Labeling for Combined Hormonal Contraceptives Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Labeling for
Combined Hormonal
Contraceptives
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact Jennifer Dao at 301-796-8189.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2017
Labeling
15419dft.doc
12/14/17

Labeling for
Combined Hormonal
Contraceptives
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2017
Labeling

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	LABELING RECOMMENDATIONS............................................................................ 2

Contains Nonbinding Recommendations
Draft — Not for Implementation
1 	Labeling for Combined Hormonal Contraceptives
2 	Guidance for Industry1
3
4
5
6
7 	This draft guidance, when finalized, will represent the current thinking of the Food and Drug
8 	Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
9 	binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
10 	applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
11 	for this guidance as listed on the title page.
12
13
14
15
16 	I. 	INTRODUCTION
17
18 	This guidance provides recommendations on information that should be included in the
19 	prescribing information for combined hormonal contraceptives (CHCs) that contain estrogen and
20 	progestin. CHCs include combined oral contraceptives (COCs), as well as non-oral products
21 	such as transdermal systems and vaginal rings. Many of the labeling recommendations in this
22 	guidance represent class labeling that should be included in all CHC prescribing information.
23 	General advice is provided [within brackets in bold font] where modifications of the prescribing
24 	information for specific products are needed.
25
26 	This guidance follows the content and format requirements of the final rule “Requirements on
27 	Content and Format of Labeling for Human Prescription Drug and Biological Products,” issued
28 	in 2006, that amended human prescription and biological product labeling (commonly referred to
29 	as the physician labeling rule (PLR)),2,3 as well as the final rule “Content and Format of Labeling
30 	for Human Prescription Drug and Biological Products; Requirements for Pregnancy and
1
1 This guidance has been prepared by the Division of Bone, Reproductive, and Urologic Products in the Center for
Drug Evaluation and Research at the Food and Drug Administration.
2 21 CFR 201.56 and 201.57; final rule “Requirements on Content and Format of Labeling for Human Prescription
Drug and Biological Products” (71 FR 3922, January 24, 2006);
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm
3 See the guidance for industry Labeling for Human Prescription Drug and Biological Products — Implementing the
PLR Content and Format Requirements. We update guidances periodically. To make sure you have the most recent
version of a guidance, check the FDA Drugs guidance web page at
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

Contains Nonbinding Recommendations
Draft — Not for Implementation
31 	Lactation Labeling” (commonly referred to as the pregnancy and lactation labeling rule (PLLR))
32 	that was issued in 2014, which amended the 2006 PLR regulations.4,5
33
34 	This guidance does not address the content of patient labeling, which is required for COCs under
35 	21 CFR 310.501. Applicants are advised to consider 21 CFR 310.501 and recently approved
36 	patient labeling for other contraceptive products when developing patient labeling for their
37 	products.
38
39 	In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
40 	Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
41 	as recommendations, unless specific regulatory or statutory requirements are cited. The use of
42 	the word should in Agency guidances means that something is suggested or recommended, but
43 	not required.
44
45
46 	II. 	BACKGROUND
47
48 	The content and format requirements of the PLR and the PLLR (21 CFR 201.56 and 201.57)
49 	required revisions to CHC labeling under certain circumstances. In addition, the labeling for
50 	recently approved CHCs is consistent with the labeling requirements set forth in the PLR and the
51 	PLLR. This newer CHC labeling may be different from the labeling for some older CHC
52 	products. The updates to this guidance set forth labeling recommendations that represent newer
53 	class labeling that should be included in all CHC prescribing information consistent with the
54 	labeling requirements set forth in the PLR and PLLR (21 CFR 201.56 and 201.57). We note that
55 	the specific advice provided in this guidance is not intended to cover every aspect of the PLR
56 	and PLLR requirements for CHC labeling. Accordingly, we refer the reader to 21 CFR 201.56
57 	and 201.57, which set forth the PLR and PLLR content and format labeling requirements. We
58 	also refer the reader to the PLR Requirements for Prescribing Information web page, which lists
59 	additional guidances that address specific requirements under PLR and PLLR. 6
60
61
62 	III. 	LABELING RECOMMENDATIONS
63
64 	This section provides FDA recommendations for CHC labeling other than patient labeling.
65 	Because all CHCs contain an estrogen and a progestin, FDA believes that class labeling based on
66 	information known about estrogens/progestins generally is appropriate for many sections of
67 	CHC labeling. This section provides the recommended class labeling statements. However,
4 21 CFR 201.56 and 201.57(c)(9); final rule “Content and Format of Labeling for Human Prescription Drug and
Biological Products; Requirements for Pregnancy and Lactation Labeling” (79 FR 72064, December 4, 2014);
https://federalregister.gov/a/2014-28241
5 See the draft guidance for industry Pregnancy, Lactation, and Reproductive Potential: Labeling for Human
Prescription Drug and Biological Products — Content and Format. When final, this guidance will represent the
FDA’s current thinking on this topic.
6 https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm
2

Contains Nonbinding Recommendations
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68 	there are sections in labeling that should contain product-specific information (e.g., data on the
69 	efficacy outcome or bleeding profile demonstrated in clinical trials of the specific product, or
70 	results of a drug-drug interaction study conducted with a particular CHC product). These
71 	labeling sections are identified in this section, and general guidance is provided as to the type of
72 	information that should be included.
73
74 	For the Highlights of Prescribing Information, recommendations for product-specific text are
75 	listed in the appropriate footnotes directly below the labeling example. Where labeling sections
76 	are listed without any recommended language, the reader is encouraged to review approved CHC
77 	labeling in the PLR format for guidance.
78 HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
[DRUG NAME] safely and effectively. See full prescribing
information for [DRUG NAME].
[NAME (established name of progestin component, followed by
established name of estrogen component)] tablets, for oral use[1]
Initial U.S. Approval: [YEAR][2]
WARNING: CIGARETTE SMOKING AND SERIOUS
CARDIOVASCULAR EVENTS
See full prescribing information for complete boxed warning.
 [NAME] is contraindicated in women over 35 years old who
smoke. (4)
 Cigarette smoking increases the risk of serious cardiovascular
events from combination hormonal contraceptive (CHC) use.
