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Resolution - RDC nº 140 of 29 May 2003(*)
Republished in the D.O.U of 09/24/2003
The
Collegiate Board of Directors of the National Sanitary Surveillance
Agency, in the use of the attributions vested in it under Article
11, item IV of the ANVISA Regulation approved by Decree Nº
3.029 dated 16 April 1999, c/c Article 111, item I, letter “b”,
Paragraph 1 of the Internal Regulation approved by Presidential
Decree nº 593 dated 25 August 2000, republished on 22 December
2000 in meeting held on 6 March 2003,
Whereas the information on a drug product and its respective therapeutic
category shall adequately guide the patient and the health professional
in favor of the rational use of drug products;
Whereas the heterogeneity of information made available to patients
and health professionals makes it necessary to re-evaluate the
insert package text of drug products;
Whereas it is the responsibility of the National Sanitary Surveillance
Agency – ANVISA – in compliance with its legal attributions,
to implement actions to hasten the operationalization of its administrative
activities concerning the registration, updating and revalidation
of products;
Whereas the devices of Law nº 6.360 dated 1976 and of Decree
nº 79.094 dated 1977, altered by Decree nº 3.961 dated
2001, of Law nº 8.926 dated 1994, of Presidential Decree/MS
nº 3.916 dated 1998, Presidential Decree nº 110 dated
1997, Law nº 8078 dated 1990 – Consumer Defense Code,
of MP nº 2190-34 dated 2001 and the definitions of the Report
of the 4th WHO - Consultative Group on the Role of the Pharmacist;
Whereas Provisional Measure nº 2.134-25, dated 28 December
2000, D.O.U dated 29 December 2000, instituted the exemption of
the payment of fee for the inclusion/alteration of registration
of package insert text;
Whereas the definitions contained in the Glossary of Legal Definitions;
Adopts the following resolution and I, the Chairman, determine
its publication:
Article 1. Besides the definitions established in items I, II,
III, IV, V and VII of Article 4 of Law nº 5.991 dated 17
December 1973, of Article 3 of Law nº 6.360 dated 23 September
1976 and of Law nº 9.787 dated 10 February 1999, the definitions
described below shall be adopted in this resolution:
Warnings: instructions or warnings that favor the correct, prudent,
safe use of drug products to prevent an aggravation of health
but that do not necessarily contraindicate its use.
Package insert for the health professional: legal sanitary document
containing guidance and technical-scientific information for the
rational use of drug products that is made available to health
professionals.
Package insert for the patient: legal sanitary document containing
guidance and technical-scientific information for the rational
use of drug products that is made available to users in clear,
simplified language in establishments that dispense drug products,
in compliance with the legislation in force.
ANVISA Electronic Package Insert List: electronic database containing
the package insert text of drug products and other information
on health-related education.
Contraindication: any health condition relating to a disease or
the diseased person that results in a limitation to the use of
a drug product (relative contraindication), or even to its non-use
(absolute contraindication). The non-observance of this condition
may result in serious consequences to the health of the drug product
user.
Medicine Package Insert Compendium (CBM): yearly publication edited
by ANVISA of the set of package inserts of marketed drug products
including the package insert for the patient and for the health
Professional.
Risk group: sub-group of the population having characteristics
in common, such as: nursing women, diabetics, people who are allergic
to one or more components of the pharmaceutical formulation, cardiac
patients or chronic renal patients that require special medical
attention to use a drug product.
Drug interaction: a pharmacological or clinical response caused
by the combination of drug products that is different from the
effect of the two drug products administered individually. The
final result may increase or reduce the desired and/or adverse
effects.
These can be drug-drug, drug -foodstuff, drug-laboratory exam
and drug -chemical substance. The reliability of the results of
laboratory exams may be affected by their interaction with drug
products.
Therapeutic memento: set of guiding technical-scientific information
edited by official laboratories for the rational use of drug products
made available to health professionals.
Adverse reaction to drug products: any response to a drug product
that is harmful, unintentional and that occurs in doses normally
used in human beings for the mitigation, diagnosis and treatment
of disease or to modify a physiologic function.
