New Drug Development and Approval Process

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New Drug Development and Approval Process. NEW DRUG DEVELOPMENT PROCESS NEW CHEMICAL ENTITY SOURCES: Organic Synthesis Molecular Modification Isolation from plants Genetic Engineering. PRECLINICAL STUDIES Including Chemistry Physical Properties Biological Pharmacology - PowerPoint PPT Presentation


  • New Drug Development andApproval Process

  • NEW DRUG DEVELOPMENT PROCESSNEW CHEMICAL ENTITYSOURCES: Organic Synthesis Molecular Modification Isolation from plants Genetic Engineering

  • PRECLINICAL STUDIESIncluding Chemistry Physical Properties BiologicalPharmacologyADMEToxicology Preformulation

  • CLINICAL TRIALS Phase I Phase II Phase IIIPRECLINICAL STUDIES (Continued) long term animal toxicity product formulation Manufacturing and controls Package and label design

  • NEW DRUG APPLICATION (NDA) Submission FDA Review Pre-approval Plant inspection FDA action

  • POST MARKETING TRIALS Phase IV Clinical Trialsclinical pharmacology/Toxicologyadditional indications Adverse Reaction Reporting Product Defect Reposting Product Line Extension

  • 4 Phases Of Clinical Studies In Man

    PHASE 1 (Clinical Pharmacology) fewer than 100 healthy people design to determine that the drug is safe and the side effects might be provide basic information about how drug works in the body(Pharmacokinetic activity)

  • PHASE II (Clinical Investigation) several 100 patients disorders evaluate dosage needed detail how and why drug works in the body and side effect it causes the drug must be effective and safe

  • PHASE III (Clinical Trials) larger group of patients (2,000 to 3,000) compare the drug with the existing drugs provide statistics on adverse reaction

  • PHASE IV (Post Marketing Clinical Trials) postmarketing surveillance may be required unexpected reactions are detected, reported, and evaluated new indications for using the drug, problems of people who take the drug

  • Some products, however, have been approved and later removed from the market for safety reasons, including the following:

    Grepafloxacin HCL (Raxar) Brofenac sodium (Duract) Cisapride (Propulsid) Alosetron HCL (Lotrovec) Fenfluramine HCL (Pondimin)

  • Dexfenfluramine HCL (Redux) Terfenadine (Seldane) Cerivastatin (Baycol) Mibefradil (Posicor) Astemizole (Hismanal) Troglitazone (Rezulin)

  • Preclinical ClinicalNDA ReviewPost Marketing Research and Research and DevelopmentSurveillance DevelopmentInitial synthesisAdverse andreaction characterization Phase 1 Phase 2 Surveys/samplingtestingPhase 3Animal testing

    Short term

    Long term Inspection

    Average 61/2Average 7 yearsAverage 1 1/2 years years

    FDA 30-day safety review NDA submitted NDA approval

    Average of approx. 15 years from initial synthesis to approval of NDA

  • Drug Discovery and Drug Design- R and D activities on new Rx drugs for human- OTC drugs, generic drugs, biotechnology products, animal health care drugs, diagnostic products, and medical devices- development of new agents, such as vaccines to protect against poliomyelitis, measles, and influenza

  • - new pharmacologic categories of drugs including oral hypoglycemic drugs effective against certain types of diabetes mellitus - antineoplastic or anticancer drugs,

    - immunosuppressive agents to assist the bodys acceptance of organ transplant- contraceptives to prevent pregnancy- tranquilizers and antidepressant drugs to treat the emotionally distressed

  • New and Important Innovative Therapeutic Agents Approved by FDA

    1. Efavirenz - Sustiva - to treat AIDS2. Didanosine - Videx EC - to treat AIDS3. Tenofovir - Viread - to treat AIDS4. Leuprolide acetate - Eligard prostate cancer5. Triptorelin pamoate - Trelstar - prostate cancer6. Lovastatin - Mevacor - hyperlipidemic7. Treprostinil sodium - Remodulin - pulmonary arterial hypertensive

