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Zohaib Ahmad(Roll#14) Jalwaz Tihami(Roll#20) Azeem Imam(Roll#25) Rizwan Rashid(Roll#43) Ali Tariq(Roll#136)
Sir Ikram Ullah Khan
B-Pharm, M.Phil, MS (TQM), R.Ph.
COLLEGE OF PHARMACY GC UNIVERSITY FAISALABAD
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
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.
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
In Phase III. Testing includes observation and careful documentation of how the drug acts in the body -. this phase usually requires one to four years of testing. Clinical testing is usually described as consisting of Phase I. community advocates and others that ensures a clinical trial is ethical and the rights of study participants are protected. Phase I studies are designed to verify safety and tolerability of the candidate drug in humans and typically take six to nine months.how it is absorbed. In each successive phase. These are the first studies conducted in humans. • Phase III Clinical Studies. Phase II and Phase III clinical studies. 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. An IRB is an independent committee of physicians. one of which receives the investigational drug. A small number of subjects. • Phase I Clinical Studies. distributed. most Phase II studies are double-blinded. this phase of development generally takes from six months up to three years. Depending upon the type of investigational drug and the condition it treats. or randomly divided into groups. In addition.volunteers sign prior to participating in a clinical study. increasing numbers of patients are tested. Phase III studies provide expanded testing of effectiveness and safety of an investigational drug. Phase II studies are designed to determine effectiveness and further study the safety of the candidate drug in humans. meaning that neither patients nor researchers evaluating the compound know who is receiving the investigational drug or placebo. Most Phase II clinical trials are randomized. • Phase II Clinical Studies. Depending upon the type of drug candidate and the condition it treats. usually from 20 to 100 healthy volunteers. usually in randomized and blinded clinical trials. take the investigational drug for short periods of time. metabolized and excreted. This testing determines safety and effectiveness of the drug in treating the condition and establishes the minimum and maximum effective dose. Testing is conducted with up to several hundred patients suffering from the condition the investigational drug is designed to treat. safety and efficacy testing is conducted with several hundred to 7 .
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. marketed drugs may continue for several months to several years. the purpose is to ensure the safety and effectiveness of marketed drugs 8 .) and MAAs (in the U. New Drug Application (NDA)/Marketing Authorization Application (MAA): NDAs (in the U. • Post-Approval Studies.K. At the conclusion of successful preclinical and clinical testing. pharmaceutical companies may conduct additional studies. Post-approval studies test a marketed drug in new age groups or patient types.S.thousands of volunteer patients suffering from the condition the investigational drug treats. Phase IIIb trials. or to the applicable regulatory authorities in other countries. • Phase IIIb/IV Studies. 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.) approves a new drug. Late-stage drug development studies of approved.S. including Phase IIIb and Phase IV studies. this series of documents is submitted to the FDA in the U. As with all stages of drug development testing.) are examples of applications to market a new drug. DOES TESTING CONTINUE AFTER A NEW DRUG IS APPROVED? After the FDA (or other regulatory agency for drugs marketed outside the U. recommended or suggested in the labeling.S. Such applications document safety and efficacy of the investigational drug and contain all the information collected during the drug development process. 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. which often begin before approval. Obtaining approval to market a new drug frequently takes between six months and two years. Some studies focus on previously unknown side effects or related risk factors.
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 .
is than converted into levofloxacin. This chemistry provides a short and efficient entry to (3S)-3-methyl-1. 14 . through a series of steps.4-benzoxazine 19. a late stage intermediate in the synthesis of levofloxacin.4benzoxazines (and quinoxalines and 1. This intermediate.2-Cyclic sulfamidates undergo efficient and regiospecific nucleophilic cleavage with 2-bromophenols (and related anilines and thiophenols). followed by Pd(0)mediated amination to provide an entry to substituted and enantiomerically pure 1.SYNTHESIS OF LEVOFLOXACIN Levofloxacin is a synthetic compound and is synthesized as follow. Procedure: 1.4-benzothiazines).
CHAPTER#04 PRECLINICAL STUDIES Chemistry Physical Properties Biological Properties • Pharmacology • Pharmacokinetics • Toxicity UNIT-1: 15 .
05.carboxylic acid hemihydrate. 16 . 2. 3.dihydro -3.6.methyl.methyl.1piperazinyl) –7 – oxo -7H – pyrido [1. 4 benzoxazine. This in vitro chelation potential has the following formation order: Al+3>Cu+2>Zn+2>Mg+2>Ca+2. 3 -de].1. ophthalmic Molecular Weight: 370.11-tetraene-11-carboxylic acid Chemical Formula: (-) . Empirical Formula: C18H20FN3O4 ½H2O Routes: Oral.13] trideca-5(13).1.8.10.(4.(S). IV.6.CHEMISTRY OF LEVOFLOXACIN IUPAC-Name: (S)-7-fluoro-6-(4-methylpiperazin-1-yl)-10-oxo-4-thia-1-azatricyclo [184.108.40.206 fluoro. Stable Coordination Compounds: Levofloxacin has the potential to form stable coordination compounds with many metal ions.3.
Structural Formula of Levofloxacin UNIT-2: 17 .
Levofloxacin is considered soluble to freely soluble in this pH range. Above pH 6.8.7.com/products/100986-85-4. Stability: Stable under ordinary conditions Melting Point: 218 ºC (http://www. the solubility increases rapidly to its maximum at pH 6. the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.7 (272 mg/mL) and is considered freely soluble in this range. Above pH 5.chemblink. the solubility of levofloxacin is essentially constant (approximately 100 mg/mL). as defined by USP nomenclature.PHYSICAL PROPERTIES Appearance: Levofloxacin is a light yellowish-white to yellow-white crystal or crystalline powder.8. Physical State: crystalline powder Odour: Odourless UNIT 3: 18 .6 to 5.9.htm) Solubility: Insoluble in water The data demonstrate that from pH 0.
It functions by inhibiting DNA gyrase. and are toxic to cultured cells and in vivo tumor models.BIOLOGICAL PROPERTIES These biological properties are based on pre-clinical studies that are carried out in animals. which is an enzyme necessary to separate replicated DNA. 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. In particular. Although the quinolone is highly toxic to mammalian cells in culture. Pharmacokinetics: Absorption: 19 . (A) PHARMACOLOGY: Pharmacotherapeutic Group: Quinolone Antibacterials. Quinolone-induced DNA damage was first reported in 1986. The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. a type II topoisomerase. Mechanism of action:(Chemical Basis) Levofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. Fluoroquinolones Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-) enantiomer of the racemic drug substance ofloxacin. thereby inhibiting cell division. and topoisomerase iv.
Peak plasma concentrations usually attained 1-2 hours after an oral dose. including skin. Approximately 87% of an oral dose eliminated in urine and <4% eliminated in feces. Half-life Terminal elimination half-life approximately 6-8 hours after oral administration. Elimination Route Eliminated principally as unchanged drug in urine. Distribution: Extent Widely distributed into body tissues and fluids. blister fluid. Steady-state plasma concentrations attained within 48 hours with once-daily regimen.Bioavailability Approximately 99%. (B) TOXICOLOGICAL STUDIES: 20 . and lungs. Rapidly absorbed from GI tract. Elimination: Metabolism Undergoes limited metabolism to inactive metabolites. Plasma Protein Binding 24-38% bound to serum proteins. It is also distributed into CSF.
