Resolution - RDC nº 137 of 29 May 2003(*)
D.O.U dated 09/22/2003

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,

Article 1 Approve the attached Technical Regulation for the registration of Similar Drugs.
Whereas the information contained in the package inserts and packaging of drug products is extremely important for professional prescribers and users giving details of the active ingredients and usage warnings;

Whereas it is in the interest of ANVISA to complement the content of the package inserts and packaging of several categories of drug products marketed in the country in order to provide greater quality and safety for users and prescribers;
Whereas several categories of drug products widely marketed in the country deserve to have warnings and special labels to protect patients;

Whereas the need to harmonize the text of package inserts and packaging of drug products;

Adopts the following resolution and I, the Chairman, determine its publication:

Article 1 the registration/renewal of drug products of the categories/active ingredients in the list attached will only be authorized if the package inserts and packaging contain the adequate warning according to the attached list.

Article 2 This resolution enters into force on the date of its publication.

CLAUDIO MAIEROVITCH PESSANHA HENRIQUES

ANNEX

Medicines whose formulations require specific warnings shall include them in the package inserts and packaging in conspicuous and easily legible type according to the model phrases listed in the items below:

1. Medicines based on boric acid and its derivates destined for adult use shall include in their package inserts, labeling, primary and secondary packaging the following warnings:

1.1. "Do not apply to large body surfaces whenever there are lesions, wounds or burns of any type".

1.2. "Adult use only. The use in children can be harmful to their health".

2. Products containing Acitretin in all its formulations shall include the following warnings in the package insert:

2.1 "Acitretin is a highly teratogenic compound. Its use in pregnant women is forbidden. It should not be used in women with the potential of getting pregnant and requires the use of potent contraceptive methods 30 days prior to, during and 3 years after treatment".

2.2. "Blood donation is expressly contraindicated during and up to 2 years after treatment with acitretin"

2.3. "The concomitant use of alcohol during and up to two months after treatment with acitretin potentializes the formation of etretinate, a highly teratogenic agent".

3. Multivitamin products for children under 12 years old or of PEDRIATRIC USE with a maximum ethanol concentration no higher than 0.5% in their formulations shall include the following warning in the package insert and labeling of the primary and secondary packaging: “Contains 0.5% ethanol”.

4. Multivitamin products for ADULT USE with a maximum concentration no higher than 2.0% in their formulations shall include the following warning in the package insert and labeling of the primary and secondary packaging: “Adult use only. The use in children can be harmful to their health".

5. Products for topical use containing camphor in their formulations shall include the following warning in the package insert and labeling of the primary and secondary packaging: "Do not use in children under 2 years old ".

6. Products containing ketorolac in their formulations shall include the following warning in the package insert:
"The duration of treatment with ketorolac shall be restricted to:

Oral use : No longer than 5 days;
Injected: No longer than 2 days

Dosage shall be restricted to:
Maximum dose for young people: 90 mg/day
Maximum dose for seniors: 60 mg/day."

7. Products containing clozapine in their formulations shall include the following warning in the package insert: "Clozapine may produce agranulocytosis (reduction of the number of defense cells in the blood) and may therefore require periodic hematological controls. It is recommended that white blood cells be counted weekly in the first six months of treatment and once every two weeks after this. This drug product may not be used in patients with a diagnosis of severe psychotic disorder that does not respond to other neuroleptics."

8. Products containing cyproterone in their formulations shall include the following warning in the package insert: “This drug product requires careful use under strict medical surveillance and accompanied by periodic controls of liver function (bilirubins and transaminases) at 8, 15, 30 and 90 days of treatment for causing hepatotoxicity (liver toxicity). This drug product is not approved for contraceptive use."

9. Products containing peripheric vasodilators in their formulations shall include the following warning in the package insert: "The efficacy of this drug product depends on the functional capacity of the patient."

10. Pediatric use products containing acetylsalicylic acid in their formulations shall include the following warning in the package insert and labeling of the primary and secondary packaging: "Do not use in children and adolescents presenting chicken pox or influenza symptoms without medical consultation on Reye’s syndrome, a rare serious disease associated to this drug product”.

