Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: A Manual for Drug Regulatory Authorities - Regulatory Support Series No. 005: ANNEXES: Annex 3: *Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability 1 : Appendix 1. Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, August 1994)

Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: A Manual for Drug Regulatory Authorities - Regulatory Support Series No. 005
(1998; 213 pages)

Índice de contenido

PREFACE
I. INTRODUCTION
II. PROVISIONS AND PREREQUISITES FOR REGULATORY CONTROL
	A. Political will and commitment
	B. Legislation
	C. Accountability
	D. Resources for the marketing authorization function
	E. Fees and cost recovery
	F. Inventory of existing products on the market
	G. Rational selection of products
	H. Special access schemes
	I. Postmarketing activities
III. OPERATING ACTIVITIES
	A. Transparency
	B. Policies
	C. Administrative procedures
	D. Guidelines for applicants
	E. Model application form
	F. Communication among departments within the DRA
	G. Relationship of evaluators with GMP inspectors
	H. Relationship of evaluators with the quality control laboratories
	I. Functional relationship of the evaluators with the expert advisory body
	J. Relationship of evaluators with the pharmaceutical industry and confidentiality of data
	K. Meetings with applicants
	L. Procedures for appeals
	M. Collaboration with other DRAs
	N. Collaboration with WHO
	O. Use of external experts as evaluators
	P. Timeframes for processing of applications
	Q. Publication of marketing authorization decisions
IV. REVIEW OF APPLICATIONS FOR MARKETING AUTHORIZATION OF MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS
	A. Applicability
	B. Initial decisions on options for premarket evaluation
	C. Evaluation of data on quality
	D. Quality of starting materials
	E. Container labelling
	F. Toxicological, pharmacological and clinical data
	G. Product Information
	H. Interchangeability
V. ISSUE OF WRITTEN MARKETING AUTHORIZATION
VI. VARIATIONS
VII. PERIODIC REVIEWS
VIII. SUSPENSION AND REVOCATION OF MARKETING AUTHORIZATION
GLOSSARY
ABBREVIATIONS
REFERENCES
ANNEXES
	Annex 1: National drug regulatory legislation: guiding principles for small drug regulatory authorities¹
		1. Introduction
		2. Drafting national legislation: points for consideration
		3. Defining the scope of the marketing authorization procedure for medicinal products
		4. Example of a legislative scheme for regulating medicinal products.
			4.1 General considerations
			4.2 Model Legislative text and commentary (in italics)
				I. Administration
				II. Provisional registration/marketing authorization and inventory of medicinal products
				III. Screening of products and issuance of product licences/authorizations
				IV. Other activities requiring authorization/licensing
				V. General provisions
				VI. Interpretation
		Appendix 1. Example of a legislation scheme for registration of pharmacy personnel
		Appendix 2. Guidelines, documents and other regulatory instruments established by WHO to support drug regulatory authorities
		Appendix 3. References and selected bibliography
	Annex 2: *Guidelines for Implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce¹
		1. Provisions and objectives
		2. Eligibility for participation
		3. Requesting a certificate
		4. Issuing a certificate
		5. Notifying and investigating a quality defect
		References
		Appendix 1. Model Certificate of a Pharmaceutical Product
		Appendix 2. Model Statement of Licensing Status of Pharmaceutical Product(s)
		Appendix 3. Model Batch Certificate of a Pharmaceutical Product
		Appendix 4. Glossary and index (not intended to be a formal part of the Scheme).
	Annex 3: *Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability¹
		Introduction
		Glossary
		Part One. Regulatory assessment of interchangeable multisource Pharmaceutical products
			1. General considerations
			2. Multisource products and interchangeability
			3. Technical data for regulatory assessment
			4. Product information and promotion
			5. Collaboration between drug regulatory authorities
			6. Exchange of evaluation reports
		Part Two. Equivalence studies needed for marketing authorization
			7. Documentation of equivalence for marketing authorization
			8. When equivalence studies are not necessary
			9. When equivalence studies are necessary and types of studies required
				In vivo studies
				In vitro studies
		Part Three. Tests for equivalence
			10. Bioequivalence studies in humans
				Subjects
				Design
				Studies of metabolites
				Measurement of individual isomers for chiral drug substance products
				Validation of analytical test methods
				Sample retention
				Statistical analysis and acceptance criteria
				Reporting of results
			11. Pharmacodynamic studies
			12. Clinical trials
			13. In vitro dissolution
		Part Four. In vitro dissolution tests in product development and quality control
		Part Five. Clinically important variations in bioavailability leading to non-approval of the product
		Part Six. Studies needed to support new post-marketing manufacturing conditions
		Part Seven. Choice of reference product
		Authors
		References
		Appendix 1. Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, August 1994)
		Appendix 2. Explanation of symbols used in the design of bioequivalence studies in humans, and commonly used pharmacokinetic abbreviations
		Appendix 3. Technical aspects of bioequivalence statistics
	Annex 4: Model Guidelines on Conflict of Interest and Model Proforma for a Signed Statement on Conflict of Interest
	Annex 5: Model Contract between a Regulatory Authority and an External Evaluator of Chemistry, Pharmaceutical and Bioavailability Data
	Annex 6: Model Application Form for new Marketing Authorizations, Periodic Reviews and Variations, with Notes to the Applicant
	Annex 7: Detailed Advice on Evaluation of Data by the Drug Regulatory Authority
	Annex 8: Ethical criteria for medicinal drug promotion¹
		Resolution WHA41.17 adopted by the Forty-first World Health Assembly, 13 May 1988
		Introduction
		Objective
		Ethical criteria
		Applicability and implementation of criteria
		Promotion
		Advertising
		Medical representatives
		Free samples of prescription drugs for promotional purposes
		Free samples of non-prescription drugs to the general pubic for promotional purposes
		Symposia and other scientific meetings
		Post-marketing scientific studies, surveillance and dissemination of information
		Packaging and labelling
		Information for patients: package inserts, leaflets and booklets
		Promotion of exported drugs
		Appendix: Sample drug information sheet²
	Annex 9: Model marketing authorization letter
	Annex 10: Model List of Variations (Changes) to Pharmaceutical Aspects of Registered Products which may be made without Prior Approval
	Annex 11: *Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms¹
		General
		Definitions
		1. Stability testing
		2. Intended market
		3. Design of stability studies
		4. Analytical methods
		5. Stability report
		6. Shelf-life and recommended storage conditions
		References
		Official, international and national guidelines
		Appendix 1: Survey on the stability of pharmaceutical preparations included in the WHO Model List of Essential Drugs: answer sheet
		Appendix 2: Stability testing: summary sheet