The NOELs were concluded to be 30 and 62.5 mg/kg/day after 1 and 6 months respectively. no toxicological changes were observed 21 . no toxicological changes in clinical signs. Repeated dose toxicity: Studies of one and six month’s duration by gavage have been carried out in the rat and monkey. in the central nervous system and fat. 800 mg/kg/day and 20. and the maximum serum concentration (2. hematology. Doses were 50. respectively. diarrhoea and decreased urinary pH in some animals at this dose. when administered orally to rats at a dose of 20 mg/kg. The “ No Observed Adverse Effect Levels” (NOEL) in the six-month studies were concluded to be 20 and 62. At a dose of 800 mg/kg.5 mg/kg/day in the rat and monkey respectively. 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. 320 mg/kg/day for 1 and 6 months in the rat and 10. 62.5 hours after administration. levofloxacin concentration in almost all tissues of the body were higher than the serum level. decreased neutrophil count and slight degeneration of the articular cartilage of limb joint were observed. except for the level. 25.5 ug/ml) was reached 0. 100 mg/kg/day and 10. 30. 80. however. increased M/E ratio of bone marrow cells. Toxicity after oral dosing in the monkey was minimal with reduced body weight at 100 mg/kg/day together with salivation. Subacute Toxicity: Following 4-weeks oral administration to rats. was absorbed primarily from the small intestine. 200.Levofloxacin.5 mg/kg/day for 1 and 6 months in the monkey. Signs of reactions to treatment were minor in the rat with slight effects principally at 200 mg/kg/day and above in reducing food consumption and slightly altering haematological and biochemical parameters. blood chemistry urinalysis and histopathology were observed in the 50 mg/kg and 200 mg/kg administered groups. Drug concentrations in the main organs were high in the kidneys and liver and lowest in the brain. Following 4 weeks oral administration to cynomolgus monkeys. No toxicity was seen in the 6-months study. demonstrating the good transference to tissues.
22 . 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.
CHAPTER#05 PREFORMULATION Bulk Characterization Solubility Analysis Stability Analysis UNIT-1: 23 .
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. DTA measures the temperature difference between the sample and a reference as a function of temperature or time when heating 24 .38. 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).BULK CHARACTERIZATION Molecular Weight: 370. 50% melt and completion) can be registered on a recorder as the melting proceeds. An additional advantage is that the sample size required is only 2-5 mg. Method: By Mass Spectroscopic Method Particle Size: Large Method: By sieving method particle size is determined. it is large in size Melting Point: 218 ºC (http://www.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. Hot stage Microscopy This is the visual observation of melting under a microscope equipped with a heated and lagged sample stage. It is more precise as the phase transitions (first melt.chemblink. and because of the high magnification the values are more accurate. The heating rate is controllable and up to three transitions can be registered.
evaporation and sublimation are obvious changes in state which can be quantified (Fig. However. 8. These are the major reasons for particle size control. typically 0.e. Crystal Habit: Microcrystalline Technique: By SEM. i. to determine crystal morphology (structure and habit). fusion. the distributions are often smaller. DSC is similar to DTA.3). Crystal Habit is observed Microscopy: The microscope has two major applications in pharmaceutical preformulation: Basic crystallography. to ensure good blend homogeneity and rapid dissolution.at a constant rate.5-50 /mi. When no physical or chemical change occurs within the sample then there is neither a temperature change nor input energy to maintain an isotherm. polymorphism and solvates Particle size analysis Most pharmaceutical powders have crystals in the range 0. Crystalline transitions. Confirmation by IR spectroscopy and X-ray diffraction is usually required. A lamp-illuminated mono-objective microscope fitted with polarizing filters above and below the stage is more than adequate. although occasionally. except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference. it measures the enthalpy of transition. Crystal Purity: 25 . with micronized powders and when following solid-solid and liquid-liquid transitions in polymorphism. The major concern in preformulation is polymorphism. However. and the measurement of melting point and other phase changes is the primary diagnostic tool.5-300 /Jim. when phase changes occur then latent heat suppresses a temperature change and the isothermal energy required registers as an electrical signal generated by thermocouples. For most preformulation work a 10 x eyepiece and a 10-x objective are ideal. 10 x 20 may be required.
Although not changing their internal structure. effervescents. A substance that loses water to form a lower hydrate or becomes anhydrous is termed efflorescent. crystals can adopt different external structures. 55% temperate and 87% tropics) can vary widely and continually depending on the weather and air temperature. There are six crystal systems (cubic. depending on the relative humidity (RH). For this reason pharmaceutical air conditioning is usually set below 50% RH. whereas those in dynamic equilibrium with water in the atmosphere are hygro-scopic. which have different internal structures and spatial arrangements. tetragonal. Crystal Morphology Crystals are characterized by repetition of atoms or molecules in a regular threedimensional structure.002% of impurity. The constant sinusoidal change in day and night temperatures is the major influence. Materials unaffected by RH are termed non-hygroscopic. triclinic and hexagonal). This is particularly pertinent at the preformulation stage.g. because early samples of a new drug are inevitably 'dirty' while Improvements in synthetic route are made. and these cyclic changes lead to constant variations in the moisture content of unprotected bulk drug and excipients. which occurs with polymorphism. which are particularly moisture sensitive. are stored and made below 40% RH. and most pharmaceutical compounds are usually either impassive to the water available in the surrounding atmosphere or lose or gain water from the atmosphere. These are extreme cases. Ambient RH (0% poles and desert. e. which is absent in glasses and some polymers. of which five types are recognized: Tabular: moderate expansion of two parallel faces Platy: plates Prismatic: columns Acicular: needle-like 26 . monoclinic. This is known as crystal habit. Hygroscopicity: Hygroscopic A substance that absorbs sufficient moisture from the atmosphere to dissolve itself is deliquescent is called hygroscopic.Thermal analysis has been widely used as a method of purity determination and the USP includes an appendix describing the methods. and very hygroscopic products. Thermal analysis is rapid and will discriminate 0. orthorhombic.
an alternative is to determine the 'angle of spatula' by picking up a quantity of powder on 27 . which tends to transform a prism or isodiametric (granular) crystals to a needle shape. A simple relationship between angle of repose. which changes habit as it changes the degree of supersaturation. The angles of repose given in Table 8. Carr's index and the expected powder flow is shown in Figure 8. Angle of Repose: 22º Explanation: A static heap of powder.6. and this is known as the angle of repose (0). but urea produces an octahedral habit. Naphthalene gives thin plates (platy) if rapidly recrystallized in cold ethanol or methanol. Sodium chloride is usually cubic. 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. When only small quantities of powder are available. the exact value for angle of repose does depend on the method of measurement. Accordingly. The addition of cosolvents or other solutes and ions which change habit by poisoning crystal growth in one or more directions. there is an empirical relationship between 6 and the ability of the powder to flow.14 may be used as a guide to flow. Powder Flow Properties: Flow Ability: Good Technique: Flow ability is determined by calculating angle of repose. If any particle temporarily lies outside this limiting angle. whereas slow evaporation yields prisms. inhibiting their growth. with only gravity acting upon it. 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. Cooling rate and agitation. However.Bladed: flat acicular. The crystallizing solvent affects habit by preferential absorption on to certain faces. Resorcinol produces needles from benzene and squat prisms from butyl acetate. Crystal habit can be modified by: Excessive supersaturation. One limitation exists: the angle to the horizontal cannot exceed a certain value. These occur in all six-crystal systems. will tend to form a conical mound.
an increase in crystal size or a more uniform shape will lead to a smaller angle of repose and a smaller Carr's index. when only small quantities of drug are available. A useful empirical guide is given by Carr's compressibility index ('Compressibility' is a misnomer.a Table 8. Of primary importance when handling a drug powder is flow.14 Angle of repose as an indication of powder flow propertiesspatula and estimating the angle of the triangular section of the powder heap viewed from the end of the spatula. This is obviously crude but is useful during preformulation. When limited amounts of drug are available this can be evaluated by measurements of bulk density and angle of repose. These are extremely useful derived parameters to assess the impact of changes in drug powder properties as new batches become available. 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. Changes in particle size and shape are generally very apparent. as compression is not involved): 28 .
Carr's index is a one-point determination and does not always reflect the ease or speed with which the powder consolidates.25 and 1. added glidant normally improves flow. some materials have a high index (suggesting poor flow) but may consolidate rapidly.25 indicates poor flow (= 33% Carr). when the powder flows at pBmin into 29 .25 indicate good flow (= 20% Carr).5.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. Between 1. Rapid consolidation is essential for uniform filling on tablet machines. Indeed. whereas greater than 1.
