Department of Health and Human Services
Public Health Service
San Juan District
August 8, 2007
RETURN RECEIPT REQUESTED
Mr. Carlo Cortinovis
Novis PR dba Kramer-Novis
P.O. Box 191775
San Juan, Puerto Rico 00919-1775
Dear Mr. Cortinovis:
This Warning Letter is in reference to the inspection of your facility, located at 112 Mayaguez Street, San Juan, Puerto Rico 00918, from November 30, 2006, to December 22, 2006, by an investigator from the U.S. Food and Drug Administration’s San Juan District Office.
During the inspection, the investigator collected labeling for products identified below that are distributed by your firm under your own label Kramer-Novis. These products include prescription and over-the-counter (OTC) drug products, and dietary supplements. Products that are offered for the cure, mitigation, treatment, or prevention of disease are drugs as defined in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (Act) (21 U.S.C. § 321(g)(l)). OTC drug products are subject to final rules in Title 21, Code of Federal Regulations. (21 C.F.R.), Part 300, that set forth acceptable labeling and formulation conditions for OTC drugs. Our review of the labels and labeling for the OTC drug products and dietary supplement products revealed violations of the Act and regulations as follows:
OTC Drug Products
Supress-DX Pediatric Drops: The product is labeled as an antitussive (cough suppressant), decongestant (nasal), and expectorant and contains 5 mg. dextromethorphan hydrobromide, 2.5 mg. phenylephrine HCL, and 50 mg. guaifenesin per 1 mL. Based on the claims, the product is a drug as defined in section 201(g) of the Act (21 U.S.C. § 321(g)), and it is subject to the final rules on cough/cold preparations at 21 C.F.R. Part 341. The product fails to fully comply with these final regulations as follows:
The product’s carton labeling bears directions for use for infants from age 1 month to 2 years of age. Under the regulations on OTC cough/cold drug products, directions for use on the consumer labeling are not permitted for children under 2 years of age for antitussive drug products (21 C.F.R. § 341.74(d)(I)(ii)), for expectorant drug products (21 C.F.R. § 341.78(d)), and for nasal decongestant drug products (21 C.F.R. § 341.80(d)(1)(1)).
Additionally, the Supress-DX Pediatric Drops product fails to bear the following required warnings for OTC cough/cold drugs:
• 21 C.F.R. § 341.74(c)(1) and 21 C.F.R. § 341.78(c)(I) – “A persistent cough may be a sign of a serious condition. If cough persists for more than 1 week, tends to recur, or is accompanied by fever, rash, or persistent headache, consult a doctor.”
• 21 C.F.R. § 341.74(c)(3) and 21 C.F.R. § 341.78(c)(3) – “Do not give this product for persistent or chronic cough such as occurs with asthma or if cough is accompanied by excessive phlegm (mucus) unless directed by a doctor.”
• 21 C.F.R. § 341.74(c)(4)(v) and 21 C.F.R. § 341.80(c)(1)(i)(D) – “Do not use in a child who is taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.”
21 C.F.R. § 341.80(c)(1)(ii)(A) – “Do not exceed recommended dosage. [first sentence in boldface type] If nervousness, dizziness, or sleeplessness occur, discontinue use and consult a doctor.”
• 21 C.F.R. § 341.80(c)(1)(ii)(B) -“If symptoms do not improve within 7 days or are accompanied by fever, consult a doctor.”
• 21 CFR § 341.80(c)(1)(ii)(C) -“Do not give this product to a child who has heart disease, high blood pressure, thyroid disease, or diabetes unless directed by a doctor.”
The Supress-DX Pediatric Drops product is misbranded under section 502(f)(1) of the Act (21 U.S.C. § 352(f)(1)) for failure to bear adequate directions for use and under section 502(f)(2) of the Act (21 U.S.C. § 352(f)(2)) for failure to bear required warnings. Further, the product is a new drug as defined in section 201(p) of the Act (21 U.S.C. § 321(p)) because the product is not generally recognized as safe and effective for OTC use in children age 1 month to 2 years of age. A new drug may not be legally marketed in the United States under section 505(a) of the Act ((21 U.S.C. § 355(a)) without an approved application.
Gumsol Spray & Oral Solution contains [redacted] and [redacted] and claims to be an anesthetic and astringent drug product. Based on these claims, the product is a drug as defined in section 201(g) of the. Act (21 U.S.C. § 321(g)). The product contains phenylalanine, but fails to comply with 21 C.F.R. § 201.21(b) in that the label and labeling fails to bear a declaration of the amount of phenylalanine present in each dose. Thus, the product is misbranded under section 502(a) of the Act (21 U.S.C. § 352(a)).
