| Public Health Service Food and Drug Administration |
555 Winder1ey Pl., Ste. 200 |
Department of Health and Human Services
WARNING LETTER
FLA-11-14
February 4, 2011
Dr. Yolanda Eustaquio
President
Tarmac Products, Inc.
d.b.a. Axara Pharmaceuticals
16311 NW 52nd Avenue
Miami, FL 33014-6209
Dear Dr. Eustaquio:
During our May 24, 2010 thru June 7, 2010 inspection of your pharmaceutical manufacturing facility, Tarmac Products, Inc., d.b.a Axara Pharmaceuticals, located at 16311 NW 52nd Avenue, Miami, FL, investigator(s) from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211.1 These violations cause your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
In addition, your Over-the-Counter (OTC) drug products are manufactured without an approved application. As described below, these drugs are unapproved new drugs and by introducing them into interstate commerce, you are in violation of sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)]. These unapproved new drugs are misbranded pursuant to section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)]. Further, your dietary supplements are also misbranded pursuant to sections 403(e)(1), 403(i)(1), 403(q)(5)(F), 403(r)(1)(B) and 403(s)(2)(B) of the Act [ 21 U.S.C. §§ 343(e)(1), 343(i)(1), 343(q)(5)(F), 343(r)(1)(B), and 343(s)(2)(B] and by introducing them into interstate commerce, you are in violation of section 301(a) of the Act [21 U.S.C. § 331(a)].
We have reviewed your firm’s response of June 24, 2010, and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
I. CGMP Violations:
1. Your firm has failed to follow written responsibilities and procedures applicable to the quality control unit [21 C.F.R. § 211.22(d)].
For example, your Quality Control Unit (QCU) failed to review your packaging batch record and release drug product as required by your Standard Operating Procedure (SOP) # QU.003.0 for lot 100159 of Eye Drops Chamomile “Colirio de Manzanilla” (Naphazoline HCl 0.12%). The packaging batch record for this product contained numerous errors including the following: (1) listing the wrong contract manufacturer; (2) inaccurate bottle quantity; (3) a Certificate of Analysis (COA) identifying a different active ingredient (i.e., Tetrahydrozoline HCl 0.05%); (4) listing the wrong dosage form (e.g., blistered capsules versus sterile drops); (5) wrong number of cases; and, (6) a label specimen without a lot number. Despite these errors, your firm released and distributed this lot.
In your response, your firm states you will generate and revise various SOPs, and that you have hired a consultant to provide comprehensive CGMP training of the responsibilities and procedures applicable to the QCU. Your response, however, is inadequate because you have failed to provide an adequate corrective action plan to ensure your QCU will follow your procedures. We recommend that you develop an internal audit program designed to ensure that your employees follow all procedures.
2. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].
For example, your firm failed to qualify the labeling and packaging equipment used for dry, liquid and cream processes. Your firm failed to demonstrate the capabilities of your manufacturing processes.
In your response, your firm provided equipment validation process flow descriptions and diagrams. However, your response is inadequate because your firm failed to provide a detailed equipment validation plan. Specifically, your plan fails to describe any studies or tests used to verify proper functionality of the equipment or system. Further, your firm has not described any activities to demonstrate that the equipment is suitable for its intended use.
3. Your firm’s drug products failed to bear an expiration date determined by appropriate stability testing to assure that they meet applicable standards of identity, strength, quality, and purity at the time of use [21 C.F.R. § 211.137(a)].
For example, your firm assigned expiration dates to lots of Sanafitil Ointment (i.e., lots 90J27 and 90J29) without any supporting stability data.
In your response, your firm acknowledges that the drug products did not bear an expiration date determined by appropriate stability data. To correct this, your firm has drafted a new SOP, Finished Product Expiration Dates (SOP # QC-008-00). Your response, however, is inadequate because your firm failed to provide a corrective action plan to evaluate and determine the appropriate expiry period for products you have distributed.
