-2 hours after an oral dose. and lungs. including skin. blister fluid. It is also distributed into CSF. Elimination: Metabolism Undergoes limited metabolism to inactive metabolites. (B) TOXICOLOGICAL STUDIES: 20 . Rapidly absorbed from GI tract. Plasma Protein Binding 24-38% bound to serum proteins. Distribution: Extent Widely distributed into body tissues and fluids. Elimination Route Eliminated principally as unchanged drug in urine. 5 hours after administration. 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. decreased neutrophil count and slight degeneration of the articular cartilage of limb joint were observed. 30. no toxicological changes were observed 21 . 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.5 mg/kg/day in the rat and monkey respectively. 62. Drug concentrations in the main organs were high in the kidneys and liver and lowest in the brain.5 mg/kg/day after 1 and 6 months respectively. except for the level. Subacute Toxicity: Following 4-weeks oral administration to rats. The NOELs were concluded to be 30 and 62. At a dose of 800 mg/kg. no toxicological changes in clinical signs. Following 4 weeks oral administration to cynomolgus monkeys. levofloxacin concentration in almost all tissues of the body were higher than the serum level. demonstrating the good transference to tissues. 320 mg/kg/day for 1 and 6 months in the rat and 10. No toxicity was seen in the 6-months study. respectively. The “ No Observed Adverse Effect Levels” (NOEL) in the six-month studies were concluded to be 20 and 62. blood chemistry urinalysis and histopathology were observed in the 50 mg/kg and 200 mg/kg administered groups. when administered orally to rats at a dose of 20 mg/kg. diarrhoea and decreased urinary pH in some animals at this dose. however. was absorbed primarily from the small intestine. 100 mg/kg/day and 10. hematology. Repeated dose toxicity: Studies of one and six month’s duration by gavage have been carried out in the rat and monkey. 80. 25. 200. increased M/E ratio of bone marrow cells.Levofloxacin. Doses were 50.5 mg/kg/day for 1 and 6 months in the monkey. 800 mg/kg/day and 20. Toxicity after oral dosing in the monkey was minimal with reduced body weight at 100 mg/kg/day together with salivation. and the maximum serum concentration (2.5 ug/ml) was reached 0. in the central nervous system and fat. diarrhea. slight inhibition of body weight gain and decrease in urine pH were observed at 100 mg/kg.at doses of 10 and 30 mg/kg. but salivation. 22 . CHAPTER#05 PREFORMULATION Bulk Characterization Solubility Analysis Stability Analysis UNIT-1: 23 . The heating rate is controllable and up to three transitions can be registered. and because of the high magnification the values are more accurate. An additional advantage is that the sample size required is only 2-5 mg. Hot stage Microscopy This is the visual observation of melting under a microscope equipped with a heated and lagged sample stage. Method: By Mass Spectroscopic Method Particle Size: Large Method: By sieving method particle size is determined. It is more precise as the phase transitions (first melt. it is large in size Melting Point: 218 ºC (http://www. 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.BULK CHARACTERIZATION Molecular Weight: 370.chemblink.38. 50% melt and completion) can be registered on a recorder as the melting proceeds. DTA measures the temperature difference between the sample and a reference as a function of temperature or time when heating 24 .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. 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). Crystal Habit is observed Microscopy: The microscope has two major applications in pharmaceutical preformulation: Basic crystallography.5-50 /mi.at a constant rate. 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. polymorphism and solvates Particle size analysis Most pharmaceutical powders have crystals in the range 0. fusion. although occasionally. it measures the enthalpy of transition. to determine crystal morphology (structure and habit). 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. with micronized powders and when following solid-solid and liquid-liquid transitions in polymorphism. the distributions are often smaller.5-300 /Jim. i.e. Crystal Purity: 25 . The major concern in preformulation is polymorphism. 10 x 20 may be required. 8. and the measurement of melting point and other phase changes is the primary diagnostic tool. However.3). except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference. DSC is similar to DTA. typically 0. Confirmation by IR spectroscopy and X-ray diffraction is usually required. to ensure good blend homogeneity and rapid dissolution. When no physical or chemical change occurs within the sample then there is neither a temperature change nor input energy to maintain an isotherm. These are the major reasons for particle size control. Crystalline transitions. Crystal Habit: Microcrystalline Technique: By SEM. evaporation and sublimation are obvious changes in state which can be quantified (Fig. There are six crystal systems (cubic. These are extreme cases.g. For this reason pharmaceutical air conditioning is usually set below 50% RH. This is known as crystal habit. depending on the relative humidity (RH). e. and these cyclic changes lead to constant variations in the moisture content of unprotected bulk drug and excipients. which is absent in glasses and some polymers. Although not changing their internal structure. 55% temperate and 87% tropics) can vary widely and continually depending on the weather and air temperature. of which five types are recognized: Tabular: moderate expansion of two parallel faces Platy: plates Prismatic: columns Acicular: needle-like 26 . whereas those in dynamic equilibrium with water in the atmosphere are hygro-scopic. monoclinic. which are particularly moisture sensitive. because early samples of a new drug are inevitably 'dirty' while Improvements in synthetic route are made. orthorhombic. and very hygroscopic products. effervescents. Hygroscopicity: Hygroscopic A substance that absorbs sufficient moisture from the atmosphere to dissolve itself is deliquescent is called hygroscopic. tetragonal. This is particularly pertinent at the preformulation stage. A substance that loses water to form a lower hydrate or becomes anhydrous is termed efflorescent. Ambient RH (0% poles and desert. Thermal analysis is rapid and will discriminate 0. and most pharmaceutical compounds are usually either impassive to the water available in the surrounding atmosphere or lose or gain water from the atmosphere. Crystal Morphology Crystals are characterized by repetition of atoms or molecules in a regular threedimensional structure. The constant sinusoidal change in day and night temperatures is the major influence. which have different internal structures and spatial arrangements.Thermal analysis has been widely used as a method of purity determination and the USP includes an appendix describing the methods. are stored and made below 40% RH. which occurs with polymorphism. Materials unaffected by RH are termed non-hygroscopic. crystals can adopt different external structures.002% of impurity. triclinic and hexagonal). Powder Flow Properties: Flow Ability: Good Technique: Flow ability is determined by calculating angle of repose.14 may be used as a guide to flow. inhibiting their growth. Sodium chloride is usually cubic. Accordingly. If any particle temporarily lies outside this limiting angle. 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. Naphthalene gives thin plates (platy) if rapidly recrystallized in cold ethanol or methanol. which changes habit as it changes the degree of supersaturation. When only small quantities of powder are available. The addition of cosolvents or other solutes and ions which change habit by poisoning crystal growth in one or more directions.Bladed: flat acicular. 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. These occur in all six-crystal systems. Resorcinol produces needles from benzene and squat prisms from butyl acetate. whereas slow evaporation yields prisms. Crystal habit can be modified by: Excessive supersaturation. will tend to form a conical mound.6. but urea produces an octahedral habit. The angles of repose given in Table 8. an alternative is to determine the 'angle of spatula' by picking up a quantity of powder on 27 . and this is known as the angle of repose (0). Cooling rate and agitation. A simple relationship between angle of repose. the exact value for angle of repose does depend on the method of measurement. Angle of Repose: 22º Explanation: A static heap of powder. Carr's index and the expected powder flow is shown in Figure 8. However. One limitation exists: the angle to the horizontal cannot exceed a certain value. which tends to transform a prism or isodiametric (granular) crystals to a needle shape. there is an empirical relationship between 6 and the ability of the powder to flow. with only gravity acting upon it. The crystallizing solvent affects habit by preferential absorption on to certain faces. A useful empirical guide is given by Carr's compressibility index ('Compressibility' is a misnomer.a Table 8. This is obviously crude but is useful during preformulation. Changes in particle size and shape are generally very apparent. 