  • 8. Moxifloxacin HCl - Avelox - infectious disease9. Montelukast sodium - Singulair - chronic asthma10. Tegaserod maleate - Zelnorm - irritable bowel syndrome in women11. Sodium oxybate -Xyrem - cataplexy in patient with narcolepsy12. Galantamine HCl - Reminyl - dementia with Alzheimers disease13. Fondaparinux sodium - Arixtra - deep vein thrombosis14. Voriconazole - Vfend - infectious disease


    Pure organic compound

    Natural or Synthetic

    3. Organometallic

  • These remedial have their origin in essentially 3 ways

    Naturally occurring materials in both plants and animalsExample: Ergot, opium, curare, cinchona

  • 2. Synthesis of organic compounds whose structure are closely related to those naturally occurring compoundsExample: morphine, atropine, cortisone, cocaine

  • 3. Pure synthesis in which no attempt has been made to pattern after a known naturally occurring compounds exhibiting some activityExample: antihistamine, barbiturates, diuretics, antiseptic, etc.

  • Sources of New Drugs

    1. Reserpine - tranquilizers and hypotensive agent - isolated from Rauwolfia serpentina

    2. Periwinkle or Vinca rosea - use as treatment of diabetes mellitus

    3. Vinblastine and Vincristine - Vinca rosea - cancer, including acute leukemia, Hodgkins disease and lymphocytic lymphoma and other malignancies

  • Paclitaxel (Taxol)- Pacific yew tree - ovarian cancer

    Dioscorea - Mexican yams - chemical steroid structure - cortisone and estrogen are semisynthetically produced

    6. Endocrine glands of cattle, sheep, and swine - hormonal substances like thyroid, insulin, and pituitary hormone replacement therapy in the human body

  • Urine of pregnant mares - rich source of estrogen

    8. Animals - serum, vaccines, toxins

    9. Renal monkey tissue - poliomyelitis vaccines

    10. Fluid of chick embryo - mumps and influenza vaccines

  • Duck embryo rubella (German measles)

    12. Skin of Bovine calves inoculated with vaccinia virus- smallpox vaccines

    13. Cell and Tissue cultures - new vaccines for diseases AIDS and cancer

  • 14. Genetic engineering - manipulation of the helix, the spiral DNA chain of life.2 basic technologies that drive the genetic field

    1. Recombinant DNA2. Monoclonal antibody production

  • Gene splicing - can be transplanted from higher species, such as human, into lower bacterium

    to produce proteins

    - human insulin, human growth hormone, hepatitis B vaccine, epoetin-alpha, and interferon are being produced in this manner.

  • 16. Monoclonal antibodies - the ability of the cells with potential to produce a desired antibody and stimulates an unending stream of pure antibody production.Example: Pregnancy testing products

  • In these test, the monoclonal antibody is highly sensitive to binding on one site on the human chorionic gonadotropin (HCG) molecule, a specific marker to pregnancy because in healthy women. HCG is synthesized exclusively by the placenta

  • In medicine: MA are being used to stage and to localize malignant cells of cancer, and it is anticipated that they will be used in the future to combat disease such as lupus erythematosus, juvenile-onset diabetes, and myasthenia gravis

  • 17. Human Gene Therapy - used to prevent, treat, cure, diagnose, or mitigate human disease caused by genetic disorders- Human body contains up to 100,000 genes

    - adenine and thymine (A and T respectively), cytosine and guanine (C and G) respectively) constitute the instructions on a gene.

  • genetic diseases, gene expression may be altered, gene sequences may be mismatched, partly missing, repeated too many times, causing cellular malfunction and disease

    - modification of the genetic material of living cells may be modified outside the body (ex vivo) for subsequent administration or modified within the body ( in vivo) by gene therapy products given directly to the patient

  • the first human gene therapy used was to treat adenosine deaminase (ADA) deficiency, a condition that results in abnormal functioning of the immune system.

