QTc Information in 
Human Prescription 
Drug and Biological 
Product Labeling 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (OCE) William Pierce at 301-796-0521 or 
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
August 2023 
Labeling
   
QTc Information in 
Human Prescription 
Drug and Biological 
Product Labeling 
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  
 
and/or 
 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room. 3128 
Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov  
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
7519 Standish Place, Rockville, MD 20855 
Phone: 240-276-9300 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
August 2023 
Labeling 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  QTC INTERVAL PROLONGATION INFORMATION IN THE CLINICAL 
PHARMACOLOGY SECTION .................................................................................................. 3 
IV.  QTC INTERVAL PROLONGATION INFORMATION IN THE DRUG 
INTERACTIONS SECTION ....................................................................................................... 5 
A.  Use With Other Products Known or Suspected to Prolong the QTc Interval .......................... 5 
B.  Use With Other Products That Affect the Pharmacokinetics (PK) of the Subject Drug ........ 6 
V.  QTC INTERVAL PROLONGATION INFORMATION IN THE WARNINGS AND 
PRECAUTIONS SECTION ........................................................................................................ 6 
VI.  QTC INTERVAL PROLONGATION INFORMATION IN OTHER SECTIONS 
OF LABELING ............................................................................................................................. 8 
A.  BOXED WARNING Section ......................................................................................................... 8 
B.  DOSAGE AND ADMINISTRATION Section ............................................................................ 9 
C.  CONTRAINDICATIONS Section .............................................................................................. 10 
D.  ADVERSE REACTIONS Section .............................................................................................. 10 
E.  PATIENT COUNSELING INFORMATION Section .............................................................. 11 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  QTc Information in Human Prescription Drug and Biological 
2  Product Labeling 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance is intended to assist applicants with incorporating QTc interval prolongation-
18  related information into the labeling of non-antiarrhythmic human prescription drug and 
19  biological products.2,3 This guidance provides recommendations to help ensure that clinically 
20  relevant information on QTc interval prolongation is included in and distributed appropriately 
21  across sections of labeling, in accordance with regulatory requirements for the content and 
22  format of human prescription drug labeling.4  
23   
24  This guidance provides illustrative examples of the content and format of QTc prolongation-
25  related information in the labeling involving a fictitious subject drug (e.g., DRUG-X (drugozide-
26  x) tablets).5  
27   
28  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
29  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
30  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
 
1 This guidance has been prepared by the Oncology Center of Excellence (OCE), Center for Drug Evaluation and 
Research (CDER), and Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.  
 
2 For the purposes of this guidance, references to drugs, drug products, and drug and biological products include 
both human drug products and biological drug products regulated by CDER and CBER, unless otherwise specified.  
 
3 See the guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs  Questions and Answers (R3) (ICH E14 Q&A (R3) guidance) (June 2017). 
We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
4 See 21 CFR 201.56(a) and (d) and 21 CFR 201.57.  
 
5 For the purposes of this guidance, the term subject drug refers to the drug for which the labeling is being 
developed.  
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
31  the word should in Agency guidances means that something is suggested or recommended, but 
32  not required. 
33   
34   
35  II.  BACKGROUND 
36   
37  An undesirable property of some non-antiarrhythmic drugs is their ability to delay cardiac 
38  repolarization, an effect that can be measured as prolongation of the QT interval on the surface 
39  electrocardiogram (ECG). A delay in cardiac repolarization creates an electrophysiological 
40  environment that favors the development of torsade de pointes (TdP), which can degenerate into 
41  ventricular fibrillation, leading to sudden death. The risk of TdP may also be increased for 
42  patients with risk factors for QT interval prolongation (e.g., elevated baseline QTc interval, heart 
43  failure, hypokalemia, history of long QT syndrome, genetic predisposition, or use of a 
44  concomitant medication that prolongs the QT interval or increases exposure to a drug that can 
45  prolong the QT interval).    
46   
47  TdP may not be captured in clinical databases, even for drugs known to have significant 
48  proarrhythmic effects. The failure to observe an episode of TdP during a drugs clinical 
49  development program is not considered sufficient grounds for dismissing the possible 
50  arrhythmogenic risks of a drug. While the degree of QT prolongation is recognized as an 
51  imperfect biomarker for proarrhythmic risk, in general, there is a qualitative relationship between 
52  QT prolongation and the risk of TdP, especially for drugs that cause prolongation of the QT 
53  interval due to inhibition of the delayed rectifier potassium channel. 
54   
55  FDA and the International Council for Harmonisation (ICH) recommend that applicants for most 
56  non-antiarrhythmic drugs with systemic bioavailability assess the effect on cardiac repolarization 
57  early in clinical development including a clinical electrocardiographic evaluation.6 The QT 
58  corrected for heart rate (QTc) assessment in early clinical development may inform the intensity 
59  and continuation of ECG monitoring in late phase clinical trials. 
60   
61  FDA/ICH recommend that sponsors conduct a single clinical trial, named the thorough QT/QTc 
62  study (TQT study), to assess the effect of a drug on the QTc interval; this trial is typically 
63  conducted in healthy subjects who may receive a placebo, a positive control, and therapeutic 
64  dose(s) and/or doses above the maximum usual or recommended dose of the drug.7 In some 
65  cases, early clinical trials (e.g., first-in-human studies, multiple-ascending dose studies) that 
66  include robust, high-quality ECGs and evaluate the QTc interval response at a sufficient multiple 
67  (commonly 2 times) of the high clinical exposure can be used as a substitute for a TQT study.8 
68  Some patient-specific or drug-specific factors may limit the ability to conduct a conventional 
 