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. Of primary importance when handling a drug powder is flow. an increase in crystal size or a more uniform shape will lead to a smaller angle of repose and a smaller Carr's index. These are extremely useful derived parameters to assess the impact of changes in drug powder properties as new batches become available. When limited amounts of drug are available this can be evaluated by measurements of bulk density and angle of repose. as compression is not involved): 28 . when only small quantities of drug are available.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. Between 1. whereas greater than 1. Carr's index is a one-point determination and does not always reflect the ease or speed with which the powder consolidates. Rapid consolidation is essential for uniform filling on tablet machines.25 indicate good flow (= 20% Carr). Indeed.25 indicates poor flow (= 33% Carr).5. added glidant normally improves flow. some materials have a high index (suggesting poor flow) but may consolidate rapidly.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 and 1. when the powder flows at pBmin into 29 . 30 . Non-linearity occurs up to two taps and after 30 taps when the bed consolidates more slowly. 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. β.737. Method: Transformation Kinetics are checked by differential scanning calorimetry (DSC). 5.the die and consolidates. 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.S.545. Further heating resulted in the formation of anhydrous form β. approaching pBmaxJ at compression. respectively. Polymorphic Forms: Three polymorphic forms (anhydrous α. Hemihydrate and monohydrate forms are mentioned in EP 0444 678 B1 and in U. An empirical linear relationship exists between the change in bulk density and the log number of taps in a jolting volumeter. Patent No. and then the formation of anhydrous form α. Transformation Kinetics: Heating the hemihydrate form resulted in a removal of the hydrated water to give anhydrous form γ. 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. γ) and two pseudopolymorphic forms (hemihydrate and monohydrate) of levofloxacin are present. atenolol.7 (272 mg/ mL) and is considered freely soluble in this range. The permeability class and efflux potential were ascertained by comparing test drug results with standard compounds (metoprolol. The permeability of ciprofloxacin. lomefloxacin. labetalol. and ofloxacin was measured in an in vitro Caco-2 assay with previously demonstrated method suitability. Based on comparison to 31 . In comparing absorptive versus secretive in vitro transport.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.8. the solubility increases rapidly to its maximum at pH 6. Above pH 5. the solubility of levofloxacin is essentially constant (approximately 100 mg/ mL). Partion Coefficient: Pka value is 6. the tested fluoroquinolones were found to be subject to efflux in varying degrees (ciprofloxacin > lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). the solubility decreases and reaches a minimum value (about 50 mg/ mL) at a pH of approximately 6. and rhodamine-123).9. Levofloxacin is considered soluble to freely soluble in this pH range. indicating active drug transport.8. All 4 quinolones drugs demonstrated concentration-dependent permeability. levofloxacin. as defined by USP nomenclature.Unit-2: SOLUBILITY ANALYSIS Solubility in water:Insoluble The data demonstrate that from pH 0. Above pH 6.7.6 to 5. Dissolution: Drug exhibit good dissolution properties. ciprofloxacin was classified as a low permeability drug. and ofloxacin were classified as high permeability drugs. Drug is placed in the Rotating Basket Apparatus and the dissolution of compound is determined 32 . Method and Equipment: Rotating Basket Apparatus is used. levofloxacin. The in vitro permeability results matched human in vivo data based on absolute bioavailabilities.labetalol. whereas lomefloxacin. the high permeability internal standard. This laboratory exercise demonstrated the applicability of an in vitro permeability method for classifying drugs as outlined in the BCS Guidance. RESULT: Significant degradation was observed during oxidative stress and the degradation product formed was identified by LCMS/MS. water hydrolysis. 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. Stability-indicating RP-HPLC method for levofloxacin in the presence of degradation products. pH 6. base. The developed LC method was found to be suitable to check the quality of bulk samples 33 . pharmaceutical dosage forms in the presence of degradation products and its process related impurities. The stressed test solutions were assayed against the qualified working standard of levofloxacin and the mass balance in each case was in between 99. oxidative. Forced degradation studies were performed on bulk sample of levofloxacin as per ICH prescribed stress conditions using acid.UNIT-3: STABILITY ANALYSIS Hydrolysis: There is no effect of moisture. The chromatographic method was optimized using the samples generated from forced degradation studies and the impurity spiked solution. 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. slight degradation in acidic stress and no degradation was observed in other stress conditions. The limit of detection and the limit of quantitation for the levofloxacin and its process related impurities were established. Validation of the developed LC method was carried out as per ICH requirements.4 and 99.0) and methanol using a simple linear gradient.8% indicating that the developed LC method was stability indicating. thermal stress and photolytic degradation to show the stability indicating power of the method.5% (v/v) triethyl amine in sodium dihydrogen orthophosphate dihydrate (25 mM. The detection was carried out at 294 nm. 34 .of levofloxacin at the time of batch release and also during its stability studies (long term and accelerated stability). CHAPTER#06 INVESTIGATIONAL NEW DRUG APPLICTION 35 . Final protocol. Adverse Event Reporting Form . Pre.Receipts from Civil Administration and other Functions.e names and designation of members.Documents required by Ministry of Health for the approval of Clinical Trials in Pakistan Documents Investigator Brochure.clinical/ Clinical data/ Safety studies. CV’s of Investigators. 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. with complete composition of committee i. Ethics committee approval of sites. GMP Certificate along with CPP/Free Sale Certificate of Country of Origin. Informed Consent (English and Urdu )Form Fees 5000. 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 . C028-Social Services. Summary of the Protocol Summary of the IB ( for quick review on drug). (Head of Account) C-Non Tax Revenue C02. CHAPTER#07 CLINICAL TRIALS 37 . The clinical research on ranitidine is preceded to phase-2 because phase 1 studies showed promise and no drug reaction. Results: We conducted study under careful circumstances by personals trained in clinical pharmacology. 38 . Procedure: We administered 1/10 of no effect dose of animals. Duration: Phase-1 survives usually for 1-2 years. In this phase. All preclinical studies mentioned and took permission for clinical trials. This purloins gets stable so we increased the dose gradually and checked the response. PHASE-2 CLINICAL TRIALS: Phase II studies are sometimes divided into Phase IIA and Phase IIB. PHASE-1 CLINICAL TRIALS: Aims: To study the safety of the drug in healthy volunteers No. distribution and elimination and pharmacological action preferred route of administration and safe dosage. Than we submitted investigational to FDA. absorption. which became evident.CLINICAL TRIALS Our product is converted into a suitable dosage form. Phase IIA is specifically designed to assess dosing requirements (how much drug should be given). Parmacokinetics and Pharmacodynamic studies of a drug are undertaken to determine its toxicity. of Patients: We selected 20-100 healthy voluntaries for phase 1 trials. metabolism. No.Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)). Duration: It took 1-2 years for its completion. Pharmacokinetics Study An Open-Label Randomized Multiple-Dose Study to Evaluate Levofloxacin Steady-State Pharmacokinetics and Safety in Subjects With Varying Degrees of Renal Function Official Title 39 . 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. Parallel Assignment. Randomized. 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. Pharmacokinetics of a drug should be investigated in patients because they may handle it differently from healthy people. Aims: This trial aims to demonstrate conclusively efficacy of drug in relation to its safety. of Patients: We recruited hundred of patients for the conformation of phase-1 trials. Open Label. Condition Renal Diseases Study Type Study Design Intervention Drug: Levofloxacin Interventional Phase Phase 2 Treatment. subsequent doses of either 250. for a total of 6 patients per group. Blood samples were collected from each patient from Day 1 to Day 14 for pharmacokinetic evaluation. Estimated Enrollment: Study Start Date: Study Completion Date: 60 October 2007 April 2009 Detailed Description: In this multiple-dose study conducted at 4 centers. a 7-day open label treatment phase. or 750 mg of levofloxacin (q24h or q48h) were based on renal function. Patients were randomized into 1 of 10 treatment groups. Dialysate samples were collected on Day 7 from HD patients immediately before dosing (as 40 . 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. 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.FURTHER STUDY DETAILS AS PROVIDED Primary Outcome Measures: Evaluation of the pharmacokinetics of two dosing regimens of Levofloxacin in renally impaired and dialysis patients. 500. All patients received a single 750-mg dose of levofloxacin on Day 1. 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. Secondary Outcome Measures: Safety of two dosing regimens of Levofloxacin in renally impaired and dialysis patients. and a 7 day posttreatment phase (or a follow-up phase for subjects with early study withdrawal). Fifty-nine patients were enrolled in the study. 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. 1. Patients were confined overnight at the study unit on Days 0. and physical examination findings. electrocardiograms (ECGs). vital sign measurements. hypertension) must be on a stable treatment plan (medicines. doses. 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 Years Genders 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. well-controlled diabetes. 41 . Single 750-mg dose of levofloxacin on Day 1. toxicology. and antibody screens. antigen. and severity of treatment-emergent adverse events and on changes in clinical laboratory values (hematology. and remained confined until the 24 hour blood samples were collected on Days 2 and 8. Safety was based on the incidence. HIV. 6.. and 7. 500 mg. 12-lead electrocardiograms.dialysis began) and at the end of the dialysis treatment. physical examination.g. subsequent doses of Levofloxacin 250 milligram (mg). and urinalysis). relationship to therapy. 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. chemistry. hepatitis B and hepatitis C Medically stable based on medical history. Basically phase-3 involves the comparison between the existing therapies of a particular disease and the new drug. Phase-3 Clinical Trials: The phase-3 studies are intended to assess the drug-s safety. 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. effectiveness and most desirable dosage in treating a specific disease in a large group of subjects. The clinical research on ranitidine is preceded to phase-3 because phase-2 studies showed promise and no drug reaction. We conducted following phase-3 clinical studies 42 .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. which became evident. Condition Pneumonia Intervention Drug: levofloxacin Phase Phase II Phase III Study Type: Study Design: Interventional Treatment. Safety/Efficacy Study A Multicenter. and by type of bacteria. Active-Controlled.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. Randomized Study To Evaluate The Safety And Efficacy Of Levofloxacin Versus Ceftriaxone Sodium Or Cefuroxime Axetil In The Treatment Of CommunityAcquired Pneumonia In Adults Official Title: Further study details as provided Primary Outcome Measures: Clinical response rate (reduction in signs and symptoms. changes in physical examination and laboratory tests after treatment with study drug 43 . Open Label. incidence of adverse events. Active Control. by patient. Parallel Assignment. compared with ceftriaxone sodium or cefuroxime axetil in the treatment of adults with pneumonia.7 days after the last dose of study drug). Randomized. improvement in x-ray findings) at post-therapy (5 . Secondary Outcome Measures: Rate of elimination of disease-causing bacteria. Safety evaluations (incidence of adverse events. or cefuroxime axetil (500 mg by mouth twice daily).7 days after the last dose of the study drug. one visit [posttherapy] 5 . 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.14 days) or cefuroxime axetil (500 mg by mouth twice daily for 7 . and laboratory tests) are performed throughout the study. and changes in x-ray findings. Cost-effectiveness is also assessed for the study drugs. ceftriaxone sodium (1 . 44 . Levofloxacin 500 mg by mouth once daily. and 3 visits for assessment of safety and effectiveness (one visit on Day 2 . Levofloxacin is an antibacterial agent used for the treatment of many types of infections in adults.2 grams administered into a vein or muscle once daily or in divided doses twice daily for 7 . and that it will be well tolerated.7 days after the last dose of study drug.2 grams administered into a vein or muscle once daily or in divided doses twice daily). (categorized as cured.14 days. 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. multicenter study to determine the safety and effectiveness of levofloxacin (500 mg once daily by mouth) compared with ceftriaxone sodium (1 . and one visit [post-study] 21 28 days after the last dose of the study drug). parallel group. The primary efficacy assessment is the clinical response 5 . improved. The study consists of 4 visits: one visit for screening and enrollment. The total duration of patient participation in the study is approximately 6 weeks.14 days) in adults with community-acquired pneumonia. or failed) based upon changes in signs and symptoms. open-label. Treatment duration is 7 .4 [on-therapy].Estimated Enrollment: Study Start Date: Estimated Study Completion Date: 528 September 2005 January 2007 Detailed Description: This is a randomized. physical examination. seizure disorder.Eligibility Criteria: Ages Eligible for Study: Genders Eligible for Study: Accepts Healthy Volunteers: 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. 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. Results: Levofloxacin 500 mg by mouth once daily is more efficacious as compared to ceftriaxone sodium (1 . 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. shortness of breath. or if greater than 24 hours. or cefuroxime axetil (500 mg by mouth twice daily) 18 Years and older Both No 45 . chest pain. bacteria. greenish-yellow mucus produced on coughing.2 grams administered into a vein or muscle once daily or in divided doses twice daily). cough. 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 an unstable psychiatric condition. Clinical response rates (chest xray findings and signs/symptoms) and microbiologic eradication rates at poststudy.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. 46 . Randomized. Condition Pneumonia Study Type: Study Design: Intervention Drug: levofloxacin Interventional Treatment. Incidence of adverse events. Safety/Efficacy Study Multicenter. Secondary Outcome Measures: Microbiologic eradication rates at posttherapy visit. Parallel Assignment. Levofloxacin 500 mg Once Daily for 10 Days in the Treatment of Mild to Severe Community-Acquired Pneumonia in Adults Phase Phase III Official Title: Further study details as provided Primary Outcome Measures: Clinical response rates based on signs and symptoms at posttherapy visit. Double-Blind Randomized Study to Compare the Safety and Efficacy of Levofloxacin 750 mg Once Daily for Five Days vs. Double-Blind. 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 communityacquired pneumonia in adult patients. physical examinations. skin infections. laboratory tests) are performed throughout the study. Patients receive levofloxacin by mouth or through a vein depending on the severity of their pneumonia. and 17-21 (posttherapy visits). with assessments on study days 12-16. urinary tract infections. treatment is discontinued if no significant improvement is noted. 