737. Patent No. 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. 30 .545. respectively. approaching pBmaxJ at compression. Further heating resulted in the formation of anhydrous form β. 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.the die and consolidates. Transformation Kinetics: Heating the hemihydrate form resulted in a removal of the hydrated water to give anhydrous form γ. β. and then the formation of anhydrous form α.S. 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. Non-linearity occurs up to two taps and after 30 taps when the bed consolidates more slowly. γ) and two pseudopolymorphic forms (hemihydrate and monohydrate) of levofloxacin are present. Form γ and form α adsorbed water vapor rapidly under ordinary relative humidity conditions and transformed into the hemihydrate and monohydrate. 5. Heating of the monohydrate form resulted in a removal of the hydrated water to give anhydrous form α. Method: Transformation Kinetics are checked by differential scanning calorimetry (DSC). Polymorphic Forms: Three polymorphic forms (anhydrous α.
the solubility increases rapidly to its maximum at pH 6. as defined by USP nomenclature. Based on comparison to 31 .8. levofloxacin. and ofloxacin was measured in an in vitro Caco-2 assay with previously demonstrated method suitability. Above pH 5.3 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. atenolol. and rhodamine-123). indicating active drug transport. Levofloxacin is considered soluble to freely soluble in this pH range. Above pH 6.8 ± 0. Partion Coefficient: Pka value is 6.7. In comparing absorptive versus secretive in vitro transport.9.Unit-2: SOLUBILITY ANALYSIS Solubility in water:Insoluble The data demonstrate that from pH 0.8. The permeability class and efflux potential were ascertained by comparing test drug results with standard compounds (metoprolol. All 4 quinolones drugs demonstrated concentration-dependent permeability. the solubility decreases and reaches a minimum value (about 50 mg/ mL) at a pH of approximately 6. the tested fluoroquinolones were found to be subject to efflux in varying degrees (ciprofloxacin > lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). The permeability of ciprofloxacin. lomefloxacin. the solubility of levofloxacin is essentially constant (approximately 100 mg/ mL).6 to 5. labetalol.7 (272 mg/ mL) and is considered freely soluble in this range.
whereas lomefloxacin. ciprofloxacin was classified as a low permeability drug. Method and Equipment: Rotating Basket Apparatus is used. Dissolution: Drug exhibit good dissolution properties. 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. Drug is placed in the Rotating Basket Apparatus and the dissolution of compound is determined 32 . levofloxacin.labetalol. The in vitro permeability results matched human in vivo data based on absolute bioavailabilities. and ofloxacin were classified as high permeability drugs.
5% (v/v) triethyl amine in sodium dihydrogen orthophosphate dihydrate (25 mM. The limit of detection and the limit of quantitation for the levofloxacin and its process related impurities were established.8% indicating that the developed LC method was stability indicating. oxidative. Forced degradation studies were performed on bulk sample of levofloxacin as per ICH prescribed stress conditions using acid. slight degradation in acidic stress and no degradation was observed in other stress conditions. water hydrolysis. Validation of the developed LC method was carried out as per ICH requirements. RESULT: Significant degradation was observed during oxidative stress and the degradation product formed was identified by LCMS/MS. The detection was carried out at 294 nm.UNIT-3: STABILITY ANALYSIS Hydrolysis: There is no effect of moisture. pharmaceutical dosage forms in the presence of degradation products and its process related impurities.4 and 99. 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. Stability-indicating RP-HPLC method for levofloxacin in the presence of degradation products. The chromatographic method was optimized using the samples generated from forced degradation studies and the impurity spiked solution. Good resolution between the peaks corresponds to process related impurities and degradation products from the analyte were achieved on ACE C18 column using the mobile phase consists a mixture of 0. thermal stress and photolytic degradation to show the stability indicating power of the method. pH 6. The developed LC method was found to be suitable to check the quality of bulk samples 33 . The stressed test solutions were assayed against the qualified working standard of levofloxacin and the mass balance in each case was in between 99.0) and methanol using a simple linear gradient. base.
of levofloxacin at the time of batch release and also during its stability studies (long term and accelerated stability). 34 .
CHAPTER#06 INVESTIGATIONAL NEW DRUG APPLICTION 35 .
with complete composition of committee i. Informed Consent (English and Urdu )Form Fees 5000. Ethics committee approval of sites. C02841-Health-Other Receipts List of participating countries.Documents required by Ministry of Health for the approval of Clinical Trials in Pakistan Documents Investigator Brochure. GMP Certificate along with CPP/Free Sale Certificate of Country of Origin. 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. 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 .clinical/ Clinical data/ Safety studies. C028-Social Services. Pre. Summary of the Protocol Summary of the IB ( for quick review on drug). (Head of Account) C-Non Tax Revenue C02.e names and designation of members.Receipts from Civil Administration and other Functions. Final protocol. CV’s of Investigators. Adverse Event Reporting Form .
CHAPTER#07 CLINICAL TRIALS 37 .
Than we submitted investigational to FDA. Phase IIA is specifically designed to assess dosing requirements (how much drug should be given).CLINICAL TRIALS Our product is converted into a suitable dosage form. metabolism. Results: We conducted study under careful circumstances by personals trained in clinical pharmacology. Procedure: We administered 1/10 of no effect dose of animals. The clinical research on ranitidine is preceded to phase-2 because phase 1 studies showed promise and no drug reaction. Parmacokinetics and Pharmacodynamic studies of a drug are undertaken to determine its toxicity. distribution and elimination and pharmacological action preferred route of administration and safe dosage. 38 . 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. Duration: Phase-1 survives usually for 1-2 years. of Patients: We selected 20-100 healthy voluntaries for phase 1 trials. All preclinical studies mentioned and took permission for clinical trials. In this phase. which became evident. absorption. This purloins gets stable so we increased the dose gradually and checked the response.
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 . Randomized. No. Open Label. 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. Pharmacokinetics of a drug should be investigated in patients because they may handle it differently from healthy people.Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)). Condition Renal Diseases Study Type Study Design Intervention Drug: Levofloxacin Interventional Phase Phase 2 Treatment. Duration: It took 1-2 years for its completion. Parallel Assignment. of Patients: We recruited hundred of patients for the conformation of phase-1 trials. Aims: This trial aims to demonstrate conclusively efficacy of drug in relation to its safety. 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.
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.FURTHER STUDY DETAILS AS PROVIDED Primary Outcome Measures: Evaluation of the pharmacokinetics of two dosing regimens of Levofloxacin in renally impaired and dialysis patients. Estimated Enrollment: Study Start Date: Study Completion Date: 60 October 2007 April 2009 Detailed Description: In this multiple-dose study conducted at 4 centers. or 750 mg of levofloxacin (q24h or q48h) were based on renal function. Patients were randomized into 1 of 10 treatment groups. Fifty-nine patients were enrolled in the study. Dialysate samples were collected on Day 7 from HD patients immediately before dosing (as 40 . the pharmacokinetics of two dosing regimens of levofloxacin were assessed in medically stable men and women with varying degree of renal function. 500. and a 7 day posttreatment phase (or a follow-up phase for subjects with early study withdrawal). a 7-day open label treatment phase. Secondary Outcome Measures: Safety of two dosing regimens of Levofloxacin in renally impaired and dialysis patients. 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. Blood samples were collected from each patient from Day 1 to Day 14 for pharmacokinetic evaluation. for a total of 6 patients per group. The study consisted of a 21 day pretreatment screening phase. subsequent doses of either 250. All patients received a single 750-mg dose of levofloxacin on Day 1.
g. subsequent doses of Levofloxacin 250 milligram (mg). 12-lead electrocardiograms. 41 . Single 750-mg dose of levofloxacin on Day 1. vital sign measurements. antigen. 500 mg. doses. toxicology. electrocardiograms (ECGs)..dialysis began) and at the end of the dialysis treatment. physical examination. Safety was based on the incidence. HIV. 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. well-controlled diabetes. 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. Patients were confined overnight at the study unit on Days 0. and physical examination findings. hepatitis B and hepatitis C Medically stable based on medical history. and remained confined until the 24 hour blood samples were collected on Days 2 and 8. hypertension) must be on a stable treatment plan (medicines. 1. and severity of treatment-emergent adverse events and on changes in clinical laboratory values (hematology. relationship to therapy. 6. chemistry. and urinalysis). 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. and antibody screens. and 7.