Tussi-Pres Pediatric Liquid: The product contains the combination of [redacted] and [redacted] and is offered as an expectorant, antitussive, and nasal decongestant. The product is misbranded under section 502(f)(2) of the Act (21 U.S.C. § 352(f)(2)) because it fails to bear the “overdose” warning required under 21 C.F.R. § 330.1(g). The Tussi-Pres Pediatric Liquid is subject to the final regulations covering OTC cough/cold preparations at 21 C.F.R. Part 341. The product is labeled as a “pediatric° preparation, but the directions for use section includes dosing instructions for “children 12 and over.” Under the final regulations at 21 C.F.R. Part 341, products that are
labeled for children 12 years and older must bear certain warnings that are not required if the product is labeled only for children under 12 years of age. The product does not bear the”smoking” or “emphysema” or “chronic bronchitis” portions of the warnings required under 21 C.F.R. § 341.74(c)(2) and 21 C.F.R. § 341.78(c)(2), or the “difficulty in urination due to enlargement of the prostate gland” portion of the warning required under 21 C.F.R. § 341.80(ci(1)(C). Tussi-Pres- Pediatric is therefore misbranded under section 502(f)(2) of the Act (21 U.S.C. § 352(f)(2)) because if fails to bear the warnings listed above.
Bicarsim Antiflatuient Tablets and Bicarsim Forte Antiflatulent Tablets: These products contain the combination of [redacted] and [redacted] in each tablet. According to the bottle labels, both products are offered as antiflatulents for the relief of gas. Based on that claim, these products are subject to the final rules covering OTC antiflatulent drug products at 21 C.F.R. Part 332. Those rules do not permit the use of [redacted] as an antiflatulent. Therefore, Bicarsim Antiflatulent tablets and Bicarsim Forte Antiflatulent tablets are not generally recognized as safe and effective for that use. Promotional material also bears claims that the products may be used as an adjunctive treatment in which gas retention may be a problem, such as peptic ulcers, irritable colon, or diverticulosis. The final rules do not permit those claims for the BiCarsim products. The products are new drugs as defined in section 201(p) of the Act (21 U.S.C. § 321(p)) that may not be legally marketed in the United States under section 505(a) of the At (21 U.S.C. § 355(a)) without an approved application.
Drug Facts Format Labeling: OTC drug products must comply with 21 C.F.R. § 201.66, which requires the Drug Facts Format. The Simeped Drops and Supress-DX Pediatric Drops products are not labeled according to those format requirements. The products are, therefore, misbranded under section 502(c) of the Act (21 U.S.C. § 352(c)).
Tamper-Evident Packaging Statements: The tamper-evident packaging (TEP) statements on the Dologen caplets (“safety seal under cap …”), Bicarsim and Bicarsim Forte tablets (“do not use if seal around cap . . .”), Tussi-Pres Liquid (“do not use if cap seal . . .”), and Tussi-Pres Pediatric Liquid (“heat seal under cap . . .”), which specify these products’ TEP features; fail to reference the identifying characteristic of the TEP features (21 C.F.R. § 211.132(b)) as required by 21 C.F.R. § 211.12(c)(2). Thus, the products are misbranded under section 502(a) of the Act(21 U.S.C. § 352(a)). .
Vasoflex Tablets, Vasoflex Forte Capsules, and Vasoflex HD Caplets
The labeling and promotional material for these products contains statements that represent or imply that these products are intended to be utilized in the cure, mitigation, treatment or prevention of diseases. Such claims cause the products to be drugs under section 201(g)(1)(B) of the Act (21 U.S.C. § 321(g)(1)(B)).
1. Vasoflex Tablets (60 & 4 tablets presentations)
Disease claims in the product’s label and labeling (promotional material) include: Label – “Helps in treatment of abnormal capillary permeability”.
Labeling -“For prevention & treatment of abnormal capillary permeability fragility & capillary bleeding. As an aid in the palliative treatment of varicose veins”.
2. Vasoflex Forte Capsules (90 & 4 capsules presentations)
Label -“Clinically proven to relieve venous circulatory disorders such as tired legs, heaviness in the legs, swelling or pain”.
Labeling -“For the symptomatic relief of venous insufficiency including swelling of the legs (edema), pain in the extremities (dull aching, heaviness or cramping), varicose veins and itching”.
