Source | Medpage Today

By Neil Osterweil, Senior Associate Editor, MedPage Today
March 02, 2007

The FDA has ordered 20 companies to stop marketing grandfathered prescription versions of the vasoconstrictor ergotamine tartrate, an old remedy for treatment of vascular headaches, including migraine. 

The agency’s complaint was outlined in warning letters to eight drug makers and 12 distributors. It hinges on the lack of approval and of proper package labeling on the older formulations which, while sold only by prescription, came on the market before changes to the Food, Drug, and Cosmetics Act required more thorough warning labels. 

Five FDA-approved ergotamine-containing products will remain on the market, albeit with a black-box warning against concomitant use of such products with drugs that potently inhibit the cytochrome p450 3A4 isoform (CYP 3A4), including some antifungal agents, protease inhibitors, and certain antibiotics. 

According to the FDA, mixing ergotamine-containing agents with CYP 3A4 inhibitors can lead to serious, life-threatening ischemia, including gangrene and death. Most of the unapproved versions of the drug don’t carry this warning, the agency noted. 

The letters give the companies 15 days to respond to the FDA with a description of their action plans, 60 days to stop manufacturing the drugs, and 180 days to stop manufacturing them, or face sanctions. 

“This action is the next step in an aggressive FDA initiative to insure that all marketed U.S. drugs have FDA approval,” said Michael Levy, of the FDA’s Center for Drug Evaluation and Research, in a briefing. 

The approved products that will remain on the market are: 

• Migergot suppository (marketed by G and W Labs) 
• Ergotamine Tartrate and Caffeine tablets (Mikart and West Ward) 
• Cafergot tablets (marketed by Sandoz) 
• Ergomar Sublingual tablets (marketed by Rosedale Therapeutics) 

“We are taking a sensible, risk-based approach to the problem, and remain dedicated to the goal of getting unapproved drugs off the market,” said Deborah M. Autor, CDER’s director of compliance. “Doctors and patients often do not realize that not all drugs that are available on the market are backed by FDA approval. We estimate that less than 2% of prescribed drugs are unapproved.” 

The companies ordered to pull their products from the market are welcome to present data to the agency proving that their products are safe and effective, at which point they can be considered for approval, Autor said in the briefing. 

The following companies have received the warning letters. 

• Actavis Totowa LLC 
• Anabolic Laboratories 
• Bio Pharm Inc. 
• Breckenridge Pharmaceutical Inc. 
• Centrix Pharmaceutical Inc. 
• DRX Pharmaceutical Consultants Inc. 
• DSC Laboratories 
• Excellium Pharmaceutical Inc. 
• Ferndale Laboratories Inc. 
• IVAX Pharmaceuticals Inc. (formerly Goldline Laboratories Inc.) 
• Kaiser Foundation Hospitals 
• Lini Inc. 
• Murfreesboro Pharmaceutical Nursing Supply 
• Nucare Pharmaceuticals Inc. 
• Qualitest Pharmaceuticals, Inc. 
• Sandoz Inc. 
• Superior Pharmaceutical Company 
• The Harvard Drug Group LLC (formerly Major Pharmaceuticals Inc.) 
• United Research Laboratories Inc. and Mutual Pharmaceutical Company 
• Vintage Pharmaceuticals Inc. 

WARNING LETTER

February 26, 2007

William S. Propst, Sr.
President and CEO
Vintage Pharmaceuticals Inc.
150 Vintage Drive
Huntsville, Alabama 35811

Dear Mr. Propst:

This letter is written in reference to the marketing by your firm of Bellaspas Tablets, a drug product containing ergotamine tartrate.

Drug products containing ergotamine that were marketed under new drug applications approved for safety only prior to 1962 were reviewed under the Drug Efficacy Study Implementation (DESI) program. On July 27, 1972, the Agency concluded that such products are new drugs effective for the treatment or prevention of “vascular headaches” (”e.g. migraine, migraine variants or `histaminic/> cephalalgia”‘) subject to section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 355] and that approved new drug applications are required to market them. (37 Fed. Reg. 15032).

Under 21 C.F.R. § 310.6(b)(1), the ergotamine-containing product that you market is identical, related, or similar to the drugs reviewed in this DESI proceeding. Under 21 C.F.R. § 310.6(b)(2), the “new drug” determination made under this DESI proceeding applies to your product and therefore your product requires an approved new drug application before it may be lawfully sold. As there is no approved new drug application on file with the FDA for Bellaspas Tablets as marketed by your firm, the marketing of this product is in violation of sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], which prohibit the introduction or delivery for introduction into interstate commerce of a new drug without an approved new drug application.

Moreover, Bellaspas Tablets is a prescription drug within the meaning of section 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], because it is not safe for use except under the supervision of a practitioner licensed by law to administer such drug. By definition, a prescription drug’s directions for use are not adequate to enable a layperson to safely use the drug for its intended uses. See 21 C.F.R. § 201.5. Consequently, Bellaspas Tablets labeling fails to bear adequate directions for use under section 502(f)(1) of the Act, [21 U.S.C. § 352(fl(1)]. Because it lacks an approved application, it is not exempt from this requirement under 21 C.F.R. § 201.115. Bellaspas Tablets is therefore misbranded.

Further, we note that FDA has reviewed and approved several ergotamine-containing drug products and determined that such products require warning information to be placed in a prominently displayed box pursuant to 21 C.F.R. § 201.57. This boxed warning is required to prevent use of potent CYP 3A4 inhibitors with ergotamine-containing products. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use. Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics, and antifungal agents. Your failure to display this warning regarding concomitant use of Bellaspas Tablets CYP 3A4 inhibitors also renders t11e product misbranded under section 502(f)(2) of the Act, [21 U.S.C. § 352(f)(2)], because its labeling fails to bear adequate warnings.

In addition to the serious health concern presented by your omission of this important warning, unapproved drugs are a public health risk in general because they may not meet modern standards for safety, effectiveness, quality, and labeling. Even though some ergotamine products were found to be effective for certain indications via the DESI process, this does not necessarily mean that Bellaspas Tablets as currently formulated, manufactured, and labeled, is effective or safe.

The above identified violations are not intended to be an all inclusive list of violations involving your facility. It is your responsibility to assure that your firm is in compliance with all requirements of the Act. We request that you review all drug products that you are currently marketing to assure they are in compliance with the Act and FDA regulations. If you no longer market any ergotamine-containing drug products or believe that you have received this letter in error, please notify the Agency at the address below.

As described in the guidance entitled “Marketed Unapproved Drugs - Compliance Policy Guide” (”Marketed Unapproved Drugs CPG”), the Agency may exercise its enforcement discretion and identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved drug. http://www.fda.gov/cder/guidance/6911fnl.pdf. The Agency intends to exercise its enforcement discretion with regard to unapproved, ergotamine- containing drug products as follows. FDA does not intend to initiate enforcement actions related to currently manufactured unapproved ergotamine-containing products if those products are listed with FDA under section 510 of the Act, [21 U.S.C. § 360], as of the date of this letter, unless the manufacturing of those products continues after April 27, 2007. Further, FDA does not intend to initiate enforcement actions related to the shipment in interstate commerce of unapproved ergotamine- containing products made by such firms, including Bellaspas Tablets, unless they are still being shipped on or after August 25, 2007 1.

You should be aware that the Agency does not intend to exercise its enforcement discretion as described in this letter in the following circumstances: (1) if a firm is violating other provisions of the Act; (2) when it appears that a firm, in response to this letter, increases its manufacture or distribution of unapproved ergotamine drug products above its usual volume during these periods; (3) if FDA learns of new information regarding any serious health risk or hazards associated with an unapproved ergotamine drug product; or (4) if a firm marketing unapproved ergotamine products does not undertake appropriate corrective action to cease marketing the products.
To avail your firm of these periods during which the Agency intends to exercise enforcement discretion regarding unapproved ergotamine products, you must reply within fifteen (15) days of your receipt of this letter with a commitment to comply with the conditions stated above. Please include:

• a statement(s) of what action you plan to take to comply;
• a statement of the amount of Bellaspas Tablets, and any other unapproved ergotamine-containing product, that is (are) in inventory under your control;
• the time period in which you expect such inventory to be exhausted, in its entirety, and your plan for disposition of any inventory remaining after the above shipment cessation date; and
• an estimate of when products in distribution channels will become exhausted.