which became evident. We conducted following phase-3 clinical studies 42 . effectiveness and most desirable dosage in treating a specific disease in a large group of subjects. Basically phase-3 involves the comparison between the existing therapies of a particular disease and the new drug. Phase-3 Clinical Trials: The phase-3 studies are intended to assess the drug-s safety.Exclusion Criteria: Allergic reaction to quinolones Known or suspected allergy to heparin Clinically significant ECG or clinical laboratory abnormalities Creatinine clearance <80 mL/min whose medical condition was unstable Creatinine clearance >= 80 mL/min who required concomitant medication during the study Poorly controlled type 1 or type 2 diabetes Patients with creatinine clearance >= 50 mL/min with screening blood pressure outside the normal range (sitting systolic blood pressure <90 or >140 mm mercury [Hg] or diastolic blood pressure <60 or >90 mm Hg) Patients with CLCR <50 mL/min who had sitting systolic blood pressure <90 or >160 mm Hg. or diastolic blood pressure <60 or >90 mm Hg Required immunosuppressive medications for treatment of immune-mediated renal disease or kidney transplant Pregnant or breastfeeding Results: We conducted study under careful circumstances by personals trained in clinical pharmacology. The clinical research on ranitidine is preceded to phase-3 because phase-2 studies showed promise and no drug reaction.
incidence of adverse events. Active Control. improvement in x-ray findings) at post-therapy (5 .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. Condition Pneumonia Intervention Drug: levofloxacin Phase Phase II Phase III Study Type: Study Design: Interventional Treatment. Active-Controlled. and by type of bacteria. Open Label. 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. Parallel Assignment. an antibiotic.7 days after the last dose of study drug). Randomized. Safety/Efficacy Study A Multicenter. compared with ceftriaxone sodium or cefuroxime axetil in the treatment of adults with pneumonia. changes in physical examination and laboratory tests after treatment with study drug 43 . by patient. Secondary Outcome Measures: Rate of elimination of disease-causing bacteria.
Levofloxacin 500 mg by mouth once daily. and 3 visits for assessment of safety and effectiveness (one visit on Day 2 . 44 . and laboratory tests) are performed throughout the study.14 days.14 days) or cefuroxime axetil (500 mg by mouth twice daily for 7 . open-label.14 days) in adults with community-acquired pneumonia. Treatment duration is 7 . 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. The total duration of patient participation in the study is approximately 6 weeks. one visit [posttherapy] 5 . and changes in x-ray findings. The study consists of 4 visits: one visit for screening and enrollment. The primary efficacy assessment is the clinical response 5 .7 days after the last dose of the study drug. physical examination. 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.2 grams administered into a vein or muscle once daily or in divided doses twice daily for 7 . or cefuroxime axetil (500 mg by mouth twice daily). Safety evaluations (incidence of adverse events. multicenter study to determine the safety and effectiveness of levofloxacin (500 mg once daily by mouth) compared with ceftriaxone sodium (1 . parallel group.7 days after the last dose of study drug. Levofloxacin is an antibacterial agent used for the treatment of many types of infections in adults. and that it will be well tolerated. (categorized as cured.2 grams administered into a vein or muscle once daily or in divided doses twice daily). and one visit [post-study] 21 28 days after the last dose of the study drug).4 [on-therapy]. Cost-effectiveness is also assessed for the study drugs. or failed) based upon changes in signs and symptoms.Estimated Enrollment: Study Start Date: Estimated Study Completion Date: 528 September 2005 January 2007 Detailed Description: This is a randomized. improved. ceftriaxone sodium (1 .
chest pain. cough. shortness of breath.2 grams administered into a vein or muscle once daily or in divided doses twice daily). Results: Levofloxacin 500 mg by mouth once daily is more efficacious as compared to ceftriaxone sodium (1 . decrease in white blood cell count. seizure disorder. or cefuroxime axetil (500 mg by mouth twice daily) 18 Years and older Both No 45 .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. but without improvement or stabilization with that therapy Exclusion Criteria: Previous allergic or serious adverse reaction to any antibiotic similar to those used in this study or to penicillin Collection of pus in the cavity between the lung and the membrane that surrounds it Has cystic fibrosis Has a lung infection due to fungus. bacteria. greenish-yellow mucus produced on coughing. or virus known prior to the start of the study to be resistant to any of the study drugs Has severe kidney failure. or an unstable psychiatric condition. or evidence of decreased lung function during the physical examination Has chest x-ray findings consistent with acute pneumonia Previously received antibiotics for pneumonia if the duration of therapy was <= 24 hours. or if greater than 24 hours.
Condition Pneumonia Study Type: Study Design: Intervention Drug: levofloxacin Interventional Treatment. Double-Blind Randomized Study to Compare the Safety and Efficacy of Levofloxacin 750 mg Once Daily for Five Days vs. Secondary Outcome Measures: Microbiologic eradication rates at posttherapy visit. Double-Blind. Safety/Efficacy Study Multicenter. 46 . Randomized. Clinical response rates (chest xray findings and signs/symptoms) and microbiologic eradication rates at poststudy. Incidence of adverse events. 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. 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.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. Parallel Assignment.
and 31-38 (poststudy visit). skin infections. Chest x-rays and laboratory tests for presence of bacteria are performed during the study. chronic bronchitis. 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. with assessments on study days 12-16. 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 . Safety evaluations (incidence of adverse events. 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. and communityacquired pneumonia. This multicenter. physical examinations. treatment is discontinued if no significant improvement is noted. Levofloxacin. laboratory tests) are performed throughout the study. and 17-21 (posttherapy visits). Patients receive levofloxacin by mouth or through a vein depending on the severity of their pneumonia.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. Patients are assessed after 3 days of treatment. urinary tract infections. Patients showing signs of improvement continue in the study. 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. 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.
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. gender. white blood cell count is significantly increased. 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 . who had been living there < 14 days Fine Class (rating scale used to assess patients' overall condition which includes information such as age. other diseases.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. chest x-ray findings have worsened compared to the initial chest-x-ray. if in a nursing home. 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.
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. WE GIVE CONSTANT REPORTS ON PROGRESS OF EACH PHASE TO THE AUTHORITY. 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.
when administered orally to rats at a dose of 20 mg/kg. and the maximum serum concentration (2.5 ug/ml) 50 .CHAPTER#08 LONG TERM ANIMAL TOXICITY STUDIES LONG TERM ANIMAL TOXICITY STUDIES Levofloxacin. was absorbed primarily from the small intestine.
800 mg/kg/day and 20. No toxicity was seen in the 6-months study. 62. levofloxacin concentration in almost all tissues of the body were higher than the serum level. 51 .5 mg/kg/day in the rat and monkey respectively. Repeated dose toxicity: Studies of one and six month’s duration by gavage have been carried out in the rat and monkey. but salivation. Doses were 50. demonstrating the good transference to tissues.5 mg/kg/day after 1 and 6 months respectively. 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. diarrhoea and decreased urinary pH in some animals at this dose. At a dose of 800 mg/kg. The “ No Observed Adverse Effect Levels” (NOEL) in the six-month studies were concluded to be 20 and 62. 30. 25. except for the level.was reached 0. 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. hematology. The NOELs were concluded to be 30 and 62. slight inhibition of body weight gain and decrease in urine pH were observed at 100 mg/kg. Subacute Toxicity: Following 4-weeks oral administration to rats. Toxicity after oral dosing in the monkey was minimal with reduced body weight at 100 mg/kg/day together with salivation. no toxicological changes were observed at doses of 10 and 30 mg/kg. no toxicological changes in clinical signs. Following 4 weeks oral administration to cynomolgus monkeys. diarrhea.5 mg/kg/day for 1 and 6 months in the monkey. increased M/E ratio of bone marrow cells. in the central nervous system and fat. respectively. 80. 200. 320 mg/kg/day for 1 and 6 months in the rat and 10. 100 mg/kg/day and 10. however. blood chemistry urinalysis and histopathology were observed in the 50 mg/kg and 200 mg/kg administered groups.5 hours after administration. 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. decreased neutrophil count and slight degeneration of the articular cartilage of limb joint were observed.
but salivation and high urinary pH were observed at doses of 80 and 320 mg/kg. In addition. no toxicological changes were observed at doses of 10. and rabbits concurrently treated with adjuvants. Following 26-weeks oral administration to cynomolgus monkeys. 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. guinea pigs. in the absence of metabolic activation.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. Antigenicity: No specific antibody to levofloxacin was produced in mice. dominant lethal tests) did not show any genotoxic potential. Moreover lethal effect to embryos and fetuses. In-vivo tests (micronucleus. mice showed positive reaction. increased feces and enlargement of goblet cells in cecal mucosa were seen. no toxicological changes were observed at a dose of 20 mg/kg. growth retardation in fetuses and neonates or teratogenesis were not observed in rabbits after oral administration at 50 mg/kg. but 52 . sister chromatid exchange. In PCA test using serum of experimentally sensitized animals. unscheduled DNA synthesis. 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. at a dose of 320 mg/kg. Teratogenic study: No effects were observed on fetuses or neonates after oral administration to rats upto 90 mg/kg. 25 and 62.
