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Resolution - RDC nº 134 of 29 May 2003
Republished in the D.O.U of 09/25/2003
Regulates
the harmonization of already registered drug products.
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 Law nº 6.360, dated 23 September 1976, that establishes
the sanitary surveillance that drug products, pharmaceutical inputs
and correlates, cosmetics, sanitizing products and others are
subject to;
Whereas Law nº 9.787, dated 10 February 1999, that alters
Law nº 6.360, dated 23 September 1976, that disposes on sanitary
surveillance, establishes the definition of Generic Drug, Regulates
the use of generic names in pharmaceutical products and gives
other provisions;
Whereas ANVISA has as its institutional mission within the pharmaceutical
market to ensure that drug products present guarantee of safety,
efficacy and quality;
Whereas Decree nº 3.961, dated 10 October 2001, that alters
Decree nº 79.094, dated 5 January 1977 that updates the definition
of Similar Drug, Reference Drug or Generic Drug;
Whereas the guidelines of the National Medicine Policy instituted
by Presidential Decree/MS nº 3916/98, regarding sanitary
regulation, the promotion of production within the framework of
pharmaco-economics, as well as the rational promotion of drug
products,
Adopts the following resolution and I, the Chairman, determine
its publication:
Article 1 Upon the first registration renewal after the publication
of this resolution, all holders of drug product registrations
shall submit production and quality control reports as described
in specific legislation.
Sole Paragraph: Partial compliance accompanied by a detailed compliance
schedule of these demands will be accepted. Compliance with the
schedule shall not be delayed beyond 1 December 2004. The company
shall protocol the missing information at ANVISA in the form of
an addendum to the application. Information shall refer to a single
industrial lot.
Article 2
Only those centers licensed by ANVISA (REBLAS) can undertake the
pharmaceutical equivalence tests and the relative bioavailability
trials demanded by this Regulation.
Article 3
Upon the first renewal after the publication of this resolution
the holders of Similar Drug registrations that will expire on
01 December 2004 shall select one of the conditions below:
I – Maintain the classification as a Similar Drug, submitting
all the evidence and documentation consistent with this category
in compliance with this legislation.
II – Change their classification to herbal, biologic, homeopathic
or New Drug products, or register them as specific drug products
as fitting, submitting all the evidence and documentation consistent
with these categories in compliance with the legislation in force.
Article 4 The holders of registrations of drug products classified
as Similar Drugs who intend to maintain this classification, shall
address to ANVISA an official document indicating the reference
product to which the drug product shall be considered similar
during the second semester in the fourth year of the five-year
period of validity of the registration.
Sole Paragraph: ANVISA will issue an opinion within 60 (sixty)
days and will make a decision as to the Reference Drug.
Article 5 Upon the first renewal after the publication of this
resolution holders of registrations of drug products classified
as similar that will expire on 1 December 2004 shall submit pharmaceutical
equivalence tests in compliance with the GUIDE FOR THE UNDERTAKING
OF THE STUDY AND PREPARATION OF THE PHARMACEUTICAL EQUIVALENCE
REPORT.
Article 6 Upon the first renewal after the publication of this
resolution, holders of registrations of Similar Drugs that are
the unique in the market (excepting products currently registered
as new and those defined as Reference Drugs) with expiration on
December 2004 shall submit the following as supplementary information:
I - In case of isolated active ingredients, a report on clinical
tests to prove therapeutic efficacy or data in the literature
proving efficacy and safety based on clinical studies published
in indexed journals (MEDLINE, Chemical Abstracts, BIOSIS, International
Pharmaceutical Abstracts or Biological Abstracts).
II - In case of drug associations or synthetic or semi-synthetic
products or of two or more presentations in one and the same packaging
for concomitant or sequential use, the applicant shall submit
in addition to evidence of the efficacy of the active ingredient
or association:
a) Relative bioavailability studies of the associated active ingredients
and each isolated active ingredient certifying that the absorption
and distribution of the associated active ingredients are not
affected. If this is not possible, inform the bioavailability
of each isolated active ingredient.
b) rationale of the association.
c) Studies
demonstrating that the association prevents the appearance of
microbial resistance, in case of antibiotics.
Sole Paragraph.
The classification of products according to the caput of this
article gives right not to submit pharmaceutical equivalence and
relative bioavailability tests for the moment and to be published
highlighted on the ANVISA Medicine Package Insert Compendium (CBM).