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. 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. chronic bronchitis. Chest x-rays and laboratory tests for presence of bacteria are performed during the study. Patients showing signs of improvement continue in the study. 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. and communityacquired pneumonia. Levofloxacin.Enrollment: Study Start Date: Study Completion Date: 530 March 2007 June 2009 Detailed Description: Levofloxacin is an antibiotic that is approved by the FDA for the treatment of sinusitis. This multicenter. 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 . and 31-38 (poststudy visit). Safety evaluations (incidence of adverse events. Patients are assessed after 3 days of treatment. chest x-ray findings have worsened compared to the initial chest-x-ray. gender.Eligibility Criteria: Ages Eligible for Study: Genders Eligible for Study: Accepts Healthy Volunteers: 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. 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 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. white blood cell count is significantly increased. other diseases. who had been living there < 14 days Fine Class (rating scale used to assess patients' overall condition which includes information such as age. if in a nursing home. 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 18 Years and older Both No 48 . 49 .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. 5 ug/ml) 50 . when administered orally to rats at a dose of 20 mg/kg.CHAPTER#08 LONG TERM ANIMAL TOXICITY STUDIES LONG TERM ANIMAL TOXICITY STUDIES Levofloxacin. and the maximum serum concentration (2. was absorbed primarily from the small intestine. 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. 51 . Toxicity after oral dosing in the monkey was minimal with reduced body weight at 100 mg/kg/day together with salivation. No toxicity was seen in the 6-months study. but salivation. however.5 mg/kg/day in the rat and monkey respectively. Doses were 50.5 mg/kg/day after 1 and 6 months respectively.5 mg/kg/day for 1 and 6 months in the monkey. no toxicological changes were observed at doses of 10 and 30 mg/kg. increased M/E ratio of bone marrow cells. Subacute Toxicity: Following 4-weeks oral administration to rats. in the central nervous system and fat. decreased neutrophil count and slight degeneration of the articular cartilage of limb joint were observed. blood chemistry urinalysis and histopathology were observed in the 50 mg/kg and 200 mg/kg administered groups. 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. levofloxacin concentration in almost all tissues of the body were higher than the serum level. 100 mg/kg/day and 10. 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. 25. 320 mg/kg/day for 1 and 6 months in the rat and 10. 30. At a dose of 800 mg/kg. 62.was reached 0. hematology.5 hours after administration. 200. diarrhoea and decreased urinary pH in some animals at this dose. diarrhea. respectively. The “ No Observed Adverse Effect Levels” (NOEL) in the six-month studies were concluded to be 20 and 62. Repeated dose toxicity: Studies of one and six month’s duration by gavage have been carried out in the rat and monkey. except for the level. demonstrating the good transference to tissues. Following 4 weeks oral administration to cynomolgus monkeys. The NOELs were concluded to be 30 and 62. 80. slight inhibition of body weight gain and decrease in urine pH were observed at 100 mg/kg. no toxicological changes in clinical signs. 800 mg/kg/day and 20. Antigenicity: No specific antibody to levofloxacin was produced in mice. no toxicological changes were observed at a dose of 20 mg/kg. unscheduled DNA synthesis. growth retardation in fetuses and neonates or teratogenesis were not observed in rabbits after oral administration at 50 mg/kg. and rabbits concurrently treated with adjuvants. sister chromatid exchange. in the absence of metabolic activation. mice showed positive reaction. Following 26-weeks oral administration to cynomolgus monkeys.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. 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. but salivation and high urinary pH were observed at doses of 80 and 320 mg/kg. Moreover lethal effect to embryos and fetuses. guinea pigs. 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.Chronic Toxicity: Following 26 weeks oral administration to rats. no toxicological changes were observed at doses of 10. but 52 . In PCA test using serum of experimentally sensitized animals. increased feces and enlargement of goblet cells in cecal mucosa were seen. In-vivo tests (micronucleus. Teratogenic study: No effects were observed on fetuses or neonates after oral administration to rats upto 90 mg/kg. 25 and 62. at a dose of 320 mg/kg. In addition. dominant lethal tests) did not show any genotoxic potential. Juvenile dogs were more susceptible to the chondrotoxicity. and dominant lethal test were negative. Effect on eyes: Eye toxicity tests in pigmented rats orally administered 100 mg/kg/day for 14 days showed no changes in electroretiongram. induced mutation frequency test. lesions were seen in the articular cartilage in rats at 300 mg/kg or more and in dogs at 10 mg/kg or more. and systemic anaphylactic reactions were not observed in guinea pigs. Phototoxicity test: 53 . the reverse mutation test. ophthalmological examination and histopathology. mouse bone marrow micronucleus test negative. When levofloxacin was orally administered to young adult dogs (13 months of age) for 7 days. Mutagenicity: Chromosomal aberration test and sister chromatid exchange test using cultured Chinese and HGPRT sister test. no abnormalities were observed in renal function and morphology. were synthesis However. 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.guinea pigs and rabbits were negative. no toxicity was observed at a high dose of 30 mg/kg. in vivo studies for the same items. unscheduled test. Effect on kidneys: Following oral administration of upto 120 mg/kg to rabbits for 10 days. very mild toxicity was observed at 40 mg/kg. Moreover. hamster chromatid in vivo cell showed exchange test positive results DNA results. in adult dogs aged 18 months in which the drug was administered for 14 days. However. Phototoxicity (increase in thickness) was not shown at 200 mg/kg.Albino mice were orally given levofloxacin and subsequently irradiated with UVA (wave length 320-400nm). and auricular thickness was measured. 54 . CHAPTER#09 PRODUCT FORMULATION 55 . 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 .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. 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 . 22 to 2. Large batches in sizable manufacturing outlets are filtered 59 . Slugging: The mixture is than mechanically separated into units. known as dry granulation or slugging. The procedure for manufacturing levomax tablets. a part of binder-methyl hydroxypropyl cellulose and a part of lubricant -sodium steryl fumerate are next poured into one sterile canister. The active ingredient. is as follows: Weighing: The active ingredient-levofloxacin. These units are called slugs. Mixing: Sodium steryl fumerate is dispensed into cold purified water.MANUFACTURING PROCESS Levomax tablets of the same dosage amount are manufactured in batches. Documentation on each batch is kept throughout the manufacturing process and finished tablets undergo several tests before they are bottled and packaged for distribution. After careful weighing. and the canister is wheeled to a mixing machine called Glen Mixer.54 cm) in size. small batches of slugs are forced through a mesh screen by a handle-held stainless steel spatula. Mixing blends the ingredients as well as expels air from the mixture. Dry Screening: Next. which are generally from 7/8 to 1 inches (2. The slugs are than filtered to remove air and lumps. than heated and stirred until a translucent paste forms. the necessary ingredients are mixed and compressed into units of granular mixture called slugs. and are compressed again into numerous individual tablets. 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. the microcrystalline cellulose. After this. the mixture runs through a feed line into a number of die cavities that are situated on a large steel plate. This punch descends into the die compressing the mixture into a tablet. compressing the mixture into tablets. Punches. while roller-activated punches beneath the die cavities lift up and eject the tablets from the die platform.through machine called Fitzpatrick mill. 