    - many companies exploring application of Gene therapy to treat sickle cell anemia, malignant melanoma, renal cell cancer, heart disease, familial hypercholesterolemia, cystic fibrosis, lung and colorectal cancer, and AIDS

  • Goal Drug - In theory, a goal drug

    Would produce the specifically desired effect

    Be administered by the most desired route at minimal dosage and dosing frequency

    Have optimal onset and duration of activity

    Exhibit no side effects

  • Following its desired effect would be eliminated from the body efficiently and completely

    No residual side effect

    It would be easily produced at low cost

    Be pharmaceutically elegant

    9. Physically and chemically stable under various conditions of use and storage.

  • Methods of Drug Discovery

    Although some drugs may be the result of fortuitous discovery, most of drugs are the result of carefully designed research programs of screening, molecular modification, and mechanism-based drug design

  • 1. Random or untargeted screening involves the testing of large numbers of synthetic organic compounds or substances of natural origin for biologic activity

    Purposes: to detect an unknown activity of the test compound or substance to identify the most promising compounds to be studied by more sophisticated nonrandom or targeted screens to determine a specific activity

  • 2. Molecular modification

    - is chemical alteration of a known and previously characterized organic compound (frequently a lead compound) for the purpose of enhancing its useful as a drug

  • PURPOSES:Enhance its specificity for a particular body target siteIncreasing its potencyImproving its rate and extent of absorptionModifying the advantage its time-course in the bodyReducing its toxicityChanging its physical and chemical properties

  • 3. Mechanism-based drug design

    - is a molecular modification to design a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process

  • PURPOSE: The intention is the interaction of the drug with specific cell receptors, enzymes systems, or metabolic process of pathogens or tumor cells, resulting in blocking, disruption, or reversal of the disease process

  • Example of Mechanism-based drug design

    Enalaprilat -Vasotec - inhibits the angiotensin-coverting enzymes that catalyzes the conversion of AI to the vasoconstrictor substance AII. Inhibition of the enzymes results decreased plasma AII, leading to decrease vasopressor effects and lower blood pressure

  • Ranitidine - Zantac - an inhibitor of histamine at the histamine H2-receptors, including receptors on the gastric cells. Used to treat gastric ulcers

    Sertraline - Zoloft - which inhibits the central nervous systems neuronal uptake of serotonin, making the drug useful in the treatment of depression.

  • Lead compound -is a prototype chemical compound which has a fundamental desired biologic or pharmacologic activity.

  • Example of Lead Compound

    Cephalosporin antibiotics - additional H2 antagonists from the pioneer drug Cimetidine

    Large series of antianxiety drugs derived from Benzodiazepine structure and the innovator drug chlordiazepine -Librium.

  • 3. Most drugs exhibit activities secondary to their primary pharmacologic action.

    Example: Finasteride -Proscar was originally developed and approved to treat benign prostatic hyperplasia. Later, the same drug - Propecia was approved at lower recommended dosage to treat male pattern baldness

  • Prodrugs-is a term used to described a compound that requires metabolic biotransformation following administration to yield the desired pharmacologically active compound.

  • Example of Prodrug

    Enapril maleate Vasotec-which, after oral administration, bioactivated by hydrolysis to enaprilat, an ACE inhibitor used in the treatment of hypertension

    Prodrug may be design preferentially for solubility, absorption, biostability and prolonged release

  • Solubility- Enabling the use of specifically desired dosage forms and routes of administration

    Absorption- A drug may be made more water or lipid soluble, as desired, to facilitate absorption via the intended route of administration

  • Biostability- An active drug is prematurely destroyed by biochemical or enzymatic process, the design of a prodrug may protect the drug during its transport in the body

    Prolonged Release- Depending on a prodrugs rate of metabolic conversion to active drug, it may provide prolonged release and extended therapeutic activity

  • NEW DRUG - is any that is not recognized as being safe and effective in the conditions recommended for its use among experts who are qualified by scientific training and experience.A combination of two or more old drugs or a change in the usual proportions of drugs in an established combination product is considered new if the change introduces a question of safety or efficacy.FDAs Definition of a New Drug

  • - A new dosage schedule or regimen, a new rout of administration, new dosage form all cause a drug or drug products status to new and triggers reconsideration for safety and efficacy- A drug need not be a new chemical entity to be considered new. A change in a previously approved drug products formulation or method of manufacture constitutes newness under the law, since such changes can alter the therapeutic efficacy and/or safety of a product.