When levofloxacin was orally administered to young adult dogs (13 months of age) for 7 days. induced mutation frequency test.guinea pigs and rabbits were negative. Effect on kidneys: Following oral administration of upto 120 mg/kg to rabbits for 10 days. mouse bone marrow micronucleus test negative. very mild toxicity was observed at 40 mg/kg. ophthalmological examination and histopathology. and systemic anaphylactic reactions were not observed in guinea pigs. Mutagenicity: Chromosomal aberration test and sister chromatid exchange test using cultured Chinese and HGPRT sister test. Juvenile dogs were more susceptible to the chondrotoxicity. Phototoxicity test: 53 . unscheduled test. no abnormalities were observed in renal function and morphology. However. in adult dogs aged 18 months in which the drug was administered for 14 days. no toxicity was observed at a high dose of 30 mg/kg. Effect on eyes: Eye toxicity tests in pigmented rats orally administered 100 mg/kg/day for 14 days showed no changes in electroretiongram. 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. were synthesis However. the reverse mutation 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. hamster chromatid in vivo cell showed exchange test positive results DNA results. and dominant lethal test were negative. in vivo studies for the same items. Moreover.
and auricular thickness was measured. 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). 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). List of excipients: Levomax 500mg film-coated tablets contain the following excipients for a weight of 630mg respectively.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. 56 .
Machinery and Equipments: Weighing Balance Glen Mixer Fitzpatrick Mill Stainless Steel Spatula Multiple Punching Machine Fluidized Bed Dryer Trolleys 57 .
CHAPTER#10 MANUFACTURING PROCESS QUALITY CONTROLS 58 .
and the canister is wheeled to a mixing machine called Glen Mixer.MANUFACTURING PROCESS Levomax tablets of the same dosage amount are manufactured in batches. known as dry granulation or slugging. These units are called slugs. Large batches in sizable manufacturing outlets are filtered 59 . The active ingredient. Mixing blends the ingredients as well as expels air from the mixture. than heated and stirred until a translucent paste forms. the microcrystalline cellulose. 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. Documentation on each batch is kept throughout the manufacturing process and finished tablets undergo several tests before they are bottled and packaged for distribution. is as follows: Weighing: The active ingredient-levofloxacin. The procedure for manufacturing levomax tablets. the necessary ingredients are mixed and compressed into units of granular mixture called slugs. which are generally from 7/8 to 1 inches (2. and are compressed again into numerous individual tablets.22 to 2. a part of binder-methyl hydroxypropyl cellulose and a part of lubricant -sodium steryl fumerate are next poured into one sterile canister. Dry Screening: Next.54 cm) in size. Slugging: The mixture is than mechanically separated into units. small batches of slugs are forced through a mesh screen by a handle-held stainless steel spatula. The slugs are than filtered to remove air and lumps. After careful weighing. Mixing: Sodium steryl fumerate is dispensed into cold purified water.
This punch descends into the die compressing the mixture into a tablet. the mixture runs through a feed line into a number of die cavities that are situated on a large steel plate. it becomes very important to use the most optimized coating formulation in order to get the best results. On a rotary tablet machine. 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. while roller-activated punches beneath the die cavities lift up and eject the tablets from the die platform. elasticity of the resultant film and the film tablet surface interaction. The optimization of film coating may be necessary to improve adhesion of the coating to the core. The remaining lubricant is added to the mixture. Rollers on top of upper punches press the punches down onto the die cavities. This solution is sprayed on a rotating. to decrease bridging of intagliations. The coating liquid contains a polymer in suitable liquid medium together with other ingredient such as pigments and plastesizers. to increase coating hardness or to improve any other property that the formulator deems deficient. rotate in sequence with the rotation of the die cavities. The development scientist has to consider three major factor which affect the film quality –tensile strength of the film coating formulation. The lubricant keeps the mixture from sticking to the tablet machine during the compression process. Due to these considerations. Film coating involves the deposition. On single punch machines. compressing the mixture into tablets. both above and below the die cavities. 60 . After this. Coating: Film coating.through machine called Fitzpatrick mill. The plate revolves as the mixture is dispensed through the feed line. the powder is compressed into tablet with the help of a punch. 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. which is blended gently in a rotary granulator and sifter. the mixture is fed into one tablet mold (called a die cavity) by a feed shoe. Punches. rapidly filling each die cavity. of a thin film of polymer formulation around each tablet core.
mixed tablet bed. 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. The drying condition results in the removal of the solvent leaving a thin deposit of a coating material around each tablet core.0 bar 20 RPM 2.0 bar 61 .
62 . weighing 2.5mm 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. The volume of liquid is such that when the assembly is in highest position. unmoisture core sieve only fragments of coating remain on screen. one in the center and other four spaced equally on the circle of radius 6 mm from the center of the disc.181. Wall thickness is about 2mm. e) The assembly is suspended in a specific liquid medium.20.359. d) The plates are held rigidly in position and 77. c) The tubes are held vertically by two separate and superimposed rigid plastic plates 90mm in diameter and 6 mm thick. No residue remain on screen If there is a residue. each 20.85 mm in diameter and 9. Test: a) A riged basket rack assembly supporting six cylindrical transperant tubes 7580 mm long. it consist of a soft mass having no palpably firm. Disintegration is considered to be achieved when. 21.5 mm in internal diameter.65 mm thick.8-3.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. b) A cylindrical disk for each tube.2g pierced with 5 holes.55-20. made for transparent plastic with a related density of 1. the wire mesh is atleast 15mm below the surface liquid and when the assembly is in lowest position.
Method: Unless otherwise stated in the individual monograph. with 6 holes each about 24mm in diameter equidistant from the center of the plates and equally spaced from one another. Adjust the apparatus so that it descends to 1±0. 2. The tablet has passed the tst if all 6 have disintegrated. the harder the tablet is. In general tablets should be sufficiently hard to resist breaking during normal handling and yet soft enough to disintegrate properly after swallowing. 3. Procedure: 1. Generally the greater the pressure applies. Suspend the assembly in the beaker containing the specified liquid and operate the apparatus for the specified time. 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. if prescribed. Use the medium as specified and proceed as directed in the individual monograph. The tubes are held in vertical position by two plastic plates. Special dedicated hardness 63 . Disintegration Test: Apparatus: Basket Rack Assembly Description: The basket rack assembly consist of six open glass tubes each 7. introduce one tablet into each of the 6 tubes and. Remove the assembly from the liquid.75±0. add the disc to each tube. each about 9mm in diameter and 6mm in thickness.25cm long having inside diameter of approximately 21.1cm from the bottom of the vessel on the downward stroke. 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. Although the granulation also have a baring on hardness.5mm and wall approximately 2mm thick.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.
Unless otherwise stated in the monograph. Tablet Thickness: The thickness of a tablet is determined by The diameter of the die. If one or more units don’t meet these criteria. Content Uniformity: By the USP method. care must be exercised to employ the same factors ogf fill. The USP contain a test for determination of dosage form uniformity by weight variation for uncoated tablets. During production. 10 tablets are weighed individually and the average weight calculated. thickness. die and pressure. since it can affect 64 . sample tablets are periodically removed for visual inspection and automated physical measurement. 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. 10 dosage units are individually assayed for their content according to the method described in the individual monograph. 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 degree of pressure affects not only thickness but also hardness of the tablets. Multifunctional automated equipments can determine weight. The amount of fill permitted to enter the die. 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 tablets are assayed and the contents of active ingredient in each of the 10 tablets are calculated assuming homogeneous drug distribution. In this test.tester or multifunctional systems are used to measure the degree of force required to break the tablet. hardness is perhaps the more important criteria. hardness and diameter of the tablet. additional tests as prescribed in the USP are required. The volume fill is adjusted with the first few tablets to yield the desired weight and content.
Thus.disintegration and dissolution. Tablet thickness can be measured by hand gauge during production or by automated equipment 65 . it is doubly important to control pressure. for tablets of uniform thickness and hardness.