4. Your firm has failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product [21 C.F.R. § 211.188].
For example, the investigator observed drug products in your inventory that lacked batch production and control records for the following:
• T-Rapiel Antibiotic Cream (lot 100588), Exp. 05/14 (19 boxes/(b)(4) tubes each)
• Estomaquil (lot 091152), Exp. 11/12, (3 boxes/(b)(4) boxes each)
• Cuadriderma Cream (lot 10037501), Exp. 3/14, ( (b)(4) tubes)
• Sanafitil Liquid 1oz (lot 900525), Exp. 5/12, (10 boxes/(b)(4) btls each & 1 box/(b)(4) each)
• Sanafitil ointment (lot 901030), Exp. 10/14, ((b)(4) tubes & 7 cases/(b)(4) tubes each)
Your response is inadequate because your firm failed to provide an action plan to address the distributed products that do not have batch records. Furthermore, your firm failed to adequately evaluate the drug products without batch records to determine compliance with all established written procedures.
II. Unapproved and Misbranded OTC Drugs:
Your firm repacks, relabels, and distributes numerous drug products for over-the-counter (OTC) use. During the inspection noted above, the investigators collected labeling for many of these drug products. As presently formulated, labeled and promoted, these products are unapproved and/or misbranded drugs in violation of sections 505(a) and 502 of the Act [21 U.S.C. §§ 355 and 352]. These violations are described in more detail below.
Vermocks Suspension
The package labeling for Vermocks Suspension identifies pyrantel pamoate as the sole active ingredient. This product is labeled as a parasiticide for the treatment of pinworms, and the directions for use state “1 tsp twice daily for 3 days.”
Based on the labeling described above, Vermocks Suspension is a drug as defined by section 201(g)(1) of the Act [21 U.S.C. § 321(g)(1)] because it is intended to treat a disease and to affect the structure or function of the body of man. Based on the product’s labeled indications for use, Vermocks Suspension is subject to the requirements of the OTC Final Monograph for Anthelmintics (21 C.F.R. Part 357). However, Vermocks Suspension is not labeled in conformance with this final monograph.
According to 21 C.F.R. § 357.150(d)(1), pyrantel pamoate is permitted, under the OTC Final Monograph for Anthelmintics, as a suspension dosage form that is to be dosed as follows:
“Adults and children 2 years to under 12 years of age: oral dosage is a single dose of 5 milligrams of pyrantel pamoate base per pound, or 11 milligrams per kilogram, of body weight not to exceed 1 gram. This medication should only be taken one time as a single dose; do not repeat treatment unless directed by a doctor.”
Although there is a weight based dosing schedule on your package labeling, your directions for use state “1 tsp. twice a day for 3 days.” Such dosing directions do not comply with the final rule because they fail to consider the weight based dosing required in 21 C.F.R. § 357.150(d)(1). Therefore, based on your product’s novel directions for use, Vermocks Suspension is a new drug as defined by section 201(p) of the Act [21 U.S.C. § 321(p)] because we are not aware of sufficient evidence to show that it is generally recognized as safe and effective for this dosing schedule. Therefore, as presently labeled and promoted, Vermocks Suspension is an unapproved new drug in violation of section 505(a) of the Act, respectively [21 U.S.C. § 355(a)].
Under section 301(d) of the Act [21 U.S.C. § 331(d)], a new drug may not be introduced or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for it. Vermocks Suspension does not have an approved application, and its introduction into interstate commerce violates these provisions of the Act.
In addition to new drug charges, Vermocks Suspension is misbranded under section 502(f)(1) of the Act as further described under 21 C.F.R. §§ 201.5(b), (c), and (d) because the following information on the package labeling fails to comply with that in the final rule: quantity of dose, frequency of administration, and duration of administration.
Vermocks Suspension is also misbranded under section 502(c) [21 U.S.C. § 352(c)] because the front panel of the package labeling has a statement that appears only in Spanish. Under 21 C.F.R. § 201.15(c)(1): “All words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear thereon in the English language: Provided, however, That in the case of articles distributed solely in the Commonwealth of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English.” Since your drug products are not solely distributed in Puerto Rico or other Territory, your product labeling needs to appear in English, which can then be followed by a Spanish translation (See 21 C.F.R.
§ 201.15(c)).
Vermocks Tableta
The package labeling for Vermocks Tableta identifies pyrantel pamoate as the sole active ingredient. This product is labeled “For the treatment of pinworms.” The directions for use state, “1 tablet twice daily for 3 days.”
Based on the labeling described above, Vermocks Tableta is a drug as defined by section 201(g)(l) of the Act [21 U.S.C. § 321(g)(1)] because it is intended to treat a disease and to affect the structure or function of the body of man. According to the product’s labeled indications for use, Vermocks Tableta is subject to the requirements of the OTC Final Monograph for Anthelmintics (21 C.F.R. part 357). However, Vermocks Tableta is not labeled in conformance with this final monograph.