Appendix 1. Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, August 1994)

General

National requirements for equivalence studies for specific drug products differ from country to country. National decisions for the requirement of equivalence studies of a specific drug product can be based on any of the following:

- case by case study;
- criteria established by a national advisory committee; or
- application of the national regulatory guidelines.

A list of examples is presented in Table l. It is intended to be illustrative only, in accordance with the guidelines, and does not represent a formal recommendation.

The list is based on substances and products included in the WHO Model List of Essential Drugs (1), but only includes essential drugs for which in vivo studies are required because of the nature of the dosage form. Some dosage forms, e.g. solutions and injections, have therefore been omitted from the list as they have not been identified as requiring studies in one of the three countries covered.

Examples of decisions on criteria taken by national authorities:

Canada

At present, demonstration of bioequivalence is required for those drugs which are not considered to have been marketed in Canada for their intended purpose(s) for sufficient time, and in sufficient quantity to establish safety and efficacy (new drugs). Bioequivalence may be demonstrated by comparative bioequivalence studies or by clinical studies including, where applicable, acceptable surrogate models. Scientific criteria, similar to those of the European community and Australia, are being developed for deciding in which situations in vivo demonstration of bioequivalence is required for drugs that are not new.

Germany

Over the past years, the National Advisory Committee has taken the decision on the need for a comparative bioavailability/bioequivalence study as a requirement for marketing authorization. These decisions have been based on published data for the drug substance and its dosage form, and on the use of an algorithm. Details of the algorithm, the criteria and the resulting decisions have been published in the German Federal Register. In certain circumstances, the regulatory authority takes decisions on a case-by-case basis.

USA

Drug products introduced before 1938 in USA do not require an approval for marketing and therefore no in vivo equivalence study is needed. The majority of drug products other than solution dosage forms, approved between 1938 and 1962, and known to have potential bioavailability problems, require in vivo equivalence studies. Generally, drug products approved after 1962, with the exception of solution dosage forms require in vivo equivalence studies.

