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`Food and Drug Administration, HHS
`
`Air Act for all products containing or manu(cid:173)
`factured with chloronuorocarbons tCFC's)
`[or name of other class I substance, if appli(cid:173)
`cable]:
`WARNING: Contains [or Manufactured wit h,
`if applicable] [insert name of substance]. a sub(cid:173)
`stance which harms public health and the
`environment by destroying ozone in the
`upper atmosphere.
`A notice similar to the above WARNING
`has been placed in the information for the
`patient [or patient information leanet, if ap(cid:173)
`plicable] of this product under the Environ(cid:173)
`mental Protection Agency's <EPA's) regula(cid:173)
`tions. The patient's warning states that the
`patient should consult his or her physician if
`there are questions about alternatives.
`(c)(l ) For over -the-counter drug prod(cid:173)
`ucts for human use , t he following al(cid:173)
`ternative warning statement may be
`used:
`NOTE: The indented statement below is re(cid:173)
`quired by the Federal government's Clean
`Air Act for all products containing or manu(cid:173)
`factured with chloronuorocarbons (CFC's)
`[or other class I substance, if applicable]:
`WARNTNG: Contains [or Manufactured with.
`if applicable] [insert name of substance], a sub(cid:173)
`stance which harms public health and envi(cid:173)
`ronment by destroying ozone in the upper at(cid:173)
`mosphere.
`CONSULT WITH YOUR PHYSICIAN OR
`HEALTH PROFESSIONAL IF YOU HA VE
`ANY QUESTION ABOUT THE USE OF THIS
`PRODUCT.
`(2) The warning statement shall be
`clearly legible and conspicuous on the
`product, its immediate contain er, its
`outer packaging, or other labeling in
`accordance with the requirements of 40
`CFR part 82 and appear with such
`prominence and conspicuousness as to
`render it likely to be read and under(cid:173)
`stood by consumers under n ormal con(cid:173)
`ditions of purchase.
`(d) This section does not replace or
`relieve a person from any requirements
`imposed under 40 CFR part 82.
`[61 FR 20100. May 3, 1996]
`
`§ 201.323 Aluminum in large and small
`volume parenterals used in total
`paren teral nutrition.
`(a) The aluminum content of large
`volume parenteral (LVP) drug products
`used
`in
`total parenteral nutrition
`(TPN)
`t herapy must not exceed 25
`micrograms per liter (µg/L).
`(b) The package insert of LVP's used
`in TPN therapy must state that t he
`
`§201.323
`
`drug product contains no more than 25
`µg/L of aluminum. This information
`must be contained
`in
`the
`--Pre(cid:173)
`cautions" section o f the labeling of all
`large vol ume parenterals used in T PN
`therapy.
`(c) Except as provided in paragraph
`(d) of this section, the maximum level
`of aluminum present at expiry must be
`stated on the immediate contain er
`label of all small volume parenteral
`(SVP) drug products and pharmacy
`bulk packages (PBPs) used in the prep(cid:173)
`aration of TPN solutions. The alu(cid:173)
`minum content must be stated as fol(cid:173)
`lows: ··contains no more than
`µg/L
`of aluminum." The immediate con(cid:173)
`tainer label of all SVP's and PBP 's
`that are lyophilized powders used in
`the preparation of TP N soluti ons must
`contain
`the
`following
`statement:
`"When reconstitu ted
`in accordance
`with the package insert instructions,
`the concentration of aluminum will be
`no more than
`µg/L." This m ax(cid:173)
`imum level of aluminum must be stat(cid:173)
`ed as the highest of:
`(1) The highest level for the batches
`produced during the l ast 3 years:
`(2) The highest level for the latest
`five batches. or
`(3) The maximum historical level,
`but only until completion of produc(cid:173)
`tion of t he first five batches after July
`26, 2004.
`(d) If the maximum level of alu(cid:173)
`minum is 25 µg/L or less, instead of
`stating the exact amount of aluminum
`as required in paragraph (c) of this sec(cid:173)
`tion, the immediate container label
`may state: "Contains no m ore than 25
`µg/L of aluminum.,. If the SVP or PBP
`is a lyophilized powder, the immediate
`container label may state: '·When r e(cid:173)
`constitute d
`in accordance with the
`package insert instructions, the con(cid:173)
`centration of aluminu m will be no
`more than 25 µg/L ''.
`(e) The package insert for all LVP's,
`all SVP's, and PBP's used in TPN must
`con tain a warning statement. This
`warning must be con tained in the
`"Warnings" section of the labelin g.
`The warning must state:
`WARN!J.'IG: This product contains alu(cid:173)
`minum that may be toxic. Aluminum may
`reach toxic levels wit h prolonged parenteral
`administration if kidney function is
`im(cid:173)
`paired. Premature neonates are particularly
`
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`§201 .325
`
`at risk because their kidneys are immat ure,
`and they require large amounts of calcium
`and phosphate solutions. which contain alu(cid:173)
`minum.