(5.1)[3]
----------------------RECENT MAJOR CHANGES[4]---------------------
----------------------INDICATIONS AND USAGE------------------------
[NAME] is a progestin/estrogen [text][5] indicated for use by females
of reproductive potential to prevent pregnancy. (1)[6],[7]
----------------------DOSAGE AND ADMINISTRATION--------------
 One tablet by mouth at the same time every day in the order
directed on the blister pack.[8] (2.1)[9]
-----------------------DOSAGE FORMS AND STRENGTHS------------
-----------------------CONTRAINDICATIONS-----------------------------
 High risk of arterial or venous thrombotic diseases (4)
 Breast cancer or other estrogen- or progestin-sensitive cancer (4)
 Liver tumors, acute viral hepatitis or decompensated cirrhosis (4)
 Undiagnosed abnormal uterine bleeding (4)
 Pregnancy (4, 8.1)
 Hypersensitivity reactions to components of [NAME][10] (4)
79 	[1] Should be modified as appropriate for non-oral formulations.
------------------------WARNINGS AND PRECAUTIONS---------------
 Vascular risks: Stop if a thrombotic or thromboembolic event
occurs. Stop at least 4 weeks before and through 2 weeks after
major surgery. Start no earlier than 4 weeks after delivery, in
females who are not breast-feeding. Consider cardiovascular risk
factors before initiating in all females, particularly those over 35
years. (5.1, 5.4)
 Liver disease: Discontinue if jaundice occurs. (5.2)
 Hypertension. If used in females with well-controlled hypertension,
monitor blood pressure and stop use if blood pressure rises
significantly. (5.3)
 Gallbladder disease: May cause or worsen gallbladder disease.
(5.5)
 Adverse carbohydrate and lipid effect: Monitor glucose in
prediabetic and diabetic females using [NAME]. Consider an
alternate contraceptive method for females with uncontrolled
dyslipidemia. (5.6)
 Headache. Evaluate significant change in headaches and
discontinue if indicated. (5.7)
 Uterine bleeding: May cause irregular bleeding or amenorrhea.
Evaluate for other causes if symptoms persist. (5.8)
----------------------ADVERSE REACTIONS------------------------------
Most common adverse reactions reported in clinical trials (≥ x%)[11]
are: [text].[12] (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
(MANUFACTURER) at [text][13] or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-----------------------DRUG INTERACTIONS------------------------------
Enzyme inducers (e.g., CYP3A4): May decrease the effectiveness of
[NAME] or increase breakthrough bleeding. Counsel patients to use a
back-up or alternative method of contraception when enzyme inducers
are used with [NAME]. (7.1)
-----------------------USE IN SPECIFIC POPULATIONS---------------
 Pregnancy: Discontinue if pregnancy occurs. (8.1)
 Lactation: Advise use of another method; [NAME] can decrease
milk production. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: [month/year]
80 	[2] The year of the first approval of the combination of hormones should be inserted.
81 	[3] For oral hormonal contraceptives, it is acceptable to use the term combination oral contraceptives (COCs) in place of CHCs.
82 	[4] If applicable
83 	[5] COC or CHC
84 	[6] If other indications are approved, they should be provided in bullet form in the same order as in the Full Prescribing Information.
85 	Recommended language for specific secondary indications is provided as follows:
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Contains Nonbinding Recommendations
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86 	[Acne: Treat moderate acne in females who choose to use a combined hormonal contraceptive for contraception. (1.x)
87 	Folate supplementation: Raise folate levels in females who choose to use a combined hormonal contraceptive for contraception. (1.x)
88 	Premenstrual Dysphoric Disorder (PMDD): Treat symptoms of PMDD for females who choose to use a combined hormonal
89 	contraceptive for contraception. (1.x)]
90 	In the case of multiple indications, the format should be:
91 	“[NAME] is a progestin/estrogen [text][5] indicated for use by females of reproductive potential to:”
92 	 	[then list each indication as a separate bullet, beginning with “prevent pregnancy”]
93 	[7] If there were entry criteria in the clinical trials that excluded females above a certain weight or body mass index (BMI), the following language
94 	should be added:
95 	[Limitation of Use: The efficacy in females with a [weight/BMI above x] has not been evaluated.]
96 	[8] This should be revised as needed if a different dispenser is used.
97 	[9] For COCs, a bulleted format should be used to summarize if different pills are taken at different times during the cycle. It should be noted if
98 	the product must be taken with water or with respect to meals. This section should be modified as appropriate for non-oral formulations. Day 1
99 	or Sunday start should be described as appropriate for clarity.
100 	[10] Only if evidence of hypersensitivity reactions exists, not if hypothetical concern.
101 	[11] The rate used as the cutoff for reporting should be specified.
102 	[12] All at or above the frequency cutoff should be specified, with terms likely to represent the same phenomenon grouped, and listed in
103 	descending order of frequency. Frequency for individual terms should not be provided. If approved for multiple indications, applicants should
104 	discuss with FDA whether to provide separate lists or to pool the adverse reaction data.
105 	[13] The manufacturer’s phone number should be inserted.