If FDA receives your commitment within fifteen (15) days of your receipt of this letter, the agency intends to exercise its enforcement discretion as described above, unless the circumstances listed above or lack of compliance with the conditions set forth in this letter warrant further action . If FDA does not receive a commitment within fifteen (15) days of receipt of this letter or a firm or person fails to comply with the stop manufacture or stop shipment date, the agency may take immediate regulatory action, including but not limited to seizure and/or injunction. If FDA takes action, to preserve limited agency resources, FDA may also take simultaneous enforcement action relating to any other unapproved new drugs manufactured, distributed, or shipped by the defendant. (See, e.g., United States v. Sage Pharmaceuticals, 210 F.3d 475, 479-480 (5th Cir. 2000) (the agency can combine all violations of the act in one proceeding, rather than taking action against a firm with multiple violations of the act in “piecemeal fashion”).)

In addition, FDA cautions firms against reformulating their products into ergotamine-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name). In the Marketed Unapproved Drugs CPG, FDA states that it intends to give higher priority to enforcement actions involving unapproved drugs that are reformulated to evade an FDA enforcement action. In addition, reformulated products marketed under a name previously identified with a different active ingredient or combination of active ingredients have the potential to confuse health care practitioners and harm patients .

Please send your reply via fax, as well as mail or overnight delivery to: Valerie L. Whipp, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of New Drugs and Labeling Compliance, 11919 Rockville Pike, HFD-310, Rockville, MD 20852, fax number (301) 827-8904.

For information regarding the drug approval process see www.fda.gov/cder/regulatory/applications/default.htm
Should you wish to seek approval for your ergotamine product, you may contact Sally Loewke, MD, the Agency’s unapproved drugs coordinator at (301) 796-0710, who can help you identify the appropriate review division or office for further direction. However, until such time as you have FDA approval for your product, you must comply with this letter.

Sincerely yours,

/S/

Michael Levy
Director
Division of New Drugs and Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research

WARNING LETTER

February 26, 2007

Richard H. Roberts, M.D., Ph.D.

President and CEO
United Research Laboratories Inc . and Mutual Pharmaceutical Company
1100 Orthodox Street
Philadelphia, Pennsylvania 19124
Dear Dr. Roberts:

This letter is written in reference to the marketing by your firm of Bel-Tabs tablets, a drug product containing ergotamine tartrate.
Drug products containing ergotamine that were marketed under new drug applications approved for safety only prior to 1962 were reviewed under the Drug Efficacy Study Implementation (DESI) program. On July 27, 1972, the Agency concluded that such products are new drugs effective for the treatment or prevention of “vascular headaches” (”e.g. migraine, migraine variants or `histaminic cephalalgia”‘) subject to section 505 of’ the Federal Food, Drug, and Cosmetic Act (the Act) [21U.S.C. § 355] and that approved new drug applications are required to market them. (37 Fed. Reg. 15032).

Under 21 C.F.R. § 310.6(b)(1), the ergotamine-containing product that you market is identical, related, or similar to the drugs reviewed in this DESI proceeding. Under 21 C.F.R. § 310.6(b)(2), the “new drug” determination made under this DESI proceeding applies to your product and therefore your product requires an approved new drug application before it maybe lawfully sold. As there is no approved new drug application on file with the FDA for Bel-Tabs tablets as marketed by your firm, the marketing of this product is in violation of sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], which prohibit the introduction or delivery for introduction into interstate commerce of a new drug without an approved new drug application.
Moreover, Bel-Tabs tablets is a prescription drug within the meaning of section 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], because it is not safe for use except under the supervision of a practitioner licensed by law to administer such drug. By definition, a prescription drug’s directions for use are not adequate to enable a layperson to safely use the drug for its intended uses. See 21 C.F.R. § 201.5. Consequently, Bel-Tabs tablets’ labeling fails to bear adequate directions for use under section 502(f)(1) of the Act, [21 U.S.C. § 352(f)(1)]. Because it lacks an approved application, it is not exempt from this requirement under 21 C.F.R. § 201.115. Bel-Tabs tablets is therefore misbranded.

Further, we note that FDA has reviewed and approved several ergotamine-containing drug products nd determined that such products require warning information to be placed in a prominently displayed box pursuant to 21 C.F.R. § 201.57. This boxed warning is required to prevent use of potent CYP 3A4 inhibitors with ergotamine-containing products. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use. Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics, and antifungal agents. Your failure to display this warning regarding concomitant use of Bel-Tabs tablets with CYP 3A4 inhibitors also renders the product misbranded under section 502(f)(2) of the Act, [21 U.S.C. § 352(f)(2)], because its labeling fails to bear adequate warnings.

In addition to the serious health concern presented by your omission of this important warning, unapproved drugs are a public health risk in general because they may not meet modem standards for safety, effectiveness, quality, and labeling. Even though some ergotamine products were found to be effective for certain indications via the DESI process, this does not necessarily mean that Bel-Tabs tablets as currently formulated, manufactured, and labeled, is effective or safe.

The above identified violations are not intended to be an all inclusive list of violations involving your facility. It is your responsibility to assure that your firm is in compliance with all requirements of the Act.

We request that you review all drug products that you are currently marketing to assure they are in compliance with the Act and FDA regulations. If you no longer market any ergotamine-containing drug products or believe that you have received this letter in error, please notify the Agency at the address below.

As described in the guidance entitled “Marketed Unapproved Drugs - Compliance Policy Guide”(”Marketed Unapproved Drugs CPG”), the Agency may exercise its enforcement discretion and identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved drug. http://www.fda.gov/cder/guidance/6911fnl.pdf. Agency intends to exercise its enforcement discretion with regard to unapproved, ergotamine-containing drug products as follows. FDA does not intend to initiate enforcement actions related to currently manufactured unapproved ergotamine-containing products if those products are listed with FDA under section 510 of the Act, [21 U.S.C. § 360], as of the date of this letter, unless the manufacturing of those products continues after April 27, 2007. Further, FDA does not intend to initiate enforcement actions related to the shipment in interstate commerce of unapproved ergotamine-containing products made by such firms, including Bel-Tabs tablets, unless they are still being shipped on or after August 25, 2007 1.

You should be aware that the Agency does not intend to exercise its enforcement discretion as described in this letter in the following circumstances: (1) if a firm is violating other provisions of the Act; (2) when it appears that a firm, in response to this letter, increases its manufacture or distribution of unapproved ergotamine drug products above its usual volume during these periods; (3) if FDA learns of new information regarding any serious health risk or hazards associated with an unapproved ergotamine drug product; or (4) if a finn marketing unapproved ergotamine products does not undertake appropriate corrective action to cease marketing the products.

To avail your firm of these periods during which the Agency intends to exercise enforcement discretion regarding unapproved ergotamine products, you must reply within fifteen (15) days of your receipt of this letter with a commitment to comply with the conditions stated above. Please include:

• a statement(s) of what action you plan to take to comply;
• . a statement of the amount of Bel-Tabs tablets, and any other unapproved ergotamine-containing product, that is (are) in inventory under your control;
• the time period in which you expect such inventory to be exhausted, in its entirety,and your plan for disposition of any inventory remaining after the above shipment cessation date; and
• an estimate of when products in distribution channels will become exhausted.

If FDA receives your commitment within fifteen (15) days of your receipt of this letter, the agency intends to exercise its enforcement discretion as described above, unless the circumstances listed above or lack of compliance with the conditions set forth in this letter warrant further action. If FDA does not receive a commitment within fifteen (15) days of receipt of this letter or a firm or person fails to comply with the stop manufacture or stop shipment date, the agency may take immediate regulatory action, including but not limited to seizure and/or injunction. If FDA takes action, to preserve limited agency resources, FDA may also take simultaneous enforcement action relating to any other unapproved new drugs manufactured, distributed, or shipped by the defendant. (See, e.g., United States v. Sage Pharmaceuticals, 210 F3d 475, 479-480 (5th Cir. 2000) (the agency can combine all violations of the act in one proceeding, rather than taking action against a firm with multiple violations of the act in “piecemeal fashion”).)

In addition, FDA cautions firms against reformulating their products into ergotamine-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name). In the Marketed Unapproved Drugs CPG, FDA states that it intends to give higher priority to enforcement actions involving unapproved drugs that are reformulated to evade an FDA enforcement action. In addition, reformulated products marketed under a name previously identified with a different active ingredient or combination of active ingredients have the potential to confuse health care practitioners and harm patients.

Please send your reply via fax, as well as mail or overnight delivery to: Valerie L. Whipp, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of New Drugs and Labeling Compliance, 11919 Rockville Pike, HFD-310, Rockville, MD 20852, fax number (301)827-8904.

For information regarding the drug approval process see www.fda.gov/cder/regulatory/applications/default.htm. Should you wish to seek approval for your ergotamine product, you may contact Sally Loewke, MD, the Agency’s unapproved drugs coordinator at (301) 796-0710, who can help you identify the appropriate review division or office for further direction. However, until such time as you have FDA approval for your product, you must comply with this letter.

