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for completing the form may be obtained from the Division Pharmacovigilance and Epidemiology (HFD-730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. More than 10 copies of the form may be obtained by writing to the Consolidated Forms and Publications Distribution Center, Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.

(e) Patient privacy. Manufacturers, packers, and distributors should not include in reports under this section the names and addresses of individual patients;

instead, the manufacturer,

packer, and distributor should assign a unique code number to each report, preferably not more than eight characters in length. The manufacturer, packer, and distributor should include the name of the reporter from whom the information was received. Names of patients, individual reporters, health care professionals, hospitals, and geographical identifiers in adverse drug experience reports are not releasable to the public under FDA's public information regulations in part 20 of this chapter.

(f) Recordkeeping. (1) Each manufacturer, packer, and distributor shall maintain for for a period of 10 years records of all adverse drug experiences required under this section to be reported, including raw data and any correspondence relating to the adverse drug experiences, and the records required to be maintained under paragraph (c)(4) of this section.

(2) Manufacturers and packers may retain the records required in paragraph (f)(1) of this section as part of its complaint files maintained under § 211.198 of this chapter.

(3) Manufacturers, packers, and distributors shall permit any authorized FDA employee, at all reasonable times, to have access to and copy and verify the records established and maintained under this section.

(g) Disclaimer. A report or information submitted by a manufacturer, packer, or distributor under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the manufacturer, packer, or distributor,

or by FDA, that the report or information constitutes an admission that the drug caused or contributed to an adverse effect. The manufacturer, packer, or distributor need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the drug caused or contributed to an adverse effect.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0210)

[51 FR 24779, July 3, 1986, as amended at 52 FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, June 25, 1997; 62 FR 52249, Oct. 7, 1997]

EFFECTIVE DATE NOTE: At 62 FR 52249, Oct. 7, 1997, § 310.305 was amended by adding a new sentence at the end of paragraph (a); by revising paragraphs (b), (c), (d)(1), (d)(3)(ii), and (d)(4); by removing in paragraph (d)(2), the introductory text of paragraph (d)(3), and paragraph (d)(3)(i) the words "Form FDA1639" or "FDA-1639" and adding in their place "FDA Form 3500A", effective Apr. 6, 1998. For the convenience of the user, the superseded text is set forth as follows: $310.305 Records and reports concerning adverse drug experiences on marketed prescription drugs for human use without approved new drug applications.

(b) Definitions. The following definitions of terms apply to this section:

(1) FDA means the Food and Drug Administration.

(2) Adverse drug experience means any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: an adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose, whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action.

(3) Unexpected means an adverse drug experience that is not listed in the current labeling for the drug product and includes an event that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism

179-070 0-98——2

and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents.

(4) Serious means an adverse drug experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or overdose.

(c) Reporting requirements-15-day "Alert reports." (1)(1) Any person whose name appears on the label of a marketed prescription drug product as its manufacturer, packer, or distributor shall report to FDA each adverse drug experience received or otherwise obtained that is both serious and unexpected as soon as possible but in any case within 15 working days of initial receipt of the information. Each report shall be accompanied by a copy of the current labeling for the drug product.

(ii) A person identified in paragraph (c)(1)(1) of this section is not required to submit a 15-day "Alert report" for an adverse drug experience obtained from a postmarketing study (whether or not conducted under an investigational new drug application) unless the applicant concludes that there is a reasonable possibility that the drug caused the adverse experience.

(2) Each person identified in paragraph (c)(1) of this section shall submit one copy of each report to the Division of Epidemiology and Surveillance (HFD–730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

(3) Each person identified in paragraph (c)(1) of this section shall promptly investigate all serious, unexpected adverse drug experiences that are the subject of these 15day Alert reports and shall submit followup reports within 15 working days of receipt of new information or as requested by FDA. If additional information is not obtainable, a followup report may be required that describes briefly the steps taken to seek additional information and the reasons why it could not be obtained.