106 FULL PRESCRIBING INFORMATION: CONTENTS* 	8 	USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
WARNING: CIGARETTE SMOKING AND SERIOUS 	8.2 Lactation
CARDIOVASCULAR EVENTS 	8.3 Females and Males of Reproductive Potential
1 	INDICATIONS AND USAGE 	8.4 Pediatric Use
2 	DOSAGE AND ADMINISTRATION 	8.5 Geriatric Use
2.1 How to Start and Take [NAME] 	8.6 Hepatic Impairment
2.2 Dosing [NAME] 	8.7 Renal Impairment
2.3 	Missed Doses 	8.8 Race/Ethnicity
2.4 Advice in Case of Gastrointestinal Disturbances 	8.9 Body Mass Index (BMI)/Body Weight
3 	DOSAGE FORMS AND STRENGTHS 	10 OVERDOSAGE
4 	CONTRAINDICATIONS 	11 DESCRIPTION
5 	WARNINGS AND PRECAUTIONS 	12 CLINICAL PHARMACOLOGY
5.1 Thromboembolic Disorders and Other Vascular Conditions 	12.1 	Mechanism of Action
5.2 	Liver Disease 	12.2 	Pharmacodynamics
5.3 Hypertension 	12.3 	Pharmacokinetics
5.4 Age-related Considerations 	13 NONCLINICAL TOXICOLOGY
5.5 Gallbladder Disease 	13.1 	Carcinogenesis, Mutagenesis, Impairment of Fertility
5.6 Adverse Carbohydrate and Lipid Metabolic Effects 	13.2 	Animal Toxicology and/or Pharmacology
5.7 Headache 	14 CLINICAL STUDIES
5.8 	Bleeding Irregularities and Amenorrhea 	15 REFERENCES
5.9 Depression 	16 HOW SUPPLIED/STORAGE AND HANDLING
5.10 Cervical Cancer 	17 PATIENT COUNSELING INFORMATION
5.11 Effect on Binding Globulins
5.12 Hereditary Angioedema 	*Sections or subsections omitted from the full prescribing information
5.13 Chloasma 	are not listed.
6 	ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 	DRUG INTERACTIONS
7.1 Effects of Other Drugs on Combined Hormonal
Contraceptives
7.2 Effects of Combined Hormonal Contraceptives on Other
Drugs
7.3 Effect on Laboratory Tests
4
107

Contains Nonbinding Recommendations
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108 	WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS
109
110 	Cigarette smoking increases the risk of serious cardiovascular events from combined
111 	hormonal contraceptive (CHC) use. This risk increases with age, particularly in women
112 	over 35 years of age, and with the number of cigarettes smoked. For this reason, CHCs,
113 	including [NAME], are contraindicated in women who are over 35 years of age and smoke.
114 	[See Contraindications (4) and Warnings and Precautions (5.1).]
115
116
117 	1 INDICATIONS AND USAGE
118 	[NAME] is indicated for use by females of reproductive potential to prevent pregnancy.
119
120 	[Any important limitations of use should be added under the header “Limitations of Use:”. If
121 	there were entry criteria in the clinical trials that excluded females above a certain weight or
122 	BMI, the following language should be added: “Limitation of Use: The efficacy in females with
123 	a [weight/BMI above x] has not been evaluated.”]
124
125 	[If the product has multiple indications, the section should be formatted using subsections (e.g.,
126 	1.1, 1.2). Recommended language for specific secondary indications is provided below;
127 	however, the proposed language can be discussed with the division if refinement is needed
128 	based on the specific clinical trials conducted in support of the secondary indication:
129
130 	Acne: [NAME] is indicated for the treatment of moderate acne vulgaris in females who choose to use
131 	a combined hormonal contraceptive as their method of contraception.
132
133 	Premenstrual Dysphoric Disorder (PMDD): [NAME] is indicated for the treatment of symptoms of
134 	PMDD in females who choose to use a combined hormonal contraceptive as their method of
135 	contraception. The effectiveness of [NAME] when used for more than [the duration of clinical
136 	trial(s) for this indication should be inserted] has not been evaluated. Limitation of use: [NAME]
137 	is not indicated for treatment of premenstrual syndrome (PMS).]
138
139 	2 DOSAGE AND ADMINISTRATION
140
141 	2.1 How to Start and Take [NAME]
142 	[Should be modified as warranted for non-oral formulations.]
143
144 	[Information on Day 1 and/or Sunday start should be included, according to the method used in
145 	the registration trials. A template for providing this information with respect to COCs in
146 	tabular form is provided in Table 1. The table should be modified as necessary to reflect dosing
147 	instructions in the registration trials (e.g., if dosing with respect to meals or fed/fasted was
148 	required). Additional text may be needed to describe different dosing regimens, such as a
149 	multiphasic dosing regimen. Guidance on how to initiate use after pregnancy or childbirth
150 	should be provided (addressing use in lactating females); the general recommendation is not to
151 	start CHCs until 4 weeks postpartum. Guidance should also be provided about switching from
152 	a different method, including a different COC, a transdermal system, vaginal ring, or a
153 	progestin-only method; instructions provided in Table 1 should be modified if warranted for
154 	the specific product.]
155
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156 	Table 1. Instructions for Administration
Starting [NAME] in females with no current
use of hormonal contraception
[Instructions for Day 1 start or Sunday start
based on the method(s) used in the registration
clinical trial(s) should be included.]
Day 1 start
 	Take first tablet without regard to
meals on the first day of menses
 	Take subsequent tablets once daily at
the same time each day
 	Begin each subsequent pack on the
same day of the week as the first cycle
pack (i.e., on the day after taking the
last tablet)
Sunday start
 	Take first tablet without regard to
meals on the first Sunday after the
onset of menstrual period
 	Take subsequent tablets once daily at
the same time each day
 	Use additional nonhormonal
contraception for the first seven days
of product use
 	Begin each subsequent pack on the
same day of the week as the first cycle
pack (i.e., on the day after taking the
last tablet)
Switching from another contraceptive
method
 	A COC
 	Transdermal patch
 	Vaginal ring
 	Injection
 	Intrauterine contraceptive
 	Implant
Start [NAME]:
 	On the day when the new pack of the
previous COC would have been started
 	On the day when next application
would have been scheduled
 	On the day when next insertion would
have been scheduled
 	On the day when next injection would
have been scheduled
 	On the day of removal
 	On the day of removal
157
158 	2.2 Dosing [NAME]
159 	[Should be modified as warranted for non-oral formulations.]
160 	Instruct patients to take one tablet by mouth at the same time every day. To achieve maximum
161 	contraceptive effectiveness, patients must take [NAME] as directed, in the order directed on the
162 	blister pack [should be revised as needed if a different dispenser is used]. The failure rate may
163 	increase when pills are missed or taken incorrectly. [Should be revised as appropriate for non-oral
164 	CHCs.]
165
166 	[If relevant, it should be noted if the product must be taken with water or with respect to
167 	meals.]
168
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169 	2.3 Missed Doses
170 	[Should be modified as warranted for non-oral formulations.]
171 	Instruct patients about the handling of missed doses (e.g., to take single missed pills as soon as
172 	possible) and to follow the dosing instructions provided in the FDA-approved patient labeling.
173
174 	[Specific instructions should be provided about handling of missed doses and the need for back-
175 	up contraception. A tabular display such as that shown in Table 2 can be helpful, but the
176 	specific recommendations should be based on instructions used in the clinical trial(s).]
177
178 	Table 2. Instructions for Missed [NAME] Tablets
 	If one active tablet is missed in Weeks 1, 2,
or 3
Take the tablet as soon as possible. Continue
taking one tablet a day until the pack is
finished.
 	If two active tablets are missed in Week 1
or Week 2
Take the two missed tablets as soon as possible
and the next two active tablets the next day.
Continue taking one tablet a day until the pack
is finished. Additional nonhormonal
contraception (such as condoms and
spermicide) should be used as back-up if the
patient has sex within 7 days after missing
tablets.
 	If two active tablets are missed in the third 	Day 1 start: Throw out the rest of the pack and
week or three or more active tablets are 	start a new pack that same day.
missed in a row in Weeks 1, 2, or 3 	Sunday start: Continue taking one tablet a day
until Sunday, then throw out the rest of the
pack and start a new pack that same day.