Form and content of package inserts
Article 2 Without prejudice of articles 93, 94, 95 and 96, of
Decree nº 79094/77, the font of package inserts shall be
of at least 1.5 mm and follow the content sequence described below:
I) Identification of the drug product
Trademark of brand name of the drug product.
Generic name of the active ingredients used in the Common Brazilian
Denomination (CBD), International Nonproprietary Nommenclature
(INN) and name listed in the Chemical Abstracts Service (CAS).
For herbal products, use the official botanical nomenclature.
Pharmaceutical forms, routes of administration and commercial
presentations.
Insert the phrase “Pediatric and/or Adult Use” in
conspicuous, easily legible type.
Composition: qualitative and quantitative description (indicate
salt-base equivalence) for the active ingredients, and qualitative
(indicating the name of the substance) for any other components
in the formulation.
Weight, liquid volume or number of units, as fitting.
II) Information for the patient
Information for the patient is mandatory and shall be written
in simplified language in accordance with the terminology described
in the International Classification of Diseases – ICD 10
when referring to signs, symptoms and diseases. The text shall
be easy to understand by the patient and may be in the form of
questions and answers. The following information shall be included
in conspicuous and easily legible type:
1. Drug product action or How does this medicine work?
Summarize the pharmacological actions. Inform the average estimated
time of onset of the drug product’s pharmacologic action.
2. Indications or What was the medicine indicated for?
Describe the indications of use of the drug product.
3. Risks of drug product or When should I not use this medicine?
Describe the contraindications, warnings, precautions and main
drug product interactions, including foodstuffs and laboratory
tests. Highlight risk per non-recommended administration route.
Include restrictions to risk groups. Include warning phrases in
compliance with the Guide for “Warning phrases associated
to the risk categories of active ingredients destined for pregnant
women". Include the following expressions in conspicuous
and easily legible type:
"This medicine is contraindicated for the following age range:
_____." or "No contraindication exits regarding age
range";
"Inform your doctor or dental surgeon of any undesirable
reactions";
"Inform your doctor or dental surgeon if you are using any
other medicine” and
"Do not use this medicine without informing your doctor.
It could be dangerous to your health” (for Prescription
Drugs).
4. Package insert or How should I use this medicine?
Describe the physical aspect and organoleptic characteristics
of the product. Describe how to use the drug product. Indicate
the posology by describing the dose for each pharmaceutical form
with the respective package insert, administration intervals,
treatment length and route of administration. Detail the posology
for specific diseases and special situations, when fitting. Describe
the necessary conduct in case the patient forgets to administer
a dose (omitted dose), when fitting. Include the following expressions
in conspicuous and easily legible type:
"Follow your doctor’s advice respecting time schedules,
dosage and length of treatment” for Prescription Drugs;
"Do not interrupt treatment without your doctor’s consent”
for Prescription Drugs;
"Follow instructions. If symptoms persist, contact your doctor
or dental surgeon " for Over the Counter Drugs;
"Do not use this medicine after it has expired. Observe the
aspect of the drug product before using" and
"This drug product may not be cut or chewed” for coated
tablets and drug products of controlled release, capsules, lozenges
and pills.
5. Adverse reactions or What harm may this medicine cause?
List the most important adverse reactions by order of frequency
or gravity. Include the following expressions in conspicuous and
easily legible type:
"Warning: this medicine is new and, although studies have
indicated efficacy and safety acceptable for marketing, undesirable
and unknown side effects may occur. If this happens, inform your
doctor.” This phrase shall be included during the first
five years of use of a New Drug, in normal trade and dispensation
conditions.
6. Conduct in case of overdose or What to do if someone ingests
a large amount of the medicine at once?
Describe the symptoms that characterize and overdose and what
to do before seeking medical help.
7. Conservation and usage care or Where and how should I store
this medicine?
Describe the specific care to store the drug product before and
after opening the packaging or preparing the product. Include
the following expressions in conspicuous and easily legible type:
"Keep medicines out of reach of children";
"This medicine may only be consumed up to ___ days after
open” for drug products that become less stable once open,
even before their original expiration date.
III) Technical information for health professionals
Information for health professionals is mandatory and shall respect
the terminology adopted in the International Classification of
Diseases, ICD 10, when referring to signs, symptoms and diseases.