Article 7 Upon the second renewal after the publication of this
resolution holders of registrations of Similar Drugs for sale
with medical prescription only and not exempt of the relative
bioavailability test, shall submit the results of this test, excepting
those products defined in articles 8 and 9, in the format established
in the GUIDE FOR THE ELABORATION OF TECHNICAL REPORT OF RELATIVE
BIOAVAILABILITY/BIOEQUIVALENCE STUDIES. In these cases the company
will be free of the obligation to submit to this test the same
lot submitted to the pharmaceutical equivalence test upon the
first renewal.
Paragraph 1. Whenever the pharmacokinetic parameters (C max, AUC,
and T max) between the test and Reference Drugs indicate the need
for adjustment, the formula may be altered until such parameters
are compatible. A company that chooses not to modify the formula
shall propose a dosage that ensures safety and efficacy whenever
the pharmacokinetic curves are below the safety limit and above
the therapeutic limit. In this case the drug product shall be
renewed as a product resulting from change in pharmacokinetic
properties, shall be exempted from the presentation of a clinical
study and its use as a reference product shall not be allowed.
Paragraph 2 In exceptional cases in which the relative bioavailability
tests are not ready by the date of the renewal protocol for reasons
out of the company’s control, the registration renewal may
be granted. The renewal concession will depend on the inclusion
of the following documents in the registration renewal petition:
I) report on the measures adopted by the company as proof of the
intention to comply with the new legislation;
II) proof of the entry date of the test in the certified center;
III) report of the certified center containing the justification
for the delayed results.
Paragraph 3 Registration renewals in cases dealt with in Paragraph
2 will be granted for temporary use and can be cancelled depending
of the final result of the test.
Article 8. Upon the first renewal after publication of this resolution,
the holders of registration of Similar Drugs classified as antibiotics,
antiretroviral, and antineoplasic not exempt of relative bioavailability
test with expiration on 1 December 2004, shall submit the results
of bioavailability test, in the format established in the GUIDE
FOR THE ELABORATION OF TECHNICAL REPORT OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE
STUDIES
Paragraph 1. Whenever the pharmacokinetic parameters (C max, AUC,
and T max) between the test and Reference Drugs indicate the need
for adjustment, the formula may be altered until such parameters
are compatible. A company that chooses not to modify the formula
shall propose a dosage that ensures safety and efficacy whenever
the pharmacokinetic curves are below the safety limit and above
the therapeutic limit. In this case the registration shall be
renewed as a product resulting from change in pharmacokinetic
properties, shall be exempted from the presentation of a clinical
study and its use as a reference product will not be allowed.
Paragraph 2 In exceptional cases in which the relative bioavailability
tests are not ready by the date of the renewal protocol for reasons
out of the company’s control, the registration renewal may
be granted. The renewal concession will depend on the inclusion
of the following documents in the registration renewal petition:
I) report on the measures adopted by the company as proof of the
intention to comply with the new legislation;
II) proof of the entry date of the test in the certified center;
III) report of the certified center containing the justification
for the delayed results.
Paragraph 3 Registration renewals in cases dealt with in Paragraph
2 will be granted for temporary use and can be cancelled depending
on the final result of the test.
Article 9° Within a maximum period of one and a half years
after the publication of this resolution the holders of registrations
of Similar Drugs containing the active ingredients listed below,
isolated or in association and in the form of all their salts
and isomers shall submit the results of the relative bioavailability
studies in the format established in the GUIDE FOR THE ELABORATION
OF TECHNICAL REPORT OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE
STUDIES. In these cases the company will be free of the obligation
to submit to this test the same lot submitted to the pharmaceutical
equivalence test upon the first renewal.
Active Ingredient Pharmaceutical Form Reference
Valproic acid
Capsules Depakene - Abbott
Aminophylin Tablets Aminophylin - Novartis
Carbamazepine Tablets and oral suspension Tegretol - Novartis
Cyclosporine Capsules Sandimun - Novartis
Clindamycin Capsules Dalacin C - Pharmacia do Br
Clonidine Tablets Atensina - Boehringer Ingelheim
Clozapine Tablets Leponex - Novartis
Digoxin Tablets Digoxine - Glaxo Wellcome
Disopyramid Tablets Dicorantil - Aventis
Phenitoin Tablets, Capsules and Oral Suspension Hidantal - Aventis
Lithium Tablets Carbolithium - Eurofarma
Isotretinoin Capsules Roacutan-Roche
Minoxidyl Tablets Loniten - Pharmacia do Br
Oxcarbazepine Tablets and Oral Suspension Trileptal-Novartis
Prazoxin Capsules Minipress - Pfizer
Primidone Tablets and Oral Suspension Epidona - Wyeth_Whitehall
Procainamide Tablets Procamide - Zambon
Quinidine Tablets Quinidine Duriles - AstraZeneca
Teofiline Capsules Teolong - Knoll
Verapamil Tablets Dilacoron - Knoll
Warfarin Tablets Marevan - Zest Ftca
Paragraph 1 Companies holding registrations of drug products that
contain the active ingredients listed above in isolation or in
associations that fail to submit the required information within
the stipulated time will have their registrations cancelled.