(4) To avoid unnecessary duplication in the submission of, and followup to, reports required in this section, a packer's or distributor's obligations may be met by submission of all reports of serious adverse drug experiences to the manufacturer of the drug product. If a packer or distributor elects to submit these adverse drug experience reports to the manufacturer rather than to FDA, it shall submit each report to the manufacturer within 3 working days of its receipt by the packer or distributor, and the manufacturer shall then comply with the requirements of this section even if its name does not appear on the label of the drug product. Under this circumstance, the packer or distributor shall maintain a record of this action which shall include:

(1) A copy of each drug experience report.

(ii) Date the report was received by the packer or distributor.

(iii) Date the report was submitted to the manufacturer.

(iv) Name and address of the manufacturer. (5) Each report submitted to FDA under this section shall bear prominent identification as to its contents, i.e., "15-day Alert report" or "15-day Alert report-followup."

(d) Reporting form. (1) Except as provided in paragraph (d)(3) of this section, each person identified in paragraph (c)(1) of this section shall submit each report of a serious and unexpected adverse drug experience on a Form FDA-1639 (Adverse Reaction Report).

(3)* * * (1)* * *

(ii) The format is agreed to in advance by the Division of Epidemiology and Surveillance (HFD-730).

(4) Single copies of Form FDA-1639 may be obtained from the Division of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Supplies of Form FDA-1639 may be obtained from the PHS Forms and Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD 20857.

Subpart E-Requirements for Specific New Drugs or Devices

§310.500 Digoxin products for oral use; conditions for marketing.

(a) Studies have shown evidence of clinically significant differences in bioavailability in different batches of certain marketed digoxin products for oral use from single manufacturers as well as in batches of these products produced by different manufacturers. These differences were observed despite the fact that the products met compendial specifications. Other studies have shown that there is a sufficient correlation between bioavailability in vivo and the dissolution rate of digoxin tablets in vitro to make the dissolution test an important addition to the compendial standards. Because of the potential for serious risk to cardiac patients using digoxin products which may vary in bioavailability, the Commissioner of Food and Drugs has determined that immediate action must be taken to assure the uniformity

of all digoxin products for oral use. The Commissioner is of the opinion that digoxin products for oral use are new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act for which approved new drug applications are required. The Commissioner has determined that, because of questions raised regarding the bioavailability of digoxin products for oral use, there is sufficient evidence to invoke the authority under section 505(j) of the act to fully investigate this question and to facilitate a determination of whether there is a ground for withdrawal of approval of the drug product under section 505(e) of the act. Marketing of these products may be continued only under the following conditions:

(1) Digoxin products for oral use, other than tablets: Any person marketing digoxin products for oral use, other than tablets, shall submit to the Food and Drug Administration on or before February 21, 1974, an abbreviated new drug application for these products. Any such drug product then on the market which is not the subject of an application submitted for the drug product shall be subject to regulatory procedures under section 505 of the act. In addition to the information specified in §314.50 of this chapter, the application shall contain:

(i) A full list of the articles used as components of the digoxin product, specifications for components, detailed identification and analytical procedures used to assure that the components meet established specifications of identity, strength, quality, and purity and a complete description of the manufacturing process.

(ii) The source of the digoxin used in the formulation including the name and address of the supplier.

(iii) A statement that stability studies will be conducted to establish a suitable expiration date for the digoxin product in the form in which it is distributed.

(iv) A statement that the product label will contain a suitable expiration date. In the absence of any stability test data, this expiration date shall be no longer than one year after the batch is manufactured. If the expiration date is greater than one year, supporting

stability data shall be included in the application.

(v) Labeling that is in compliance with all requirements of the act and regulations promulgated thereunder, the pertinent parts of which are as indicated in paragraph (e) of this section.

(vi) A statement that the applicant will initiate recall of all stocks of the drug product outstanding when so requested by the Food and Drug Administration.

