allergic-type reactions in certain susceptible persons, especially asthmatics. The labeling for any prescription drug product to which sulfites have been added as an inactive ingredient, regardless of the amount added, must bear the warning specified in paragraph (b) or (c) of this section.

(b) The labeling required by §§ 201.57 and 201.100(d) for prescription drugs for human use containing a sulfite, except epinephrine for injection when intended for use in allergic or other emergency situations, shall bear the warning statement "Contains (insert the name of the sulfite, e.g., sodium metabisulfite), a sulfite that may cause allergic-type reactions including anaphylactic symptoms and lifethreatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people." This statement shall appear in the "Warnings" section of the labeling.

(c) The labeling required by §§ 201.57 and 201.100(d) for sulfite-containing epinephrine for injection for use in allergic emergency situations shall bear the warning statement "Epinephrine is the preferred treatment for serious allergic or other emergency situations even though this product contains (insert the name of the sulfite, e.g., sodium metabisulfite), a sulfite that may in other products cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite(s) in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations." This statement shall appear in the "Warnings" section of the labeling.

[51 FR 43904, Dec. 5, 1986]

§201.23 Required pediatric studies.

(a) A manufacturer of a marketed drug product, including a biological drug product, that is used in a substantial number of pediatric patients, or that provides a meaningful therapeutic

benefit over existing treatments for pediatric patients, as defined in §§ 314.55(c)(5) and 601.27(c)(5) of this chapter, but whose label does not provide adequate information to support its safe and effective use in pediatric populations for the approved indications may be required to submit an application containing data adequate to assess whether the drug product is safe and effective in pediatric populations. The application may be required to contain adequate evidence to support dosage and administration in some or all pediatric subpopulations, including neonates, infants, children, and adolescents, depending upon the known or appropriate use of the drug product in such subpopulations. The applicant may also be required to develop a pediatric formulation for a drug product that represents a meaningful therapeutic benefit over existing therapies for pediatric populations for whom a pediatric formulation is necessary, unless the manufacturer demonstrates that reasonable attempts to produce a pediatric formulation have failed.

(b) The Food and Drug Administration (FDA) may by order, in the form of a letter, after notifying the manufacturer of its intent to require an assessment of pediatric safety and effectiveness of a pediatric formulation, and after offering an opportunity for a written response and a meeting, which may include an advisory committee meeting, require a manufacturer to submit an application containing the information or request for approval of a pediatric formulation described in paragraph (a) of this section within a time specified in the order, if FDA finds that:

(1) The drug product is used in a substantial number of pediatric patients for the labeled indications and the absence of adequate labeling could pose significant risks to pediatric patients;

or

(2) There is reason to believe that the drug product would represent a meaningful therapeutic benefit over existing treatments for pediatric patients for one or more of the claimed indications, and the absence of adequate labeling could pose significant risks to pediatric patients.

(c)(1) An applicant may request a full waiver of the requirements of paragraph (a) of this section if the applicant certifies that:

(i) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed, or

(ii) There is evidence strongly suggesting that the product would be ineffective or unsafe in all pediatric age groups.

(2) An applicant may request a partial waiver of the requirements of paragraph (a) of this section with respect to a specified pediatric age group, if the applicant certifies that:

(i) The product:

(A) Does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in that age group, and

(B) Is not likely to be used in a substantial number of patients in that age group, and

(C) The absence of adequate labeling could not pose significant risks to pediatric patients; or

(ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group is so small or geographically dispersed, or

(iii) There is evidence strongly suggesting that the product would be ineffective or unsafe in that age group, or

(iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed.

(3) FDA shall grant a full or partial waiver, as appropriate, if the agency finds that there is a reasonable basis on which to conclude that one or more of the grounds for waiver specified in paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is granted on the ground that it is not possible to develop a pediatric formulation, the waiver will cover only those pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that the product would be ineffective or unsafe in pediatric populations, this information will be included in the product's labeling.

(d) If a manufacturer fails to submit a supplemental application containing the information or request for approval

of a pediatric formulation described in paragraph (a) of this section within the time specified by FDA, the drug product may be considered misbranded or an unapproved new drug or unlicensed biologic.

[63 FR 66668, Dec. 2, 1998]

Subpart B-Labeling Requirements for Prescription Drugs and/or Insulin

§201.50 Statement of identity.

(a) The label of prescription and insulin-containing drugs in package form shall bear as one of its principal features a statement of the identity of the drug.

(b) Such statement of identity shall be in terms of the established name of the drug. In the case of a prescriptio drug that is a mixture and that has no established name, the requirement for statement of identity shall be deemed to be satisfied by a listing of the quantitative ingredient information as prescribed by § 201.10.

(c) The statement of identity of a prescription drug shall also comply with the placement, size and prominence requirements of § 201.10.

[40 FR 13998, Mar. 27, 1975, as amended at 63 FR 26698, May 13, 1998]

§201.51 Declaration of net quantity of

contents.