Sincerely yours,
/S/
Michael Levy
Director
Division of New Drugs and Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research

WARNING LETTER

February 26, 2007

Jay Levine
President and CEO
The Harvard Drug Group LLC (formerly Major Pharmaceuticals Inc .)
31778 Enterprise Drive
Livonia, Michigan 48150

Dear Mr. Levine:

This letter is written in reference to the marketing by your firm of drug products containing ergotamine tartrate, specifically, Bellamine Tablets, Cafatine PB Tabs tablets, and caffeine,ergotamine, and pentobarbital suppositories.

Drug products containing ergotamine that were marketed under new drug applications approved for safety only prior to 1962 were reviewed under the Drug Efficacy Study Implementation (DESI) program. On July 27, 1972, the Agency concluded that such products are new drugs effective for the treatment or prevention of “vascular headaches” (”e.g. migraine, migraine variants or `histaminic cephalalgia”‘) subject to section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 355] and that approved new drug applications are required to market them. (37 Fed. Reg. 15032).

Under 21 C.F.R. § 310.6(b)(1), the ergotamine-containing products that you market are identical,related, or similar to the drugs reviewed in this DESI proceeding. Under 21 C.F.R. § 310.6(b)(2), the “new drug” determination made under this DESI proceeding applies to your products and therefore your products require an approved new drug application before they may be lawfully sold. As there are no approved new drug applications on file with the FDA for any of the drug products, Bellamine Tablets, Cafatine PB Tabs tablets, and caffeine, ergotamine, and pentobarbital suppositories as marketed by your firm, the marketing of these products is in violation of sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], which prohibit the introduction or delivery for introduction into interstate commerce of a new drug without an approved new drug application.

Moreover, Bellamine Tablets, Cafatine PB Tabs tablets, and caffeine, ergotamine, and pentobarbital suppositories are prescription drugs within the meaning of section 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], because they are not safe for use except under the supervision of a practitioner licensed bylaw to administer such drugs. By definition, a prescription drug’s directions for use are not adequate to enable a layperson to safely use the drug for its intended uses. See 21 C.F.R. § 201.5. Consequently, Bellamine Tablets, Cafatine PB Tabs tablets, and caffeine, ergotamine, and pentobarbital suppositories’ labeling fail to bear adequate directions for use under section 502(f)(1) of the Act, [21 U.S.C. § 352(f)(1)]. Because each lacks an approved application, each is not exempt from this requirement under 21 C.F.R. § 201.115. Bellamine Tablets, Cafatine PB Tabs tablets, and caffeine, ergotamine, and pentobarbital suppositories are therefore misbranded.

Further, we note that FDA has reviewed and approved several ergotamine-containing drug products and determined that such products require warning information to be placed in a prominently displayed box pursuant to 21 C.F.R. § 201.57. This boxed warning is required to prevent use of potent CYP3A4 inhibitors with ergotamine-containing products. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use. Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics, and antifungal agents. Your failure to display this warning regarding concomitant use of Bellamine Tablets, Cafatine PB Tabs tablets, and caffeine, ergotamine, and pentobarbital suppositories with CYP3A4 inhibitors also renders these products misbranded under section 502(f)(2) of the Act, [21 U.S.C. 352(fl(2)], because each product’s labeling fails to bear adequate warnings.

In addition to the serious health concern presented by your omission of this important warning, unapproved drugs are a public health risk in general because they may not meet modem standards for safety, effectiveness, quality, and labeling. Even though some ergotamine products were found to be effective for certain indications via the DESI process, this does not necessarily mean that Bellamine Tablets, Cafatine PB Tabs tablets, and caffeine, ergotamine, and pentobarbital suppositories as currently formulated, manufactured, and labeled, are effective or safe.

The above identified violations are not intended to be an all inclusive list of violations involving your facility. It is your responsibility to assure that your firm is in compliance with all requirements of the Act. We request that you review all drug products that you are currently marketing to assure they are in compliance with the Act and FDA regulations. If you no longer market any ergotamine-containing drug products or believe that you have received this letter in error, please notify the Agency at the
address below.

As described in the guidance entitled “Marketed Unapproved Drugs - Compliance Policy Guide”(”Marketed Unapproved Drugs CPG”), the Agency may exercise its enforcement discretion and identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved drug. http://www.fda.gov/cder/guidance/6911fnl.pdf .The Agency intends to exercise its enforcement discretion with regard to unapproved, ergotamine-containing drug products as follows. FDA does not intend to initiate enforcement actions related to currently manufactured unapproved ergotamine-containing products if those products are listed with FDA under section 510 of the Act, [21 U.S.C. § 360], as of the date of this letter, unless the manufacturing of those products continues after April 27, 2007. Further, FDA does not intend to initiate enforcement actions related to the shipment in interstate commerce of unapproved ergotamine-containing products made by such firms, including Bellamine Tablets, Cafatine PB Tabs tablets, and caffeine, ergotamine, and pentobarbital suppositories, unless they are still being shipped on or after August 25, 2007 1.

You should be aware that the Agency does not intend to exercise its enforcement discretion as described in this letter in the following circumstances: (1) if a firm is violating other provisions of the Act; (2) when it appears that a firm, in response to this letter, increases its manufacture or distribution of unapproved ergotamine drug products above its usual volume during these periods; (3) if FDA learns of new information regarding any serious health risk or hazards associated with an unapproved ergotamine drug product; or (4) if a firm marketing unapproved ergotamine products does not undertake appropriate corrective action to cease marketing the products.

To avail your firm of these periods during which the Agency intends to exercise enforcement discretion regarding unapproved ergotamine products, you must reply within fifteen (15) days of your receipt of this letter with a commitment to comply with the conditions stated above. Please include:

• a statement(s) of what action you plan to take to comply;
• a statement of the amount of each drug, Bellamine Tablets, Cafatine PB Tabs tablets, and caffeine, ergotamine, and pentobarbital suppositories, and any other unapproved ergotamine-containing product, that is (are) in inventory under your control;
• the time period in which you expect such inventory to be exhausted, in their entirety, and your plan for disposition of any inventory remaining after the above shipment cessation date; and
• an estimate of when products in distribution channels will become exhausted.

If FDA receives your commitment within fifteen (15) days of your receipt of this letter, the agency intends to exercise its enforcement discretion as described above, unless the circumstances listed above or lack of compliance with the conditions set forth in this letter warrant further action. If FDA does not receive a commitment within fifteen (15) days of receipt of this letter or a firm or person fails to comply with the stop manufacture or stop shipment date, the agency may take immediate regulatory action, including but not limited to seizure and/or injunction. If FDA takes action, to preserve limited agency resources, FDA may also take simultaneous enforcement action relating to any other unapproved new drugs manufactured, distributed, or shipped by the defendant. (See, e.g., United States v. Sage Pharmaceuticals, 210 F3d 475, 479-480 (5th Cir. 2000) (the agency can combine all violations of the act in one proceeding, rather than taking action against a firm with multiple violations of the act in “piecemeal fashion”).)

In addition, FDA cautions firms against reformulating their products into ergotamine-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name). In the Marketed Unapproved Drugs CPG, FDA states that it intends to give higher priority to enforcement actions involving unapproved drugs that are reformulated to evade an FDA enforcement action. In addition, reformulated products marketed under a name previously identified with a different active ingredient or combination of active ingredients have the potential to confuse health care practitioners and harm patients.

Please send your reply via fax, as well as mail or overnight delivery to: Valerie L. Whipp, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of New Drugs and Labeling Compliance, 11919 Rockville Pike, HFD-310, Rockville, MD 20852, fax number (301) 827-8904.

For information regarding the drug approval process see
www.fda.gov/cder/regulatory/applications/default.htm. Should you wish to seek approval for your ergotamine product, you may contact Sally Loewke, MD, the Agency’s unapproved drugs coordinator at (301) 796-0710, who can help you identify the appropriate review division or office for further direction. However, until such time as you have FDA approval for your product, you must comply with this letter.

Sincerely yours,

Michael Levy
Director
Division of New Drugs and Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research

WARNING LETTER

February 26, 2007

President and/or CEO
Superior Pharmaceutical Company
1385 Kemper Meadow Drive
Cincinnati, Ohio 45240

Dear Mr. or Ms. President and/or CEO:

This letter is written in reference to the marketing by your firm of Migracet-PB Suppositories, a drug product containing ergotamine tartrate.
Drug products containing ergotamine that were marketed under new drug applications approved for safety only prior to 1962 were reviewed under the Drug Efficacy Study Implementation (DESI) program. On July 27, 1972, the Agency concluded that such products are new drugs effective for the treatment or prevention of “vascular headaches” (”e.g. migraine, migraine variants or `histaminic cephalalgia”‘) subject to section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 355] and that approved new drug applications are required to market them. (37 Fed. Reg. 15032).