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). usually by a spray method. The remaining lubricant is added to the mixture. the powder is compressed into tablet with the help of a punch. The lubricant keeps the mixture from sticking to the tablet machine during the compression process. The plate revolves as the mixture is dispensed through the feed line. 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 mixture is fed into one tablet mold (called a die cavity) by a feed shoe. Rollers on top of upper punches press the punches down onto the die cavities. rotate in sequence with the rotation of the die cavities. Film coating involves the deposition. Coating: Film coating. to increase coating hardness or to improve any other property that the formulator deems deficient. of a thin film of polymer formulation around each tablet core. The coating liquid contains a polymer in suitable liquid medium together with other ingredient such as pigments and plastesizers. to decrease bridging of intagliations. Due to these considerations. On single punch machines. which is blended gently in a rotary granulator and sifter. rapidly filling each die cavity. 60 . elasticity of the resultant film and the film tablet surface interaction. it becomes very important to use the most optimized coating formulation in order to get the best results. The optimization of film coating may be necessary to improve adhesion of the coating to the core. On a rotary tablet machine. The development scientist has to consider three major factor which affect the film quality –tensile strength of the film coating formulation. both above and below the die cavities. This solution is sprayed on a rotating. 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 Exhaust Air Temperature Air Flow Spray Rate Atomization Air Pan Speed Pattern Air 50°C 60°C 245 CMH 06 g/min 2.0 bar 61 .mixed tablet bed.0 bar 20 RPM 2. 2g pierced with 5 holes.20.65 mm thick.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. 21. one in the center and other four spaced equally on the circle of radius 6 mm from the center of the disc. e) The assembly is suspended in a specific liquid medium. No residue remain on screen If there is a residue.181. c) The tubes are held vertically by two separate and superimposed rigid plastic plates 90mm in diameter and 6 mm thick.8-3. The volume of liquid is such that when the assembly is in highest position. made for transparent plastic with a related density of 1. weighing 2. the wire mesh is atleast 15mm below the surface liquid and when the assembly is in lowest position. unmoisture core sieve only fragments of coating remain on screen. it consist of a soft mass having no palpably firm.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. Wall thickness is about 2mm. Test: a) A riged basket rack assembly supporting six cylindrical transperant tubes 7580 mm long. d) The plates are held rigidly in position and 77. 62 .85 mm in diameter and 9. each 20. b) A cylindrical disk for each tube. Disintegration is considered to be achieved when.55-20.359.5 mm in internal diameter. Disintegration Test: Apparatus: Basket Rack Assembly Description: The basket rack assembly consist of six open glass tubes each 7. Special dedicated hardness 63 . Generally the greater the pressure applies.1cm from the bottom of the vessel on the downward stroke. The tablet has passed the tst if all 6 have disintegrated. In general tablets should be sufficiently hard to resist breaking during normal handling and yet soft enough to disintegrate properly after swallowing. Adjust the apparatus so that it descends to 1±0. The tubes are held in vertical position by two plastic plates.75±0. Procedure: 1. the harder the tablet is. introduce one tablet into each of the 6 tubes and. add the disc to each tube. Although the granulation also have a baring on hardness. Use the medium as specified and proceed as directed in the individual monograph. Suspend the assembly in the beaker containing the specified liquid and operate the apparatus for the specified time.5mm and wall approximately 2mm thick.25cm long having inside diameter of approximately 21. 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. 2. with 6 holes each about 24mm in diameter equidistant from the center of the plates and equally spaced from one another. 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. 3. each about 9mm in diameter and 6mm in thickness. Remove the assembly from the liquid.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. if prescribed. Method: Unless otherwise stated in the individual monograph. care must be exercised to employ the same factors ogf fill. Multifunctional automated equipments can determine weight. 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%. The degree of pressure affects not only thickness but also hardness of the tablets. If one or more units don’t meet these criteria.tester or multifunctional systems are used to measure the degree of force required to break the tablet. additional tests as prescribed in the USP are required. In this test. The tablets are assayed and the contents of active ingredient in each of the 10 tablets are calculated assuming homogeneous drug distribution. The USP contain a test for determination of dosage form uniformity by weight variation for uncoated tablets. since it can affect 64 . 10 tablets are weighed individually and the average weight calculated. die and pressure. 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 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. Content Uniformity: By the USP method. Unless otherwise stated in the monograph. During production. The volume fill is adjusted with the first few tablets to yield the desired weight and content. 10 dosage units are individually assayed for their content according to the method described in the individual monograph. The amount of fill permitted to enter the die. sample tablets are periodically removed for visual inspection and automated physical measurement. hardness is perhaps the more important criteria. thickness. Tablet Thickness: The thickness of a tablet is determined by The diameter of the die. hardness and diameter of the tablet. it is doubly important to control pressure.disintegration and dissolution. for tablets of uniform thickness and hardness. Thus. Tablet thickness can be measured by hand gauge during production or by automated equipment 65 . CHAPTER#11 PACKAGE AND LABEL DESIGN 66 . The user exposes the product for easy removal by their customer using the perforated section.PACKAGE AND LABEL DESIGN PACKAGE DESIGN PRIMARY PACKAGING: Tablets after manufacturing was packed into aluminum foil.5cm 10 500 mg 271186 51536 11-12-2009 11-12-2011 Kenstars Pharmaceuticals Secondary Packaging: Folding Cartons: Provide excellent secondary protection for individually packaged multiple unit packs. Other specifications are given below. There are a great many styles of folding cartons available at numerous specialized features that can be added to these designs styles.4cm 6.shelf items. For multiple unit packs. Manufacturing Date Expiry Date Manufactured by Aluminium Foil 10. of Tablets per Blister Tablet Strength Batch No. 67 . the carton can be designed as a dispenser carton by including a perforated area into the carton. Although some simple styles dcan be ordered as of –the. Packaging Material Length Width No. 