Paragraph 2 In exceptional cases in which the relative bioavailability
tests are not ready within the period determined in this resolution
for reasons out of the company’s control, the registration
will not be cancelled. However, the non-cancellation will depend
on the presentation of the following documents:
I) report on the measures adopted by the company as proof of the
intention to comply with the new legislation;
II) proof of the entry date of the test in the certified center;
III) report of the certified center containing the justification
for the delay and the date the results will be ready.
Paragraph 3 The registration of the cases listed in Paragraph
2 may be canceled depending on the final results of the tests.
Article 10 Upon the first renewal after the publication of this
resolution, the holders of registration with expiration on 1 December
2004, of drug products based on synthetic, semi-synthetic or biologic
drug products associated with herbal drug products, vitamins/mineral
salts/amino acids, homeopathic drug products, homeopathic and/or
opotherapic preparations in fixed doses in the same formula or
in two or more presentations in one and the same packaging for
concomitant or sequential use, oral or injected, or of the association
of these categories, having the intention of maintaining all these
categories in the market, shall be required to submit clinical
studies demonstrating the efficacy of the association, published
in indexed journals (Medline, Chemical Abstracts, Biosis, International
Pharmaceutical Abstracts, or Biological Abstracts) or clinical
studies showing the efficacy of each isolated active ingredient,
provided that a technical justification submits evidence that
the association is rational, i.e., that the effects of each active
ingredient are additive or synergic, do not alter the formula,
and do not present increased risks for the patient.
Paragraph 1 - Any drug products that do not meet the caput of
this article will not have their registrations renewed since the
association will not have proved to be beneficial and exposes
the population to unnecessary sanitary risks.
Paragraph 2 – If a company chooses to alter the formula
of a drug product, it may maintain the brand as long as all the
documentation and proofs are submitted in compliance with the
legislation in force for each category.
Paragraph 3 – If a company chooses to submit clinical studies
of efficacy that are already in the data collection stage, it
shall submit proof of the stage of the study and timeframe for
its conclusion. This paragraph also serves for cases of changes
in formula that result in a New Drug here in the country.
Paragraph 4 – Company’s that work with injected associations
shall submit justification of the risk/benefit when compared to
oral presentations already existent in the market.
Article 11 Upon the first renewal after the publication of this
resolution, the holders of registration with expiration after
1 December 2004, of drug products based on associations between
four or more synthetic and/or semi-synthetic active ingredients
in fixed doses in one and the same formula or in two or more presentations
in one and the same packaging for concomitant or sequential use,
oral and/or injected that intend to remain in the market, shall
be required to submit clinical studies demonstrating the efficacy
of the association, published in indexed journals (Medline, Chemical
Abstracts, Biosis, International Pharmaceutical Abstracts, or
Biological Abstracts) or clinical studies showing the efficacy
of each isolated active ingredient, provided that a technical
justification submits evidence that the association is rational,
i.e., that the effects of each active ingredient are additive
or synergic, do not alter the formula, and do not submit increased
risks for the patient.
Paragraph 1 - Any drug products that do not meet the caput of
this article will not have their registrations renewed since the
association will not have proved to be beneficial and exposes
the population to unnecessary sanitary risks.
Paragraph 2 – If a company chooses to alter the formula
of a drug product, it may maintain the registration and the brand
as long as all the documentation and proofs are submitted in compliance
with GUIDE FOR MAKING POST-REGISTRATION ALTERATIONS, INCLUSION,
NOTIFICATIONS AND CANCELLATIONS IN MEDICINES.
Paragraph 3 – If a company chooses to submit clinical studies
of efficacy that are already in the data collection stage, it
shall submit proof of the stage of the study and timeframe for
its conclusion. This paragraph also serves for cases of changes
in formula that result in a New Drug here in the country.