1. Pharmacological characteristics
Describe the drug product with its pharmacological properties
(pharmacodynamic and pharmacokinetic) based on technical and scientific
evidence.
2. Efficacy results
Specify the percentage of cure or prevention of the intervention
group and the comparison group when available, including bibliographic
references. Their absence shall be justified to ANVISA.
3. Indications
Describe the therapeutic indications as registered at ANVISA.
4. Contraindications
Describe the contraindications.
5. Package insert and conservation after open
Describe conservation conditions and instructions for the correct
preparation, handling, application and route of administration.
6. Posology
Dosage and length of treatment, maximum daily dose, route of administration;
detail posology for specific diseases and special situations,
when fitting. Describe conduct in case the patient forgets to
administer a dose (omitted dose), when fitting. Detail the equivalence
in weight between the chemical compounds of the pharmaceutical
presentations with the therapeutically active substance. Include
the following expression for Similar Drugs, when fitting:
"Warning: this is a Similar Drug that has undergone tests
and studies to ensure its efficacy, quality and safety, in compliance
with the legislation in force ".
7. Warnings
Describe the warnings, recommendations for adequate use and restrictions
of the drug product. Call attention to the risk in involved in
using an administration route other than that recommended. Indicate
risk of use during pregnancy including the warning phrases described
in the Guide for “Warning Phrases Associated to the Risk
Category of Active Ingredients for Pregnant Women".
8. Use in senior citizens, children and other risk groups
Describe the warnings and recommendations on the adequate use
of drug products per risk group.
9. Drug interactions
Inform, in order of gravity and/or frequency drug interactions
with food, laboratory exams, other drug products, tobacco, alcohol,
as well as any incompatibilities, specifying the substances or
group of substances, when fitting. For New Drugs, describe potential
interactions.
10. Adverse reactions to drug products
Inform adverse reactions in order of gravity and/or frequency.
Include the following expression:
"Warning: this drug product is new and, although studies
have indicated efficacy and safety acceptable for marketing, undesirable
and unknown effects may occur. In this case, inform your doctor.”
This phrase shall be included during the first five years of use
of a New Drug, in normal trade and dispensation conditions.
11. Overdose
Describe the general and specific conduct in case of overdose.
12. Storage
Describe the environmental conservation conditions of the drug
product for storage.
IV) Legal sayings
Registration number at ANVISA/MS; there is option to list only
the first nine digits.
Pharmacist in charge and respective inscription number in the
Regional Pharmacy Council of the Federative Unit.
Complete name and address of the manufacturer and holder of the
registration.
National Directory of Legal Entities, CNPJ number
Telephone number of the company’s Consumer Service.
Include the following expression, when fitting:
"Hospital use only";
"Prescription sale only";
"Dispensation with medical prescription" (for official
laboratories) and
"Commercialization forbidden".
Article 3 Any mandatory phrase included in the patient package
insert shall be modified so as to ensure easy understanding on
behalf of the user. The content may not be modified to the point
in which it compromises the information.
Article 4 Two or more logos of manufacturing companies may be
used in package inserts provided that this request has been previously
approved in the act of registration or in the post-registration
labeling alteration.
Article 5 The sayings of package inserts of drug products subject
to specific sanitary legislation shall comply with it without
prejudice to this resolution.
Sole Paragraph. For imported drug products, comply with paragraph
2, article 12 of Decree 79094/77.
Article 6 Package inserts of pharmaceutical products with liquid
presentations for systemic use shall contain in the package insert
(item II, article 2) and posology (item III, article 2) the dose
expressed in weight unit of the drug product/kg of body weight
and/or weight unit of the drug product/body surface and the concentration
of the drug product(s) per volume unit, that is, weight unit of
the drug product(s) per (1) milliliter (ml).
Paragraph1 Medicines that use International Units (IU) can describe
the IU of the active ingredient/kg of body weight and/or the IU
of the active ingredient/body surface in the posology.
Paragraph 2 All pharmaceutical products with presentation in drops
shall submit the equivalence for each milliliter in the package
insert in conspicuous and easily legible type.
Paragraph 3 In case of concentrated solution or in powder, the
reconstitution procedure and/or dilution before the administration
and the final volume of the drug product shall be included in
detail.