CHAPTER#11 PACKAGE AND LABEL DESIGN 66 .
Packaging Material Length Width No. the carton can be designed as a dispenser carton by including a perforated area into the carton. 67 . For multiple unit packs. There are a great many styles of folding cartons available at numerous specialized features that can be added to these designs styles. Registration No. of Tablets per Blister Tablet Strength Batch 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. Although some simple styles dcan be ordered as of –the. The user exposes the product for easy removal by their customer using the perforated section.4cm 6.5cm 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.shelf items. Manufacturing Date Expiry Date Manufactured by Aluminium Foil 10. Other specifications are given below.PACKAGE AND LABEL DESIGN PACKAGE DESIGN PRIMARY PACKAGING: Tablets after manufacturing was packed into aluminum foil.
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) 14.6cm 1 cm 11cm 1.6 cm 2.7 cm 7.5 cm 7.2 cm 0. The opening can be located on the top or the side.7cm 0.7cm 7.Packaging Specifications for Unit Carton Dimensions: Dimensions are described based on the opening of an assembled box. depending on how the product will load into the box.5 cm 1cm Text: AS PER REFERENCE 68 .
In case of community acquired Pneumonia and nosocomial Pneumonia. Swallowing. Chemically.500mg CLINICAL PHARMACOLOGY: Machaniism Off Acttiion:: Machan sm O Ac on It involves the inhibition of DNA Gyrase. DOSAGE AND ADMINISTRATION: AN AD Levomax (levofloxacin) 500mg tablets are administered once daily. a chiral fluorinated carboxyquinolone. Metabolism and Elimination: It undergo limited metabolism in body and mainly eliminated from body in unchanged drug in urine. which is essential in the reproduction of bacterial DNA. Peak plasma concentration is attained 1-2 hours after oral dosing. levofloxacin. levomax tablet is administered once daily for 07-14 days. Distribution: Mean volume of distribution ranges from 74-112 litres after single and multiple dosing.LABEL DESIGN Levomax (Levofloxacin) 500mg Tablet DESCRIPTION: Levomax (levofloxacin) is a synthetic broad spectrum anti-bacterial agent. Qualitative and quantitative composition: Levomax(levofloxacin) is available for oral administration in film coated tablets as: Levofloxacin…………………………. The duration of v Le treatment depends on the type and severity of the infection and the sensitivity of the pathogen. Pharmacokiinettiics:: Pharmacok ne cs Absorption: It is rapidly and essentially completely absorbed after oral administraion. let adm ADVERSE REACTIONS: Allergic reaction may include: Rash. Swelling of 70 . THERAPUTIC INDICATION: Levomax (levofloxacin) tablets are indicated for the treatment of community acquired Lev ta Pneumonia and nosocomial Pneumonia. Breathing Problems. It is often bactericidal at concentration equal to or slightly greater than inhibitory concentration. is the pure (-)-(S)enanciomer of the racmic drug substance ofloxacin.
or Tongue. Drowseness. Feeling Sick (nausea) and Diarrhea. NURSING MOTHERS: No adequate and well-controlled studies. Face. Keep out of the reach of children. Nausea and Diarrhea. PRECAUTIONS: Tablet should be swallowed without crushing. Throat. Paresthesia. LOGO: Kenstars Pharmaceuticals 71 . Sleeping Problems. adolescents and in patients with a history of hypersensitivity to this drug.Your Lips. It should be discontinue if the patient experiences pain. Skin rash and Itching. Protect from sunlight and moisture. It may be taken during meal and between meals. Arthralgia. It should not be administered with antacids. STORAGE: Store below 30ºC. PREGNENCY: There are no adequate and well-controlled studies in pregnant women. Fsd. MANUFACTURED BY: Industrial area. CONTRAINDICATIONS: Levomax is contraindicated in children. Should be taken two hours before or after antacids. It should be taken taken with sufficient amount of water. inflammation or rupture of a tendon during therapy. PLEASE READ THE CONTENTS CAREFULLY BEFORE USE.
CHAPTER#12 NEW DRUG APPLICATION (NDA) 72 .
Lahore. Director 73 . Subject: Application for Registration of a Drug for Local Manufacturer Dear Sir. Islamabad.The Secretory. details of which are enclosed. Lahore. Drug Registration Board. We. hereby apply for registration of drug namely LEVOMAX.. Kenstar Pharmaceuticals (Pvt) Ltd. Yours Truly. Thanking You.being fee of registration is enclosed. 8000/. Government of Pakistan. Treasury Challan of Rs. Kenstars Pharmaceuticals (Pvt) Ltd..
Director Kenstar Pharmaceuticals (Pvt) Ltd. Lahore. Kenstars Pharmaceuticals (Pvt) Ltd.UNDERTAKING We. 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. 74 .. Lahore.. We also declare that the name of LEVOMAX bears no resemblance to any other registered drug in Pakistan.
as appropriate and available. Brand (Proprietary) name of the drug: Levomax 3.11. Strength of active ingredient(s) per unit.2009 Place: Lahore Signed: ENCLOSURES OF THE APPLICATION FOR REGISTRATION OF A NEW DRUG OR A NEW COMBINATION / DOSAGE FORM Dosage Form:Tablet 1. Name and address of the manufacturer: Kenstar Pharmaceuticals (Pvt) Ltd. each tablet or 5 ml. Date: 27. I / We Kenstars Pharmaceuticals (Pvt) Ltd. FOR LOCAL MANUFACTURE. contains: 75 . The chemical name(s) and. 2. e.. namely Levomax Tablet containing a new drug molecule for a local manufacturer. Lahore.g.. Lahore hereby apply for registration of the drug.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. etc. the established (generic) and synonyms of the drug: Levofloxacin 4. Details of which are enclosed.
Composition (actives & excepients) including statement of the quantitative composition.38 76 . quality. 5. 9. For the treatment of Pneumonia in adult patients. giving the weight or measure for each active substance used in the manufacture of the dosage form. Formulation: As given on page#56 of chapter-09 Manufacturing: As given on page#58 of chapter-10 8. Proposed route of administration: Oral 7. RAW MATERIAL SPECIFICATIONS Quality Control Laboratory General Profile Name Category Formula Molecular Weight Levofloxacin Flouroquinolone Antibiotic C18H20FN3O4 ½H2O 370.Each film-coated tablet of Levomax contains 500mg of levofloxacin as active ingredient corresponding to 512.46mg of levofloxacin hemihydrate. Recommended clinical use. strength. Pharmacological group: Flouroquinolone Antibiotic 6. Full description of the specifications and analytical methods necessary to assure the identity. purity and homogeneity through out the shelf life of the drug product.
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. 77 . This medicine has been prescribed for you. You may need to read it again.Characteristics/Parameters Physical state Description/Limits Light yellowish-white to yellowwhite crystal or crystalline powder. LEAFLET Levomax® 500 mg tablets Levofloxacin Read all of this leaflet carefully before you start taking this medicine. Store in air tight contained. ask your doctor or your pharmacist. Insoluble in water Positive Complies to B. 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. If you have any further questions. Keep this leaflet.P 20ppm Stable under ordinary conditions.
If you are not sure.Do not pass it on to others. face. 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. What Tavanic tablets are and what they are used for: The name of your medicine is Levomax tablets. in people with long-term breathing problems or pneumonia Urinary tract. Tavanic tablets can be used to treat infections of the: Sinuses Lungs. where you have a long lasting infection Skin and underneath the skin. including muscles. 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'. swallowing or breathing problems. 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. talk to your doctor or pharmacist before taking Levomax tablets. any other quinolone antibiotic such as moxifloxacin. please tell your doctor or pharmacist. Levofloxacin is a ‘quinolone’ antibiotic. This belongs to a group of medicines called antibiotics. swelling of your lips. Levomax tablets contain a medicine called levofloxacin. 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. A tendon is the cord that joins your muscle to your skeleton You are a child or a growing teenager You are pregnant. even if their symptoms are the same as yours. or if you notice any side effects not listed in this leaflet. It works by killing the bacteria that cause infections in your body. 78 . If any of the side effects gets serious. including your kidneys or bladder Prostate gland. It may harmthem.