(vii) A statement that the applicant intends to conduct in vivo bioavailability tests and that the applicant, under the records and reports provisions of section 505(k) of the act, will:

(a) Within 30 days after the submission of the application, submit to the Food and Drug Administration the protocol which the applicant proposes to follow in conducting these in vivo bioavailability tests. The protocol shall contain all of the essential elements set forth in paragraph (d) of this section. The tests shall not be initiated prior to receiving notification from the Food and Drug Administration that the bioavailability protocol has been reviewed and either approved or its deficiencies delineated.

(b) Within 180 days after receiving notification from the Food and Drug Administration that the bioavailability protocol has been reviewed, submit to the Food and Drug Administration the results of the in vivo bioavailability tests.

(2) Digoxin tablets: Any person marketing digoxin tablets, in addition to complying with all of the requirements of paragraph (a)(1) of this section, shall include in their abbreviated new drug application:

(1) A statement that the applicant will establish procedures to test each lot of digoxin tablets prior to releasing the batch for distribution to assure that the batch meets all of The United States Pharmacopeia (USP XVII) requirements for digoxin tablets including, but not limited to, potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not

more than 90 percent of the assayed amount of digoxin.

(ii) A statement that finished product specifications shall be established to include provisions to assure that the range of average one-hour dissolution values among batches of digoxin tablets does not exceed 20 percent.

(3) Before releasing for distribution any batch of digoxin tablets manufactured after January 22, 1974, the manufacturer shall:

(i) Test a sample of the batch to assure that the batch meets all of the requirements of The United States Pharmacopeia (USP XVIII) including but not limited to, potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin.

(ii) Submit a sample of the batch to the Food and Drug Administration according to the procedures set forth in paragraph (g) of this section. Results of tests conducted on the batch by or for the manufacturer and the batch production record shall accompany the sample.

(iii) Withhold the batch from distribution until he is notified by the Food and Drug Administration that the sample was tested and found to meet all of the requirements in The United States Pharmacopeia (USP XVIII) for potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin.

(iv) Submit a sample of each batch of digoxin tablets as provided for in paragraph (a)(3)(ii) of this section until he is notified by the Food and Drug Administration that he is released from the certification program. This notification will be made on the basis of sample test results, inspectional findings regarding compliance with current good manufacturing practice, and compliance with all other requirements of this section and any other directives issued by the Food and Drug Adminis

tration as a condition for release from the certification program.

(4) Any manufacturer who has distributed any batch of digoxin tablets which does not meet the compendial requirement for dissolution, when tested by the method in The United States Pharmacopeia (USP XVIII), shall initiate recall of the subject batch when so requested by the Food and Drug Administration.

(b) Failure of an applicant to submit the protocol and/or the results of the in vivo bioavailability tests showing adequate evidence of the product's bioavailability within the times specified in paragraph (a)(1)(vii) of this section and/or to comply with all of the certification requirements of paragraph (a)(3) of this section shall be justification for withdrawal of approval of the application under section 505(e) of the act.

(c) Any product reformulation or change in manufacturing process will require the submission of a supplement to the approved abbreviated new drug application containing adequate data to demonstrate the bioavailability of the reformulated product. Food and Drug Administration approval of the supplement is required before the reformulated product is marketed. The Food and Drug Administration recommends that, where digoxin tablets are reformulated, manufacturers reformulate their product to achieve dissolution of 70 to 90 percent at one hour when tested by all three methods (i.e., the USP method, and the "paddlewater" and "paddle-acid" methods) described in paragraph (h) of this section. (d) The protocol for the in vivo bioavailability tests required in paragraphs (a) and (c) of this section shall employ a three-way crossover design using the digoxin test product; a reference digoxin tablet supplied, on request, by the Food and Drug Administration; and bulk digoxin USP in an oral solution. Appropriate venous blood and urinary samples are to be collected and analyzed. The method shall be capable of detecting the difference between the reference tablet and the reference oral solution. Bioavailability of the test product shall be demonstrated if a mean absorption of at least 75 percent of the combined mean of the two

reference standards is observed. Assistance in developing a protocol for a particular dosage formulation may be obtained by contacting the Food and Drug Administration, Center for Drug Evaluation and Research (HFD-420), 5600 Fishers Lane, Rockville, MD 20857. (e) Parts of the digoxin product labeling indicated below shall be as follows: DIGOXIN LABELING GUIDELINES

(ADULT AND PEDIATRIC)

DESCRIPTION

Digoxin is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific and powerful effects on the myocardium. These drugs are found in a number of plants. The term "digitalis" is used to designate the whole group. Typically, the glycosides are composed of three portions: a steroid nucleus, a lactone ring, and a sugar (hence "glycosides").