Vermocks Tableta comes in 144 milligram tablets. The consumer is directed to take “1 tablet twice daily for 3 days.” The total daily dose for all consumers would be 288 milligrams. As indicated in the final monograph, 21 C.F.R Part 357, the dosing of the product is dependent on body weight and therefore does not provide a fixed dose for all patients. In addition, the final rule states that children weighing under 25 pounds or under two years old should not use pyrantel pamoate unless directed by a doctor. These directions do not appear on the external carton labeling for Vermocks Tableta. According to the directions provided in the final rule, a child weighing 25 to 37 pounds is directed to take a single dose of 125 milligrams. If a consumer were to follow the Vermocks Tableta’s directions for a child weighing between 25 and 37 pounds, the child would take 288 milligrams daily, which would be 163 milligrams over the daily dose (125 milligrams) provided in the final rule.
Moreover, Vermocks Tableta's directions state that this dose is to be taken for three days. However, the final rule states that the dose should be taken once unless instructed otherwise by a physician. Therefore, at the end of three days, the child who is administered Vermocks may have taken over six times the dose set forth in the final rule. In addition, overdosing would occur for anyone weighing between 25 to 62 pounds who takes Vermocks according to the directions on the product labeling. In addition, according to the dosage schedule, Vermocks would most likely be sub-therapeutic for anyone weighing over 63 pounds since the dose in the final rule exceeds the 288 milligrams provided by the package labeling.
Based on the above, Vermocks Tableta is a new drug within the meaning of section 201(p) of the Act [ 21 U.S.C. § 321(p)] because we are not aware of sufficient evidence to show that it is generally recognized as safe and effective for the labeled dosing regimen. The marketing of this new drug product without an approved drug application violates sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)].
In addition to new drug charges, Vermocks Tableta is misbranded under section 502(f)(1) of the Act [21 U.S.C. §§ 352(f)(1)] as further described under 21 C.F.R. §§ 201.5(b), (c), (d), and (f) because the following information on the package labeling is incorrect: quantity of dose, frequency of administration, duration of administration, and route of method of administration. Furthermore, Vermocks Tableta is misbranded under section 502(c) of the Act [21 U.S.C. § 352(c)] because it does not fully comply with the “Drug Facts” labeling requirements under 21 C.F.R. § 201.66.
Vermocks Tableta is further misbranded under section 502(c) of the Act [21 U.S.C. § 352(c)] because the front panel of the package labeling has a statement that appears only in Spanish. Under 21 C.F.R. § 201.15(c)(1): “All words, statements, and other information required by or under authority of the Act to appear on the label or labeling shall appear thereon in the English language: Provided, however, That in the case of articles distributed solely in the Commonwealth of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English.” Since your drug products are not solely distributed in Puerto Rico or other Territory, your product labeling needs to appear in English, which can then be followed by a Spanish translation (See 21 C.F.R.
§ 201.15(c)).
Estomaquil
The package labeling for Estomaquil identifies bismuth subsalicylate as the sole active ingredient. This product’s labeled uses include “provides soothing relief for upset stomach, indigestion, diarrhea, heartburn, nausea,” and may also be used to “reduce gas.”
Based on the labeling described above, Estomaquil is a drug as defined by section 20l(g)(l) of the Act [21 U.S.C. § 321(g)(l)] because it is intended to affect the structure or function of the body of man. According to the product’s labeled indications for use, Estomaquil is subject to the Antidiarrheal Products Final Monograph (21 C.F.R. Part 335) and Antiflatulent Products for Over-the-Counter Human Use (21 C.F.R. Part 332) and is covered by the Tentative Final Monograph for Overindulgence in Food and Drink [56 Fed. Reg. 66742 (Dec. 24, 1991)]. While bismuth subsalicylate is an acceptable active ingredient for use as an antidiarrheal and is covered by the TFM for Overindulgence in Food and Drink, bismuth subsalicylate is not an acceptable active ingredient for use as an antiflatulent to “reduce gas” (21 C.F.R. § 332.10). Because Estomaquil is labeled for use as an antiflatulent and suggesting that this product can be used to “reduce gas,” the labeled indications for use may be misleading to consumers. Therefore, the product is misbranded under section 502(a) of the Act [21 U.S.C. § 352(a)].