3. Vasoflex HD Caplets (90 caplets presentation)
Label -°°INDICATIONS: For the treatment of capillary permeability, chronic venous insufficiency and hemorrhoidal disease”.
-Labeling – “For the treatment of hemorrhoidal disease, capillary permeability and chronic
4. Apetigen, Apetigen Plus Liquid, and Apetigen Plus Tablets:
Labeling – “Indications . . . chronic diseases . . . debilitated, alcoholics . . . stressed by
5. Bio-Immunex (60 capsules)
Label – states “[I]mmuno-competence to aid in the prevention of cancer . . .
Because we are unaware of any evidence that these products are generally recognized as safe and effective when used as indicated in their labeling, they are new drugs as defined under section 201(p) of the Act (21 U.S.C. § 321(p)). New drugs may not be legally marketed in the U.S. without prior approvaL from FDA as described in section 505(a) of the Act (21 USC § 355(a)).
Your Apetigen-Plus – A palatable mixture of B-Complex vitamins with Zinc, Iron, and Lysine (1 and 8 fl. oz.), Lysiplex Plus Tables – Appetite Stimulant Formula with Iron, Zinc, B-Complex, Folic Acid and Branch Chain Amino Acids (BCAAs) (90 tablets), Lysiplex Plus – Appetite Stimulant Formula with Iron & Zinc (1, 6, 16 fl. oz.), and Lysiplex Plus – Appetite Stimulant Formula with Iron, Zinc & B-Complex (6, 16 fl. oz.) products are misbranded within the meaning of sections 403(a)(1) and 201(n) of the Act (21 U.S.C. § 343(a)(1) and 21 U.S.C. § 321(n)) because the labels for these products, which contain added iron, fail to bear the following warning statement as required by 21 CFR § 101.17(e):
“WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.”
Your Lysiplex product is misbranded within the meaning of section 403(a)(1) of the Act (21 U.S.C § 343(a)(1)) because the label bears the “Rx” symbol and the National Drug Code (NDC) numbers. The use of this symbol and NDC numbers are false and misleading in that it represents the product as a prescription drug when, in fact, it is not because your product is also labeled as a dietary supplement.
Your Calcibon, Apetigen-Plus Fortified with Zinc, Dietex Forte, Pre-Protein Tablets (6 tablets and 90 tablets count), and Vasoflex HD (90 caplets) products are misbranded within the meaning of sections 1403(i)(1) and 403(s) (2) (B) of the Act (21 U.S.C. §§ 343(i)(1),343(s)(2)(B)). Although some of these products are identified as a dietary supplement in the information panel on the product label, the labels fail to identify the products using the term “dietary supplement,” or a similar term- describing the type of supplement (e.g., “herbal supplement”) as part of the statement of identity on the principal display panel, as required under 21 CFR §§ 101.3(d) and (g).
Further, your products Apetigen-Plus Fortified with Zinc (60 tablets), Lysiplex Plus Appetite Stimulant Formula with Iron, Zinc, & B-Complex, Lysiplex Plus Tablets Appetite Stimulant Formula with Iron, Zinc, B-Complex, Folic Acid and BCAAs an d Pre-Protein Liquid Predigested Protein are misbranded within the meaning of section 403(q)(5)(F) of the Act (21 U.S.C. § 343(q)(5)(F)) in that the labels fail to bear nutrition labeling in “Supplement Facts” format as required under 21 CFR § 101.36. The following are examples:
• The labels for your product Apetigen-Plus Fortified with Zinc (60 tablets ) and Lysiplex Plus Appetite Stimulant Formula with Iron, Zinc, & B-Complex do not have the title, “Supplement Facts,” and Apetigen-Plus Fortified with Zinc does not enclose the nutrition information using hairlines as required by 21 CFR §§ 101.36(e)(1) and (e)(2), respectively.
Further, the listing of dietary ingredients that have a Reference Daily Intake (RDI) or a Daily Reference Value (DRV), for example, Vitamin E, must be listed in the order as required by 21 CFR § 101.36(b)(2).
• The label for your product Lysiplex Plus Tablets Appetite Stimulant Formula with Iron, Zinc, B-Complex, Folic Acid and BCAAs lists both dietary ingredients with an established RDI I(e.g., Vitamin A, Vitamin C, Vitamin E) and dietary ingredients for which FDA has not set a DRV or RDI (e .g., Lysine, Leucine) as defined under 21 CFR §§ 101.36(b)(2) and (b)(3), respectively. However, the label does not segregate the 21 CFR §§ 101.36(b)(2) and (b)(3) dietary ingredients into separate sections of the supplement facts panel as required by 21 CFR 101.36(b)(3)(i).