Additional nonhormonal contraception
(such as condoms and spermicide) should be
used as back-up if the patient has sex within
7 days after missing tablets.
179
180 	2.4 Advice in Case of Gastrointestinal Disturbances
181 	[This section is for COCs only.]
182 	[In general, guidance provided here should reflect instructions given to subjects in the clinical
183 	trial(s).]
184 	If vomiting occurs within [X] hours after taking [NAME] [this can be individualized if the
185 	product’s pharmacokinetic profile indicates faster or slower absorption], the patient should
186 	proceed as if she missed a tablet. In case of prolonged vomiting or diarrhea, [if no trial
187 	instructions were provided in the case of prolonged vomiting or diarrhea (greater than 48 hours),
188 	applicants should consider referring the reader to the CDC Selected Practice Recommendations
189 	web page (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6205a1.htm#Fig5)].
190
191 	3 DOSAGE FORMS AND STRENGTHS
192 	[The dosage of the progestin component should be described in milligrams and the estrogen
193 	component described in micrograms.]
194
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195 	4 CONTRAINDICATIONS
196 	[NAME] is contraindicated in females who are known to have the following conditions:
197 	 	A high risk of arterial or venous thrombotic diseases. Examples include females who are
198 	known to:
199 	‒ 	Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]
200 	‒ 	Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings
201 	and Precautions (5.1)]
202 	‒ 	Have cerebrovascular disease [see Warnings and Precautions (5.1)]
203 	‒ 	Have coronary artery disease [see Warnings and Precautions (5.1)]
204 	‒ 	Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example,
205 	subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings
206 	and Precautions (5.1)]
207 	‒ 	Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]
208 	‒ 	Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and
209 	Precautions (5.3)]
210 	‒ 	Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or
211 	vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration
212 	[see Warnings and Precautions (5.6)]
213 	‒ 	Have headaches with focal neurological symptoms, migraine headaches with aura, or
214 	over age 35 with any migraine headaches [see Warnings and Precautions (5.8)]
215 	 	Current or history of breast cancer or other estrogen- or progestin-sensitive cancer
216 	 	Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and
217 	Precautions (5.2)]
218 	 	Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9)]
219 	 	Pregnancy, because there is no reason to use CHCs during pregnancy [see Use in Specific
220 	Populations (8.1)]
221 	 	Hypersensitivity to any components of [NAME]. [Only if evidence of hypersensitivity
222 	reactions exists, not if hypothetical concern; if this bullet is used, a statement should be added:
223 	“Observed reactions include…”]
224
225 	5 WARNINGS AND PRECAUTIONS
226
227 	5.1 Thromboembolic Disorders and Other Vascular Conditions
228 	 	Stop [NAME] if an arterial or venous thrombotic/thromboembolic event occurs.
229
230 	 	Stop [NAME] if there is unexplained loss of vision, proptosis, diplopia, papilledema, or
231 	retinal vascular lesions and evaluate for retinal vein thrombosis immediately.
232
233 	 	Discontinue [NAME] during prolonged immobilization. If feasible, stop [NAME] at least
234 	four weeks before and through two weeks after major surgery, or other surgeries known to
235 	have an elevated risk of thromboembolism.
236
237 	 	Start [NAME] no earlier than four weeks after delivery in females who are not breast-
238 	feeding. The risk of postpartum thromboembolism decreases after the third postpartum
239 	week, whereas the likelihood of ovulation increases after the third postpartum week.
240
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241 	 	Before starting [NAME] evaluate any past medical history or family history of thrombotic or
242 	thromboembolic disorders and consider whether the history suggests an inherited or acquired
243 	hypercoagulopathy. [NAME] is contraindicated in females with a high risk of arterial or
244 	venous thrombotic/thromboembolic diseases [see Contraindications (4)].
245
246 	Arterial Events
247 	CHCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial
248 	infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and
249 	females with hypertension, dyslipidemia, diabetes, or obesity.
250
251 	[NAME] is contraindicated in women over 35 years of age who smoke [see Contraindications
252 	(4)]. Cigarette smoking increases the risk of serious cardiovascular events from CHC use. This
253 	risk increases with age, particularly in women over 35 years of age, and with the number of
254 	cigarettes smoked.
255
256 	Venous Events
257 	Use of CHCs increases the risk of venous thromboembolic events (VTEs), such as deep vein
258 	thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family
259 	history of VTE, in addition to other factors that contraindicate use of CHCs [see Contraindications
260 	(4)]. While the increased risk of VTE associated with use of CHCs is well-established, the rates of
261 	VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1).
262 	The rate of VTE in females using COCs [or CHCs] has been estimated to be [the appropriate risk
263 	estimate should be used depending on whether the product is a COC or a non-oral CHC; either 3 to 9
264 	cases per 10,000 woman-years for COCs or 3 to 12 cases per 10,000 women-years for non-oral
265 	CHCs].
266
267 	The risk of VTE is highest during the first year of use of a COC and when restarting hormonal
268 	contraception after a break of four weeks or longer. Based on results from a few studies, there is
269 	some evidence that this is true for non-oral products as well. The risk of thromboembolic
270 	disease due to CHCs gradually disappears after CHC use is discontinued.
271
272 	[The figure and text statement of risks of users should be modified as indicated for non-oral
273 	products. The rate range for CHCs (non-oral products) is 3 to 12; COC should be revised to
274 	CHC.]
275
276 	Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use
277 	oral [or hormonal] contraceptives, for females who use oral [or hormonal] contraceptives, for
278 	pregnant females, and for females in the postpartum period. To put the risk of developing a VTE
279 	into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are
280 	followed for one year, between 1 and 5 of these females will develop a VTE.
281
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282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
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Figure 1: 	Likelihood of Developing a VTE
[For extended cycle COCs, a statement should be provided if the annual hormonal exposure is
greater than that with conventional monthly COCs that contain the same strength estrogen and
progestin.]
Epidemiologic Studies Pertaining to [NAME]
[If epidemiologic studies have evaluated [NAME] or progestin class, applicants should discuss with
FDA whether and how the data should be presented in labeling.]
5.2 Liver Disease
Elevated Liver Enzymes
[NAME] is contraindicated in females with acute viral hepatitis or severe (decompensated)
cirrhosis of liver [see Contraindications (4)]. Discontinue [NAME] if jaundice develops. Acute
liver test abnormalities may necessitate the discontinuation of CHC use until the liver tests return
to normal and CHC causation has been excluded.