  • NOMENCLATURE OR NAMING OF DRUGThe task of designating appropriate non-proprietary names for newly found chemical agents rests primarily with the USAN Council.

    The official name for a drug is referred to as the drug nonproprietary or public name

  • in contrast to the proprietary or brand names or trademark names given by the specific manufacturers or distributors of the drug.

    The term generic name, has been used extensively in referring to the nonproprietary names of the drugs. Brand name is registered as a trademark with the United States Patent Office


    In general, drugs exert their effects by one of three means:

    1. By exerting a physical action such as the protective effects of ointments and lotions upon topical application

  • By reacting chemically outside the body cells. Example: antacids counteract excess acidity in the stomach or antibiotics to act against invading pathogenic microorganism.

  • 3. By modifying the metabolic activity of the bodys cell. Majority of the drugs belong to the 3rd manner where brain, liver, kidney, etc. are affected

  • Proposals for Nonproprietary Names

    1. Be short and distinctive in sound and spelling and not be such that it is easily confused with existing names

  • Indicate the general pharmacologic or therapeutic class into which the substance falls or the general chemical nature of the substance if the latter is associated with the specific pharmacologic activity

    3. Embody the syllable or syllables characteristic of a related group of compounds

  • Pharmacology

    pharmaco= drugs; logos = study of; is the science concerned with drugs, their sources, appearance, chemistry, actions, and uses.

  • The term can be expanded to include

    1. Properties2. Biological and physiologic effects3. Mechanism of actions4. ADME

  • Pharmacodynamics = the study of the biochemical and physiologic effects of drugs and their mechanism of action

    Pharmacokinetics = ADME

    Clinical Pharmacology = applies pharmacologic principles to the study of the effects and actions of drugs in humans

  • Pharmacologic profile = In vitro cultures of cells and enzymes systems and in vivo animal models are used to define a chemicals pharmacologic profile

    = Most animal testing is done on small animals, usually rodents (mouse, rats) for a number of reasons including cost, availability, the small amount of drug required for a study,

  • the ease of administration by various routes (oral, inhalation, intravenous) and experience with drug testing in these species

    Animal models: dog or rat - for hypertension; dog and guinea pig - for respiratory effects; dog- for diuretic activity; rabbit - for blood coagulation; mouse and rats - for CNS studies

  • Drug Metabolism

    1. The extent and rate of drug absorption from various routes of administration, including the one intended for human use

    2. The rate of distribution of the drug through the body and the site or sites and duration of the drugs residence

  • The rate, primary and secondary sites, and mechanism of the drugs metabolism in the body and the chemistry and pharmacology of any metabolites

    4. The proportion of administered dose eliminated from the body and its rate and route of elimination

  • Toxicology

    Deals with the adverse or undesired effects of drugsNot all side effects of new drugs to be tested in animals will be detected but the greater the likelihood the effect will also be seen in humans Example: headache

  • Purpose of Safety Evaluation and Toxicity Studies

    The substances potential for toxicity with short-term (acute effects) or long- term use (chronic effects)

    The substances potential for specific organ toxicity

    The mode, site, and degree of toxicity

  • Dose-response relationships for low, high, and intermediate doses over a specified time

    Gender, reproductive, or teratogenic toxicities

    6. The substances carcinogenic and genotoxic potential

  • Acute or Short-Term Toxicity Studies

    These studies are designed to determine the toxic effects of a test compound when administered in a single dose and/or in multiple dose doses over a short period, usually a single day.