(a) The label of a prescription or insulin-containing drug in package form shall bear a declaration of the net quantity of contents. This shall be expressed in the terms of weight, measure, numerical count, or a combination of numerical count and weight or measure. The statement of quantity of drugs in tablet, capsule, ampule, or other unit dosage form shall be expressed in terms of numerical count; the statement of quantity for drugs in other dosage forms shall be in terms of weight if the drug is solid, semi-solid, or viscous, or in terms of fluid measure if the drug is liquid. When the drug quantity statement is in terms of the numerical count of the drug units, it shall be augmented to give the weight or measure of the drug units or the quantity of each active ingredient in each drug unit or, when quantity does

not accurately reflect drug potency, a statement of the drug potency.

(b) Statements of weight of the contents shall in the case of prescription drugs be expressed in terms of avoirdupois pound, ounce, and grain or of kilogram, gram, and subdivisions thereof. A statement of liquid measure of the contents shall in the case of prescription drugs be expressed in terms of the U.S. gallon of 231 cubic inches and quart, pint, fluid-ounce, and fluid-dram subdivisions thereof, or of the liter and milliliter, or cubic centimeter, and shall express the volume at 68 °F. (20 °C.). A statement of the liquid measure of the contents in the case of insulincontaining drugs shall be expressed in terms of the liter and milliliter, or cubic centimeter, and shall express the volume at 68 °F. (20 °C.).

(c) The declaration shall contain only such fractions as are generally used in expressing the quantity of the drug. A common fraction shall be reduced to its lowest terms; a decimal fraction shall not be carried out to more than three places, except in the case of a statement of the quantity of an active ingredient in a unit of a drug.

(d) The declaration shall appear as a distinct item on the label and, in the case of large volume parenterals, may be embossed on the glass.

(e) The declaration shall accurately reveal the quantity of drug in the package exclusive of wrappers and other material packed therewith.

(f) A statement of the quantity of a prescription or insulin-containing drug in terms of weight or measure applicable to such drug, under the provisions of paragraph (a) of this section, shall express with prominence and conspicuousness the number of the largest whole unit, as specified in paragraph (b) of this section, that are contained in the package. Any remainder shall be expressed in terms of common or decimal fractions of such unit or in terms of the next smaller whole unit and common or decimal fractions thereof.

(g) The declaration of net quantity of contents shall express an accurate statement of the quantity of contents of the package. Reasonable variations caused by loss or gain of moisture during the course of good distribution practice or by unavoidable deviations

in good manufacturing practice will be recognized. Variations from stated quantity of contents shall not be unreasonably large. In the case of a liquid drug in ampules or vials, intended for injection, the declaration shall be considered to express the minimum quantity and the variation above the stated measure shall comply with the excess volume prescribed by the National Formulary or the U.S. Pharmacopeia for filling of ampules. In the case of a solid drug in ampules or vials, the declaration shall be considered to express the accurate net weight. Variations shall comply with the limitations provided in the U.S. Pharmacopeia or the National Formulary.

(h) A drug shall be exempt from compliance with the net quantity declaration required by this section if it is an ointment labeled "sample", "physician's sample", or a substantially similar statement and the contents of the package do not exceed 8 grams.

$201.55 Statement of dosage.

Section 201.100(b)(2) requires that labels for prescription drugs bear a statement of the recommended or usual dosage. Since the dosage for some prescription drugs varies within extremely wide limits, depending upon the conditions being treated, it may not be possible in all cases to present an informative or useful statement of the recommended or usual dosage in the space available on the label or carton of the package. It is the view of the Food and Drug Administration that when such a situation prevails, compliance with this requirement would be met by a statement such as "See package insert for dosage information”, where the detailed information is contained in such insert. However, if an informative, realistic, recommended or usual dosage can readily be set forth on the label, it should appear thereon.

$201.56 General requirements on content and format of labeling for human prescription drugs.

Prescription drug labeling described in §201.100(d) shall contain the information in the format required by §201.57 and shall meet the following general requirements:

(a) The labeling shall contain a summary of the essential scientific information needed for the safe and effective use of the drug.

(b) The labeling shall be informative and accurate and neither promotional in tone nor false or misleading in any particular.

on

(c) The labeling shall be based whenever possible on data derived from human experience. No implied claims or suggestions of drug use may be made if there is inadequate evidence of safety or a lack of substantial evidence of effectiveness. Conclusions based animal data but necessary for safe and effective use of the drug in humans shall be identified as such and included with human data in the appropriate section of the labeling, headings for which are listed in paragraph (d) of this section.

(d)(1) The labeling shall contain specific information required under §201.57 under the following section headings and in the following order:

Description.

Clinical Pharmacology.

Indications and Usage.

Contraindications.

Warnings.

Precautions.

Adverse Reactions.

Drug Abuse and Dependence.

Overdosage.

Dosage and Administration.
How Supplied.

(2) The labeling may contain the following additional section headings if appropriate and if in compliance with §201.57 (1) and (m):

Animal Pharmacology and/or Animal Toxicology.

Clinical Studies. References.