Under 21 C.F.R. § 310.6(b)(1), the ergotamine-containing product that you market is identical, related, or similar to the drugs reviewed in this DESI proceeding. Under 21 C.F.R. § 310.6(b)(2), the”new drug” determination made under this DESI proceeding applies to your product and therefore your product requires an approved new drug application before it maybe lawfully sold. As there is no approved new drug application on file with the FDA for Migracet-PB Suppositories as marketed by your firm, the marketing of this product is in violation of sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], which prohibit the introduction or delivery for introduction into interstate commerce of a new drug without an approved new drug application.

Moreover, Migracet-PB Suppositories is a prescription drug within the meaning of section 503(b)(1)of the Act, [21 U.S.C. § 353(b)(1)], because it is not safe for use except under the supervision of a practitioner licensed by law to administer such drug. By definition, a prescription drug’s directions for use are not adequate to enable a layperson to safely use the drug for its intended uses. See 21 C.F.R. § 201.5. Consequently, Migracet-PB Suppositories’ labeling fails to bear adequate directions for use under section 502(f)(1) of the Act, [21 U.S.C. § 352(f)(1)]. Because it lacks an approved application, it is not exempt from this requirement under 21 C.F.R. § 201.115. Migracet-PB Suppositories is therefore misbranded.

Further, we note that FDA has reviewed and approved several ergotamine-containing drug products and determined that such products require warning information to be placed in a prominently displayed box pursuant to 21 C.F.R. § 201.57. This boxed warning is required to prevent use of potent CYP 3A4 inhibitors with ergotamine-containing products. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use. Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics, and antifungal agents. Your failure to display this warning regarding concomitant use of Migracet-PB Suppositories with CYP3A4 inhibitors also renders the product misbranded under section 502(f)(2) of the Act, [21 U.S.C. § 352(f)(2)], because its labeling fails to bear adequate warnings.

In addition to the serious health concern presented by your omission of this important warning, unapproved drugs are a public health risk in general because they may not meet modern standards for safety, effectiveness, quality, and labeling. Even though some ergotamine products were found to be effective for certain indications via the DESI process, this does not necessarily mean that Migracet-PB Suppositories as currently formulated, manufactured, and labeled, is effective or safe.

The above identified violations are not intended to be an all inclusive list of violations involving your facility. It is your responsibility to assure that your firm is in compliance with all requirements of the Act. We request that you review all drug products that you are currently marketing to assure they are in compliance with the Act and FDA regulations. If you no longer market any ergotamine-containing drug products or believe that you have received this letter in error, please notify the Agency at the
address below.

As described in the guidance entitled “Marketed Unapproved Drugs -Compliance Policy Guide”(”Marketed Unapproved Drugs CPG”), the Agency may exercise its enforcement discretion and identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved. http://www.fda.gov/cder/guidance/6911fnl.pdf. The Agency intends to exercise its enforcement discretion with regard to unapproved, ergotamine-containing drug products as follows. FDA does not intend to initiate enforcement actions related to currently manufactured unapproved ergotamine-containing products if those products are listed with FDA under section 510 of the Act, [21 U.S.C. § 360], as of the date of this letter, unless the manufacturing of those products continues after April 27, 2007. Further, FDA does not intend to initiate enforcement actions related to the shipment in interstate commerce of unapproved ergotamine-containing products made by such firms, including Migracet-PB Suppositories, unless they are still being shipped on or after August 25, 2007 1.

You should be aware that the Agency does not intend to exercise its enforcement discretion as described in this letter in the following circumstances: (1) if a firm is violating other provisions of the Act; (2) when it appears that a firm, in response to this letter, increases its manufacture or distribution of unapproved ergotamine drug products above its usual volume during these periods; (3) if FDA learns of new information regarding any serious health risk or hazards associated with an unapproved ergotamine drug product; or (4) if a firm marketing unapproved ergotamine products does not undertake appropriate corrective action to cease marketing the products.

To avail your firm of these periods during which the Agency intends to exercise enforcement discretion regarding unapproved ergotamine products, you must reply within fifteen (15) days of your receipt of this letter with a commitment to comply with the conditions stated above. Please include:

• a statement(s) of what action you plan to take to comply;
• a statement of the amount of Migracet-PB Suppositories, and any other unapproved ergotamine-containing product, that is (are) in inventory under your control;
• the time period in which you expect such inventory to be exhausted, in its entirety, and your plan for disposition of any inventory remaining after the above shipment cessation date; and
• an estimate of when products in distribution channels will become exhausted.

If FDA receives your commitment within fifteen (15) days of your receipt of this letter, the agency intends to exercise its enforcement discretion as described above, unless the circumstances listed above or lack of compliance with the conditions set forth in this letter warrant further action. If FDA does not receive a commitment within fifteen (15) days of receipt of this letter or a firm or person fails to comply with the stop manufacture or stop shipment date, the agency may take immediate regulatory action, including but not limited to seizure and/or injunction. If FDA takes action, to preserve limited agency resources, FDA may also take simultaneous enforcement action relating to any other unapproved new drugs manufactured, distributed, or shipped by the defendant. (See, e.g., United States v. Sage Pharmaceuticals, 210 F3d 475, 479-480 (5th Cir. 2000) (the agency can combine all violations of the act in one proceeding, rather than taking action against a firm with multiple violations of the act in “piecemeal fashion”).)

In addition, FDA cautions firms against reformulating their products into ergotamine-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name). In the Marketed Unapproved Drugs CPG, FDA states that it intends to give higher priority to enforcement actions involving unapproved drugs that are reformulated to evade an FDA enforcement action. In addition, reformulated products marketed under a name previously identified with a different active ingredient or combination of active ingredients have the potential to confuse health care practitioners and harm patients.

Please send your reply via fax, as well as mail or overnight delivery to: Valerie L. Whipp, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of New Drugs and Labeling Compliance, 11919 Rockville Pike, HFD-310, Rockville, MD 20852, fax number (301) 827-8904.

For information regarding the drug approval process see
www.fda.gov/cder/regulatory/applications/default.htm. Should you wish to seek approval for your ergotamine product, you may contact Sally Loewke, MD, the Agency’s unapproved drugs coordinator at (301) 796-0710, who can help you identify the appropriate review division or office for further direction. However, until such time as you have FDA approval for your product, you must comply with this letter.

Sincerely yours,

/S/

Michael Levy
Director
Division of New Drugs and Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research

WARNING LETTER

February 26, 2007

Beth Brannan
c/o President or CEO
Sandoz Inc.
506 Carnegie Center Blvd, Ste. 400
Princeton, New Jersey 08540

Dear Ms. Brannan:

This letter is written in reference to the marketing by your firm of phenobarbital, ergotamine, and belladonna tablets, a drug product containing ergotamine tartrate.

Drug products containing ergotamine that were marketed under new drug applications approved for safety only prior to 1962 were reviewed under the Drug Efficacy Study Implementation (DESI) program. On July 27, 1972, the Agency concluded that such products are new drugs effective for the treatment or prevention of “vascular headaches” (”e.g. migraine, migraine variants or `histaminic cephalalgia”‘) subject to section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 355] and that approved new drug applications are required to market them. (37 Fed. Reg. 15032).

Under 21 C.F.R. § 310.6(b)(1), the ergotamine-containing product that you market is identical,related, or similar to the drugs reviewed in this DESI proceeding. Under 21 C.F.R. § 310.6(b)(2), the “new drug” determination made under this DESI proceeding applies to your product and therefore your product requires an approved new drug application before it may be lawfully sold. As there is no approved new drug application on file with the FDA for phenobarbital, ergotamine, and belladonna tablets as marketed by your firm, the marketing of this product is in violation of sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], which prohibit the introduction or delivery for introduction into interstate commerce of a new drug without an approved new drug application.

Moreover, phenobarbital, ergotamine, and belladonna tablets is a prescription drug within the meaning 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], because it is not safe for use except under the supervision of a practitioner licensed by law to administer such drug. By definition, a prescription drug’s directions for use are not adequate to enable a layperson to safely use the drug for its intended uses. See 21 C.F.R. § 201.5. Consequently, phenobarbital, ergotamine, and belladonna tablets’ labeling fails to bear adequate directions for use under section 502(f)(1) of the Act, [21 U.S.C. § 352(f)(1)]. Because it lacks an approved application, it is not exempt from this requirement under 21 C.F.R. § 201.115. phenobarbital, ergotamine, and belladonna tablets is therefore misbranded.