Liver Tumors
[NAME] is contraindicated in females with benign or malignant liver tumors [see
Contraindications (4)]. CHCs increase the risk of hepatic adenomas. An estimate of the
attributable risk is 3.3 cases/100,000 CHC users. Rupture of hepatic adenomas may cause death
from abdominal hemorrhage.
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8
years) CHC users. The attributable risk of liver cancers in CHC users is less than one case per
million users.
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309
310 	5.3 Hypertension
311 	[NAME] is contraindicated in females with uncontrolled hypertension or hypertension with vascular
312 	disease [see Contraindications (4)]. For all females, including those with well-controlled
313 	hypertension, monitor blood pressure at routine visits and stop [NAME] if blood pressure rises
314 	significantly.
315
316 	An increase in blood pressure has been reported in females using CHCs, and this increase is more
317 	likely in older women with extended duration of use. The effect of CHCs on blood pressure may
318 	vary according to the progestin in the CHC.
319
320 	5.4 Age-related Considerations
321 	The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease
322 	increase with age. Certain conditions, such as smoking and migraine headache without aura, that
323 	do not contraindicate CHC use in younger females, are contraindications to use in women over
324 	35 years of age [see Contraindications (4) and Warnings and Precautions (5.1)]. Consider the
325 	presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE,
326 	particularly before initiating a CHC for women over 35 years, such as:
327
328 	 	Hypertension
329 	 	Diabetes
330 	 	Dyslipidemia
331 	 	Obesity
332
333 	5.5 Gallbladder Disease
334 	Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of
335 	CHCs may also worsen existing gallbladder disease.
336
337 	A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use.
338 	Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC-
339 	related cholestasis.
340
341 	5.6 Adverse Carbohydrate and Lipid Metabolic Effects
342 	Hyperglycemia
343 	[NAME] is contraindicated in diabetic women over age 35, or females who have diabetes with
344 	hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with
345 	diabetes of > 20 years duration [see Contraindications (4)]. [NAME] may decrease glucose
346 	tolerance. Carefully monitor prediabetic and diabetic females who are using [NAME]. [Applicants
347 	should summarize here if product-specific information on the effect on carbohydrate metabolism is
348 	available.]
349
350 	Dyslipidemia
351 	Consider alternative contraception for females with uncontrolled dyslipidemia. [NAME] may cause
352 	adverse lipid changes. [Applicants should summarize here if product-specific information on the
353 	effect on lipids is available.]
354
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355 	Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum
356 	triglyceride concentrations when using [NAME], which may increase the risk of pancreatitis.
357
358 	5.7 Headache
359 	[NAME] is contraindicated in females who have headaches with focal neurological symptoms or
360 	have migraine headaches with aura, and in women over age 35 years who have migraine
361 	headaches with or without aura [see Contraindications (4)].
362
363 	If a woman using [NAME] develops new headaches that are recurrent, persistent, or severe,
364 	evaluate the cause and discontinue [NAME] if indicated. Consider discontinuation of [NAME] if
365 	there is an increased frequency or severity of migraines during CHC use (which may be prodromal
366 	of a cerebrovascular event).
367
368 	5.8 Bleeding Irregularities and Amenorrhea
369 	Unscheduled Bleeding and Spotting
370 	Females using [NAME] may experience unscheduled (breakthrough or intracyclic) bleeding and
371 	spotting, especially during the first three months of use. Bleeding irregularities may resolve over
372 	time or by changing to a different contraceptive product. If bleeding persists or occurs after
373 	previously regular cycles, evaluate for causes such as pregnancy or malignancy.
374
375 	[The following sections should summarize data from product-specific clinical trials that describe
376 	the occurrence of unscheduled (breakthrough) bleeding, frequency of amenorrhea, and absence of
377 	scheduled (withdrawal) bleeding. The frequency of discontinuation due to bleeding complaints
378 	should be provided. Suggested language is provided below.]
379
380 	Based on subject diaries from [number] clinical trial(s) of [NAME], [range of frequency, in percent
381 	of subjects, should be given] of females experienced unscheduled bleeding per 28-day cycle [should
382 	be modified as appropriate for extended cycle products]. A total of [number out of total sample size]
383 	subjects [percent] discontinued due to menstrual disorders including [Preferred Terms should be
384 	specified].
385
386 	Amenorrhea and Oligomenorrhea
387 	Females who use [NAME] may experience absence of scheduled (withdrawal) bleeding, even if
388 	they are not pregnant. Based on subject diaries from clinical trials of [NAME] for up to [number]
389 	cycles, [percent] of females experienced cycles with no scheduled bleeding.
390
391 	If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not
392 	adhered to the prescribed dosing schedule (missed one or two active tablets or started taking them
393 	on a day later than she should have [should be modified as needed for multiphasic regimens or non-
394 	oral formulations]), consider the possibility of pregnancy at the time of the first missed period and
395 	perform appropriate diagnostic measures. If the patient has adhered to the prescribed dosing
396 	schedule and misses two consecutive periods, rule out pregnancy. [Should be modified as needed to
397 	account for extended cycle products and/or products with a short half-life.]
398
399 	After discontinuation of a CHC, amenorrhea or oligomenorrhea may occur, especially if these
400 	conditions were pre-existent.
401
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402 	5.9 Depression
403 	Carefully observe females with a history of depression and discontinue [NAME] if depression
404 	recurs to a serious degree. Data on the association of CHCs with onset of depression or
405 	exacerbation of existing depression are limited.
406
407 	5.10 Cervical Cancer
408 	Some studies suggest that CHCs are associated with an increase in the risk of cervical cancer or
409 	intraepithelial neoplasia. There is controversy about the extent to which these findings are due to
410 	differences in sexual behavior and other factors.
411
412 	5.11 Effect on Binding Globulins
413 	The estrogen component of [NAME] may raise the serum concentrations of thyroxine-binding
414 	globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement
415 	thyroid hormone or cortisol therapy may need to be increased.
416
417 	5.12 Hereditary Angioedema
418 	In females with hereditary angioedema, exogenous estrogens may induce or exacerbate
419 	symptoms of angioedema.
420
421 	5.13 Chloasma
422 	Chloasma may occur with [NAME] use, especially in females with a history of chloasma
423 	gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or
424 	ultraviolet radiation while using [NAME].