11. Products containing the excipient Yellow Tartrazine (FDC nº 5) in their formulations shall include the following warning in the package insert and labeling of the primary and secondary packaging: "This product contains Yellow TARTRAZINE and may cause allergic reactions including asthma, particularly in those allergic to acetylsalicylic acid".

12. Products containing clemastine and promelizine in their formulations shall include the following warning in the package insert: "Do not use in children under 3 years old."

13. Products containing Cough Sedatives and Expectorants in their formulations shall include the following warning in the package insert and labeling of the primary and secondary packaging: "Do not use in children under 2 years old".
13.1. Cough sedatives with codeine in their formulation shall include the following expression in the package insert: "This drug product contains a narcotic capable of causing physical and psychic dependence with prolonged use".

14. Medicines containing the excipient gluten in their formulations shall include the following warnings in the package insert and labeling of the primary and secondary packaging:
14.1. "Attention people affected by Celiac Disease or Celiac Syndrome: contains Gluten".
14.2. "Warning: This drug product contains Gluten and is therefore contraindicated for people affected by Celiac Disease or Celiac Syndrome".

15. Products for pediatric use containing flufenamic and mefenamic acids in their formulations shall include the following warning in the package insert: "Treatment may not be longer than 7 days".

16. Products containing the excipient sucrose or other saccarides harmful for diabetics shall include the following warnings in the package insert and labeling of the primary and secondary packaging:
16.1. "Attention diabetics: contains sugar".
16.2. "Warning: This drug product contains Sugar and should therefore be used with caution by diabetics".

17. Products containing artificial sweeteners with phenylalanine shall include the following warning in the package insert and labeling of the primary and secondary packaging: "Attention phenylketonurians: contains phenylalanine"

18. Medicines containing noretisterone and medroxiprogesterone in their formulations shall include the following warning in the package insert: "This drug product may interrupt menstruation for a prolonged period of time and/or cause severe inter-menstrual bleeding."

19. Medicines containing nitroimidazol in their formulations shall include the following warning in the package insert: "The substance nitroimidazol produced cancer in laboratory animals and should therefore be considered potentially harmful to humans."

20. Medicines containing paracetamol in their formulations shall include the following warning in the package insert and labeling of the primary and secondary packaging: "Do not use other products containing Paracetamol".

21. Medicines based on sodium diclophenac and potassium diclophenac shall include the following warning in the package insert: "Do not use in children under 14 years old except in cases of chronic juvenile arthritis ".
21.1. Injected drug products based on sodium diclophenac and potassium diclophenac shall include the following warning in the package insert and labeling of the primary and secondary packaging: "Warning: Apply only on the gluteus. Do not inject in the arms".

22. Medicines based on ansiolitics (except Ipsapirone), anti-histamines (except antazoline and pentigetide), anti-psychotics, opioid analgesics, antidepressives (except amineptine, dibenzepine and sibutramine) shall include the following warning in the package insert: "Driving and operating machinery is not recommended during treatment for ability and attention may be compromised".

23. Products containing tacrine in their formulations shall include the following warning in the package insert: "This drug product requires careful use under strict medical surveillance and accompanied by periodic controls of liver function (bilirubins and transaminases) at 8, 15, 30 and 90 days of treatment for causing hepatotoxicity (liver toxicity)”.

24. Medicines containing tolrestat in their formulations shall include the following warning in the package insert: "This drug product requires careful use under strict medical surveillance and accompanied by periodic controls of liver function (bilirubins and transaminases) at 8, 15, 30 and 90 days of treatment for causing hepatotoxicity (liver toxicity)".

25. Medicines containing immunosuppressants in their formulations shall include the following warning in the package insert: “Immunosuppressive drug products may activate primary focuses of tuberculosis. Doctors supervising patients with a depressed immune system shall be alert to the possibility of the active disease, taking every possible precaution for early diagnosis and treatment".