  • Animals are observed: eating and drinking habits; weight changes; toxic effects; psychomotor changes; feces and urine are collected.

    Animal death: recorded; study on histology; pathology and statistically evaluated on the basis of dose response

  • Subacute or Subchronic Studies

    Animal toxicity studies of a minimum of 2 weeks of daily drug administration at three or more dosage levels to two animal species are required to support the initial ad ministration of a single dose in human clinical testing.

  • Chronic toxicity studies

    The initial human dose is usually one-tenth of the highest nontoxic dose (in milligrams per kilogram of subjects weight) shown during the animal studies. For drugs intended to be given to humans for a week or more, animal studies of 90 to 180 days must demonstrate safety.

  • If the drug is to be used for a chronic human illness, animal studies 1 year or longer must be undertaken to support human use.Compare the strain, sex, age, dose levels and ranges, routes of administration, duration of treatment, observed effects, mortality, body weight changes, food and water consumption,

  • physical examination (electrocardiography, ophthalmic, examination), hematology, clinical chemistry, organ weights, gross pathology, neoplastic pathology, histopathology, urinalysis, ADME data

  • Carcinogenicity Studies

    Usually component of chronic testing and is undertaken when compound has shown sufficient promise as a drug to enter human clinical trials.Carcinogenicity studies are long term (18-24 months), with surviving animals killed and studied at defined weeks during the test period

  • Data on the causes of animal death, tumor incidence, type and site, and necropsy findings are collected and evaluated

    Preneoplastic lesions and/or tissue-specific proliferation effects are important findings

  • Reproduction Studies

    Reproduction studies are undertaken to reveal any effect of an active ingredient on mammalian reproduction

    Included in these studies are fertility and mating behavior; early embryonic, prenatal, and postnatal development, multigenerational effects, teratology

  • In these studies, the maternal parent, fetus, neonates, and weaning offspring are evaluated for anatomic abnormalities, growth, and development. The animal used in other toxicity studies in reproductive studies, usually the rats.

  • In embryotoxicity studies only, a second mammalian species traditionally has been required. The rabbit is the preferred choice for practically and the extensive background knowledge accumulated on this species.

  • Genotoxicity or Mutagenicity Studies

    Performed to determine whether the test compound can affect gene mutation or cause chromosome or DNA damage. Strains Salmonella typhimurium are routinely used in assays to detect mutations.

  • Early Formulation Studies

    - As a promising compound is characterized for biological activity, it is also evaluated with regard to chemical and physical properties that have bearing on its ultimate and successful formulation into stable and effective pharmaceutical product

  • - This is the area of responsibility of pharmaceutical scientists and formulation pharmacists trained in pharmaceutics

  • Preformulation Studies

    - Each drug substance has intrinsic chemical and physical characteristic that must be considered before the development of a pharmaceutical formulation

    - Among these are the drugs solubility, partition coefficient, dissolution rate, physical form, and stability

  • Drug Solubility

    - A drug substance administered by any route must posses some aqueous solubility for systemic absorption and therapeutic response

    - Poorly soluble compounds (example less than 10mg per ml aqueous solubility) may exhibit incomplete, erratic, and or slow absorption and thus produce a minimal response at desired dosage

  • Partition Coefficient

    A drug partition coefficient is a measure of its distribution in a lipophilic-hydrophilic phase system and indicates its ability to penetrate biologic multiphase system

    Dissolution Rate

    - Is the speed at which a drug substance dissolves in a medium

  • Physical Form

    The crystal or amorphous forms and or the particle size of a powdered drug can affect the dissolution rate, thus the rate and extent of absorption, for a number of drugs


    - The chemical and physical stability of a drug substance alone, and when combined with formulation components, is a critical to preparing a successful pharmaceutical product

  • Initial Product Formulation and Clinical Trial Materials

    - Prepared for Phase 1 and Phase 2 for clinical trials

    - Phase 1 studies, for orally administered drugs, capsules are employed containing the active ingredient alone, without pharmaceutical excipients