Further, we note that FDA has reviewed and approved several ergotamine-containing drug products and determined that such products require warning information to be placed in a prominently displayed box pursuant to 21 C.F.R. § 201.57. This boxed warning is required to prevent use of potent CYP 3A4 inhibitors with ergotamine-containing products. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use. Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics, and antifungal agents. Your failure to display this warning regarding concomitant use of phenobarbital, ergotamine, and belladonna tablets with CYP 3A4 inhibitors also renders the product misbranded under section 502(f)(2) of the Act, [21 U.S.C. § 352(f)(2)], because its labeling fails to bear adequate warnings.

In addition to the serious health concern presented by your omission of this important warning,unapproved drugs are a public health risk in general because they may not meet modern standards for safety, effectiveness, quality, and labeling. Even though some ergotamine products were found to be effective for certain indications via the DESI process, this does not necessarily mean that phenobarbital, ergotamine, and belladonna tablets as currently formulated, manufactured, and labeled, is effective or safe.

The above identified violations are not intended to be an all inclusive list of violations involving your facility. It is your responsibility to assure that your firm is in compliance with all requirements of the Act. We request that you review all drug products that you are currently marketing to assure they are in compliance with the Act and FDA regulations. If you no longer market any ergotamine-containing drug products or believe that you have received this letter in error, please notify the Agency at the address below.

As described in the guidance entitled “Marketed Unapproved Drugs -Compliance Policy Guide” (”Marketed Unapproved Drugs CPG”), the Agency may exercise its enforcement discretion and identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved drug. http://www.fda.gov/cder/guidance/6911fnl.pdf. The Agency intends to exercise its enforcement discretion with regard to unapproved, ergotamine-containing drug products as follows. FDA does not intend to initiate enforcement actions related to currently manufactured unapproved ergotamine-containing products if those products are listed with FDA under section 510 of the Act, [21 U.S.C. § 360], as of the date of this letter, unless the manufacturing of those products continues after April 27, 2007. Further, FDA does not intend to initiate enforcement actions related to the shipment in interstate commerce of unapproved ergotamine-containing products made by such firms, including phenobarbital, ergotamine, and belladonna tablets, unless they are still being shipped on or after August 25, 2007 1.

You should be aware that the Agency does not intend to exercise its enforcement discretion as described in this letter in the following circumstances: (1) if a firm is violating other provisions of the Act; (2) when it appears that a firm, in response to this letter, increases its manufacture or distribution of unapproved ergotamine drug products above its usual volume during these periods; (3) if FDA learns of new information regarding any serious health risk or hazards associated with an unapproved ergotamine drug product; or (4) if a firm marketing unapproved ergotamine products does not undertake appropriate corrective action to cease marketing the products.

To avail your firm of these periods during which the Agency intends to exercise enforcement discretion regarding unapproved ergotamine products, you must reply within fifteen (15) days of your receipt of this letter with a commitment to comply with the conditions stated above. Please include:

• a statement(s) of what action you plan to take to comply;
• a statement of the amount of phenobarbital, ergotamine, and belladonna tablets, and any other unapproved ergotamine-containing product, that is (are) in inventory under your control;
• the time period in which you expect such inventory to be exhausted, in its entirety,and your plan for disposition of any inventory remaining after the above shipment cessation date; and
• an estimate of when products in distribution channels will become exhausted.

If FDA receives your commitment within fifteen (15) days of your receipt of this letter, the agency intends to exercise its enforcement discretion as described above, unless the circumstances listed above or lack of compliance with the conditions set forth in this letter warrant further action. If FDA does not receive a commitment within fifteen (15) days of receipt of this letter or a firm or person fails to comply with the stop manufacture or stop shipment date, the agency may take immediate regulatory action, including but not limited to seizure and/or injunction. If FDA takes action, to preserve limited agency resources, FDA may also take simultaneous enforcement action relating to any other unapproved new drugs manufactured, distributed, or shipped by the defendant. (See, e.g., United States v. Sage Pharmaceuticals, 210 F3d 475, 479-480 (5th Cir. 2000) (the agency can combine all violations of the act in one proceeding, rather than taking action against a firm with multiple violations of the act in “piecemeal fashion”).)

In addition, FDA cautions firms against reformulating their products into ergotamine-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name). In the Marketed Unapproved Drugs CPG, FDA states that it intends to give higher priority to enforcement actions involving unapproved drugs that are reformulated to evade an FDA enforcement action. In addition, reformulated products marketed under a name previously identified with a different active ingredient or combination of active ingredients have the potential to confuse health care practitioners and harm patients.

Please send your reply via fax, as well as mail or overnight delivery to: Valerie L. Whipp, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of New Drugs and Labeling Compliance, 11919 Rockville Pike, HFD-310, Rockville, MD 20852, fax number (301) 827-8904.

For information regarding the drug approval process see www.fda.gov/cder/regulatory/applications/default.htm
Should you wish to seek approval for your ergotamine product, you may contact Sally Loewke, MD, the Agency’s unapproved drugs coordinator at (301) 796-0710, who can help you identify the appropriate review division or office for further direction. However, until such time as you have FDA approval for your product, you must comply with this letter.

Sincerely yours,
/S/
Michael Levy
Director
Division of New Drugs and Labeling Compliance Office of Compliance
Center for Drug Evaluation and Research

WARNING LETTER

February 26, 2007

Tom Young
CEO
Qualitest Pharmaceuticals, Inc .
130 Vintage Drive NE
Huntsville, Alabama 35811-8216

Dear Mr. Young:

This letter is written in reference to the marketing by your firm of Bellaspas Tablets, a drug product containing ergotamine tartrate.

Drug products containing ergotamine that were marketed under new drug applications approved for safety only prior to 1962 were reviewed under the Drug Efficacy Study Implementation (DESI) program. On July 27, 1972, the Agency concluded that such products are new drugs effective for the treatment or prevention of “vascular headaches” (”e.g. migraine, migraine variants or `histaminic cephalalgia”‘) subject to section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 355] and that approved new drug applications are required to market them. (37 Fed. Reg. 15032).

Under 21 C.F.R. § 310.6(b)(1), the ergotamine-containing product that you market is identical,related, or similar to the drugs reviewed in this DESI proceeding. Under 21 C.F.R. § 310.6(b)(2), the “new drug” determination made under this DESI proceeding applies to your product and therefore your product requires an approved new drug application before it may be lawfully sold. As there is no approved new drug application on file with the FDA for Bellaspas Tablets as marketed by your firm,the marketing of this product is in violation of sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], which prohibit the introduction or delivery for introduction into interstate commerce of a new drug without an approved new drug application.

Moreover, Bellaspas Tablets is a prescription drug within the meaning of section 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], because it is not safe for use except under the supervision of a practitioner licensed by law to administer such drug. By definition, a prescription drug’s directions for use are not adequate to enable a layperson to safely use the drug for its intended uses. See 21 C.F.R. § 201.5 .Consequently, Bellaspas Tablets’ labeling fails to bear adequate directions for use under section 502(f)(1) of the Act, [21 U.S.C. § 352(fl(1)]. Because it lacks an approved application, it is not exempt from this requirement under 21 C.F.R. § 201.115. Bellaspas Tablets is therefore misbranded.

Further, we note that FDA has reviewed and approved several ergotamine-containing drug products and determined that such products require warning information to be placed in a prominently displayed box pursuant to 21 C.F.R. § 201.57. This boxed warning is required to prevent use of potent CYP 3A4 inhibitors with ergotamine-containing products. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use. Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics, and antifungal agents. Your failure to display this warning regarding concomitant use of Bellaspas Tablets with CYP 3A4 inhibitors also renders the product misbranded under section 502(fl(2) of the Act, [21 U.S.C. § 352(f)(2)], because its labeling fails to bear adequate warning.

In addition to the serious health concern presented by your omission of this important warning, unapproved drugs are a public health risk in general because they may not meet modern standards for safety, effectiveness, quality, and labeling. Even though some ergotamine products were found to be effective for certain indications via the DESI process, this does not necessarily mean that Bellaspas Tablets as currently formulated, manufactured, and labeled, is effective or safe.

The above identified violations are not intended to be an all inclusive list of violations involving your facility. It is your responsibility to assure that your firm is in compliance with all requirements of the Act. We request that you review all drug products that you are currently marketing to assure they are in compliance with the Act and FDA regulations. If you no longer market any ergotamine-containing drug products or believe that you have received this letter in error, please notify the Agency at the address below.