26. Products containing ribavarin, lovastatin, flurastatin, provastatin, sinvastatin,
aminopterin, iodinated glycerol, etretinate, leuprolide, phencyclidin, quazepam, temazepam, triazolam, chenodiol, danazol, mifepristone, radioactive ingredients, estrogens and progestins in their formulations shall include the following warning in their package insert: "This drug product causes malformations to the baby during pregnancy".

27. Medicines subject to special control whose formulations require specific warnings shall include them in the package inserts and primary and secondary packaging in a conspicuous and easily legible type according to the model phrases listed in the items below:
27.1. The front and back side of the secondary packaging of drug products based on the substance misoprostol that are on the "C1" list (other substances subject to special control) of Presidential Decree SVS/MS nº 344/98, and its updates shall include a clearly visible symbol of pregnant woman within circle that is cut in half and have the following expressions in conspicuous easily legible type inserted in the red strip: "Warning: Prescription Use Only" - "Warning: Risk to Pregnant Women" - "Sale and Use Restricted to Hospitals".
27.1.1. Medicines containing misoprostol shall include the following expression in the package insert: "Warning: Risk to Pregnant Women" - "Sale and Use Restricted to Hospitals".
27.2. Manufactured or manipulated topical use drug products containing retinoic substances on the "C2" list of Presidential Decree SVS/MS nº 344/98 and its updates shall include the following expressions: "Prescription Sale Only" - Warning: Risk to Pregnant Women. May cause problems to the fetus".
27.3. Medicines for systemic use based on the substances on the "C2" list (retinoic) of Presidential Decree SVS/MS nº 344/98 and its updates shall include the following expressions in the red strip of the labeling: "Prescription Sale Only" – “Warning: Risk to Pregnant Women, Causes Serious Defects in the Face, Ears, Heart and Nervous System of the Fetus”.
27.4. Medicines containing antiretrovirals on the “C4” list of Presidential Decree SVS/MS nº 344/98 and its updates shall include the following expressions: “Prescription Sale Only” – “Warning – Incorrect Use Causes Resistance of the AIDS virus and Treatment Failure".
27.5. The labeling of drug products containing the substances on the “C3” list of Presidential Decree SVS/MS nº 344/98 (immunosuppressants) and its updates and those of the drug product thalidomide shall follow the rules of the items below.
27.5.1. The primary packaging of the pharmaceutical product thalidomide shall include the expression PANTONE PROCESS BLACK C printed in black in a clear and readable manner, and the pictogram of a the face of a woman taking the drug product inserted in a circle cut by an “X” indicating the prohibition with the warnings:
27.5.2. "Forbidden for Women of Childbearing Age".
27.5.3. "May cause the birth of limbless children".
27.6. The secondary packaging of the drug product thalidomide shall be white and obey to the following specifications:
27.6.1. Front
27.6.1.2. Contain the identification of the product printed in red letters.
27.6.1.3. Contain text in readable letters at least 2mm tall, respecting proportionality. They should furthermore maintain adequate distance proportions that are indispensable to easy reading with the following expression printed in conspicuous black letters "Thalidomide may cause the birth of children without arms or legs – Don’t allow this to happen to your family"
27.6.1.4. Include the drawing (pictogram) of the face of a woman taking the drug product inserted in a circle cut by an “X” indicating the prohibition.
27.6.1.5. Contain an inclined black strip covering the front of the packaging and the expressions: “Forbidden for women in childbearing age" printed in readable white letters and “Prescription Use Only” in conspicuous easily legible black letters.
27.5.6.2. Back
27.6.2.1. Contain text in readable letters at least 2mm tall, respecting proportionality. They should furthermore maintain adequate distance proportions that are indispensable to easy reading.
Identification and concentration of the product engraved in red letters.
The following text printed in red letters: "This drug product belongs to you alone. Do not pass it on to anyone".
Space for the user to write down: name, dosage, dosage schedule, duration of treatment and date.
The following text printed in black letters: "This drug product does not provoke abortion nor avoid conception".

(*) Republished for incorrections in the original, published in the DOU nº 104, dated 2 June 2003, Section 1, Pg 31.