new drug development and approval process

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

ADME

Toxicology

• Preformulation

CLINICAL TRIALS• Phase I• Phase II• Phase III

PRECLINICAL 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 Trials

clinical pharmacology/Toxicology

additional 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 Clinical NDA Review Post Marketing Research and Research and DevelopmentSurveillance Development

Initial synthesis Adverse and reaction characterization Phase 1

Phase 2 Surveys/sampling

testing

Phase 3

Animal testing

Short term

Long term Inspection

Average 61/2 Average 7 years Average 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 body’s 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

Alzheimer’s disease13. Fondaparinux sodium - Arixtra - deep vein

thrombosis14. Voriconazole - Vfend - infectious disease

SOURCES Of DRUGS

1. Pure organic compound

2. Natural or Synthetic

3. Organometallic

These remedial have their origin in essentially 3 ways

1. Naturally occurring materials in both plants and animals

Example: Ergot, opium, curare, cinchona

2. Synthesis of organic compounds whose structure are closely related to those naturally occurring compounds

Example: morphine, atropine, cortisone, cocaine

3. Pure synthesis in which no attempt has been made to pattern after a known naturally occurring

compounds exhibiting some activity

Example: 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, Hodgkin’s disease and lymphocytic lymphoma and other malignancies

4.Paclitaxel (Taxol)- Pacific yew tree - ovarian cancer

5.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

7. 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

11.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

15. 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

1.Would produce the specifically desired effect

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

3.Have optimal onset and duration of activity

4.Exhibit no side effects

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

6. No residual side effect

7. It would be easily produced at low cost

8. 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:

1. Enhance its specificity for a particular body target site

2. Increasing its potency

3. Improving its rate and extent of absorption

4. Modifying the advantage its time-course in the body

5. Reducing its toxicity

6. Changing 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

1.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

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

3. Sertraline - Zoloft - which inhibits the central nervous system’s 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

1. Cephalosporin antibiotics - additional H2 antagonists from the pioneer drug Cimetidine

2. 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.

FDA’s 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 product’s 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 product’s 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 DRUG

The 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

CATEGORY OR USE

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

2. 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 body’s 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

2.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 chemical’s 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 drug’s residence

3.The rate, primary and secondary sites, and mechanism of the drug’s 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 drugs

Not 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

1.The substance’s potential for toxicity with short-term (acute effects) or long- term use (chronic effects)

2.The substance’s potential for specific organ toxicity

3.The mode, site, and degree of toxicity

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

5.Gender, reproductive, or teratogenic toxicities

6. The substance’s 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 subject’s 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 drug’s 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

Stability

- 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

INVESTIGATIONAL NEW DRUG

1.Full description of new drug

2.Where and how it is manufactured

2.All quality control information and standards

4.Stability

5. Analytical method

6. Pharmacology

7. Toxicology

8. 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 drug’s 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:

1.Characteristics of the drug substance

2.The dosage form and its route of administration

3.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 drug’s 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 drug’s 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 drug’s median toxic dose and its median effective dose, TD50/ED50.

Some factors of patients considered in determining a drug’s dose in clinical

investigations and in medical practice include the following:

• Age

• Body Weight

• Body Surface Area

• Sex

• Pathologic State

• Tolerance

Therapeutic and Toxic Blood Level Concentrations of Some Drugs

Drug Substances concentration, mg/L Drug Substance Therapeutic Toxic Lethal

Acetaminophen 10-20 400 1500

Amitriptyline 0.5-.20 0.4 10-20

Barbiturate

Short Acting 1 7 10Intermediate 1-5 10-30 30Long Acting ~10 40-60 80-100

Dextropropoxyphene 0.05-0.2 5-10 57

Diazepam 0.5-2.5 5-20 :50

Digoxin 0.0006-0.0013 0.002-0.009 --

Imipramine 0.05-0.16 0.7 2

Lidocaine 1.2-5.0 6 --

Lithium 4.2-8.3 13.9 13.9-34.7

Meperidine 0.6-0.65 5 30

Morphine 0.1 --0.05-4

Phenytoin 5-22 50100

Quinidine 3-6 10 30-50

Theophylline 20-100 -- --

Therapeutic Indices For Various Drug Substances

Less Than 5 Between 5 and 10 Greater Than 10

Amitriptyline Barbiturates Acetaminophen

Chlordiazepoxide Diazepam Bromide

Diphenhydramine Digoxin Chloral hydrate

Ethchlorvynol Imipramine Glutethimide

Lidocaine Meperidine Meprobamate

Methadone Paraldehyde Nortriptyline

Procainamide Primidone Pentazocine

Quinidine Thioridazine Propoxyphene

Routes Of Drug Administration

TERM SITE

oral mouth

peroral (per os, p.o.) gastrointestinal tract via mouth

sublingual under the tongue

parenteral other than GIT (by injection)

intravenous vein

intraarterial artery

intracardiac heartintraspinal/intrathecal spineintraosseous boneintraarticular jointintrasynovial joint-fluid areaintracutaneous/intradermal skinsubcutaneous beneath the skinintramuscular muscle

TERM SITE

Routes Of Drug Administration

TERM SITE

epicutaneous (topical) skin surface

transdermal skin surface

conjunctival conjunctiva

intraocular eyeintranasal noseaural earintrarespiratory lungrectal rectumvaginal vaginaurethral urethra

TERM SITE

Drug Product Labeling (Package Inserts)

1. Description of the product

2. Clinical Pharmacology

3. Indications and usage

4. Contraindications

5. Warnings

6.Precautions

7.Adverse reactions

8.Drug abuse and Dependence

9.Over dosage

10.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