  • Phase 2, the final dosage form is selected and developed for Phase 3 trials, this is the formulation that is submitted to the FDA for marketing approval

    Clinical Supplies or Clinical Trial Materials

    - Comprise all dosage formulations used in the clinical evaluation of a new drug

    - This includes the proposed new drug, placebos (inert substances for controlled studies) and drug products against which the new drug is to be compared (compactor drugs or drug products)

  • Blinded Studies

    Are controlled studies in which at least one of the parties (example, patient, physician) does not know which product is being administered

    = Some studies are open label, in which case all parties may know what products are administered

  • In all clinical study programs, the package label of the investigational drug must bear the statement Caution: new drug limited by federal ( or United States) law to investigational use

    - Blister packaging is commonly used in clinical studies, with intermediate labels containing the clinical study or protocol number, patient identification number, sponsor number, directions for use, code number to distinguish between investigational drug, placebo, and or compactor product, and other relevant information


    Full description of new drug

    Where and how it is manufactured

    All quality control information and standards


  • 5. Analytical method



    Efficacy in animals

    9. Persons who will do the clinical studies

  • Content of the IND

    The content of an IND is prescribed in the Code of Federal Regulations and is submitted under a cover sheet (Form FDA-1571):

    Name, address, and telephone number of the sponsor of the drug

    Name and title of the person responsible for monitoring the conduct and progress of the investigation

  • Names and titles of the persons responsible for the review and evaluation of information relevant to the safety of the drug

    Name and address of any contract research organization involved in the study

    Identification of the phase or phases of the clinical investigation to be conducted

  • Introductory statement and general investigational plan

    Description of the investigational plan

    Brief summary of previous human experience with the drug (domestic or foreign)

    Chemistry, manufacturing, control information

    Pharmacology and toxicology information

  • If the new drug is a combination of previously investigated components, a complete preclinical summary of these components when administered singly and any data or expectations relating to the effect when combined

    Clinical protocol for each planned study

    Commitment that an Institutional Review Board has approved the clinical study and will continue to review and monitor the investigation

  • Investigator brochure

    Commitment not to begin clinical investigations until the IND is in effect, the signature of the sponsor or authorized representative, and the date of the signed application

  • Clinical Protocol

    As a part of IND application, clinical protocol must be submitted to ensure the appropriate design and conduct of the investigationClinical Protocol include:

    Statement of the purpose and objectives of the study

    Outline of the investigational plan and study design

  • Estimate of the number of patients to be involved

    Basis for subject selection, with inclusion and exclusion criteria

    Description of the dosing plan, including dose levels, route of administration, and duration of patient exposure

    Description of the patient observations, measurements, and tests to be used

  • Clinical procedures, laboratory tests, and monitoring to be used in minimizing patient risk

    Names, addresses, and credentials of the principal investigators and co investigators

    Locations and descriptions of the clinical research facilities to be used

  • FDA Review of an IND Application

    To protect the safety and rights of the human subjects and to help ensure that the study allows the evaluation of the drugs safety and effectiveness.

  • FDA Drug Classification System

    By Chemical Type

    Type 1 New Molecular entity, not marketed in US

    Type 2 New ester, new salt, or other derivative of an approved active moiety

    Type 3 New formulation of a drug marketed in US

  • Type 4 New combination of two or more compounds

    Type 5 New manufacturer of a drug marketed in US

    Type 6 New therapeutic indication for an approved drug

  • By Therapeutic Classification

    Type P Priority review, a therapeutic gain

    Type S Standard review, similar to other approved drugs

  • Additional Classification

    Type AA For treatment of AIDS or HIV-related disease

    Type E For life-threatening or severely debilitating disease

    Type F Review deferred pending data validation

  • Type G Data validated, removal of F rating

    Type N Nonprescription drug

    Type V Drug having orphan drug status

  • Drug Dosage and Terminology

    The safe and effective dose of a drug depends on different FACTOR:

    Characteristics of the drug substance

    The dosage form and its route of administration

    Variety patient factors - age, body weight, general health status, pathologic conditions

    4. Concomitant drug therapy

  • Usual adult dose - the amount of drug that will produce the desired effect in most adult patients.