(This section should include a chemical and physical description of digoxin and the same quantitative ingredient information as that required on the label.)

ACTION

The digitalis glycosides have qualitatively the same therapeutic effects on the heart. They (1) increase the force of myocardial contraction, (2) increase the refractory period of the atrioventricular (A-V) node, and (3) to a lesser degree, affect the sinoatrial (S-A) node and conduction system via the parasympathetic and sympathetic nervous

systems.

Gastrointestinal absorption of digoxin is a passive process. About 50-75 percent of digoxin in tablet form is absorbed. Digoxin is only 20-25 percent bound to plasma proteins and is predominantly excreted by the kidneys unmetabolized unless there is significant renal failure. Renal excretion of digoxin is proportional to glomerular filtration rate and is largely independent of urine flow. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass, presumably because of tissue binding. In subjects with normal renal function, digoxin is excreted exponentially with an average half-life of 36 hours, resulting in the loss of 35-40 percent of the body stores daily.

Serum levels and pharmacokinetics are essentially unchanged by massive weight loss, suggesting that lean body mass should be used in dosage calculations. The peak blood level from oral dosing with tablets occurs 13 hours after administration. The onset of therapeutic action of digoxin after oral tablets is 1-2 hours, with the peak therapeutic effect occurring 6-8 hours after dosing.

INDICATIONS

1. Congestive heart failure, all degrees, is the primary indication. The increased cardiac output due to digoxin results in diuresis and general amelioration of the disturbances characteristic of right (venous congestion, edema) and left (dyspnea, orthopnea, cardiac asthma) heart failure.

Digoxin, generally, is most effective in "low output" failure and less effective in "high output" (bronchopulmonary insufficiency, infection, hyperthyroidism) heart failure.

Digoxin should be continued after heart failure is abolished unless some known precipitating factor is corrected.

2. Atrial fibrillation, especially when the ventricular rate is elevated. Digoxin rapidly reduces ventricular rates and eliminates the pulse deficit. Palpitation, precordial distress or weakness are relieved and any concomitant congestive failure ameliorated.

Digoxin should be continued in doses necessary to maintain the desired ventricular rate and other clinical effects.

3. Atrial flutter. Digoxin slows the heart and regular sinus rhythm may appear. Frequently the flutter is converted to atrial fibrillation with a slow ventricular rate. Stopping digoxin at this point may be followed by restoration of sinus rhythm, especially if the flutter was of the paroxysmal type. It is preferable, however, to continue digoxin if failure ensues or if atrial flutter is a frequent occurrence.

4. Paroxysmal atrial tachycardia. Oral digoxin may be used, especially if the condition is resistant to lesser measures. Depending on the urgency, a more rapid acting parenteral preparation may be preferable to initiate digitalization, although if heart failure has ensued or paroxysms recur frequently, digoxin should be maintained by oral administration.

Digoxin is not indicated in sinus tachycardia unless due to heart failure.

5. Cardiogenic shock. The drug is often employed, especially when the condition is accompanied by pulmonary edema. Digoxin seems to affect adversely shock due to septicemia from gram negative bacteria.

CONTRAINDICATIONS

The presence of toxic effects (See ADVERSE REACTIONS section) induced by any digitalis preparation is a contraindication to all of the gylcosides.

Allergy, though rare, does occur. It may not extend to all preparations, and another may be tried.

Ventricular fibrillation.

WARNINGS

Digitalis alone or with other drugs has been promoted for use in the treatment of obesity. This use of digoxin or other

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