Estomaquil is also misbranded under 502(c) [21 U.S.C. § 352(c)] because the package labeling is inconsistent in that some language appears in Spanish, but the language does not consistently appear in English followed by a Spanish translation. Under 21 C.F.R. §§ 201.15(c)(1), (2), and (3): “All words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear thereon in the English language: Provided, however, That in the case of articles distributed solely in the Commonwealth of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English.” Since your drug products are not solely distributed in Puerto Rico or other Territory, your product labeling needs to appear in English which can then be followed by a Spanish translation and needs to remain consistent throughout (See 21 C.F.R.§ 201.15(c)).
Sanafitil Antifungal Liquid
The labeling for your product includes the following claim:
“For the Treatment of Athlete’s Foot, Jock Itch, and Ringworm.”
Based on the labeling described above, Sanafitil Antifungal Liquid is a drug as defined by Section 20l(g)(l) of the Act [21 U.S.C. § 321(g)(l)] because it is intended to treat disease or to affect the structure or function of the body of man.
Based on the package ingredient listing, the formulation for your product includes the following: “Active ingredients: Undecylenic Acid 10.0g, Salicylic Acid 2.0g, Benzoic Acid 1.0g, Boric Acid 1.0g, Benzocaine 5.0g, Methyl Salicylate 1.0g, Thymol 0.1g, Chorobufanol H. 0.5g, Sodium Propionate 1.0g, Isopropyl Alcohol 65.0 ml, Water 13.4 ml, Color 0.0002g.” Sanafitil Antifungal Liquid is subject to the Final Monograph for Topical Antifungal Drug Products (21 C.F.R. part 333, subpart C), because of its claim “For the Treatment of Athlete’s Foot, Jock Itch, and Ringworm.” All of the ingredients are identified under the label heading “Active Ingredients,” and therefore are all represented as contributing to the claimed effect and, thus, are “active ingredients” as defined by 21 C.F.R. § 201.66(b)(2). Such a combination of active ingredients, as listed under the heading “Active Ingredients,” is not acceptable under the Final Monograph for Topical Antifungal Drug Products.
Sanafitil Antifungal Liquid as formulated and labeled does not conform to the final monograph stated above and is not generally recognized as safe and effective for its intended use. Therefore, Sanafitil Antifungal Liquid is a new drug under section 201(p) of the Act [21 U.S.C. § 321(p)]. Because Sanafitil Antifungal Liquid is not the subject of an FDA-approved application, its marketing in the United States violates section 505(a) of the Act [21 U.S.C. § 355(a)].
Your product is also misbranded under section 502(a) [21 U.S.C. § 352(a)] in that the label lists the amount of each ingredient in “grams.” The Final Monograph for Topical Antifungal Drug Products at 21 C.F.R. § 333.210 specifies that active ingredients be listed in percent (%) concentration established for each ingredient.
In addition, the labels for Sanafitil Antifungal Liquid, Sanatifil Antifungal Powder, and Sanatifil Antifungal Spray all list “uses” that include “the treatment of athlete’s foot, jock itch, ringworm and other fungus infections.” The principal display panel for your Sanatifil Antifungal Powder product also states “other fungus infections.” Under 21 C.F.R. § 333.250, OTC antifungals are approved for use only in the treatment of athlete’s foot, jock itch, and ringworm. By including the indication for use “other fungus infections,” your products as formulated and labeled do not conform to the final monograph stated above and are not generally recognized as safe and effective for their intended use. Therefore, your products are new drugs under section 201(p) of the Act [21 U.S.C. § 321(p)]. Because these products are not the subject of a FDA-approved application, their marketing in the United States violates sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)].
Neomeolubryna
The labeling for Neomeolubryna contains the following statements of intended uses:
• “Migraine and headache relief”
• “Purpose[:] Treat Migraine and Headaches”
• “Temporarily relieves minor aches and pains due to: Migraines, headache, common cold, toothache, muscular aches, backache, menstrual cramps, minor pain of arthritis and temporarily reduces fever.”
As labeled, Neomeolubryna is a drug under section 201(g)(1)(B) of the Act [21 U.S.C. § 321(g)(1)(B)] because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man and under section 201(g)(1)(C) of the Act [21 U.S.C. § 321(g)(1)(C)], because it is intended to affect the structure or function of the human body.