Paragraph 4 – Company’s that work with injected associations
shall submit justification of the risk/benefit when compared to
oral presentations already existent in the market.
Paragraph 5 – If the association includes up to 4 active
ingredients one of which is caffeine, the caput of this article
does not apply.
Article 12
Upon the first renewal after the publication of this resolution,
the holders of registrations that will expire on 15 April 2004,
of drug products containing the following active ingredients in
their formulas associated in fixed doses in one same formula or
two or ore presentations in one and the same packaging for concomitant
or sequential use or in isolation: Gomenol; Eucalyptol for systemic
use; Salicilamide; “Limão bravo” (spiruna brasiliensis);
Cinarizine; Sodium Camphossulphonate, Garlic; Supra-renal; Vitamin
C; Ammonium Chloride; Beech Creosote; Aluminum Hydroxide; and
active ingredients that are therapeutically indicated for the
symptomatic treatment of influenza, shall:
I - Submit the clinical studies of efficacy of a single drug product
or association of drug products published in indexed journals
(Medline, Chemical Abstracts, Biosis, International Pharmaceutical
Abstracts, or Biological Abstracts) or clinical studies of efficacy
of each isolated active ingredient, provided that a technical
justification is submitted explaining that the association is
rational, i.e., the effects of each active ingredient are additive
or synergic without major risk to patients, or
II - Alter
the formula to eliminate these active ingredients in case of associations,
or
III – Alter the therapeutic indication with proved efficacy
by submitting clinical studies of efficacy of a single drug product
or association of drug products published in indexed journals
(Medline, Chemical Abstracts, Biosis, International Pharmaceutical
Abstracts, or Biological Abstracts) or clinical studies of efficacy
of each isolated active ingredient, provided that a technical
justification is submitted explaining that the association is
rational, i.e., the effects of each active ingredient are additive
or synergic without major risk to patients.
Paragraph 1 – Products that do not meet the caput of this
article will not have their registrations renewed since according
to the report of the “Evaluation Panel of Anti-Influenza
Medicines” (See ANVISA website) these products expose the
population to unnecessary sanitary risks.
Paragraph 2 - If the company chooses to alter the formula of a
drug product it may maintain its brand provided it submits all
the documentation and proofs in compliance with the legislation
in force for each category.
Paragraph 3 – If a company chooses to submit clinical studies
of efficacy that are already in the data collection stage, it
shall submit proof of the stage of the study and timeframe for
its conclusion. This paragraph also serves for cases of changes
in formula that result in a New Drug here in the country.
Paragraph 4 - Injected presentations with therapeutic indication
for the symptomatic treatment of influenza shall submit a risk/benefit
justification when compared to oral presentations already existent
in the market.
Article 13 Upon the first renewal after the publication of this
resolution, the holders of registrations that will expire on 15
April 2004, of drug products containing the following active ingredients
in their formulas associated in fixed doses in one same formula
or two or more presentations in one and the same packaging for
concomitant or sequential use or in isolation: Adenosine; Ripason;
(trademark), Glycyrrhiza glabra L. - (Licorice); Foeniculum vulgare
Hill. - (Anise); Mint sp. extract and oil (Mint); Mentol; Zingiber
officinale Rosc. - (Ginger); Remijia ferruginea DC - (Quina mineira);
Atropa belladonna L. extract - (belladonna extract); Cynara scolymus
L.extract - (Artichoke); Rhamnus purshiana DC. extract - (Extrato
de Cáscara Sagrada); Solanum paniculatum L. extract - (nightshade
extract); B-complex Vitamins; Pothomorphe umbellata (L.) Miq.
- (elixir, Capeba extract); Gastric mucosa extract, Pancreatic
extract, Hepatic extract, Bile extract; Liver detoxification ingredient
and those with prophylactic indication of hepaprotector, shall:
I - Submit the clinical studies of efficacy of a single drug product
or association of drug products published in indexed journals
(Medline, Chemical Abstracts, Biosis, International Pharmaceutical
Abstracts, or Biological Abstracts) or clinical studies of the
efficacy of each isolated active ingredient, provided that a technical
justification is submitted explaining that the association is
rational, i.e., the effects of each active ingredient are additive
or synergic without major risk to patients, or
II - Alter the formula to eliminate these active ingredients in
case of associations, or
III - Alter the therapeutic indication with proved efficacy by
submitting clinical studies of efficacy of a single drug product
or association of drug products published in indexed journals
(Medline, Chemical Abstracts, Biosis, International Pharmaceutical
Abstracts, or Biological Abstracts) or clinical studies of efficacy
of each isolated active ingredient, provided that a technical
justification is submitted explaining that the association is
rational, i.e., the effects of each active ingredient are additive
or synergic without major risk to patients.