425
426 	6 ADVERSE REACTIONS
427 	The following serious adverse reactions with the use of CHCs are discussed elsewhere in
428 	labeling:
429
430 	 	Serious cardiovascular events [see Boxed Warning and Warnings and Precautions (5.1)]
431 	 	Vascular events [see Warnings and Precautions (5.1)]
432 	 	Liver disease [see Warnings and Precautions (5.2)]
433
434 	6.1 Clinical Trials Experience
435 	Because clinical trials are conducted under widely varying conditions, adverse reaction rates
436 	observed in the clinical trials of one product cannot be directly compared to rates in the clinical
437 	trials of another product and may not reflect the rates observed in practice.
438
439 	[Clinical trials experience: See the guidance for industry Adverse Reactions Section of Labeling
440 	for Human Prescription Drug and Biological Products — Content and Format for detailed
441 	instructions. The following should be provided: (1) common adverse reactions; (2) adverse
442 	reactions leading to study discontinuation; and (3) serious adverse reactions, in a text list or
443 	tables, sorted by decreasing order of frequency. The frequency cutoff should be noted and
444 	should be appropriate for the safety database. Terms that may represent the same
445 	phenomenon before calculating frequency (e.g., disorders of menstrual frequency/volume,
446 	nausea/vomiting) should be grouped.]
447
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448 	6.2 Postmarketing Experience
449 	The following adverse reactions have been identified during postapproval use of [NAME].
450 	Because these reactions are reported voluntarily from a population of uncertain size, it is not
451 	always possible to reliably estimate their frequency or establish a causal relationship to product
452 	exposure.
453
454 	[Postmarketing experience: See the guidance for industry Adverse Reactions Section of Labeling
455 	for Human Prescription Drug and Biological Products — Content and Format for detailed
456 	instructions. Typically, adverse reactions already described elsewhere in labeling should not be
457 	repeated in subsection 6.2. However, if a serious adverse reaction (such as a pulmonary
458 	embolus) is described in class labeling for CHCs and there are no such events that occurred in
459 	the clinical trial(s) of the product but such events have occurred in the postmarketing setting
460 	with the product, then those postmarketing events should be included here.]
461
462 	7 DRUG INTERACTIONS
463 	The sections below provide information on substances for which data on drug interactions with
464 	CHCs are available. There is little information available about the clinical effect of most drug
465 	interactions that may affect CHCs. However, based on the known pharmacokinetic effects of
466 	these drugs, clinical strategies to minimize any potential adverse effect on contraceptive
467 	effectiveness or safety are suggested.
468
469 	Consult the approved product labeling of all concurrently used drugs to obtain further
470 	information about interactions with CHCs or the potential for metabolic enzyme or transporter
471 	system alterations.
472
473 	[If no studies were conducted with the product, this fact should be indicated as shown below;
474 	the general class labeling provided in the following sections should still be included.]
475
476 	No drug-drug interaction studies were conducted with [NAME].
477
478 	7.1 Effects of Other Drugs on Combined Hormonal Contraceptives
479 	Substances Decreasing the Plasma Concentrations of CHCs and Potentially Diminishing the
480 	Efficacy of CHCs:
481
482 	Table 3 includes substances that demonstrated an important drug interaction with [NAME].
483
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484 	Table 3. Significant Drug Interactions Involving Substances That Affect CHCs
Metabolic Enzyme Inducers
Clinical effect
 	Concomitant use of CHCs with metabolic enzyme inducers
may decrease the plasma concentrations of the estrogen and/or
progestin component of CHCs [see Clinical Pharmacology
(12.3)].
 	Decreased exposure of the estrogen and/or progestin
component of CHCs may potentially diminish the
effectiveness of CHCs and may lead to contraceptive failure
or an increase in breakthrough bleeding.
Prevention or management
 	Counsel females to use an alternative method of contraception
or a backup method when enzyme inducers are used with
CHCs.
 	Continue backup contraception for 28 days after discontinuing
the enzyme inducer to maintain contraceptive reliability.
Examples
Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz,
felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin,
rifabutin, rufinamide, topiramate, products containing St. John’s
wort,a and certain protease inhibitors (see separate section on
protease inhibitors below).
Colesevelam
Clinical effect
 	Concomitant use of CHCs with colesevelam significantly
decreases systemic exposure of ethinyl estradiol [see Clinical
Pharmacology (12.3)].
 	Decreased exposure of the estrogen component of CHCs may
potentially reduce contraceptive efficacy or result in an
increase in breakthrough bleeding, depending on the strength
of ethinyl estradiol in the CHC.
Prevention or management 	Administer 4 or more hours apart to attenuate this drug interaction.
485 	a Induction potency of St. John’s wort may vary widely based on preparation.
486
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487 	Substances increasing the systemic exposure of CHCs:
488 	Co-administration of atorvastatin or rosuvastatin and CHCs containing ethinyl estradiol increase
489 	systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and
490 	acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of
491 	conjugation. CYP3A inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit
492 	juice,7 or ketoconazole may increase systemic exposure of the estrogen and/or progestin
493 	component of CHCs.
494
495 	Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-
496 	nucleoside reverse transcriptase inhibitors:
497 	Significant decreases in systemic exposure of the estrogen and/or progestin have been noted
498 	when CHCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir,
499 	darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some
500 	HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse
501 	transcriptase inhibitors (e.g., nevirapine).
502
503 	In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been
504 	noted when CHCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir
505 	and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g.,
506 	etravirine).
507
508 	7.2 Effects of Combined Hormonal Contraceptives on Other Drugs
509 	Table 4 provides significant drug interaction information for drugs co-administered with
510 	[NAME].
511
7 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent.
Studies have shown that it could be classified as a “strong CYP3A inhibitor” when a certain preparation was used
(e.g., high dose, double-strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low
dose, single strength).
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512 	Table 4. Significant Drug Interaction Information for Drugs Co-Administered With CHCs
Lamotrigine
Clinical effect
 	Concomitant use of CHCs with lamotrigine may significantly
decrease systemic exposure of lamotrigine due to induction of
lamotrigine glucuronidation [see Clinical Pharmacology
(12.3)].
 	Decreased systemic exposure of lamotrigine may reduce
seizure control.
Prevention or management Dose adjustment may be necessary. Consult the approved product
labeling for lamotrigine.
Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy
Clinical effect
Concomitant use of CHCs with thyroid hormone replacement
therapy or corticosteroid replacement therapy may increase
systemic exposure of thyroid-binding and cortisol-binding
globulin [see Warnings and Precautions (5.11)].