Table 1
Examples of national requirements for equivalence studies¹

¹ +: in vivo studies required; +b: bioequivalence studies; +p: pharmacodynamic studies; +c: clinical trials;

-: no in vivo studies required; ?: decision on the type of in vivo studies pending; o: no information available, no final decision taken, or not available on national market. See also pp. 118-128.

Drug substance	Dosage form	Canada	Germany	USA
bacitracin zinc	ointment, 500 IU + neomycin sulfate, 5 mg/g	o	+c	-
beclometasone dipropionate	inhalation, 50 µg/dose	?	+p+c	+p
benzathine benzylpenicillin	powder for injection, 1.44 g of benzylpenicillin (= 2.4 million IU) in 5-ml vials	o	-	+b
benznidazole	tablet, 100 mg	o	+b	o
benzoic acid	cream, 6% + salicylic acid, 3%	-	+p+c	o
	ointment, 6% + salicylic acid, 3%	-	+p+c	-
benzoyl peroxide	cream, 5%	-	+p+c	-
	lotion, 5%	-	+p+c
benzyl benzoate	lotion, 25%	-	+p+c	o
betamethasone	cream, 0.1 % of betamethasone	+p	+p+c	+p
valerate	ointment, 0.1 % of betamethasone	+p	+p+c	+p
biperiden hydrochloride	tablet, 2 mg	+b	+b	+b
calamine	lotion	-	+p+c	-
calcium folinate	tablet, 15 mg	+b	o	+b
captopril	tablet, 25 mg	+b	-	+b
carbamazepine	tablet,100 mg, 200 mg	+b	+b	+b
carbidopa	tablet, 10 mg + levodopa, 100 mg	+b	+b	+b
	25 mg + levodopa, 250 mg	+b	+b	+b
chloramphenicol	capsule, 250 mg	?	+b	+b
chloramphenicol palmitate	oral suspension, 150 mg of chloramphenicol/5 ml	?	+b	+b
chloramphenicol	oily suspension, injection	o	+b	o
sodium succinate	0.5 g of chloramphenicol/ml in 2-ml ampoule
chloroquine	injection, 40 mg of chloroquine/ml hydrochloride in 5-ml ampoule	o	-	-
chloroquine phosphate	tablet, 150 mg of chloroquine	o	+b	-
chloroquine sulfate	tablet, 150 mg of chloroquine	o	+b	o
bacitracin zinc	ointment, 500 IU + neomycin sulfate, 5 mg/g	o	+c	-
beclometasone dipropionate	inhalation, 50 µg/dose	?	+p+c	+p
benzathine benzylpenicillin	powder for injection,1.44 g of benzylpenicillin (= 2.4 million IU) in 5-ml vials	o	-	+b
benznidazole	tablet, 100 mg	o	+b	o
benzoic acid	cream, 6% + salicylic acid, 3%	-	+p+c	o
	ointment, 6% + salicylic acid, 3%	-	+p+c	-
benzoyl peroxide	cream, 5%	-	+p+c	-
	lotion, 5%	-	+p+c
benzyl benzoate	lotion, 25%	-	+p+c	o
betamethasone	cream, 0.1 % of betamethasone	+p	+p+c	+p
valerate	ointment, 0.1 % of betamethasone	+p	+p+c	+p
biperiden hydrochloride	tablet, 2 mg	+b	+b	+b
calamine	lotion	-	+p+c	-
calcium folinate	tablet, 15 mg	+b	o	+b
captopril	tablet, 25 mg	+b	-	+b
carbamazepine	tablet,100 mg, 200 mg	+b	+b	+b
carbidopa	tablet, 10 mg + levodopa, 100 mg	+b	+b	+b
	25 mg + levodopa, 250 mg	+b	+b	+b
chloramphenicol	capsule, 250 mg	?	+b	+b
chloramphenicol palmitate	oral suspension, 150 mg of chloramphenicol/5 ml	?	+b	+b