Paragraph 1 – Products that do not meet the caput of this
article will not have their registrations renewed since according
to the report of the “Evaluation Panel of Hepaprotectors”
(See ANVISA website) these products expose the population to unnecessary
sanitary risks.
Paragraph 2 - If the company chooses to alter the formula of a
drug product it may maintain its trademark provided it submits
all the documentation and proofs in compliance with the legislation
in force for each category.
Paragraph 3 – If a company chooses to submit clinical studies
of efficacy that are already in the data collection stage, it
shall submit proof of the stage of the study and timeframe for
its conclusion. This paragraph also serves for cases of changes
in formula that result in a New Drug here in the country.
Article 14 Upon the first renewal after the publication of this
resolution, the holders of registrations that will expire on 1
December 2004, of drug products based on vitamins and/or minerals
and/or aminoacids containing at least one active ingredient above
the maximum safety levels for vitamins and/or minerals in drug
products or a therapeutic indication that implies in prescription
sales only shall submit proof of efficacy and safety or alter
the formula to levels considered safe.
Paragraph 1 – If no values exist for maximum safety levels
for a certain active ingredient in the Brazilian legislation,
the maximum safety levels of other countries may be used provided
proof of the maximum safety levels specified in the official codes
of those countries is submitted.
Paragraph 2 – The company shall submit to ANVISA all the
documentation in compliance with the TECHNICAL REGULATION FOR
THE REGISTRATION OF SPECIFIC DRUG PRODUCTS AND INSCRIPTION OF
DRUG PRODUCTS EXEMPT OF REGISTRATION, item II, excepting the notification
protocol for the production of pilot batches. Products that do
not meet the caput of this article will not have their registrations
renewed.
Article 15 Upon the first renewal after the publication of this
resolution, the holders of registrations that will expire on 1
December 2004, of drug products sold with medical prescription
only for some therapeutic indications and without medical prescription
for others may choose the Sales category of the drug product.
If the two categories are desired, one will be the object of renewal
and the other of a new registration. In this case different trademarks
shall be adopted since the sales category is not the same. The
same rationale applies to associations containing at least one
active ingredient with these characteristics in fixed doses in
one same formula or two or more presentations in one same packaging
for concomitant or sequential use.
Article 16 – Companies with products that have already been
listed by ANVISA as exempt of registration shall request an update
of their inscription up to three years after the last concession
of the inscription. On this occasion they shall submit the documentation
established in the TECHNICAL REGULATION FOR THE REGISTRATION OF
SPECIFIC DRUG PRODUCTS AND INSCRIPTION OF DRUG PRODUCTS EXEMPT
OF REGISTRATION, item II, excepting the copy of the protocol of
the pilot batch production notification.
Paragraph 1 Products already exempt of registration whose updating
period ends up to 30 days after the publication of this resolution
shall be granted and extension of up to 180 days to adapt to this
resolution.
Paragraph 2 Products that do not comply with the dispositions
of the caput of this article will have previously granted exemptions
cancelled.
Article 17 Upon the first renewal after the publication of this
resolution, holders of registrations of injected homeopathic drug
products shall submit risk/benefit studies compared to the oral
presentation of the same product.
Sole Paragraph - Companies that hold registrations of injected
homeopathic drug products that do not submit the information required
in the caput of this article shall not have their registrations
renewed.
Article 18 Herbal drug products registered before 01/31/1995 excepting
those already classified as traditional herbal drug products shall
submit the following upon the first registration renewal after
the publication of this resolution:
I – evaluation of pre-clinical toxicity of the herbal drug
product including at least the DL50 determination in 2 animal
species, one of which shall be a non-rodent (rabbit, dog, cat,
etc.); chronic toxicity (minimum of 90 days), in case of drug
products of frequent use or used for extended periods of time
(+ than 2 weeks); dermal toxicity, in case of products for topical
use..
II – up-to-date production and quality control reports in
compliance with the legislation in force.
Article 19 This resolution enters into force on the date of its
publication.
CLAUDIO MAIEROVITCH PESSANHA HENRIQUES
(*) Republished
due to incorrections in the original, published in the DOU nº
104, dated 2 June 2003, Section 1, pg. 26.
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