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. Registration No. 5 cm 7.5 cm 1cm Text: AS PER REFERENCE 68 .7 cm 7. depending on how the product will load into the box.7cm 0. Length of Carton Width of Carton Length of Front Flap Width of Front Flap Width of Folding Flap (top) Width of Folding Flap (bottom) Length of Folding Flap Cut of Lock Length of Side Flap Width of side Flap (top) Width of side Flap (bottom) 14.7cm 7.6 cm 2.2 cm 0.Packaging Specifications for Unit Carton Dimensions: Dimensions are described based on the opening of an assembled box.6cm 1 cm 11cm 1. The opening can be located on the top or the side. 69 . Peak plasma concentration is attained 1-2 hours after oral dosing. Breathing Problems.500mg CLINICAL PHARMACOLOGY: Machaniism Off Acttiion:: Machan sm O Ac on It involves the inhibition of DNA Gyrase. Pharmacokiinettiics:: Pharmacok ne cs Absorption: It is rapidly and essentially completely absorbed after oral administraion. levomax tablet is administered once daily for 07-14 days. is the pure (-)-(S)enanciomer of the racmic drug substance ofloxacin. It is often bactericidal at concentration equal to or slightly greater than inhibitory concentration. Qualitative and quantitative composition: Levomax(levofloxacin) is available for oral administration in film coated tablets as: Levofloxacin…………………………. Metabolism and Elimination: It undergo limited metabolism in body and mainly eliminated from body in unchanged drug in urine. Swallowing. In case of community acquired Pneumonia and nosocomial Pneumonia. levofloxacin. Swelling of 70 . Distribution: Mean volume of distribution ranges from 74-112 litres after single and multiple dosing. let adm ADVERSE REACTIONS: Allergic reaction may include: Rash. DOSAGE AND ADMINISTRATION: AN AD Levomax (levofloxacin) 500mg tablets are administered once daily. which is essential in the reproduction of bacterial DNA. Chemically. THERAPUTIC INDICATION: Levomax (levofloxacin) tablets are indicated for the treatment of community acquired Lev ta Pneumonia and nosocomial Pneumonia. a chiral fluorinated carboxyquinolone. The duration of v Le treatment depends on the type and severity of the infection and the sensitivity of the pathogen.LABEL DESIGN Levomax (Levofloxacin) 500mg Tablet DESCRIPTION: Levomax (levofloxacin) is a synthetic broad spectrum anti-bacterial agent. Sleeping Problems. Paresthesia. It should not be administered with antacids. It should be discontinue if the patient experiences pain. Should be taken two hours before or after antacids. Protect from sunlight and moisture. Face. It should be taken taken with sufficient amount of water. MANUFACTURED BY: Industrial area. Nausea and Diarrhea. CONTRAINDICATIONS: Levomax is contraindicated in children. PLEASE READ THE CONTENTS CAREFULLY BEFORE USE. inflammation or rupture of a tendon during therapy.Your Lips. Keep out of the reach of children. Drowseness. Throat. STORAGE: Store below 30ºC. Arthralgia. NURSING MOTHERS: No adequate and well-controlled studies. Skin rash and Itching. adolescents and in patients with a history of hypersensitivity to this drug. or Tongue. PRECAUTIONS: Tablet should be swallowed without crushing. Fsd. LOGO: Kenstars Pharmaceuticals 71 . Feeling Sick (nausea) and Diarrhea. It may be taken during meal and between meals. PREGNENCY: There are no adequate and well-controlled studies in pregnant women. CHAPTER#12 NEW DRUG APPLICATION (NDA) 72 . Yours Truly. Lahore. 8000/.. Thanking You.. hereby apply for registration of drug namely LEVOMAX. Kenstar Pharmaceuticals (Pvt) Ltd. Director 73 . Treasury Challan of Rs.The Secretory. Subject: Application for Registration of a Drug for Local Manufacturer Dear Sir. Drug Registration Board. Lahore.being fee of registration is enclosed. Government of Pakistan. Kenstars Pharmaceuticals (Pvt) Ltd. Islamabad. We. details of which are enclosed. . Director Kenstar Pharmaceuticals (Pvt) Ltd. do hereby declare that the Label/Carton/Color Scheme and printed Matter of LEVOMAX is not a copy/counterfeit of any other registered drug in Pakistan.UNDERTAKING We. Kenstars Pharmaceuticals (Pvt) Ltd.. 74 . Lahore. Lahore. We also declare that the name of LEVOMAX bears no resemblance to any other registered drug in Pakistan. 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. contains: 75 . as appropriate and available. Brand (Proprietary) name of the drug: Levomax 3. The chemical name(s) and. 2. FOR LOCAL MANUFACTURE. etc.11. Date: 27. Lahore hereby apply for registration of the drug.g. e. the established (generic) and synonyms of the drug: Levofloxacin 4. Lahore.2009 Place: Lahore Signed: ENCLOSURES OF THE APPLICATION FOR REGISTRATION OF A NEW DRUG OR A NEW COMBINATION / DOSAGE FORM Dosage Form:Tablet 1. each tablet or 5 ml. Strength of active ingredient(s) per unit. I / We Kenstars Pharmaceuticals (Pvt) Ltd. Name and address of the manufacturer: Kenstar Pharmaceuticals (Pvt) Ltd. namely Levomax Tablet containing a new drug molecule for a local manufacturer. Details of which are enclosed... strength. 5. For the treatment of Pneumonia in adult patients. Recommended clinical use.38 76 . Composition (actives & excepients) including statement of the quantitative composition. Formulation: As given on page#56 of chapter-09 Manufacturing: As given on page#58 of chapter-10 8. giving the weight or measure for each active substance used in the manufacture of the dosage form. 9. Pharmacological group: Flouroquinolone Antibiotic 6. Proposed route of administration: Oral 7.46mg of levofloxacin hemihydrate.Each film-coated tablet of Levomax contains 500mg of levofloxacin as active ingredient corresponding to 512. quality. Full description of the specifications and analytical methods necessary to assure the identity. RAW MATERIAL SPECIFICATIONS Quality Control Laboratory General Profile Name Category Formula Molecular Weight Levofloxacin Flouroquinolone Antibiotic C18H20FN3O4 ½H2O 370. purity and homogeneity through out the shelf life of the drug product. P 20ppm Stable under ordinary conditions. You may need to read it again. 77 . LEAFLET Levomax® 500 mg tablets Levofloxacin Read all of this leaflet carefully before you start taking this medicine. Keep this leaflet. If you have any further questions. Description/Limits Light yellowish-white to yellowwhite in colour Positive for levofloxacin 500 mg Labeling and prescribing information (to be mentioned on the pack/leaflet) specimen or draft shall be submitted.P Complies to B.Characteristics/Parameters Physical state Description/Limits Light yellowish-white to yellowwhite crystal or crystalline powder. ask your doctor or your pharmacist. Insoluble in water Positive Complies to B. Store in air tight contained. This medicine has been prescribed for you. Protect from light Identification Acidity and Alkalinity Halogenated Compounds Heavy Metals Storage FINISHED GOODS SPECIFICATIONS Quality Control Laboratory Brand Name Generic Name Dasage Form Shelf Life Levomax Levofloxacin Tablet 2 years Characteristics/Parameters Physical inspection Identification Strength 10. Levomax tablets contain a medicine called levofloxacin. It may harmthem. This belongs to a group of medicines called antibiotics. in people with long-term breathing problems or pneumonia Urinary tract. 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. including muscles. 78 . 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. swallowing or breathing problems. 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. talk to your doctor or pharmacist before taking Levomax tablets. swelling of your lips. If any of the side effects gets serious. Levofloxacin is a ‘quinolone’ antibiotic. face. If you are not sure. please tell your doctor or pharmacist. What Tavanic tablets are and what they are used for: The name of your medicine is Levomax tablets.Do not pass it on to others. A tendon is the cord that joins your muscle to your skeleton You are a child or a growing teenager You are pregnant. Tavanic tablets can be used to treat infections of the: Sinuses Lungs. or if you notice any side effects not listed in this leaflet. where you have a long lasting infection Skin and underneath the skin. 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'. any other quinolone antibiotic such as moxifloxacin. It works by killing the bacteria that cause infections in your body. even if their symptoms are the same as yours. including your kidneys or bladder Prostate gland. tell your doctor if you are taking any of the following medicines. 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’.used for breathing problems.Take special care with Levomax tablets. You may be more likely to have inflammation and/or breakage of your tendons. Also some medicines can affect the way Levomax tablets work. 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. Taking other medicines Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. Check with your doctor or pharmacistbefore taking your medicine if: You are 65 years of age or older You are using corticosteroids. You may be more likely to have a bleed.used to thin the blood. talk to your doctor or pharmacist before taking Levomax tablets. This is because Levomax tablets can affect the way some other medicines work. This includes medicines you buy without a prescription. This is because it can increase the chance of you getting side effects. when taken with Levomax tablets: Corticosteroids. In particular. including herbal medicines. sometimes called steroids – used for inflammation. Your doctor may need to take regular blood tests to check how well your blood clot. Warfarin . Theophylline . You are more likely to have afit (seizure) if taken with Levomax tablets 79 . azithromycin and Clarithromycin). Special care should be taken when taking either of these medicines with Levomax. You are more likely to have a fit (seizure) if taken with Levomax tablets Ciclosporin . If you have kidney problems. magnesium or aluminum-containing antacids (for acid or heartburn) or sulcralfate (for stomach ulcers). ibuprofen.used after organ transplants. and cimetidine . Driving and using machines You may get side effects after taking this medicine. a spinning feeling (vertigo) or changes to your eyesight. fenbufen. If this happens. ketoprofen and indomethacin. Do not take Levomax tablets at the same time as the following medicines. You may be more likely to get the side effects of Ciclosporin Medicines known to affect the way your heart beats. Some of these side effects can affect you being able to concentrate and your reaction speed. Urine tests for opiates Urine tests may show ‘false-positive’ results for strong painkillers called ‘opiates’ in people taking Levomax tablets. 