Based on its labeled uses, Neomeolubryna is a new drug within the meaning of section 201(p) of the Act [21 U.S.C. § 321(p)]. Neomeolubryna is marketed as an internal analgesic and several of its uses and the combination of its active ingredients are addressed under the tentative final monograph (TFM) for OTC Internal Analgesics [56 Fed. Reg. 46204 (Nov. 16, 1988)]. However, Neomeolubryna's use for treating migraines, as demonstrated by the above labeling claims, is not a use that is covered under the TFM for OTC internal analgesics or any other OTC internal analgesic rulemaking [42 Fed. Reg. 35346 (July 8, 1977)]. Moreover, Neomeolubryna is not covered by FDA’s OTC Drug Review because no product formulated with this combination of active ingredients and labeled for intended uses related to migraines has previously been commercially marketed on or before the inception of that review, and the Agency has never proposed that such a product be included in that Review. We are not aware of evidence to show that Neomeolubryna, as formulated and labeled, is generally recognized as safe and effective. Therefore, Neomeolubryna is a new drug within the meaning of section 201(p) of the Act [21 U.S.C. § 321(p)], as further described in 21 C.F.R. § 310.3(h). Furthermore, we are not aware of Neomeolubryna being the subject of an approved application. As a new drug without an approved application the current marketing of Neomeolubryna violates section 505(a) of the Act [21 U.S.C. § 355(a)].2
Neomeolubryna is also misbranded under Section 502 of the Act [21 U.S.C. § 352] for several reasons. Neomeolubryna fails to bear required warnings, including the Reye's Syndrome Warning, the Liver Warning and all other warnings required under 21 C.F.R. § 201.314 and 21 C.F.R. § 201.326. Therefore, the product is misbranded because it lacks adequate warnings and is misleading, under sections 502(f)(2) and 502(a) of the Act [21 U.S.C. §§ 352(f)(2) and 352(a), respectively]. Neomeolubryna's label does not list any inactive ingredients, and therefore, Neomeolubryna is misbranded under section 502(e)(1)(A)(ii) of the Act [21 U.S.C. § 352(e)(1)(A)(ii)]. Neomeolubryna is also misbranded under section 502(c) of the Act [21 U.S.C. § 352(c)], because the product is not labeled in accordance with the “Drug Facts” labeling requirements described in 21 C.F.R. § 201.66. For example, there is neither a “Warnings” section nor an "Inactive Ingredients" section under the “Drug Facts” as required by 21 C.F.R. §§ 201.66(c)(5) and (8), respectively. Finally, Neomeolubryna is misbranded under 502(a) of the Act [21 U.S.C. § 352(a)] because its labeling is misleading in that it fails to disclose that the claim for treating migraines is a use that is outside FDA's OTC Drug Review, requires FDA approval with respect to Neomeolubryna, and has not been approved by FDA.
Ampitrexyl Antibiotico
The labeling for your product includes the following claim:
“Ampitrexyl Antibiotico…Unguento Topico de Uso Externo Solamente”
“Uses: First Aid Antibiotic”
“Indications: For the temporary relief of burns rashes itching minor cuts…scrapes and minor skin infections”
The product’s label lists the following components as ingredients for Ampitrexyl Antibiotico:
“Active Ingredient in each gr. Chlortetracycline HCL, 30 mg.. in a suitable ointment base…Purpose…Topical Antibiotic…First Aid Antibiotic”
“Inactive Ingredients: Benzocaine USP, Salicylic Acid, Bonc Acid, Benzoic Acid, Methyl Salicylate, Sodium Propionate NF, Chlorobutanol Hydrous NF, Thymol NF, Re#22 Pylam, Paraffin NF and White Petrolatum”
The above statements demonstrate that Ampitrexyl Antibiotico is a drug under section 201(g)(1)(B) of the Act [21 U.S.C. § 321(g)(1)(B)], because the product is intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the Act [21 U.S.C. § 321(g)(1)(C)], because the product is intended to affect the structure or any function of the body of man. Specifically, this product is promoted as an OTC combination topical first aid antibiotic and external analgesic and the product’s active ingredients are chlortetracycline and benzocaine.