chloramphenicol sodium succinate	oily suspension, injection 0.5 g of chloramphenicol/ml in 2-ml ampoule	o	+b	o
chloroquine	injection, 40 mg of chloroquine/ml hydrochloride in 5-ml ampoule	o	-	-
chloroquine phosphate	tablet, 150 mg of chloroquine	o	+b	-
chloroquine sulfate	tablet, 150 mg of chloroquine	o	+b	o
chlorphenamine hydrogen maleate	tablet, 4 mg	-	?	-
chlorpromazine hydrochloride	tablet, 100 mg	?	+b	+b
ciclosporin	capsule, 25 mg	+b	+b	+b
cimetidine	tablet, 200 mg	+b	-	+b
ciprofloxacin hydrochloride	tablet, 250 mg of ciprofloxacin	+b	+b	+b
clofazimine	capsule, 50 mg, 100 mg	o	+b	+b
clomifene citrate	tablet, 50mg	+b	+b	+b
clomipramine hydrochloride	capsule, 10 mg, 25 mg	+b	o	+b
cloxacillin sodium	capsule, 500 mg of cloxacillin	?	+b	+b
codeine phosphate	tables, 10 mg, 30 mg	o	-	-
colchicine	tablet, 500 µg	?	+b	-
cyclophosphamide	tablet, 25 mg	+b	+b	+b
dapsone	tablet, 50 mg, 100 mg	?	+b	+b
desmopressin acetate	nasal spray, 10 µg/metered dose	+b+p	+p+c	?
dexamethasone	tablet, 500 µg. 4 mg	?	?	+b
diazepam	scored tablet, 2 mg, 5 mg	+b	-	+b
diethylcarbamazine dihydrogen citrate	tablet, 50 mg	o	+b	+b
digitoxin	tablet, 50 µg, 100 µg	?	+b	-
digoxin	tablet, 62.5 µg., 250 µg	?	+b	-
diloxanide furoate	tablet, 500 mg	o	+b	o
dimercaprol	injection, in oil 50, mg/ml in 2-ml ampoule	+b+c	+b²	-
dioxybenzone	cream	?	+p+c	o
	lotion	?	+p+c	o
	gel	?	+p+c	o
dithranol	ointment, 0.1-2%	-	+p+c	-
doxycycline hyclate	capsule, 100 mg of doxycycline	+b	+b	+b
	tablet, 100 mg of doxycycline	+b	+b	+b
ergocalciferol	capsule, 1.25 mg (50 000 IU)	o	+b	-
	tablet, 1.25 mg (50000 IU)	o	+b	-
ergometrine hydrogen maleate	tablet, 200 µg	?	+b	-
ergotamine tartrate	tablet, 2 mg	o	+b	-
erythromycin	capsule, 250 mg of erythromycin	?	+b	+b
ethylsuccinate	powder for oral suspension, 125 mg of erythromycin	?	+b	+b
	tablet, 250 mg of erythromycin	?	+b	+b
erythromycin stearate	capsule, 250 mg of erythromycin	?	+b	+b
	powder for oral suspension, 125 mg of erythromycin	?	+b	+b
	tablet, 250 mg of erythromycin	?	+b	+b
ethambutol hydrochloride	tablet, 100-400 mg	+b	+b	+b
ethinylestradiol	tablet, 50 µg	+b	+b	+b
	tablet, 30µg + levonorgestrel 150 µg	+b	+b	+b
	50 µg + levonorgestrel, 250 µg	+b	+b	+b
	tablet, 35 µg + norethisterone, 1.0 mg	+b	+b	+b
ethosuximide	capsule, 250 mg	?	+b	+b
etoposide	capsule, 100 mg	+b	+b	+b
ferrous sulfate	tablet, 60 mg of Fe	-	o	-
	tablet, 60 mg of Fe + folic acid, 250 µg	-	o	-
flucytosine	capsule, 250 mg	+b	+b	+b
fludrocortisone acetate	tablet, 100 µg	+b	+b	+b
fluorouracil	ointment, 5%	+c	+p+c	?
fluphenazine decanoate	injection, 25 mg in 1-ml ampoule	?	+b²	-
fluphenazine enantate	injection, 25 mg in 1-ml ampoule	?	+b²	-