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. tell them you are taking Levomax tablets. sleepy. for depression (tricyclic antidepressants such as amitriptylineand imipramine) and for bacterial infections (‘macrolide’ antibiotics such as erythromucin. This is because it can affect the way Levomax tablets work: Iron tablets (for anemia). including feeling dizzy.Non-steroidal anti-inflammatory drugs (NSAIDS) .used for gout. Probenecid . This includes medicines used for abnormal heart rhythm (antiarrhythmics such as quinidine and amiodarone). If your doctor is due to take a urine test.used for pain and inflammation such as aspirin. Pregnancy and breast-feeding Do not take this medicine if: You are pregnant. do not drive or carry out any work that requires a high level of attention 80 .used for ulcers and heartburn. your doctor may want to give you a lower dose. including your kidneys or bladder 81 . once or twice each day Urinary tract. do not change the dose yourself. antacids or sulcralfate Do not take these medicines at the same time as Levomax. but ask your doctor Adults and the elderly Sinuses One tablet of Levomax 500 mg. once each day Lungs.How to take Levomax tablets Always take Levomax tablets exactly as your doctor has told you. once each day Pneumonia One tablet of Levomax 500 mg. 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. in people with long-term breathing problems 1/2 tablet or one tablet of Levomax 500 mg. This is because your skin will become much more sensitive to the sun and may burn. 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. 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. 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 microcrystalline cellulose and sodium stearyl fumarate For the tablet coating: hypromellose. 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. titanium dioxide. 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. yellow ferric oxide and red ferric oxide 85 . or if you notice any side effects not listed in this leaflet. Do not use Levomax tablets after the expiry date (EXP) which is stated on the carton and foil. please tell your doctor or pharmacist. hypromellose. These measures will help to protect the environment Further information What Levomax tablets contain The active ingredient is levofloxacin. The other ingredients are: For the tablet core: crospovidone. macrogol. talc. 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.Other side effects include: Lowering in red blood cells (anemia). Medicines should not be disposed of via wastewater or household waste. How to store Levomax tablets Keep out of the reach and sight of children. Each tablet of Levomax 500 mg tablets contains 500 mg of levofloxacin. including pain in the back. Ask your pharmacist how to dispose of medicines no longer required. 86 . per 5ml. Proposed dosage: Oral route 500mg OD for pneumonia 12. namely:- a. Proposed shelf life of the drug: 01 years 13. the tablets are provided in pack sizes of 10 tablets. If you have any questions or are not sure about anything. Name. per tablet. ask your doctor or pharmacist. Store in dry cool place Protect from sun. 11. Total number of technical staff 08 personnals b. Proposed storage conditions of finished product. For Levomax 500 mg. Price of 500 mg tablet= 19 Rs 14.g. Unit price of the drug. etc.What Levomax tablets look like and contents of the pack Levomax tablets are film-coated tablets for oral use. qualification and designation of the persons directly supervising the manufacture of the drug applied for registration. This leaflet does not contain all the information about your medicine. per capsule. and any change shall be properly documented and record maintained by the manufacturer. light and heat Store away from children 15. e. Persons under whose direct supervision and control the drug applied for registration shall be manufactured with the following details. No.Name of equipments that will manufacture of the applied drug: LIST OF EQUIPMENTS Oral Tablet Manufacturing Section Sr. No. 1 2 3 4 Name of Machinery and Equipments Printing Machine (Local) Printing Machine (Manual) Printing Machine (Automatic) K 420 Printing Machine (Automatic) K 550 Quantity 1 2 1 2 87 . 1 2 3 4 5 6 7 Name of Machinery and Equipments Weighing Balance Glen Mixer Fitzpatrick Mill Stainless Steel Spatula Multiple Punching Machine Fluidized Bed Dryer Trolleys Quantity 1 1 1 1 4 4 2 be used in the Oral Tablet Packaging Section Sr.Zohaib Ahmad 17. No. 1 2 3 4 5 6 Name of Machinery and Equipments Turn Table (after air blowing) Air Blower Conveyer (before filling and after filling) Turn Table (after filling and sealing) Labeling Machine Conveyer (packing) Quantity 1 1 1 1 1 1 Over Printing Section Sr. 01.P. Name of Equipments H.A officer) b) Q. 04.C Incharge Jalwaz Tihami (Senior Q. 08.C (Spectra physics U.L. 05. 07. No.S.A) Infrared Spectrophotometer(FTIR) Melting Point Apparatus (Gallenkamp U. under their supervision. Sr. qualification and designation of the persons who will be responsible for the quality control of the drug.K) Moisture Analyzer (Mitsubishi Japan) Precision Balance (Sartorioue) Drying Oven (Mamart) Fludized Bed Dryer (China) pH Meter (Micro processor) 88 . 03. 02. 06.A Incharge Zohaib Ahmad (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.18.Name. Following will be responsible for the completion of various steps. a) Q. Apply the polish/cream properly on floor with clean cloth. Use this moist mop accordingly to clean the floor. 13. 10. 89 . 21-Environment control processing with details. If required use the detergent to remove the spots on the floor for proper cleaning.S. Floor Polishing: After washing allow the floor to air dry. Floor Moping: Squeezed the clean mop and moist it with potable water. 14.A) Automatic Titrator GT-100 (Mitsubishi Japan) Conductivity / TDS Meter (Jenway 4510 England) 20. Use the polishing machine to polish the floor. 11. 15. Drainage and Sewerage: Clean the inside and outsidethe plant drainage and sewerage points by using germicidal agents. 12. Clean the mod after use with potable water. Glass Apparatus Autoclave Incubator Sterile Filtration System U-2800 Double Beam Spectrophotometer (Hitachi Japan) Moisture Balance MB-45 (Ohaus U. We donnot use water in our preparation because it is insoluble in water. Insecticide Spray: Acoording to the sop for pest control and disinfection. 16.Facility of the water processing with specifications.09. Inside base preparation room. Clinically it is a better option because it is more efficacious and less hazards. Clinical justification. 22-Attach the last Inspection Report conducted by the Ministry of Health. N/A 90 . Inside syrup manufacturing area. As given in Chapter-07 24. N/A 23-Clinical data (along with data of clinical trials conducted and safety data of the drug. Outside the raw material in corridor. 26-Any other relevant information that may be required by the Board. with reported side effects and adverse drug reactions in the indigenous community). 25. Dosage form stability profile: Levofloxacin is film-coated and packed in aluminium foil to protect it from heat light and moisture.Following points of outer sewerage are cleaned. • • • • In the washing area of tablet section. 91 . Zohaib Ahmad Production Manager Jalwaz Tihami Quality Control Manager.UNDERTAKING I / We hereby undertake that the above given information is true and correct to the best of my / our knowledge and belief. CHAPTER#13 POST MARKETING SURVEILLANCE 92 . Iron salts. may exceeding 10. It is recommended that preparations containing divalent cations such as iron salts. of Patients: These trials are undertaken in larger population. No. or magnesium-or aluminum-containing antacids are administered concomitantly with Levomax tablets. Phase 4 trials should be constructed to demonstrate. Magnesium-or Aluminum-containing Antacids: Levofloxacin absorption is significantly reduced when iron salts. or magnesium-or aluminum-containing antacids should not be taken 2 hours before or 93 . 