As an OTC topical first aid antibiotic, Ampitrexyl Antibiotico is subject to the requirements of the OTC Final Monograph for First Aid Antibiotic Drug Products (21 C.F.R. Part 333 Subpart B). However, Ampitrexyl Antibiotico is not formulated and labeled in conformance with the final monograph. Therefore, Ampitrexyl Antibiotico is a new drug under section 201(p) of the Act [21 U.S.C. § 321(p)] and may not be legally marketed in the United States without approved applications under section 505(a) of the Act [21 U.S.C. § 355(a)]. Since Ampitrexyl Antibiotico is not the subject of an approved new drug application, its marketing in the United States violates sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)]. Furthermore, this product is misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)] because the indications go beyond the labeling allowed by the final monograph and lack adequate directions (See 21 C.F.R. § 333.150).
In evaluating the regulatory status of this product, we consider benzocaine an active ingredient for Ampitrexyl Antibiotico that is intended to act as an external analgesic even though benzocaine is listed as an inactive ingredient on the product label. First, Ampitrexyl Antibiotico’s label indicates the product is to be used in part as an external analgesic. Secondly, benzocaine is a known “caine”-type local anesthetic active ingredient. Under 21 C.F.R. § 201.66(b)(2), any component in a drug that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans, is considered an active ingredient.
For your information and guidance, the OTC Final Monograph for First Aid Antibiotic Drug Products permits the combination of certain first aid antibiotic active ingredients with certain amine or “caine”-type local anesthetic active ingredients. However, the final monograph does not permit the combination of chlortetracycline, the first aid antibiotic active ingredient in Ampitrexyl Antibiotico with any amine or “caine”-type local anesthetic active ingredient [21 C.F.R. § 333.120].
Ampitrexyl Antibiotico is also misbranded under section 502(c) of the Act [21 U.S.C. § 352(c)] because the statement of identity for Ampitrexyl Antibiotico is in Spanish but the “Drug Facts” panel statements required by the Act and on the label of the product is only in English. According to 21 C.F.R. §§ 201.15(c)(1) and (2) if the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label shall appear on the label in the foreign language in addition to English.
Hemorrodil
The product labeling for Hemorrodil represents the product as an OTC drug for the treatment of hemorrhoids. Specifically, the product’s uses are described in the product name itself, Hemorrodil and the following statements on its label:
“Uses: to aid in shrinking both internal and external hemorrhoids.”
The product’s label lists the following components as ingredients for Hemorrodil, but its labeling does not declare what component of the product acts as the active ingredient:
“Ingredients: Proprietary blend (A. montana, L. usitatissimum, R. aculeatus, S. alba, flavonoids (diosmin, hesperidin), P. ovata, Z. officinale rhizome, A. hippocastanum, H. virginiana…Other Ingredients: Gelatin, Glycerin, Soybean oil”
The above statement demonstrate that Hemorrodil is a drug as defined by section 201(g)(1)(B) of the Act, [21 U.S.C. § 321(g)(1)(B)] because the product is intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the Act, [21 U.S.C. § 321(g)(1)(C)] intended to affect the structure or any function of the body of man.
As an OTC product for the treatment of hemorrhoids, Hemorrodil is subject to the requirements of the OTC Final Monograph for Anorectal Drug Products (21 C.F.R. Part 346). However, Hemorrodil is not formulated and labeled in conformance with the final monograph. Specifically, the ingredients described above are not those permitted by the final rule. Therefore, Hemorrodil is a new drug under section 201(p) of the Act [21 U.S.C. § 321(p)] and may not be legally marketed in the United States without approved applications under Section 505(a) of the Act [21 U.S.C. § 355(a)]. Since Hemorrodil is not the subject of an approved new drug application, its marketing in the United States violates sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)].
In evaluating the regulatory status of this product, we considered that the labeling does not differentiate between the active and inactive ingredients. Therefore, it is our position that the components for Hemorrodil listed above as “Ingredients” and “Other Ingredients” are all active ingredients. Under 21 C.F.R. § 201.66(b)(2) any component in a drug that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans, would be considered an active ingredient. Therefore, Hemorrodil is misbranded under section 502(e)(1)(A)(ii) of the Act [21 U.S.C. § 352(e)(1)(A)(ii)] because it fails to distinguish between its active and inactive ingredients.
Furthermore, this product is misbranded under sections 502(f)(1) and (f)(2) of the Act [21 U.S.C. §§ 352(f)(1) and (f)(2)] because it does not bear the indications, directions, and warnings required by the final monograph [21 C.F.R. § 346.50].