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’. In particular. You are more likely to have afit (seizure) if taken with Levomax tablets 79 . 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.Take special care with Levomax tablets.used for breathing problems. Your doctor may need to take regular blood tests to check how well your blood clot. Theophylline . You may be more likely to have inflammation and/or breakage of your tendons. Check with your doctor or pharmacistbefore taking your medicine if: You are 65 years of age or older You are using corticosteroids. sometimes called steroids – used for inflammation. This is because it can increase the chance of you getting side effects. Taking other medicines Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines you buy without a prescription. tell your doctor if you are taking any of the following medicines. This is because Levomax tablets can affect the way some other medicines work. when taken with Levomax tablets: Corticosteroids. You may be more likely to have a bleed. Warfarin . talk to your doctor or pharmacist before taking Levomax tablets. Also some medicines can affect the way Levomax tablets work. including herbal medicines.used to thin the blood.
including feeling dizzy. magnesium or aluminum-containing antacids (for acid or heartburn) or sulcralfate (for stomach ulcers). your doctor may want to give you a lower dose. Special care should be taken when taking either of these medicines with Levomax.used for ulcers and heartburn. This is because it can affect the way Levomax tablets work: Iron tablets (for anemia). Driving and using machines You may get side effects after taking this medicine. a spinning feeling (vertigo) or changes to your eyesight. Pregnancy and breast-feeding Do not take this medicine if: You are pregnant. Some of these side effects can affect you being able to concentrate and your reaction speed.used for gout. ketoprofen and indomethacin.used after organ transplants. If you have kidney problems. ibuprofen.used for pain and inflammation such as aspirin. You may be more likely to get the side effects of Ciclosporin Medicines known to affect the way your heart beats. You are more likely to have a fit (seizure) if taken with Levomax tablets Ciclosporin .Non-steroidal anti-inflammatory drugs (NSAIDS) . Urine tests for opiates Urine tests may show ‘false-positive’ results for strong painkillers called ‘opiates’ in people taking Levomax tablets. If this happens. This includes medicines used for abnormal heart rhythm (antiarrhythmics such as quinidine and amiodarone). 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. azithromycin and Clarithromycin). do not drive or carry out any work that requires a high level of attention 80 . sleepy. If your doctor is due to take a urine test. Probenecid . for depression (tricyclic antidepressants such as amitriptylineand imipramine) and for bacterial infections (‘macrolide’ antibiotics such as erythromucin. tell them you are taking Levomax tablets. Do not take Levomax tablets at the same time as the following medicines. and cimetidine . fenbufen.
How to take Levomax tablets Always take Levomax tablets exactly as your doctor has told you. in people with long-term breathing problems 1/2 tablet or one tablet of Levomax 500 mg. do not change the dose yourself. 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. including your kidneys or bladder 81 . You should check with your doctor or pharmacist if you are not sure. but ask your doctor Adults and the elderly Sinuses One tablet of Levomax 500 mg. antacids or sulcralfate Do not take these medicines at the same time as Levomax. This is because your skin will become much more sensitive to the sun and may burn. once or twice each day Urinary tract. 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. once each day Lungs. 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. once each day Pneumonia One tablet of Levomax 500 mg.
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
macrogol. microcrystalline cellulose and sodium stearyl fumarate For the tablet coating: hypromellose. Ask your pharmacist how to dispose of medicines no longer required. Do not use Levomax tablets after the expiry date (EXP) which is stated on the carton and foil. How to store Levomax tablets Keep out of the reach and sight of children. The other ingredients are: For the tablet core: crospovidone. titanium dioxide. 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. Each tablet of Levomax 500 mg tablets contains 500 mg of levofloxacin.Other side effects include: Lowering in red blood cells (anemia). including pain in the back. talc. 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. please tell your doctor or pharmacist. 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. hypromellose. These measures will help to protect the environment Further information What Levomax tablets contain The active ingredient is levofloxacin. Medicines should not be disposed of via wastewater or household waste. yellow ferric oxide and red ferric oxide 85 . or if you notice any side effects not listed in this leaflet.
qualification and designation of the persons directly supervising the manufacture of the drug applied for registration. Unit price of the drug. For Levomax 500 mg. Persons under whose direct supervision and control the drug applied for registration shall be manufactured with the following details. etc. e. Store in dry cool place Protect from sun. Proposed dosage: Oral route 500mg OD for pneumonia 12. per 5ml. 11. If you have any questions or are not sure about anything. Total number of technical staff 08 personnals b. Proposed shelf life of the drug: 01 years 13. Name. per tablet. and any change shall be properly documented and record maintained by the manufacturer. per capsule. ask your doctor or pharmacist. the tablets are provided in pack sizes of 10 tablets. Proposed storage conditions of finished product. Price of 500 mg tablet= 19 Rs 14. light and heat Store away from children 15.What Levomax tablets look like and contents of the pack Levomax tablets are film-coated tablets for oral use.g. This leaflet does not contain all the information about your medicine. 86 . namely:- a.
Name of equipments that will manufacture of the applied drug: LIST OF EQUIPMENTS Oral Tablet Manufacturing Section Sr. 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. No.Zohaib Ahmad 17. 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 . No. 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.
K) Moisture Analyzer (Mitsubishi Japan) Precision Balance (Sartorioue) Drying Oven (Mamart) Fludized Bed Dryer (China) pH Meter (Micro processor) 88 . 07. 05.Name.C Incharge Jalwaz Tihami (Senior Q. 03. Following will be responsible for the completion of various steps.A Incharge Zohaib Ahmad (Senior Q. 06.S.L.C officer) c) Person for physical testing Rizwan Rashid (Analyst) d) Person for chemical testing Azeem Imam (Analyst) e) Person for microbiological and pharmacological testing Ali Tariq (Microbiologist) 19-Description of the equipment to be used for the quality control of the active raw material and the finished products. Sr. Name of Equipments H. No.C (Spectra physics U. 01. under their supervision. qualification and designation of the persons who will be responsible for the quality control of the drug. 08. a) Q. 04. 02.A officer) b) Q.A) Infrared Spectrophotometer(FTIR) Melting Point Apparatus (Gallenkamp U.18.P.
If required use the detergent to remove the spots on the floor for proper cleaning. 10. Floor Moping: Squeezed the clean mop and moist it with potable water. Drainage and Sewerage: Clean the inside and outsidethe plant drainage and sewerage points by using germicidal agents. 21-Environment control processing with details.09. Floor Polishing: After washing allow the floor to air dry. 16. Use this moist mop accordingly to clean the floor. Clean the mod after use with potable water.A) Automatic Titrator GT-100 (Mitsubishi Japan) Conductivity / TDS Meter (Jenway 4510 England) 20. We donnot use water in our preparation because it is insoluble in water. 15.S. 12. 13. 14. Use the polishing machine to polish the floor. Insecticide Spray: Acoording to the sop for pest control and disinfection. Apply the polish/cream properly on floor with clean cloth.Facility of the water processing with specifications. 11. 89 . Glass Apparatus Autoclave Incubator Sterile Filtration System U-2800 Double Beam Spectrophotometer (Hitachi Japan) Moisture Balance MB-45 (Ohaus U.
Following points of outer sewerage are cleaned. 25. Clinically it is a better option because it is more efficacious and less hazards. • • • • In the washing area of tablet section. Inside base preparation room. N/A 23-Clinical data (along with data of clinical trials conducted and safety data of the drug. Clinical justification. N/A 90 . Outside the raw material in corridor. Dosage form stability profile: Levofloxacin is film-coated and packed in aluminium foil to protect it from heat light and moisture. 26-Any other relevant information that may be required by the Board. As given in Chapter-07 24. Inside syrup manufacturing area. 22-Attach the last Inspection Report conducted by the Ministry of Health. with reported side effects and adverse drug reactions in the indigenous community).
UNDERTAKING I / We hereby undertake that the above given information is true and correct to the best of my / our knowledge and belief. 91 . Zohaib Ahmad Production Manager Jalwaz Tihami Quality Control Manager.
CHAPTER#13 POST MARKETING SURVEILLANCE 92 .