As described in the guidance entitled “Marketed Unapproved Drugs - Compliance Policy Guide” (”Marketed Unapproved Drugs CPG”), the Agency may exercise its enforcement discretion and identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved drug. http://www.fda.gov/cder/guidance/6911fnl.pdf. The Agency intends to exercise its enforcement discretion with regard to unapproved, ergotamine-containing drug products as follows. FDA does not intend to initiate enforcement actions related to currently manufactured unapproved ergotamine-containing products if those products are listed with FDA under section 510 of the Act, [21 U.S.C § 360], as of the date of this letter, unless the manufacturing of those products continues after April 27, 2007. Further, FDA does not intend to initiate enforcement actions related to the shipment in interstate commerce of unapproved ergotamine-containing products made by such firms, including Bellaspas Tablets, unless they are still being shipped on or after August 25, 2007 1.

You should be aware that the Agency does not intend to exercise its enforcement discretion as described in this letter in the following circumstances: (1) if a firm is violating other provisions of the Act; (2) when it appears that a firm, in response to this letter, increases its manufacture or distribution of unapproved ergotamine drug products above its usual volume during these periods; (3) if FDA learns of new information regarding any serious health risk or hazards associated with an unapproved ergotamine drug product; or (4) if a firm marketing unapproved ergotamine products does not undertake appropriate corrective action to cease marketing the products.

To avail your firm of these periods during which the Agency intends to exercise enforcement discretion regarding unapproved ergotamine products, you must reply within fifteen (15) days of your receipt of this letter with a commitment to comply with the conditions stated above. Please include:

• a statement(s) of what action you plan to take to comply;
• a statement of the amount of Bellaspas Tablets, and any other unapproved ergotamine-containing product, that is (are) in inventory under your control;
• the time period in which you expect such inventory to be exhausted, in its entirety, and your plan for disposition of any inventory remaining after the above shipment cessation date; and
• an estimate of when products in distribution channels will become exhausted.

If FDA receives your commitment within fifteen (15) days of your receipt of this letter, the agency intends to exercise its enforcement discretion as described above, unless the circumstances listed above or lack of compliance with the conditions set forth in this letter warrant further action. If FDA does not receive a commitment within fifteen (15) days of receipt of this letter or a firm or person fails to comply with the stop manufacture or stop shipment date, the agency may take immediate regulatory action, including but not limited to seizure and/or injunction. If FDA takes action, to preserve limited agency resources, FDA may also take simultaneous enforcement action relating to any other unapproved new drugs manufactured, distributed, or shipped by the defendant. (See, e.g., United States v. Sage Pharmaceuticals, 210 F3d475, 479-480 (5th Cir. 2000) (the agency can combine all violations of the act in one proceeding, rather than taking action against a firm with multiple violations of the act in “piecemeal fashion”),)

In addition, FDA cautions firms against reformulating their products into ergotamine-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name). In the Marketed Unapproved Drugs CPG, FDA states that it intends to give higher priority to enforcement actions involving unapproved drugs that are reformulated to evade an FDA enforcement action. In addition, reformulated products marketed under a name previously identified with a different active ingredient or combination of active ingredients have the potential to confuse health care practitioners and harm patients.

Please send your reply via fax, as well as mail or overnight delivery to: Valerie L. Whipp, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of New Drugs and Labeling Compliance, 11919 Rockville Pike, HFD-310, Rockville, MD 20852, fax number (301)827-8904.

For information regarding the drug approval process see www.fda.gov/cder/regulatory/applications/default.htm. Should you wish to seek approval for your ergotamine product, you may contact Sally Loewke, MD, the Agency’s unapproved drugs coordinator at (301) 796-0710, who can help you identify the appropriate review division or office for further direction. However, until such time as you have FDA approval for your product, you must comply with this letter.

Sincerely yours,

/S/

Michael Levy
Director
Division of New Drugs and Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research

WARNING LETTER

February 26, 2007

Douglas Ginter
President
Nucare Pharmaceuticals Inc.
622 West Katella Avenue
Orange, California 92867

Dear Mr. Ginter:

This letter is written in reference to the marketing by your firm of Bellamine S Tablets, a drug product containing ergotamine tartrate.

Drug products containing ergotamine that were marketed under new drug applications approved for safety only prior to 1962 were reviewed under the Drug Efficacy Study Implementation (DESI) program. On July 27, 1972, the Agency concluded that such products are new drugs effective for the treatment or prevention of “vascular headaches” (”e.g. migraine, migraine variants or `histaminic cephalalgia”‘) subject to section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) [21U.S.C. § 355] and that approved new drug applications are required to market them. (37 Fed. Reg. 15032).

Under 21 C.F.R. § 310.6(b)(1), the ergotamine-containing product that you market is identical, related, or similar to the drugs reviewed in this DESI proceeding. Under 21 C.F.R. § 310.6(b)(2), the”new drug” determination made under this DESI proceeding applies to your product and therefore your product requires an approved new drug application before it maybe lawfully sold. As there is no approved new drug application on file with the FDA for Bellamine S Tablets as marketed by your firm, the marketing of this product is in violation of sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], which prohibit the introduction or delivery for introduction into interstate commerce of a new drug without an approved new drug application.

Moreover, Bellamine S Tablets is a prescription drug within the meaning of section 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], because it is not safe for use except under the supervision of a practitioner licensed by law to administer such drug. By definition, a prescription drug’s directions for use are not adequate to enable a layperson to safely use the drug for its intended uses. See 21 C.F.R. §201.5. Consequently, Bellamine S Tablets’ labeling fails to bear adequate directions for use under section 502(f)(1) of the Act, [21 U.S.C. § 352(f)(1)]. Because it lacks an approved application, it is not exempt from this requirement under 21 C.F.R. § 201.115. Bellamine S Tablets is therefore misbranded.

Further, we note that FDA has reviewed and approved several ergotamine-containing drug products and determined that such products require warning information to be placed in a prominently displayed box pursuant to 21 C.F.R. § 201.57. This boxed warning is required to prevent use of potent CYP 3A4 inhibitors with ergotamine-containing products. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use. Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics, and antifungal agents. Your failure to display this warning regarding concomitant use of Bellamine S Tablets with CYP 3A4 inhibitors also renders the product misbranded under section 502(fl(2) of the Act, [21 U.S.C. § 352(f)(2)], because its labeling fails to bear adequate warnings.

In addition to the serious health concern presented by your omission of this important warning, unapproved drugs are a public health risk in general because they may not meet modern standards for safety, effectiveness, quality, and labeling. Even though some ergotamine products were found to be effective for certain indications via the DESI process, this does not necessarily mean that Bellamine S Tablets as currently formulated, manufactured, and labeled, is effective or safe.

The above identified violations are not intended to be an all inclusive list of violations involving your facility. It is your responsibility to assure that your firm is in compliance with all requirements of the Act. We request that you review all drug products that you are currently marketing to assure they are in compliance with the Act and FDA regulations. If you no longer market any ergotamine-containing drug products or believe that you have received this letter in error, please notify the Agency at the address below.

As described in the guidance entitled “Marketed Unapproved Drugs -Compliance Policy Guide”(”Marketed Unapproved Drugs CPG”), the Agency may exercise its enforcement discretion and identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved drug. www.fda.gov/cder/guidance/6911fnl.pdf. The Agency intends to exercise its enforcement discretion with regard to unapproved, ergotamine-containing drug products as follows. FDA does not intend to initiate enforcement actions related to currently manufactured unapproved ergotamine-containing products if those products are listed with FDA under section 510 of the Act, [21 U.S.C. § 360], as of the date of this letter, unless the manufacturing of those products continues after April 27, 2007. Further, FDA does not intend to initiate enforcement actions related to the shipment in interstate commerce of unapproved ergotamine- containing products made by such firms, including Bellamine S Tablets, unless they are still being shipped on or after August 25, 2007 1.

You should be aware that the Agency does not intend to exercise its enforcement discretion as described in this letter in the following circumstances: (1) if a firm is violating other provisions of the Act; (2) when it appears that a firm, in response to this letter, increases its manufacture or distribution of unapproved ergotamine drug products above its usual volume during these periods; (3) if FDA learns of new information regarding any serious health risk or hazards associated with an unapproved ergotamine drug product; or (4) if a firm marketing unapproved ergotamine products does not undertake appropriate corrective action to cease marketing the products.