Hemorrodil Plus Hemorrhoidal Ointment with Hidrocortisone 1%
The product labeling for Hemorrodil Plus Hemorrhoidal Ointment represents the product as an OTC drug for the treatment of hemorrhoids and its active ingredient is hidrocortisone, 1%.
The product’s uses are described in the product name itself, Hemorrodil Plus Hemorrhoidal Ointment and the following statements on its label:
“...Relieves Pain & Itch caused by hemorrhoid…”
“Uses: Temporary relief of external anal itch & minor skin irritations and rashes.”
The above statements demonstrate that Hemorrodil Plus Hemorrhoidal Ointment is a drug as defined by section 201(g)(1)(B) of the Act [21 U.S.C. § 321(g)(1)(B)], because the product is intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the Act [21 U.S.C. § 321(g)(1)(C)], intended to affect the structure or any function of the body of man.
As an OTC product for the treatment of hemorrhoids, Hemorrodil Plus Hemorrhoidal Ointment is subject to the requirements of the OTC Final Monograph for Anorectal Drug Products (21 C.F.R. Part 346). However, Hemorrodil Plus Hemorrhoidal Ointment is not formulated and labeled in conformance with the final monograph. For example, hydrocortisone is not an ingredient that is included in the Anorectal Final Monograph nor does the rule include indications for “rashes.” Therefore, Hemorrodil Plus Hemorrhoidal Ointment is a new drug under section 201(p) of the Act [21 U.S.C. § 321(p)] and may not be legally marketed in the United States without approved applications under section 505(a) of the Act [21 U.S.C. § 355(a)]. Since Hemorrodil Plus Hemorrhoidal Ointment is not the subject of an approved new drug application, its marketing in the United States violates sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)].
For your information and guidance, topical analgesics which include topical hydrocortisone products are being evaluated under the developing monograph for OTC External Analgesics within the overall OTC Drug Review. The Tentative Final Monograph (TFM), published in the Federal Register on February 8, 1983 [48 Fed. Reg. 5852] includes hydrocortisone products that are indicated for “anal itching.” However, hemorrhoid claims for hydrocortisone products are not included in the developing monograph for OTC external analgesics.
T-Rapiel Antibiotic Cream, Cream Cuadriderma Simple, Cuadriderma Ointment, Ampitrexyl Nasal Spray, and Ampitrexyl Suspension
T-Rapiel Antibiotic Cream, Cream Cuadriderma Simple, Cuadriderma Ointment, Ampitrexyl Suspension, and Ampitrexyl Nasal Spray are misbranded under 502(c) of the Act [21 U.S.C. § 352(c)] because the package labeling is inconspicuous in that it appears only in Spanish. Under 21 C.F.R. § 201.15(c)(1): “All words, statements, and other information required by or under authority of the Act to appear on the label or labeling shall appear thereon in the English language: Provided, however, That in the case of articles distributed solely in the Commonwealth of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English.
III. Misbranded Dietary Supplements
During the inspection, our investigators collected labeling for some of your products labeled as dietary supplements. As presently labeled, these products are unapproved new drugs in violation of section 505(a) of the Act [21 U.S.C. § 355(a)]. Even if your products did not contain disease claims in their labeling that cause them to be drugs, they would still be misbranded dietary supplement in violation of sections 403(e)(1), 403(i)(1), 403(q)(5)(F), 403(r)(1)(B) and 403(s)(2)(B) of the Act [ 21 U.S.C. §§ 343(e)(1), 343(i)(1), 343(q)(5)(F), 343(r)(1)(B), and 343(s)(2)(B]. These violations are described in more detail below.
Under section 201(g)(1)(B) of the Act [21 U.S.C. 321(g)(1)(B)], articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease are drugs. The therapeutic claims on your labeling establish that these products are intended to be used as drugs. The marketing of these products with these claims violates the Act.
Specific examples of claims in your product labeling that promote your products as drugs are as follows:
B Doce Suspension Dietary Supplement (8 fl. oz.)
Your product is misbranded within the meaning of section 403(s)(2)(B) of the Act [21 U.S.C. § 343(s)(2)(B)] because the label fails to identify the product as a dietary supplement as part of the product's statement of identity on the principle display panel as specified under 21 C.F.R. § 101.3 (a) and (g).