folic acid	tablet, 5 mg,1 mg	+b	+b	-
	tablet, 250 µg + ferrous sulfate, 60 mg of Fe	-	+b	-
furosemide	tablet, 40mg	+b	+b	+b
gentamicin	sulfate solution (eye drops), 0.3%	+c	+p+c	-
glyceryl trinitrate	tablet (sublingual), 500 µg	?	+b	-
griseofulvin	capsule, 125 mg, 250 mg	?	+b	+b
	tablet, 125 mg, 250 mg	?	+b	+b
haloperidol	tablet, 2 mg, 5 mg	+b	-	+b
hydralazine	tablet, 25 mg, 50 mg	o	+b	-
hydrochloride hydrochlorothiazide	tablet, 25 mg, 50 mg	?	-	+b
hydrocortisone acetate	cream, 1%	o	+p+c	-
	ointment, 1%	o	+p+c	-
	suppository, 25 mg	o	+p+c	?
ibuprofen	tablet, 200 mg	+b	-	+b
idoxuridine	eye ointment, 0.2%	o	+p+c	+c
	solution (eye drops) 0.1 %	o	-	-
indometacin	capsule, 25 mg	+b	-	+b
	tablet, 25 mg	+b	-	o
insulin:
insulin (soluble)	injection, 40 IU/ml in 10-ml vial,	+b	-	+b+p
	80 IU/ml in 10-ml vial,	+b	-	+b+p
	100 IU/ml in 10-ml vial	+b	-	+b+p
insulin zinc suspension	injection, 40 IU of insulin/ml in 10-ml vial	+b	o	+b+p
	80 IU of insulin/ml in 10-ml vial	+b	o	+b+p
insulin (intermediate-acting)	100 IU of insulin/ml in 10-ml vial	+b	-	+b+p
isophane insulin	injection, 40 IU of insulin/ml in 10-ml vial	+b	+b	+b+p
	80 IU of insulin/ml in 10-ml vial	+b	+b	+b+p
	100 IU of insulin/ml in 10-ml vial	+b	+b	+b+p
iodized oil	capsule, 200 mg	?	o	o
iopanoic acid	tablet, 500 mg	o	o	-
iron dextran	injection, 50 mg of Fe/ml in 2-ml ampoule	+c	-	+b+p
isoniazid	tablet, 100-300 mg	+b	+b	-
	tablet, 100 mg + rifampicin, 150 mg	o	+b	+b
	150 mg + rifampicin, 300 mg	o	+b	+b
	tablet, 100 mg + thioacetazone, 50 mg	o	+b	o
	300 mg + thioacetazone, 150 mg	o	+b	o
isosorbide dinitrate	tablet (sublingual), 5 mg	+b	+b	+b
ivermectin	scored tablet, 6 mg o	+b	o
ketoconazole	oral suspension, 100 mg/5 ml	+b	+b	+b
	tablet, 200 mg	+b	+b	+b
levamisole hydrochloride	tablet, 50 mg, 150 mg	+b	+b	+b
levodopa	tablet, 100 mg + carbidopa, 10 mg	+b	+b	+b
	250 mg + carbidopa, 25 mg	+b	+b	+b
levonorgestrel	tablet, 150 µg + ethinylestradiol, 30 µg	+b	+b	+b
	250 µg + ethinylestradiol, 50 µg	+b	+b	+b
levothyroxine sodium	tablet, 50 µg,100 µg	?	+b	-
lithium carbonate	capsule, 300 mg	+b	+b	+b
	tablet, 300 mg	+b	+b	+b
mebendazole	chewable tablet, 100 mg	+b	+b	+b+c
medroxyprogesterone	injection, 150 mg/ml in 1 -ml vial,	?	+*b	+b
acetate (depot)	50 mg/ml in 3-ml vial	?	+*b	+b
mefloquine hydrochloride	tablet, 250 mg	+b	+b	+b
mercaptopurine	tablet, 50 mg	+c+b	+b	+b
methionine (DL-)	tablet, 250 mg	?	?	-
methotrexate sodium	tablet, 2.5 mg of methotrexate	+b+c	+b	+b
methyldopa	tablet, 250 mg	?	+b	+b
metoclopramide hydrochloride	tablet, 10 mg of metoclopramide	+b	-	+b
metrifonate	tablet, 100 mg	o	+b	o
metronidazole	suppository, 500 mg, 1 g	o	+b	o