Further, heavy bars are required immediately after the listing of the last dietary ingredient required to be declared pursuant to 21 CFR §§ 101.36(b)(2) and (b)(3), respectively (21 CFR §§ 101 .36,(e)(6)(ii) and (iii)).
• The label for your product Pre-Protein Liquid Predigested Protein lists individual amino acids as part of the 15 grams of protein provided as indicated on your “Supplements Facts” panel. However, these dietary ingredients, for which FDA has not established RDIs or DRVs, must be listed within the nutrition labeling (“Supplement Facts”) as required by 21 CFR § 101.36(b)(3).
The label for your products Apetigen – A palatable mixture of B-Complex vitamins with Lysine, and Lysiplex Plus Tablets – Appetite Stimulant Formula with Iron, Zinc, B-Complex, Folic Acid and BCAAs are misbranded within the meaning section 403(r)(1)(A) of the Act (21 U.S.C. § 343(r)(1)(A)) because the labels make the unauthorized nutrient content claims “A palatable mixture . . . with Lysine” and “Appetite Stimulant Formula . . . with BCAA’s.” For your information, Lysine and BCCAs are dietary ingredients that do no have established RDI (21 CFR § 101.9(c)(8)(iv)) or DRV (21 CFR § 101.9(c)(9)). Therefore, these claims are not authorized for substances without a DRV or RDI. FDA considers “with” to be synonymous with “contains” in the context used on these labels.
Your 483 Response and Previous FDA Regulatory Meeting
We acknowledge receipt of your letter dated January 10, 2007, in response to the current inspectional findings brought to your attention verbally and in the written FDA-483, Inspectional Observations, issued and discussed with you at the closing meeting on December 22, 2006
Your response did not include any reference to specific labeling deviations discussed with you during the course of the inspection and during the closing. discussion with management. You should review the labeling (including promotional materials such as flyers) for all of the products that you market, taking particular note of the types of claims that may cause your products to be unapproved or misbranded under the Act.
We also acknowledge receipt of your letter dated December 5, 2006, in which you state that you will no longer market the Tussi-Pres B prescription drug product that contains the combination of [redacted] and [redacted]. You ask if you may distribute the product inventory that you have on hand. The product is labeled as an antihistamine, nasal decongestant, and expectorant. The product is a new d rug within the meaning of section 201(p) of the Act and it lacks an approved application filed pursuant to section 505 of the Act; it is also misbranded pursuant to section 502(f)(1) of the Act because it does not bear adequate directions for use. The interstate distribution of this product without approved new drug applications violates sections 301(a)and (d) of the Act (21 U.S.C. §§ 331(a) and (d)). Because the product is an unapproved new drug and misbranded, we are unable to grant your request to distribute the existing inventory in your possession.
You also ask in your December 5 letter for permission to distribute selected drug products held in inventory (Dologen, Bicarsim, and Bicarsim Forte) that lack imprinting on the solid oral dosage form that is required under 21 C.F.R. Part 206. Failure to bear the required imprinting on drug solid dosage forms causes the products to be misbranded under section 502(a) of the Act (21 U.S.C. § 352(a)). Although the corrective action taken by your firm in this case will prevent continued violation of this requirement, we are unable to grant your request to deplete your current inventory of the above mentioned products because they are misbranded.
You have been previously advised that your products do not comply with applicable requirements in the Act and its implementing regulations. On May 11, 2005, a Regulatory Meeting was held at the FDA San Juan District Office. At that meeting, you were advised of your firm’s deviations from the requirements for dietary supplements and OTC drug products.
You promised, but failed, to correct these deviations. Your corrective action plan will be evaluated taking into consideration the inspectional history of your firm during our next inspection of your firm.
The violations cited in this letter are not intended to be an all-inclusive list of deficiencies regarding your products. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, with limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct the referenced violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. Your reply should be directed to: the Food and Drug Administration, attention: Carlos A. Medina, Compliance Officer, at 466 Fernandez Juncos Avenue, San Juan, Puerto Rico 00901-3223. If you have any questions regarding any issue in this letter, please contact Mr . Medina at (787) 474-9538, firstname.lastname@example.org. You can also find the Act, regulations, and guidelines through links in FDA’s Internet homepage at http://www.fda.gov.
Maridalia Torres Irizarry
San Juan District
This page was posted on March 27, 2019.