Paragraph 4 For lyophilized injected drug products and powder
for reconstituted oral presentations, inform the diluent(s) and
the period of use after dilution per conservation condition.
Article 7 Package inserts of drug products with presentations
of controlled release for transdermic absorption shall include
in the package insert (item II, article 2) and posology (item
III, article 2) the concentration of the active ingredient in
each posological unit as well as the average dose absorbed by
the patient per unit of time.
Adaptation to the new form and content of Reference Drug package
insert text
Article 8 Companies that market drug products on the “List
of Reference Drugs for package insert text” shall submit
to ANVISA the package inserts of marketed drug products containing
the information described in article 2 of this resolution, and
declaring their sales status in compliance with the legislation
in force together with the documents and formats specified in
the paragraphs of this article up to one hundred and eighty (180)
days from the republication of this resolution,
Paragraph 1 The package inserts referred to in the caput of this
article shall be submitted electronically in compliance with the
GUIDE TO SUBMIT PACKAGE INSERTS ELECTRONICALLY, available at the
ANVISA website. Any information sent through the Electronic Package
Insert Management System including data updates are of the entire
responsibility of the company.
Paragraph 2 The company shall submit a document that proves sales
in the last twelve (12) months containing the numbers of the invoices
with their respective purchasing establishments at a maximum of
three (3) invoices per pharmaceutical form of the product. Exceptions
shall be judged individually.
Paragraph 3 The company that holds the registration of the Reference
Drug for the package insert that obtained the first registration
of the drug product abroad shall submit a copy of the most recent
package insert registered in that country accompanied by a legal
translation whenever the original language is neither English
nor Spanish without leaving out or altering any information in
the package insert originally approved by the sanitary authority
of the country at hand. Any changes implemented in the package
insert of the country where the drug product was originally registered
shall be submitted to ANVISA accompanied by a translation under
the legal and technical responsibility of the company to be analyzed
by ANVISA. The documents shall be submitted electronically in
compliance with the GUIDE TO SUBMIT PACKAGE INSERTS ELECTRONICALLY.
Paragraph 4 The company that holds a registration of a Reference
Drug for package insert text first registered in Brazil shall
submit an up-to-date copy of the package insert in compliance
with this resolution including bibliographic references of indexed
journals (Medline, Chemical Abstracts, Biosis, International Pharmaceutical
Abstracts, Biological Abstracts), duly indicated in the body of
the text. The documents shall be submitted electronically in compliance
with the GUIDE TO SUBMIT PACKAGE INSERTS ELECTRONICALLY.
Paragraph 5 The "List of Reference Drugs for package insert
text", available in the pharmacovigilance area of the ANVISA
website shall be updated as new Reference Drugs for package inserts
are recognized. Holders of registrations shall have a period of
one hundred and eighty (180) days counting form the inclusion
of the drug product in this list to submit the respective package
inserts, in compliance with the GUIDE TO SUBMIT PACKAGE INSERTS
ELECTRONICALLY.
Paragraph 6° Package insert texts analyzed by the Pharmacovigilance
area of ANVISA shall be attached to the original application of
the drug product at the end of the analysis in order to document
any changes made.
Paragraph 7 Not sending any of the documents described above by
the deadline stipulated in the caput of this article shall constitute
a sanitary infraction.
Article 9 Official laboratories may choose between using a package
insert or a therapeutic memento observing the updates published
in the Medicine Package Insert Compendium.
The harmonization period of the package inserts of generic, similar
and herbal drug products
Article 10 After the publication in the DOU of the availability
of the package insert in the Electronic Register of Package Inserts
of the ANVISA website, the package inserts of generic, similar
and herbal drug products shall be harmonized with those of their
respective Reference Drug for package insert text and submitted
to ANVISA within one hundred and eighty (180) days in compliance
with the GUIDE TO SUBMIT PACKAGE INSERTS ELECTRONICALLY, following
the criteria below:
Paragraph 1 Package inserts of generic, similar and herbal drug
products, shall not contain less information than that contained
in the Reference Drug for package insert text.