Magnesium-or Aluminum-containing Antacids: Levofloxacin absorption is significantly reduced when iron salts. Phase 4 trials should be constructed to demonstrate. or magnesium-or aluminum-containing antacids should not be taken 2 hours before or 93 . of Patients: These trials are undertaken in larger population. It is recommended that preparations containing divalent cations such as iron salts. may exceeding 10.000 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. No. Iron salts. 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. or magnesium-or aluminum-containing antacids are administered concomitantly with Levomax tablets.
at the tested doses in the study. especially in renally impaired patients. Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). or other agents that lower the seizure threshold. Vitamin K antagonist: Increased coagulation tests (PT/INR) and/or bleeding. Fenbufen or Similar Non-Steroidal Anti-Inflammatory Drugs: No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. No interaction was found with calcium carbonate. Probenecid and Cimetidine: Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin. have been reported in patients treated with levofloxacin in combination with a vitamin K 94 . If the patient is to receive both sucralfate and Levomax. However a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline. Sucralfate: The bioavailability of Levomax tabltes is significantly reduced when administered together with sucralfate. it is best to administer sucralfate 2 hours after the Levomax tablet administration. nonsteroidal antiinflammatory drugs. This is because both drugs are capable of blocking the renal tubular secretion of levofloxacin.after Levomax tablet administration. the statistically significant kinetic differences are unlikely to be of clinical relevance. However. Cyclosporin: The half life of cyclosporin was increased by 33% when coadministered with levofloxacin. Caution should be exercised when levofloxacin is coadministered with drugs that affect the tubular renal secretion such as probenecid and cimetidine. which may be severe. Theophylline.
and liver function tests. itching). renal. urticaria. dyspnea. Coagulation tests. restlessness. Notify physician if vomiting. Obtain baseline CBC. or vital disturbances occur. tremor. fatigue. ranitidine. pharyngeal or facial edema.g. Encourage fluid intake. The pharmacokinetics of levofloxacin were not affected to any clinically relevant extent when levofloxacin was administered together with the following drugs: calcium carbonate. Obtain patient history. including drug history and any known allergies. therefore. Obtain baseline vital signs. glibenclamide. Frequently assess patency of IV site and observe for signs of phlebitis during therapy. should be monitored in patients treated with vitamin K antagonists. 95 . PATIENT MONITORING Following parameters should be monitored during therapy. Notify physician if skin rash occurs. confusion). Monitor patterns of elimination and stool consistency. seizures. Monitor vital signs at least bid while administering medication. increased liver function test results. loose or foul-smelling stools) or if symptoms of CNS stimulation occur (eg. warfarin. Monitor for signs of superinfection. Meals: There is no clinically relevant interaction with food. Levomax tablets may therefore be administered regardless of food intake. Notify physician if symptoms of pseudomembranous colitis occur (eg. lymphocytopenia.antagonist (e. and electrolytes. Assess for any skin rashes. digoxin. Other relevant information: Clinical pharmacology studies were carried out to investigate possible pharmacokinetic interactions between levofloxacin and some commonly prescribed drugs. warfarin). Monitor for signs of anaphylaxis (eg.
diarrhoea. rash. Very rare: hypoglycaemia. including pseudomembranous colitis. Rare: urticaria. dyspepsia. Rare: bloody diarrhoea which in very rare cases may be indicative of enterocolitis. Gastro-Intestinal. agitation.0. confusion. insomnia.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. Very rare: angio-oedema. vomiting. Rare: depression. anaphylactic-like shock. Metabolism: Common: nausea.g. 96 . anaphylactic/-oid reactions may sometimes occur even after the first dose.dizziness/vertigo. tremor. The following frequency rating has been used: Very common . abdominal pain.1 to 1% Rare . drowsiness.particularly in diabetic patients. anxiety. hypotension. Uncommon: anorexia. toxic epidermal necrolysis (Lyell’s syndrome) and erythema exsudativum multiforme. paraesthesia.1% Very rare .more than 10% Common . photosensitisation Isolated cases: severe bullous eruptions such as Stevens Johnson syndrome.0. Muco-cutaneous.01% Isolated cases Allergic Reactions: Uncommon: pruritus.less than 0.01 to 0. hallucinations). psychotic reactions (with e. bronchospasm/dyspnoea. convulsions.1 to 10% Uncommon . Neurological: Uncommon: headache.
acute kidney failure (e. disturbances of taste and smell. Achilles tendon). Muscular weakness. hypotension Very rare: shock (anaphylactic) Isolated cases: QT-interval prolongation Musculo-Skeletal: Rare: arthralgia. increase in serum creatinine.g.g. Isolated cases: Psychotic reactions with self endangering behaviour including suicidal ideation or acts. Very rare: liver reactions such as hepatitis . ALT. Liver. leukopenia. pancytopenia Others Uncommon: asthenia. Achilles tendon).g. tendon disorders including tendinitis (e. Cardiovascular: Rare: tachycardia. fungal overgrowth and proliferation of other resistant microorganisms. 97 . Kidney: Common: increased liver enzyme levels (e. Very rare: agranulocytosis. due to interstitial nephritis) Blood Uncommon: eosinophilia. thrombocytopenia.g.Very rare: hypoaesthesia. which may be of special importance in patients with myasthenia gravis. Isolated cases: rhabdomyolysis. Rare: neutropenia. Very rare: tendon rupture (e. as with other fluoroquinolones this undesirable effect may occur within 48 hours of starting treatment and may be bilateral . Isolated cases: haemolytic anaemia. Uncommon: increase in bilirubin. AST). visual and auditory disturbances. myalgia.
CONTRAINDICATIONS Hypersensitivity to Fluoroquinolones. 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. Psychotic reactions such as acute confusional states and depressive mood changes (these reactions may occur even after the first dose).g. hypersensitivity vasculitis. Effects on ability to drive and use machines: Some undesirable effects (e. Extrapyramidal symptoms and other disorders of muscular coordination. visual disturbances) may impair the patient’s ability to concentrate and react. drowsiness. or any product component.Very rare: allergic pneumonitis. dizziness/vertigo. Levomax tablets must not be used in breast-feeding women. Quinolone antibiotics. fever. tendonitis or tendon rupture associated with Quinolone use. CLINICAL PHARMACOLOGY/ TOXICOLOGY Not Reported PRODUCT DEFECT REPORTING Not Reported 98 . 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. Attacks of porphyria in patients with porphyria PRECAUTIONS Pregnancy: Reproductive studies in animals did not raise specific concerns. driving a car or operating machinery). Levomax tablets must not be used in pregnant women.g. and therefore may constitute a risk in situations where these abilities are of special importance (e.
CHAPTER#14 PRODUCT LINE EXTENTION 99 .
100 .PRODUCT LINE EXTENTION Levomax Infusion: Levomax infusion will available in 100ml unit dose colorless glass bottle. Each ml contains 5 mg of levofloxacin.
NY. A practical guide for candidate drug selection to commercail dosage form: Editor: Mark Gibson. Compressed Solid Products. PhP Pharmaceutical Press AMA Drug Evaluation. Volker Buhler.gov/ct2/show/NCT00236821?term=levefloxacin&rank =10 http://www. Wlliam Andrew Publishing . American Medical Association. Editors: Raymond C Rowe.gov/ http://www.org. USA Handbook of Pharmaceutical Manufacturing Formulations. Product Package http://www.gov/ct2/show/NCT00257049?term=levefloxacin&rank =26 http://emc. Generic Drug Formulations. Chicago. Norwich. 5th Edition.gov/ct2/show/NCT00645437?term=levefloxacin&rank =5 http://www.clinicaltrail. The Extra Pharmacopoeia. 29th Edition.clinicaltrail. 6th Edition. editor.uk 101 . Martindale. IHS. 3rd Edition. Paul J Sheskey & Sian C Owen.clinicaltrail.medicines. Health Group Handbook of Pharmaceutical Excipients.REFERENCES Pharmaceutical Manufacturing Encyclopedia. PhP Pharmaceutical Press Reynolds JEF.clinicaltrail. 2nd edition Pharmaceutical Preformulations and Formuation.
pharmascience.htm http://www.uk/medicine/3090/XPIL/Tavanic+250mg%2c+500m g+tablets/ http://www.com/products/100986-85-4.com http://www.org.net 102 .drugs.druginfosys.org.com http://www.chemblink.pharmainfo.com http://www.medicines.com http://www.drugguide.http://emc.uk/medicine/12796/SPC/Tavanic+500mg+tablets/ http://emc.medicines.
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