	tablet, 200-500 mg	+b	+b	+b
metronidazole benzoate	oral suspension, 200 mg of metronidazole/5 ml	o +b	o
mexenone	cream	o	+p+c	o
	lotion	o	+p+c	o
	gel	o	+p+c	o
miconazole nitrate	cream, 2%	+c	+p+c	+c
	ointment, 2%	+c	+p+c	+c
morphine sulfate	tablet, 10 mg	o	+b	-
nalidixic acid	tablet, 500 mg	+b	+b	+b
neomycin sulfate	ointment, 5 mg + bacitracin zinc, 500 IU/g	o	+p+c	-
neostigmine bromide	tablet, 15 mg	?	?	-
niclosamide	chewable tablet, 500 mg	o	+b	+b
nicotinamide	tablet, 50 mg	-	?	-
nifedipine	capsule, 10 mg	+b	+b	+b
	tablet, 10 mg	+b	+b	o
nifurtimox	tablet, 30 mg, 120 mg, 250 mg	o	+b	o
nitrofurantoin	tablet, 100 mg	?	+b	+b
norethisterone	tablet, 350 µg, 5 mg	+b	+b	o
	tablet, 1.0 mg +ethinylestradiol, 35 µg	+b	+b	o
norethisterone	oily solution, 200 mg/ml	?	+b	o
enantate	in 1-ml ampoule
nystatin	lozenge, 100 000 IU	+	?	+b
	tablet, 100 000 IU, 500 000 IU	o	-	-
oxamniquine	capsule, 250 mg	o	+b	+b
oxybenzone	cream	-	+p+c	+c
	gel	-	+p+c	+c
	lotion	-	+p+c	+c
paracetamol	suppository, 100 mg	+b	-	o
	tablet, 100-500 mg -	-	o
penicillamine	capsule, 250 mg	+b	-	+b
	tablet, 250 mg	+b	-	+b
permethrin	lotion, 1%	-	+p+c	+c
pethidine hydrochloride	tablet, 50 mg, 100 mg	o	+b	-
phenobarbital	tablet, 15-100 mg	-	o	-
phenoxymethyl-penicillin potassium	powder for oral suspension, 250 mg of phenoxymethyl penicillin/5 ml	o	+b	+b
	tablet, 250 mg of phenoxymethylpenicillin	?	+b	+b
phenytoin sodium	capsule, 25 mg, 100 mg	+b	+b	+b
	tablet, 25 mg, 100 mg	+b	+b	o
phytomenadione	tablet, 10mg	+b	o	+b
pilocarpine hydrochloride	solution (eye drops), 2%, 4%	o	+p+c	-
pilocarpine nitrate	solution (eye drops), 2%, 4%	o	+p+c	o
piperazine adipate	tablet, 500 mg of piperazine hydrate	-	o	o
piperazine citrate	tablet, 500 mg of piperazine hydrate	-	o	+b
podophyllum resin	solution, topical, 10-25%	o	+p+c	-
potassium iodide	tablet, 60 mg	-	-	-
praziquantel	tablet, 150 mg, 600 mg	o	+b	+b
prednisolone	solution (eye drops), 0.5%	o	+p+c	o
	tablet, 1 mg, 5 mg	?	+b	+b
primaquine diphosphate	tablet, 7.5 mg of primaquine, 15 mg of primaquine	?	+b	-
procainamide hydrochloride	tablet, 250 mg, 500 mg	+b	+b	+b
procaine	powder for injection,
benzylpenicillin	1 g (= 1 million IU),	?	-	+b
	3 g (= 3 million IU)	o	-	+b
procarbazine hydrochloride	capsule, 50 mg	+c+b	+b	+b
proquanil hydrochloride	tablet, 100 mg	o	+b	o
promethazine hydrochloride	tablet, 10 mg, 25 mg	?	+b	+b
propranolol hydrochloride	tablet, 10 mg, 20 mg 40 mg, 80 mg	+b	+b	+b
propyliodone	oily suspension, 500-600 mg/ml in 20-ml ampoule	o	o	-
propylthiouracil	tablet, 50 mg	?	-	+b
pyrantel embonate	oral suspension, 50 mg of pyrantel/ml	o	+b	+b
	chewable tablet, 250 mg of pyrantel	o	+b	o