To avail your firm of these periods during which the Agency intends to exercise enforcement discretion regarding unapproved ergotamine products, you must reply within fifteen (15) days of your receipt of this letter with a commitment to comply with the conditions stated above. Please include:

• a statement(s) of what action you plan to take to comply;
• a statement of the amount of Bellamine S Tablets, and any other unapproved ergotamine-containing product, that is (are) in inventory under your control;
• the time period in which you expect such inventory to be exhausted, in its entirety, and your plan for disposition of any inventory remaining after the above shipment cessation date; and
• an estimate of when products in distribution channels will become exhausted.

If FDA receives your commitment within fifteen (15) days of your receipt of this letter, the agency intends to exercise its enforcement discretion as described above, unless the circumstances listed above or lack of compliance with the conditions set forth in this letter warrant further action. If FDA does not receive a commitment within fifteen (15) days of receipt of this letter or a firm or person fails to comply with the stop manufacture or stop shipment date, the agency may take immediate regulatory action, including but not limited to seizure and/or injunction. If FDA takes action, to preserve limited agency resources, FDA may also take simultaneous enforcement action relating to any other unapproved new drugs manufactured, distributed, or shipped by the defendant. (See, e.g., United States v. Sage Pharmaceuticals, 210 F3d475, 479-480 (5th Cir. 2000) (the agency can combine all violations of the act in one proceeding, rather than taking action against a firm with multiple violations of the act in “piecemeal fashion”).)

In addition, FDA cautions firms against reformulating their products into ergotamine-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name). In the Marketed Unapproved Drugs CPG, FDA states that it intends to give higher priority to enforcement actions involving unapproved drugs that are reformulated to evade an FDA enforcement action. In addition, reformulated products marketed under a name previously identified with a different active ingredient or combination of active ingredients have the potential to confuse health care practitioners and harm patients.

Please send your reply via fax, as well as mail or overnight delivery to: Valerie L. Whipp, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of New Drugs and Labeling Compliance, 11919 Rockville Pike, HFD-310, Rockville, MD 20852, fax number (301) 827-8904.

For information regarding the drug approval process see
www.fda.gov/cder/regulatory/applications/default.htm. Should you wish to seek approval for your ergotamine product, you may contact Sally Loewke, MD, the Agency’s unapproved drugs coordinator at (301) 796-0710, who can help you identify the appropriate review division or office for further direction. However, until such time as you have FDA approval for your product, you must comply with this letter.

Sincerely yours,

/S/

Michael Levy
Director
Division of New Drugs and Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research

WARNING LETTER

February 26, 2007

Richard Reeves
President
Murfreesboro Pharmaceutical Nursing Supply
1843 Memorial Blvd
Murfreesboro, Tennessee 37129
Dear Mr. Reeves:

This letter is written in reference to the marketing by your firm of drug products containing ergotamine tartrate, specifically, Bellamine S Tablets and Eperbel S Tablets.

Drug products containing ergotamine that were marketed under new drug applications approved for safety only prior to 1962 were reviewed under the Drug Efficacy Study Implementation (DESI) program. On July 27, 1972, the Agency concluded that such products are new drugs effective for the treatment or prevention of “vascular headaches” (”e.g. migraine, migraine variants or `histaminic cephalalgia”‘) subject to section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) [21U.S.C. § 355] and that approved new drug applications are required to market them. (37 Fed. Reg. 15032).

Under 21 C.F.R. § 310.6(b)(1), the ergotamine-containing products that you market are identical, related, or similar to the drugs reviewed in this DESI proceeding. Under 21 C.F.R. § 310.6(b)(2), the “new drug” determination made under this DESI proceeding applies to your products and therefore your products require an approved new drug application before they may be lawfully sold. As there are no approved new drug applications on file with the FDA for any of the drug products, Bellamine S Tablets and Eperbel S Tablets as marketed by your firm, the marketing of these products is in violation of sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], which prohibit the introduction or delivery for introduction into interstate commerce of a new drug without an approved new drug application.

Moreover, Bellamine S Tablets and Eperbel S Tablets are prescription drugs within the meaning of section 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], because they are not safe for use except under the supervision of a practitioner licensed by law to administer such drugs. By definition, prescription drug’s directions for use are not adequate to enable a layperson to safely use the drug for a its intended uses. See 21 C.F.R. § 201.5. Consequently, Bellamine S Tablets and Eperbel S Tablets’ labeling fail to bear adequate directions for use under section 502(f)(1) of the Act, [21 U.S.C. §352(f)(1)]. Because each lacks an approved application, each is not exempt from this requirement under 21 C.F.R. § 201.115. Bellamine S Tablets and Eperbel S Tablets are therefore misbranded.

Further, we note that FDA has reviewed and approved several ergotamine-containing drug product sand determined that such products require warning information to be placed in a prominently displayed box pursuant to 21 C.F.R. § 201.57. This boxed warning is required to prevent use of potent CYP 3A4 inhibitors with ergotamine-containing products. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use. Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics, and antifungal agents. Your failure to display this warning regarding concomitant use of Bellamine S Tablets and Eperbel S Tablets with CYP 3A4 inhibitors also renders these products misbranded under section 502(fl(2) of the Act, [21 U.S.C.,. § 352(f)(2)], because each product’s labeling fails to bear adequate warnings.

In addition to the serious health concern presented by your omission of this important warning, unapproved drugs are a public health risk in general because they may not meet modern standards for safety, effectiveness, quality, and labeling. Even though some ergotamine products were found to be effective for certain indications via the DESI process, this does not necessarily mean that Bellamine S Tablets and Eperbel S Tablets as currently formulated, manufactured, and labeled, are effective or safe.

The above identified violations are not intended to be an all inclusive list of violations involving your facility. It is your responsibility to assure that your firm is in compliance with all requirements of the Act. We request that you review all drug products that you are currently marketing to assure they are in compliance with the Act and FDA regulations. If you no longer market any ergotamine-containing drug products or believe that you have received this letter in error, please notify the Agency at the address below.

As described in the guidance entitled “Marketed Unapproved Drugs -Compliance Policy Guide”(”Marketed Unapproved Drugs CPG”), the Agency may exercise its enforcement discretion and identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved drug. www.fda.gov/cder/guidance/6911fnl.pdf. The Agency intends to exercise its enforcement discretion with regard to unapproved, ergotamine-containing drug products as follows. FDA does not intend to initiate enforcement actions related to currently manufactured unapproved ergotamine-containing products if those products are listed with FDA under section 510 of the Act, [21 U.S.C § 360], as of the date of this letter, unless the manufacturing of those products continues after April 27, 2007. Further, FDA does not intend to initiate enforcement actions related to the shipment in interstate commerce of unapproved ergotamine-containing products made by such firms, including Bellamine S Tablets and Eperbel S Tablets, unless they are still being shipped on or after August 25, 2007 1.

You should be aware that the Agency does not intend to exercise its enforcement discretion as described in this letter in the following circumstances: (1) if a firm is violating other provisions of the Act; (2) when it appears that a firm, in response to this letter, increases its manufacture or distribution of unapproved ergotamine drug products above its usual volume during these periods; (3) if FDA learns of new information regarding any serious health risk or hazards associated with an unapproved ergotamine drug product; or (4) if a firm marketing unapproved ergotamine products does not undertake appropriate corrective action to cease marketing the products.

To avail your firm of these periods during which the Agency intends to exercise enforcement discretion regarding unapproved ergotamine products, you must reply within fifteen (15) days of your receipt of this letter with a commitment to comply with the conditions stated above. Please include:

• a statement(s) of what action you plan to take to comply;
• a statement of the amount of each drug, Bellamine S Tablets and Eperbel S Tablets, and any other unapproved ergotamine-containing product, that is (are) in inventory under your control;
• the time period in which you expect such inventory to be exhausted, in their entirety, and your plan for disposition of any inventory remaining after the above shipment cessation date; and
• an estimate of when products in distribution channels will become exhausted.

If FDA receives your commitment within fifteen (15) days of your receipt of this letter, the agency intends to exercise its enforcement discretion as described above, unless the circumstances listed above or lack of compliance with the conditions set forth in this letter warrant further action. If FDA does not receive a commitment within fifteen (15) days of receipt of this letter or a firm or person fails to comply with the stop manufacture or stop shipment date, the agency may take immediate regulatory action, including but not limited to seizure and/or injunction. If FDA takes action, to preserve limited agency resources, FDA may also take simultaneous enforcement action relating to any other unapproved new drugs manufactured, distributed, or shipped by the defendant. (See, e.g., United States v. Sage Pharmaceuticals, 210 F3d 475, 479-480 (5th Cir. 2000) (the agency can combine all violations of the act in one proceeding, rather than taking action against a firm with multiple violations of the act in “piecemeal fashion”).)