Paragraph 2 Companies that hold registrations of generic, similar
and herbal drug products that identify restrictive information
not incorporated in the package inserts available in the ANVISA
Electronic Package Insert List shall submit this information to
the ANVISA Pharmacovigilance Unit by means of an official document.
Article 11 After complying with article 8 of this resolution,
the company that holds the registration of a Reference Drug for
package insert text whose restrictive package insert information
suffered changes in content informed and/or altered by the matrix
company or sanitary authority of the country that originally registered
the drug product shall have a maximum of ninety (90) days to submit
the alteration to the package insert to ANVISA electronically,
in compliance with the GUIDE TO SUBMIT PACKAGE INSERTS ELECTRONICALLY.
Paragraph 1 The non-harmonization of the contents of the package
inserts of the country that originally registered the drug product
with the package insert registered in Brazil within the period
stipulated in the caput of this article shall constitute a sanitary
infraction.
Paragraph 2 It is the responsibility of the Pharmacovigilance
Unit of this Agency to update the ANVISA Electronic Package Insert
List and submit any alterations in the content of the package
inserts of Reference Drugs for package insert text to the DOU.
Article 12 Companies that hold registrations of generic, similar
and herbal drug products shall have a period of ninety (90) days
after publication in the DOU of alterations in the Reference Drugs
for package insert text to submit the harmonization of the package
inserts, in compliance with the GUIDE TO SUBMIT PACKAGE INSERTS
ELECTRONICALLY.
Sole Paragraph. The non-harmonization of the contents of the package
inserts of generic, similar and herbal drug products with the
Reference Drugs for package insert text within the period stipulated
in the caput of this article shall constitute a sanitary infraction.
The commercialization period of drug products using the new package
insert formats
Article 13 Starting from the date of the official divulgation
of the first edition of the Medicine Package Insert Compendium,
companies with drug products mentioned in it shall release the
package inserts in the market in two formats: package inserts
for patients and package inserts for health professionals, in
compliance with article 1 of this resolution.
Paragraph 1 Package inserts for patients destined for drug product
dispensation establishments foreseen by the legislation in force
shall contain items to identify the drug product, information
for the patient and legal sayings in accordance to article 2.
The exclusion of the technical information for health professionals
described in article 2 will allow printing space to be used more
profitably and allow the font to be increased to a size greater
than that required by law.
Paragraph 2 Package inserts for health professionals shall be
available in drug products for hospital use containing items to
identify the drug product, technical information for health professionals
and legal sayings in accordance to article 2. This will allow
an in-depth description of technical content without duplicating
information.
Article 14 All drug products listed in the CBM shall include the
new package inserts within one hundred and eighty (180) days after
the publication date of the 1st edition of the CBM. Any package
inserts modified thereafter shall include the new package inserts
within one hundred and eighty (180) days for all drug products
in the “List of Reference Drugs for package insert text”
and two hundred and seventy (270) days for all other drug products.
Paragraph 1 All drug products marketed and dispensed only in their
primary packaging shall include one package insert per unit.
Paragraph 2 In case of restrictive information that describes
risks to the life of the patient, ANVISA may require an addendum
to the package insert to be placed on the packaging.
Article 15 The ANVISA Pharmacovigilance Unit reserves the right
to demand the alteration and/or complementation of information
in the package insert whenever it judges necessary, for technical-scientific
reasons and/or to clarify users.
Article 16 It is the responsibility of the state and municipal
sanitary authorities to undertake routine inspections of the pharmaceutical
industries or drug product importing companies and check any alterations
in the package inserts according the manufacturing dates of the
batches and to the publication dates of the alterations in the
DOU.
Article 17 The model indicated in this resolution remains valid
for the registration of New Drugs until the first publication
of the CBM. Package inserts shall include the four items described
in article 2.
Sole Paragraph: The already approved package insert of a drug
product remains valid until it is submitted electronically for
post-registration alteration and/or inclusion.
Article 18 Cases that were omitted or not dealt with in this resolution
shall be judged by the ANVISA Pharmacovigilance Unit.
Article 19 This resolution enters into force on the date of its
publication.
CLAUDIO MAIEROVITCH PESSANHA HENRIQUES
(*) Republished for incorrections in the original, published in
the DOU nº 104, dated 2 June 2003, Section 1, Pg. 39.
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