Prevention or management
The dose of replacement thyroid hormone or cortisol therapy may
need to be increased. Consult the approved product labeling for
the therapy in use. [See Warnings and Precautions (5.11)].
Other Drugs
Clinical effect
Concomitant use of CHCs may decrease systemic exposure of
acetaminophen, morphine, salicylic acid, and temazepam.
Concomitant use with ethinyl estradiol-containing CHCs may
increase systemic exposure of other drugs (e.g., cyclosporine,
prednisolone, theophylline, tizanidine, and voriconazole).
Prevention or management
The dosage of drugs that can be affected by this interaction may
need to be increased. Consult the approved product labeling for
the concomitantly used drug.
513
514 	[If available, specific clinical pharmacology data should be added here concerning the effects of
515 	the product on human CYP enzymes at clinically relevant concentrations (see Clinical
516 	Pharmacology (12.3)).]
517
518 	7.3 Effect on Laboratory Tests
519 	The use of CHCs may influence the results of certain laboratory tests, such as coagulation
520 	factors, lipids, glucose tolerance, and binding proteins.
521
522 	8 USE IN SPECIFIC POPULATIONS
523 	[Certain subsections and headings described in the PLLR may not be pertinent to the labeling
524 	for CHCs. For example, it is not anticipated that this section would include a description of a
525 	pregnancy registry or would have information included under the Clinical Considerations
526 	heading. When information is clearly not applicable, such headings and subsections are
527 	omitted. See 21 CFR 201.56, 201.57(c)(9)(i)-(iii), and the draft guidance for industry Pregnancy,
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528 	Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological
529 	Products — Content and Format for complete details on content for PLLR labeling.]
530
531 	8.1 Pregnancy
532
533 	Risk Summary
534 	[This section should summarize the human, animal, and pharmacologic data and identify the
535 	source of the data. If the product contains a new progestin or estrogen, applicants should provide
536 	a risk statement(s) that describes, for the drug, the risk of adverse developmental outcomes based
537 	on all relevant human data, animal data, and the drug’s pharmacology. If there are no human
538 	data, then a statement that there are no human data must be made in the Risk Summary
539 	(21 CFR 201.57(c)(9)(i)(B)) and the human data section should not be included. If embryo/fetal
540 	studies were conducted, then a sentence summarizing those studies should be included here with
541 	details under “Animal Data.” If no studies were done, then a statement should be made in the Risk
542 	summary and the animal data section should not be included.
543
544 	If the product contains a well-characterized progestin and estrogen, the class language provided
545 	below should be used.]
546
547 	[NAME] is contraindicated in pregnancy because there is no reason to use CHCs in pregnancy.
548 	Discontinue [NAME] if pregnancy occurs. Epidemiologic studies and meta-analyses have not
549 	found an increased risk of genital or nongenital birth defects (including cardiac anomalies and
550 	limb-reduction defects) following exposure to CHCs before conception or during early
551 	pregnancy. In animal reproduction studies in [species], [results should be summarized]. [OR]
552 	Animal studies to evaluate embryo/fetal toxicity were not conducted.
553
554 	In the U.S. general population, the estimated background risk of major birth defects and miscarriage
555 	in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.
556
557 	Data
558 	Human Data
559 	[Applicants should describe the data regarding adverse developmental outcomes, adverse
560 	reactions, and other adverse effects, including information about the data source, number of
561 	subjects, study duration, exposure time, and limitations of the data.]
562
563 	Animal Data
564 	[Embryo/fetal (Segment II and III) studies should be reported here. If no studies were done, this
565 	heading should not be included.]
566
567 	8.2 Lactation
568
569 	Risk Summary
570 	Contraceptive hormones and/or metabolites are present in human milk. [The concentration in
571 	human milk and the actual or estimated infant dose, if available, should be described, as well
572 	as the effects on the breast-fed infant.] CHCs can reduce milk production in breast-feeding
573 	females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-
574 	established. When possible, advise the nursing female to use other methods of contraception until
575 	she discontinues breast-feeding. [See also Dosage and Administration (2.2).] The developmental
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576 	and health benefits of breast-feeding should be considered along with the mother’s clinical need
577 	for (name of drug) and any potential adverse effects on the breast-fed child from (name of drug)
578 	or from the underlying maternal condition.
579
580 	Data
581 	[If available, specific pharmacologic data should be added here concerning the percentage of
582 	the product that is present in the breast milk of postpartum females.]
583
584 	8.4 Pediatric Use
585 	Safety and efficacy of [NAME] have been established in females of reproductive potential.
586 	[Unique efficacy or safety information relevant to patients younger than 18 years of age should be
587 	provided here.] Use of [NAME] before menarche is not indicated.
588
589 	8.5 Geriatric Use
590 	[NAME] has not been studied in postmenopausal women and is not indicated in this population.
591
592 	8.6 Hepatic Impairment
593 	[Contraindication and any other statements that are relevant to this heading should be included
594 	with appropriate cross-references [see Contraindications (4) and Warnings and Precautions
595 	(5.4)]. This section should be omitted if there are no relevant data.]
596
597 	8.7 Renal Impairment
598 	[Any statements that are relevant to this heading should be added with appropriate cross-
599 	references. This section should be omitted if there are no relevant data.]
600
601 	8.8 Race/Ethnicity
602 	[Any statements that are relevant to this heading should be added and cross-referenced to other
603 	sections if appropriate. This section should be omitted if there are no relevant data.]
604
605 	8.9 Body Mass Index (BMI)/Body Weight
606 	[If studies limited eligibility on the basis of BMI/body weight:] The safety and efficacy of
607 	[NAME] in females with a BMI or body weight > [exclusion criteria should be stated] have
608 	not been evaluated [see Clinical Studies (14)].
609
610 	If data indicate an adverse effect on efficacy, that should be summarized here, and included
611 	under Limitations of Use in INDICATIONS AND USAGE and described in CLINICAL
612 	STUDIES. This section should be omitted if there are no relevant data and BMI/body weight
613 	were not exclusionary in the clinical trials.]
614
615 	10 OVERDOSAGE
616 	There have been no reports of serious adverse outcomes from overdose of CHCs, including
617 	ingestion by children. Overdose may cause uterine bleeding in females and nausea.
618
619 	[If data are available, any pharmacokinetic or clinical statements that are relevant to this
620 	heading should be added; also, what should be monitored in case of overdose of the product
621 	should be stated.]