(3) The labeling may omit any section or subsection of the labeling format if clearly inapplicable.

only

a

(4) The labeling may contain "Product Title" section preceding the "Description" section and containing the information required by §201.57(a)(1)(i), (ii), (iii), and (iv) and §201.100(e). The information required by §201.57(a)(1)(i), (ii), (iii), and (iv) shall appear in the "Description" section of the labeling, whether or not it also appears in a "Product Title."

(e) The labeling shall contain the date of the most recent revision of the labeling, identified as such, placed prominently immediately after the last section of the labeling.

[44 FR 37462, June 26, 1979]

$201.57 Specific requirements on content and format of labeling for human prescription drugs.

Each section heading listed in § 201.56(d), if not omitted under §201.56(d)(3), shall contain the following information in the following order:

(a) Description. (1) Under this section heading, the labeling shall contain:

(i) The proprietary name and the established name, if any, as defined in section 502(e)(2) of the act, of the drug; (ii) The type of dosage form and the route of administration to which the labeling applies;

(2) If appropriate, other important chemical or physical information, such as physical constants, or pH, shall be stated.

(b) Clinical Pharmacology. (1) Under this section heading, the labeling shall contain a concise factual summary of the clinical pharmacology and actions of the drug in humans. The summary may include information based on in vitro and/or animal data if the information is essential to a description of the biochemical and/or physiological mode of action of the drug or is otherwise pertinent to human therapeutics. Pharmacokinetic information that is important to safe and effective use of the drug is required, if known, e.g., degree and rate of absorption, pathways of biotransformation, percentage of

dose as unchanged drug and metabolites, rate or half-time of elimination, concentration in body fluids associated with therapeutic and/or toxic effects, degree of binding to plasma proteins, degree of uptake by a particular organ or in the fetus, and passage across the blood brain barrier. Inclusion of pharmacokinetic information is restricted to that which relates to clinical use of the drug. If the pharmacological mode of action of the drug is unknown or if important metabolic or pharmacokinetic data in humans are unavailable, the labeling shall contain a statement about the lack of information.

(2) Data that demonstrate activity or effectiveness in in vitro or animal tests and that have not been shown by adequate and well-controlled clinical studies to be pertinent to clinical use may be included under this section of the labeling only under the following circumstances:

(i) In vitro data for anti-infective drugs may be included if the data are immediately preceded by the statement "The following in vitro data are available but their clinical significance is unknown.”

(ii) For other classes of drugs, in vitro and animal data that have not been shown by adequate and well-controlled clinical studies, as defined in §314.126(b) of this chapter, to be pertinent to clinical use may be used only if a waiver is granted under $201.58 or § 314.126(b) of this chapter.

(c) Indications and Usage. (1) Under this section heading, the labeling shall state that:

(i) The drug is indicated in the treatment, prevention, or diagnosis of a recognized disease or condition, e.g., penicillin is indicated for the treatment of pneumonia due to susceptible pneumococci; and/or

(ii) The drug is indicated for the treatment, prevention, or diagnosis of an important manifestation of a disease or condition, e.g., chlorothiazide is indicated for the treatment of edema in patients with congestive heart failure; and/or

(iii) The drug is indicated for the relief of symptoms associated with a dissyndrome, e.g., chlorpheniramine is indicated for the symptomatic relief of nasal congestion

ease

or

in patients with vasomotor rhinitis; and/or

(iv) The drug, if used for a particular indication only in conjuction with a primary mode of therapy, e.g., diet, surgery, or some other drug, is an adjunct to the mode of therapy.

(2) All indications shall be supported by substantial evidence of effectiveness based on adequate and well-controlled studies as defined in §314.126(b) of this chapter unless the requirement is waived under §201.58 or §314.126(b) of this chapter.

(3) This section of the labeling shall also contain the following additional information:

(i) If evidence is available to support the safety and effectiveness of the drug only in selected subgroups of the larger population with a disease, syndrome, or symptom under consideration, e.g., patients with mild disease or patients in a special age group, the labeling shall describe the available evidence and state the limitations of usefulness of the drug. The labeling shall also identify specific tests needed for selection or monitoring of the patients who need the drug, e.g., microbe susceptibility tests. Information on the approximate kind, degree, and duration of improvement to be anticipated shall be stated if available and shall be based on substantial evidence derived from adequate and well-controlled studies as defined in §314.126(b) of this chapter unless the requirement is waived under $201.58 or §314.126(b) of this chapter. If the information is relevant to the recommended intervals between doses, the usual duration of treatment, or any modification of dosage, it shall be stated in the "Dosage and Administration” section of the labeling and referenced in this section.

(ii) If safety considerations are such that the drug should be reserved for certain situations, e.g., cases refractory to other drugs, this information shall be stated in this section.

(iii) If there are specific conditions that should be met before the drug is used on a long-term basis, e.g., demonstration of responsiveness to the drug in a short-term trial, the labeling shall identify the conditions; or, if the indications for long-term use are different from those for short-term use,