    Usual Dosage range - indicates the quantitative range or amounts of the drug that may be prescribed safely within the framework of usual medical practice.

  • Underdosage / Overdosage -doses falling outside of the usual range

    Usual Pediatric dose - dose usually given to children

    Schedule of dosage or Dosage regimen - determined during the clinical investigation and is based largely on a drugs inherent duration of action, its pharmacokinetics, and characteristics of the dosage form

  • MEC Minimum Effective Concentration - An average blood serum concentration represents the minimum concentration that can be expected to produce the drugs desired effects in a patient

    MTC Minimum toxic Concentration - The second level of serum concentration of drugs expected to produce dose-related toxic effects in the average individual

  • MED Median Effective Dose of a drug is the amount that will produce the desired intensity of effect in 50% of the individuals tested.

  • MTD Median Toxic Dose - is the amount that will produce a defined toxic effect in 50% of the individuals tested

    The relationship between the desired and undesired effects of a drug is commonly expressed as the Therapeutic index and is defined as the ratio between a drugs median toxic dose and its median effective dose, TD50/ED50.

  • Some factors of patients considered in determining a drugs dose in clinical investigations and in medical practice include the following:


    Body Weight

    Body Surface Area


    Pathologic State


  • Therapeutic and Toxic Blood Level Concentrations of Some DrugsDrug Substances concentration, mg/L Drug SubstanceTherapeuticToxicLethalAcetaminophen10-204001500Amitriptyline0.5-.200.410-20BarbiturateShort Acting1710Intermediate1-510-3030Long Acting~1040-6080-100Dextropropoxyphene0.05-0.25-1057Diazepam0.5-2.55-20:50Digoxin0.0006-0.00130.002-0.009--Imipramine0.05-0.160.72Lidocaine1.2-5.06--Lithium4.2-8.313.913.9-34.7Meperidine0.6-0.65530Morphine0.1--0.05-4Phenytoin5-2250100Quinidine3-61030-50Theophylline20-100----

  • Therapeutic Indices For Various Drug Substances

    Less Than 5Between 5 and 10Greater Than 10

    AmitriptylineBarbituratesAcetaminophenChlordiazepoxideDiazepamBromideDiphenhydramineDigoxinChloral hydrateEthchlorvynolImipramineGlutethimideLidocaineMeperidineMeprobamateMethadoneParaldehydeNortriptylineProcainamidePrimidonePentazocineQuinidineThioridazinePropoxyphene

  • Routes Of Drug AdministrationTERMSITE oralmouthperoral (per os, p.o.) gastrointestinal tract via mouthsublingualunder the tongueparenteralother than GIT (by injection)intravenousveinintraarterialartery

  • intracardiacheartintraspinal/intrathecalspineintraosseousboneintraarticularjointintrasynovialjoint-fluid areaintracutaneous/intradermalskinsubcutaneous beneath the skinintramuscularmuscleTERMSITE

  • Routes Of Drug Administration


    epicutaneous (topical)skin surfacetransdermalskin surfaceconjunctivalconjunctiva

  • intraoculareyeintranasalnoseauralearintrarespiratorylungrectalrectumvaginalvaginaurethralurethraTERMSITE

  • Drug Product Labeling (Package Inserts)1. Description of the product2. Clinical Pharmacology3. Indications and usage4. Contraindications5. Warnings

  • Precautions

    Adverse reactions

    Drug abuse and Dependence

    Over dosage

    Dosage and Administration

    11. How supplied

  • Supplemental, Abbreviated, and Other Applications

    Supplemental New Drug Application

    Abbreviated New Drug Application

    Biologics License Application

    Animal Drug Applications

    Medical Devices