pyrazinamide	tablet, 500 mg	+b	+b	+b
pyridostigmine bromide	tablet 60 mg	+b	?	+b
pyridoxine hydrochloride	tablet 25 mg	-	?	-
pyrimethamine	tablet, 25 mg + sulfadoxine, 500 mg	+b	+b	+b
quinidine sulfate	tablet, 200 mg	?	+b	+b
quinine bisulfate	tablet, 300 mg of quinine	+b	+b	-
quinine sulfate	tablet, 300 mg of quinine	?	+b	-
reserpine	tablet, 100 µg. 250 µg	?	+b	+b
retinol palmitate	capsule, 200 000 IU (110 mg) of retinol	-	?	o
	sugar-coated tablet, 10 000 IU of retinol	-	?	o
riboflavin	tablet, 5 mg	-	?	-
rifampicin	capsule, 150mg, 300 mg	+b	+b	+b
	tablet,150 mg, 300 mg	+b	+b	+b
	tablet, 150 mg + isoniazid, 100 mg	o	+b	+b
	300 mg + isoniazid, 150mg	o	+b	+b
salbutamol sulfate	inhalation (aerosol), 100 µg of salbutamol per dose	?,+p	+p+c	+p
	respirator solution for use in nebulizers, 5 mg/ml	?,+p	+p+c
	tablet, 2 mg, 4 mg of salbutamol	+b	+b	+b
salicylic acid	cream, 3% + benzoic acid, 6%	-	+p+c	o
	ointment, 3% + benzoic acid, 6%	-	+p+c	-
	solution, topical, 5%	-	+p+c	o
silver nitrate	solution (eye drops), 1%	o	+p+c	-
silver sulfadiazine	cream, 1% in 500-g container	+c	+p+c	+c
sodium cromoglicate	inhalation, 20 mg/dose	?or+c	+p+c	+p+c
sodium fluoride	tablet, 500 µg	-	-
sodium valproate	enteric coated tablet, 200 mg, 500 mg	+b	+b	+b
spironolactone	tablet, 25 mg	+b	+b	+b
sulfadimidine	tablet, 500 mg	o	+b	o
sulfadoxine	tablet, 500 mg + pyrimethamine, 25 mg	+b	+b	+b
sulfamethoxazole	oral suspension 200 mg + trimethoprim, 40 mg/5 ml	+b	+b	+b
	tablet, 100 mg + trimethoprim, 20 mg	+b	+b	+b
	400 mg + trimethoprim, 80 mg	+b	+b	+b
sulfasalazine	tablet, 500 mg	+b	+b	+b
tamoxifen citrate	tablet, 10 mg of tamoxifen, 20 mg of tamoxifen	+b	+b	+b
testosterone enantate	injection, 200 mg in 1-ml ampoule	?	+b	-
tetracaine hydrochloride	solution (eye drops), 0.5%	o	+p+c	-
tetracycline	capsule, 250 mg	?	+b	+b
hydrochloride	tablet, 250 mg	?	+b	+b
	eye ointment, 1 %	?	+p+c	-
thiamine hydrochloride	tablet, 50 mg	-	?	-
thioacetazone	tablet, 50 mg + isoniazid, 100 mg	o	+b	+b
	150 mg + isoniazid, 300 mg	o	+b	o
tolbutamide	tablet, 500 mg	+b	+b	+b
trimethoprim	oral suspension, 40 mg + sulfamethoxazole, 200 mg/5 ml	+b	+b	+b
	tablet, 100 mg, 200 mg	+b	+b	+b
	tablet, 20 mg + sulfamethoxazole, 100 mg	+b	+b	+b
	80 mg + sulfamethoxazole, 400 mg	+b	+b	+b
tropicamide	solution (eye drops), 0.5%	o	+p+c	-
verapamil hydrochloride	tablet, 40 mg, 80 mg	+b	+b	+b
warfarin sodium	tablet 1 mg, 2 mg, 5 mg	?	+b	+b
zinc oxide	cream	-	+p+c	-
	ointment	-	+p+c	-

² “Depot” preparation for injection.

Reference

1. The use of essential drugs. Sixth report of the WHO Expert Committee. Geneva, World Health Organization, 1995 (WHO Technical Report Series, No. 850).