`Research indicates that patients with im(cid:173)
`paired kidney function, including premature
`neonates, who receive parenteral levels of
`aluminum at greater than 4 to 5 µg/kg/day
`accumulate aluminum at levels associated
`with central nervous system and bone tox(cid:173)
`icity. Tissue loading may occur at even
`lower rates of administration.
`(f) Applicants and manufacturers
`must use validated assay methods to
`determine the aluminum content in
`parenteral drug products. The assay
`methods must comply with current
`good manufacturing practice require(cid:173)
`ments. Applicants must submit to the
`Food and Drug Administration valida(cid:173)
`tion of the method used and release
`data for several batches. Manufactur(cid:173)
`ers of parenteral drug products not
`subject to an approved application
`must make assay methodology avail(cid:173)
`able to FDA during inspections. Hold(cid:173)
`ers of pending a pplications must sub(cid:173)
`m it an amendment under §314.60 or
`§314.96 of this chapter.
`[65 FR 4110, Jan. 26, 2000, as amended at 67
`FR 70691, Nov. 26, 2002; 68 FR 32981, June 3,
`2003]
`
`§ 201.325 Over-the-counter drugs for
`vaginal
`contraceptive
`and
`spermicide
`use
`containing
`nonoxynol 9 as the active ingre(cid:173)
`dient; required warnings and label(cid:173)
`ing information.
`(a) Studies indicate that use of vag(cid:173)
`inal contraceptive drug products con(cid:173)
`taining nonoxynol 9 does not protect
`against infection from the human im(cid:173)
`munodeficiency virus (HIV), the virus
`that causes acquired immunodeficiency
`syndrome (AIDS), or against the trans(cid:173)
`mission of other sexually transmitted
`diseases (STDs). Studies also indicate
`that use of vaginal contraceptive drug
`products containing nonoxynol 9 can
`increase vaginal irritation, such as the
`disruption of the vaginal epithelium,
`and also can cause epithelial disruption
`when used in the rectum. These effects
`may increase the risk of transmission
`of the AIDS virus (HIV) from an in(cid:173)
`fected partner. Therefore, con sumers
`should be warned that these products
`do not protect against
`the
`trans(cid:173)
`mission of the AIDS virus (HI V) or
`
`21 CFR Ch. I (4-1-12 Edition)
`
`other STDs, that use of these products
`can increase vaginal and rectal irri ta(cid:173)
`tion, which may increase the risk of
`getting the AIDS virus (HIV) from an
`HIV infected partner, and that the
`products are not for rectal use. Con(cid:173)
`sumers should also be warned that
`these products should not be used by
`persons who have HIV/AIDS or are at
`high risk for HIV/AIDS.
`(b) The labeling of OTC vaginal con(cid:173)
`traceptive and spermicide drug prod(cid:173)
`ucts containing nonoxynol 9 as the ac(cid:173)
`tive ingredient, whether subject to t he
`ongoing OTC drug review or an ap(cid:173)
`proved drug application, must cont ain
`the following warnings under the head(cid:173)
`ing "Warnings," in accordance with 21
`CFR 201.66.
`(1) "[bullet] For vaginal use only
`[bullet] Not for rectal (anal) use" [both
`warnings in bold type].
`(2) "Sexually transmitted diseases
`(STDs) a lert [in bold type]: This prod(cid:173)
`uct does not [word " n ot" in bold type]
`protect against HIV/AIDS or other
`STDs and may increase the risk of get(cid:173)
`ting HIV from an infected partner" .
`(3) "Do not use" [in bold type] if you
`or your sex partner has HIV/AIDS. If
`you do not know if you or your sex
`partner is infected, choose another
`form of birth control'·.
`(4) '·When using this product [in bold
`type) [optional, bullet] you may get
`vaginal irritation (burning, itching, or
`a rash)".
`(5) ··stop use and ask a doctor if [in
`bold type] [optional, bullet] you or
`your partner get burning, itching, a
`rash, or other irritation of the vagina
`or penis" .
`(c) The labeling of this product states
`under the ""Other information" section
`of the Drug Facts labeling in accord(cid:173)
`ance with §201.66(c)(7), ''[bullet] when
`used correctly every t ime you have sex,
`latex condoms greatly reduce, but do
`n ot eliminate, the risk of catching or
`spreading HIV, the virus that causes
`AIDS.
`(d) The labeling of this product in(cid:173)
`cludes the following statements either
`on the outside container or wrapper of
`the retail package, under t he ' ·Other
`information·• section of the Drug Facts
`labeling
`in
`accordance
`with
`§201.66(c)(7), or in a package insert:
`
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