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.000 patients.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. Theophylline. Sucralfate: The bioavailability of Levomax tabltes is significantly reduced when administered together with sucralfate. Cyclosporin: The half life of cyclosporin was increased by 33% when coadministered with levofloxacin. However. Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone. This is because both drugs are capable of blocking the renal tubular secretion of levofloxacin. at the tested doses in the study. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). the statistically significant kinetic differences are unlikely to be of clinical relevance. have been reported in patients treated with levofloxacin in combination with a vitamin K 94 . especially in renally impaired patients. Caution should be exercised when levofloxacin is coadministered with drugs that affect the tubular renal secretion such as probenecid and cimetidine. No interaction was found with calcium carbonate. nonsteroidal antiinflammatory drugs. or other agents that lower the seizure threshold. which may be severe. Fenbufen or Similar Non-Steroidal Anti-Inflammatory Drugs: No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. Probenecid and Cimetidine: Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin. Vitamin K antagonist: Increased coagulation tests (PT/INR) and/or bleeding.after Levomax tablet administration. If the patient is to receive both sucralfate and Levomax. it is best to administer sucralfate 2 hours after the Levomax tablet administration. However a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline. or vital disturbances occur. Obtain baseline vital signs. ranitidine. The pharmacokinetics of levofloxacin were not affected to any clinically relevant extent when levofloxacin was administered together with the following drugs: calcium carbonate. Monitor patterns of elimination and stool consistency. Frequently assess patency of IV site and observe for signs of phlebitis during therapy. glibenclamide. warfarin. Notify physician if skin rash occurs.antagonist (e. Coagulation tests. seizures. therefore.g. Meals: There is no clinically relevant interaction with food. lymphocytopenia. PATIENT MONITORING Following parameters should be monitored during therapy. urticaria. 95 . Notify physician if vomiting. fatigue. restlessness. warfarin). Monitor for signs of anaphylaxis (eg. dyspnea. including drug history and any known allergies. itching). increased liver function test results. Levomax tablets may therefore be administered regardless of food intake. and liver function tests. Obtain patient history. and electrolytes. confusion). should be monitored in patients treated with vitamin K antagonists. Monitor vital signs at least bid while administering medication. renal. loose or foul-smelling stools) or if symptoms of CNS stimulation occur (eg. Encourage fluid intake. Monitor for signs of superinfection. Assess for any skin rashes. pharyngeal or facial edema. Obtain baseline CBC. digoxin. Notify physician if symptoms of pseudomembranous colitis occur (eg. tremor. Other relevant information: Clinical pharmacology studies were carried out to investigate possible pharmacokinetic interactions between levofloxacin and some commonly prescribed drugs. 96 . toxic epidermal necrolysis (Lyell’s syndrome) and erythema exsudativum multiforme. hypotension.01 to 0.1% Very rare . paraesthesia. convulsions. rash. agitation. diarrhoea. Rare: bloody diarrhoea which in very rare cases may be indicative of enterocolitis. insomnia.particularly in diabetic patients. Metabolism: Common: nausea. abdominal pain. Very rare: hypoglycaemia.1 to 10% Uncommon . including pseudomembranous colitis. anaphylactic-like shock. Muco-cutaneous. drowsiness. bronchospasm/dyspnoea. dyspepsia.01% Isolated cases Allergic Reactions: Uncommon: pruritus. confusion. hallucinations). Rare: urticaria. Very rare: angio-oedema. Rare: depression.less than 0. Uncommon: anorexia. tremor.0. anaphylactic/-oid reactions may sometimes occur even after the first dose. photosensitisation Isolated cases: severe bullous eruptions such as Stevens Johnson syndrome. vomiting. anxiety.g.dizziness/vertigo.0.1 to 1% Rare .more than 10% Common . Gastro-Intestinal. psychotic reactions (with e. The following frequency rating has been used: Very common . Neurological: Uncommon: headache.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. Achilles tendon). Liver. Cardiovascular: Rare: tachycardia. Very rare: agranulocytosis.g. Isolated cases: haemolytic anaemia.g. disturbances of taste and smell. pancytopenia Others Uncommon: asthenia. Rare: neutropenia. Kidney: Common: increased liver enzyme levels (e. Muscular weakness. fungal overgrowth and proliferation of other resistant microorganisms. tendon disorders including tendinitis (e.g. myalgia. Isolated cases: rhabdomyolysis. visual and auditory disturbances. increase in serum creatinine. thrombocytopenia. Very rare: tendon rupture (e. Very rare: liver reactions such as hepatitis . Uncommon: increase in bilirubin. which may be of special importance in patients with myasthenia gravis. AST). ALT. Achilles tendon).Very rare: hypoaesthesia. due to interstitial nephritis) Blood Uncommon: eosinophilia. 97 . as with other fluoroquinolones this undesirable effect may occur within 48 hours of starting treatment and may be bilateral . acute kidney failure (e. leukopenia.g. hypotension Very rare: shock (anaphylactic) Isolated cases: QT-interval prolongation Musculo-Skeletal: Rare: arthralgia. Isolated cases: Psychotic reactions with self endangering behaviour including suicidal ideation or acts. Levomax tablets must not be used in breast-feeding women. tendonitis or tendon rupture associated with Quinolone use. Levomax tablets must not be used in pregnant women.g.g. dizziness/vertigo. Extrapyramidal symptoms and other disorders of muscular coordination. visual disturbances) may impair the patient’s ability to concentrate and react. CONTRAINDICATIONS Hypersensitivity to Fluoroquinolones. fever. Attacks of porphyria in patients with porphyria PRECAUTIONS Pregnancy: Reproductive studies in animals did not raise specific concerns. driving a car or operating machinery). drowsiness. 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. or any product component.Very rare: allergic pneumonitis. hypersensitivity vasculitis. Psychotic reactions such as acute confusional states and depressive mood changes (these reactions may occur even after the first dose). CLINICAL PHARMACOLOGY/ TOXICOLOGY Not Reported PRODUCT DEFECT REPORTING Not Reported 98 . and therefore may constitute a risk in situations where these abilities are of special importance (e. 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. Effects on ability to drive and use machines: Some undesirable effects (e. Quinolone antibiotics. CHAPTER#14 PRODUCT LINE EXTENTION 99 . Each ml contains 5 mg of levofloxacin.PRODUCT LINE EXTENTION Levomax Infusion: Levomax infusion will available in 100ml unit dose colorless glass bottle. 100 . The Extra Pharmacopoeia.gov/ct2/show/NCT00257049?term=levefloxacin&rank =26 http://emc.gov/ct2/show/NCT00645437?term=levefloxacin&rank =5 http://www. 5th Edition. PhP Pharmaceutical Press AMA Drug Evaluation. Wlliam Andrew Publishing . 6th Edition. A practical guide for candidate drug selection to commercail dosage form: Editor: Mark Gibson. IHS. 29th Edition.gov/ct2/show/NCT00236821?term=levefloxacin&rank =10 http://www.REFERENCES Pharmaceutical Manufacturing Encyclopedia. Norwich.clinicaltrail.clinicaltrail. American Medical Association. Martindale. Volker Buhler. Chicago. Editors: Raymond C Rowe. USA Handbook of Pharmaceutical Manufacturing Formulations. PhP Pharmaceutical Press Reynolds JEF.uk 101 . NY.medicines. Generic Drug Formulations.clinicaltrail. Health Group Handbook of Pharmaceutical Excipients. Paul J Sheskey & Sian C Owen. Compressed Solid Products. 3rd Edition. 2nd edition Pharmaceutical Preformulations and Formuation. Product Package http://www. editor.clinicaltrail.gov/ http://www.org. pharmainfo.org.com/products/100986-85-4.uk/medicine/12796/SPC/Tavanic+500mg+tablets/ http://emc.uk/medicine/3090/XPIL/Tavanic+250mg%2c+500m g+tablets/ http://www.http://emc.pharmascience.com http://www.druginfosys.com http://www.net 102 .drugs.medicines.org.com http://www.htm http://www.com http://www.drugguide.medicines.chemblink.