Your product is misbranded within the meaning of section 403(e)(1) of the Act [21 U.S.C. § 343(e)(1)] in that the label does not identify the place of business of the manufacturer, packer or distributor as specified under 21 C.F.R. § 101.5(a).
Your product is misbranded within the meaning of section 403(q)(5)(F) of the Act [21 U.S.C. § 343(q)(5)(F)] in that the nutrition information on the product label does not comply with 21 C.F.R. § 101.36. Examples of the deviations from the requirements of 21 C.F.R. § 101.36 includes:
• dietary ingredients such as total fat, protein cannot be declared since they are present in amounts that can be declared as zero as specified under 21 C.F.R. § 101.36(b)(2);
• dietary ingredients must be declared in the following order under 21 C.F.R. § 101.36(b)(2) that follows 21 C.F.R. § 101.9(c). For example, the following order must be followed when the dietary ingredient exceeds zero: total calories, calories from fat, total fat, saturated fat, trans fat, cholesterol, sodium, total carbohydrate, dietary fiber, sugars, protein, vitamin A, vitamin C, calcium, and iron;
• The title, “Supplement Facts,” must be set in a type size larger than all other print size in the nutrition label and be set full width of the nutrition label as specified under 21 C.F.R. § 101.36(e)(1);
• A hairline rule that is centered between the lines of text must separate each dietary ingredient required in 21 C.F.R. § 101.36(b)(2) and (b)(3) from the dietary ingredients above and beneath it as specified under 21 C.F.R. § 101.36(e)(5).
Hemorrodil Original Formula (90 Caps)
• Your product is misbranded within the meaning of sections 403(i)(1) and 403(s)(2)(B) of the Act [21 U.S.C. §§ 343 (i)(1) and (s)(2)(B)] because the label fails to identify the product as a dietary supplement as part of the product's statement of identity on the principle display panel as specified under 21 C.F.R. § 101.3 (a) and (g).
• Your product is misbranded within the meaning of section 403(q)(5)(F) of the Act [21 U.S.C. § 343(q)(5)(F)] in that the label fails to bear nutrition information (“Supplement Facts” panel), which is required under 21 C.F.R. § 101.36, and is not exempt from this requirement.
Calcigenol Suspension Dietary Supplement (8 fl. oz.)
Your Calcigenol Dietary Supplement (8 fl. oz) is misbranded within the meaning of section 403(r)(1)(B) of the Act [21 U.S.C. § 343(r)(1)(B)] in that the label bear the unauthorized health claim “Calcium may be (sic) reduce the risk of OSTEOPROSIS.” Although this claim involves a substance-disease relationship for which this health claim is authorized by regulation, you do not meet the “high” calcium requirements under 21 C.F.R. § 101.54(b).
In addition, the product label for your products B Doce, Hemorrodil and Calcigenol lists “Ingredients" and "Other ingredients" inside the Supplement Facts box. Under 21 C.F.R. § 101.4(g), the ingredient list on dietary supplement products must be located outside the Supplement Facts box. A source ingredient that supplies a dietary ingredient may be identified within the Supplement Facts box in accordance with 101.36(d). When a source ingredient is listed in the Supplement Facts box, you must list the remaining ingredients outside the Supplement Facts box preceded by the words "Other Ingredients" to comply with 21 C.F.R. § 101.4(g).
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure compliance 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, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.
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 violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. We also request that you outline the action you are taking to discontinue the marketing of the unapproved drug products at your facility, or any other applicable drug which you may market. Additionally, your response should state if you no longer manufacture or distribute products, and provide the date(s) and reason(s) you ceased production. Please note that if you are no longer marketing this (these) product(s), you must update the Drug Listing files in accordance with 21 C.F.R. § 207.30(a)(2).
Your reply should be sent to the attention of: Winston R. Alejo, Compliance Officer, at the following address: Food and Drug Administration 555 Winderley Place, Suite 200, Maitland, Florida, 32751. If you have questions regarding any issues in this letter, please contact Mr. Alejo at (407) 475-4731.
Sincerely,
/s/
Emma R. Singleton
Director, Florida District
1 Tarmac Products. Inc., d.b.a. Axara Pharmaceuticals, repacks, relabels, and is an own-label distributor of OTC drug products and dietary supplements.
2 We note that other OTe products with similar formulations to Neomeolubryna and for use in treating pain associated with
migraines along with other internal analgesic uses are marketed under approved New Drug Applications (NDAs).
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