622
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623 	11 DESCRIPTION
624 	[This section should include the proprietary name and established name, if any, of the
625 	CHC product, as well as key descriptors of the CHC product (e.g., the type of dosage
626 	form(s) and routes of administration).]
627
628 	12 CLINICAL PHARMACOLOGY
629
630 	12.1 Mechanism of Action
631 	CHCs prevent pregnancy primarily by suppressing ovulation.
632
633 	[If studies establish additional mechanisms by which the drug prevents conception, the
634 	additional mechanisms should be described here. Speculative claims of untested mechanisms of
635 	action should not be included.
636
637 	Receptor-binding studies should not be added for the purpose of claims unless the claims were
638 	previously agreed upon with the division and are adequately supported with data from clinical
639 	studies.]
640
641 	12.2 Pharmacodynamics
642 	[If there are no relevant pharmacodynamic data, this subsection must contain a statement
643 	indicating this lack of information (21 CFR 201.57(c)(13)(i)(B)).]
644
645 	12.3 Pharmacokinetics
646 	[Available information should be provided to include the following subsections:
647
648 	 	Absorption (including food effect)
649 	 	Distribution
650 	 	Elimination
651 	‒ 	Metabolism
652 	‒ 	Excretion
653 	 	Specific populations (e.g., geriatric patients, pediatric patients, racial or ethnic groups,
654 	patients with renal impairment, patients with hepatic impairment)
655 	 	Drug interaction studies]
656
657 	13 NONCLINICAL TOXICOLOGY
658
659 	13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
660 	[If applicable, nonclinical data should be summarized if human data are not available.]
661
662 	13.2 Animal Toxicology and/or Pharmacology
663 	[If applicable, nonclinical data should be summarized if human data are not available.
664 	Embryo/fetal (Segment II and III) studies should be summarized in subsection 8.1]
665
666 	14 CLINICAL STUDIES
667 	[Contraceptive efficacy should be reported in terms of the 1-year Pearl Index and 95 percent
668 	confidence interval around the point estimate. If studies were conducted in different
669 	geographic regions, the U.S. Pearl Index should be the focus of this section.
670
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671 	This information should be preceded by a description of the clinical trial efficacy database,
672 	including the overall exposure, demographics, trial design, and any exclusions from the clinical
673 	trial database beyond the contraindications to use of hormonal contraceptives. If indications in
674 	addition to contraception are sought, presentation of those results should be discussed with
675 	FDA.
676
677 	If available, information about return to fertility following discontinuation of the product
678 	should be provided here.]
679
680 	15 REFERENCES
681 	[References should be minimized, but can include recommendations by an authoritative
682 	scientific body or a standardized methodology, scale, or technique if the labeling has to
683 	summarize or rely on this information for the safe and effective use of the CHC. Also citations
684 	of studies (e.g., epidemiologic studies) that inform labeling about the specific product should be
685 	referenced.]
686
687 	16 HOW SUPPLIED/STORAGE AND HANDLING
688 	[The United States Pharmacopeia storage temperature range, not a single storage temperature
689 	value, should be included. Contraceptive products use different dispensers; more complicated
690 	dispensers should be described here.]
691
692 	17 PATIENT COUNSELING INFORMATION
693 	[Although this provides general class counseling statements, these statements should be
694 	consistent with information provided in the preceding prescribing information. Some
695 	statements, particularly regarding instructions for missed pills or when to rule out pregnancy,
696 	should be customized for the particular product.]
697
698 	Advise the patient to read the FDA-approved patient labeling (Patient Information and
699 	Instructions for Use).
700
701 	Cigarette Smoking
702 	Cigarette smoking increases the risk of serious cardiovascular events from CHC use.
703 	Women who are over 35 years old and smoke should not use [NAME] [see Boxed Warning
704 	and Warnings and Precautions (5.1)].
705
706 	Venous Thromboembolism
707 	The increased risk of VTE compared to non-users of CHCs is greatest after initially starting a
708 	CHC or restarting (following a 4-week or greater interruption in intake) the same or a
709 	different CHC [see Warnings and Precautions (5.1)].
710
711 	Use during Pregnancy
712 	[NAME] is not to be used during pregnancy. Instruct the patient to stop further intake of
713 	[NAME] if pregnancy is confirmed during treatment [see Contraindications (4)].
714
715 	Sexually Transmitted Infections
716 	[NAME] does not protect against HIV infection and other sexually transmitted infections.
717
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Contains Nonbinding Recommendations
Draft — Not for Implementation
718 	Dosing and Missed Pill Instructions
719 	Patients should take one tablet daily by mouth at the same time every day. Advise patients
720 	about what to do in the event pills are missed. See “What to Do if You Miss Pills” section
721 	in FDA-approved patient labeling [see Dosage and Administration (2.1)]. [Should be
722 	modified as warranted for non-oral formulations.]
723
724 	Need for Additional Contraception
725 	 	Postpartum females who have not yet had a period when they start [NAME] need to
726 	use an additional method of contraception until [product-specific information about
727 	starting CHCs in postpartum females should be provided] [see Dosage and
728 	Administration (2.2)].
729 	 	There is a need for a back-up or alternative method of contraception when enzyme
730 	inducers are used with [NAME] [see Drug Interactions (7.1)].
731
732 	Lactation
733 	[NAME] may reduce breast milk production. This is less likely to occur if breast-feeding is
734 	well established. When possible, nursing women should use other methods of contraception
735 	until they have discontinued breast-feeding [see Use in Specific Populations (8.2)].
736
737 	Amenorrhea and Possible Symptoms of Pregnancy
738 	Amenorrhea may occur. Advise the patient to contact a health care provider in the event of
739 	amenorrhea in two or more consecutive cycles or in case of symptoms of pregnancy such as
740 	morning sickness or unusual breast tenderness. [Should be modified as warranted for
741 	extended-cycle products.] [See Warnings and Precautions (5.8).]
742
743 	Fertility following Discontinuation of [NAME]
744 	Resumption of fertility after discontinuing [NAME] is expected. [Product-specific
745 	information about the likely interval before fertility is restored should be provided, if
746 	available.] [See Clinical Studies (14).]
747
748 	[Other relevant information for prescribers to convey to patients to use the drug safely and
749 	effectively should be included.
750
751 	Required manufacturer information (21 CFR 201.1 and 201.100(e) for drugs and 21 CFR part
752 	610, subpart G, for biological products) should be provided at the end of the prescribing
753 	information, as well as in the patient labeling (21 CFR 310.501(c)(13)(i)), unless the patient
754 	labeling is attached to the prescribing information.]
755
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