In addition, FDA cautions firms against reformulating their products into ergotamine-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name). In the Marketed Unapproved Drugs CPG, FDA states that it intends to give higher priority to enforcement actions involving unapproved drugs that are reformulated to evade an FDA enforcement action. In addition, reformulated products marketed under a name previously identified with a different active ingredient or combination of active ingredients have the potential to confuse health care practitioners and harm patients.

Please send your reply via fax, as well as mail or overnight delivery to: Valerie L. Whipp, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of New Drugs and Labeling Compliance, 11919 Rockville Pike, HFD-310, Rockville, MD 20852, fax number (301)827-8904.

For information regarding the drug approval process see
www.fda.gov/cder/regulatory/applications/default.htm. Should you wish to seek approval for your ergotamine product, you may contact Sally Loewke, MD, the Agency’s unapproved drugs coordinator at (301) 796-0710, who can help you identify the appropriate review division or office for further direction. However, until such time as you have FDA approval for your product, you must comply with this letter.

Sincerely yours,

Michael Levy
Director
Division of New Drugs and Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research

WARNING LETTER

February 26, 2007

President and/or CEO
Lini Inc.
665 East Lincoln Avenue
Rahway, New Jersey 07065

Dear Mr. or Ms. President and/or CEO:

This letter is written in reference to the marketing by your firm of drug products containing ergotamine tartrate, specifically, Bell Phen Ergot S Tablets, Bellaspas Tablets, and Bellamine Tablets.

Drug products containing ergotamine that were marketed under new drug applications approved for safety only prior to 1962 were reviewed under the Drug Efficacy Study Implementation (DESI) program . On July 27, 1972, the Agency concluded that such products are new drugs effective for the treatment or prevention of “vascular headaches” (”e.g. migraine, migraine variants or `histaminic cephalalgia”‘) subject to section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 355] and that approved new drug applications are required to market them. (37 Fed. Reg. 15032).

Under 21 C.F.R. § 310.6(b)(1), the ergotamine-containing products that you market are identical, related, or similar to the drugs reviewed in this DESI proceeding. Under 21 C.F.R. § 310 .6(b)(2), the”new drug” determination made under this DESI proceeding applies to your products and therefore your products require an approved new drug application before they may be lawfully sold. As there are no approved new drug applications on file with the FDA for any of the drug products, Bell Phen Ergot S Tablets, Bellaspas Tablets, and Bellamine Tablets as marketed by your firm, the marketing of these products is in violation of sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], which prohibit the introduction or delivery for introduction into interstate commerce of a new drug without an approved new drug application.

Moreover, Bell Phen Ergot S Tablets, Bellaspas Tablets, and Bellamine Tablets are prescription drugs within the meaning of section 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], because they are not safe for use except under the supervision of a practitioner licensed by law to administer such drugs. By definition, a prescription drug’s directions for use are not adequate to enable a layperson to safely use the drug for its intended uses. See 21 C.F.R. §201.5. Consequently, Bell Phen Ergot S Tablets, Bellaspas Tablets, and Bellamine Tablets’ labeling fail to bear adequate directions for use under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)]. Because each lacks an approved application, each is not exempt from this requirement under 21 C.F.R. § 201.115. Bell Phen Ergot S Tablets, Bellaspas Tablets, and Bellamine Tablets are therefore misbranded.

Further, we note that FDA has reviewed and approved several ergotamine-containing drug products and determined that such products require warning information to be placed in a prominently displayed box pursuant to 21 C.F.R. § 201.57. This boxed warning is required to prevent use of potent CYP 3A4 inhibitors with ergotamine-containing products. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use.

Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics, and antifungal agents. Your failure to display this warning regarding concomitant use of Bell Phen Ergot S Tablets, Bellaspas Tablets, and Bellamine Tablets with CYP 3A4 inhibitors also renders these products misbranded under section 502(f)(2) of the Act, [21 U.S.C. § 352(f)(2)], because each product’s labeling fails to bear adequate warnings.

In addition to the serious health concern presented by your omission of this important warning, unapproved drugs are a public health risk in general because they may not meet modern standards for safety, effectiveness, quality, and labeling. Even though some ergotamine products were found to be effective for certain indications via the DESI process, this does not necessarily mean that Bell Phen Ergot S Tablets, Bellaspas Tablets, and Bellamine Tablets as currently formulated, manufactured, and labeled, are effective or safe.

The above identified violations are not intended to be an all inclusive list of violations involving your facility. It is your responsibility to assure that your firm is in compliance with all requirements of the Act. We request that you review all drug products that you are currently marketing to assure they are in compliance with the Act and FDA regulations. If you no longer market any ergotamine-containing drug products or believe that you have received this letter in error, please notify the Agency at the address below.

As described in the guidance entitled “Marketed Unapproved Drugs - Compliance Policy Guide” (”Marketed Unapproved Drugs CPG”), the Agency may exercise its enforcement discretion and identify a period of time during which the Agency does not intend to initiate an enforcement action against a currently marketed unapproved drug. http://www.fda.gov/cder/guidance/6911fnl.pdf. The Agency intends to exercise its enforcement discretion with regard to unapproved, ergotamine-containing drug products as follows. FDA does not intend to initiate enforcement actions related to currently manufactured unapproved ergotamine-containing products if those products are listed with FDA under section 510 of the Act, [21 U.S.C. § 360], as of the date of this letter, unless the manufacturing of those products continues after April 27, 2007. Further, FDA does not intend to initiate enforcement actions related to the shipment in interstate commerce of unapproved ergotamine-containing products made by such firms, including Bell Phen Ergot S Tablets, Bellaspas Tablets, and Bellamine Tablets, unless they are still being shipped on or after August 25, 2007 1.

You should be aware that the Agency does not intend to exercise its enforcement discretion as described in this letter in the following circumstances: (1) if a firm is violating other provisions of the Act; (2) when it appears that a firm, in response to this letter, increases its manufacture or distribution of unapproved ergotamine drug products above its usual volume during these periods; (3) if FDA learns of new information regarding any serious health risk or hazards associated with an unapproved ergotamine drug product; or (4) if a firm marketing unapproved ergotamine products does not undertake appropriate corrective action to cease marketing the products.

To avail your firm of these periods during which the Agency intends to exercise enforcement discretion regarding unapproved ergotamine products, you must reply within fifteen (15) days of your receipt of this letter with a commitment to comply with the conditions stated above. Please include:

• a statement(s) of what action you plan to take to comply;
• a statement of the amount of each drug, Bell Phen Ergot S Tablets, Bellaspas Tablets, and Bellamine Tablets, and any other unapproved ergotamine-containing product, that is (are) in inventory under your control;
• the time period in which you expect such inventory to be exhausted, in their entirety, and your plan for disposition of any inventory remaining after the above shipment cessation date; and
• an estimate of when products in distribution channels will become exhausted.

If FDA receives your commitment within fifteen (15) days of your receipt of this letter, the agency intends to exercise its enforcement discretion as described above, unless the circumstances listed above or lack of compliance with the conditions set forth in this letter warrant further action. If FDA does not receive a commitment within fifteen (15) days of receipt of this letter or a firm or person fails to comply with the stop manufacture or stop shipment date, the agency may take immediate regulatory action, including but not limited to seizure and/or injunction. If FDA takes action, to preserve limited agency resources, FDA may also take simultaneous enforcement action relating to any other unapproved new drugs manufactured, distributed, or shipped by the defendant. (See, e.g., United States v. Sage Pharmaceuticals, 210 F.3d 475, 479-480 (5th Cir. 2000) (the agency can combine all violations of the act in one proceeding, rather than taking action against a firm with multiple violations of the act in “piecemeal fashion”).)

In addition, FDA cautions firms against reformulating their products into ergotamine-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name). In the Marketed Unapproved Drugs CPG, FDA states that it intends to give higher priority to enforcement actions involving unapproved drugs that are reformulated to evade an FDA enforcement action. In addition, reformulated products marketed under a name previously identified with a different active ingredient or combination of active ingredients have the potential to confuse health care practitioners and harm patients.

Please send your reply via fax, as well as mail or overnight delivery to: Valerie L. Whipp, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of New Drugs and Labeling Compliance, 11919 Rockville Pike, HFD-310, Rockville, MD 20852, fax number (301) 827-8904.

For information regarding the drug approval process see
http://www.fda.gov/cder/regulatory/applications/default.htm. Should you wish to seek approval for your ergotamine product, you may contact Sally Loewke, MD, the Agency unapproved drugs coordinator at t (301) 796-0710, who can help you identify the appropriate review division or office for further direction. However, until such time as you have FDA approval for your product, you must comply with this letter.

Sincerely yours,

/S/

Michael Levy
Director
Division of New Drugs and Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research