6 See footnote 3. 
 
7 See footnote 3.  
 
8 See footnote 3.   
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
69  TQT study for certain drugs; therefore, it is recommended, when appropriate, to use alternative 
70  strategies to assess the QTc interval effects for these drugs.9,10 
71   
72  It is recommended that an integrated nonclinical and clinical QT/QTc risk assessment11 be used 
73  as a substitute for a TQT study when the clinical investigation did not include sufficient 
74  multiples of the high clinical exposure for reasons of safety or tolerability (or for other reasons 
75  such as saturable absorption), or when a conventional TQT study is not feasible. The sponsor 
76  should discuss their proposed clinical and nonclinical studies designed to assess the potential of 
77  their drug to prolong the QTc interval with the review division prior to submitting a new or 
78  supplemental marketing application.12 
79   
80   
81  III.  QTc INTERVAL PROLONGATION INFORMATION IN THE CLINICAL 
82  PHARMACOLOGY SECTION    
83   
84  When there is relevant clinical pharmacology-related information on effects of a drug on the QTc 
85  interval, such information should be described under the Cardiac Electrophysiology heading in 
86  the Pharmacodynamics subsection in the CLINICAL PHARMACOLOGY section.13 The studied 
87  dose(s) or observed exposure range should be included under this heading. Additionally, when 
88  available, an identified dose- or exposure-response (QTc interval prolongation response) 
89  relationship should be included under this heading. Table 1 below provides examples of how to 
90  describe the effect of a drug on the QTc interval under this heading. 
91   
92   
93   
94   
95   
96   
97   
98   
99   
 
9 See the guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs (October 2012). 
 
10 See S7B Q&As in the guidance for industry E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential  Questions and Answers (August 2022). 
 
11 See S7B Q&As 1.1 and 1.2 in the guidance for industry E14 and S7B Clinical and Nonclinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential  Questions and Answers (August 2022). 
 
12 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible. We 
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable, 
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.   
 
13 See the guidance for industry Clinical Pharmacology Labeling for Human Prescription Drug and Biological 
Products  Content and Format (December 2016). 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
100  Table 1: Examples of Recommended Statements to Describe the Effects of a Drug on the 
101  QTc Interval Under the Cardiac Electrophysiology Heading 
102   
QTc Assessment Results  Examples of Recommended Statements 
   
TQT study (or substitute) excludes a  At the maximum recommended dose [or At X 
mean 10-millisecond (ms) increase in  times the maximum recommended dose], clinically 
QTc intervala  significant QTc interval prolongation was not 
  observed. 
 
   
Alternative QTc study without a positive  At the recommended DRUG-X dose (or At [insert 
control excludes a mean 10-ms increase  dose] (X times the recommended dose)), a mean 
in QTc intervalb  increase in the QTc interval >20 ms was not 
observed. 
 
   
For a drug for which a QTc assessment is  There is insufficient information to characterize 
recommended,14 the effect on the QTc  the effect of DRUG-X on the QTc interval. 
interval has not been characterized or 
insufficient data are available to 
characterize the effect 
 
   
Clinically significant QTc interval  The largest mean increase in QTc interval was X 
prolongation detected  ms (upper confidence interval = Y ms) after 
administration of DRUG-X [insert dose] (X times 
the maximum recommended dose) in patients with 
[insert study population]. The increase in the QTc 
interval was (was not) concentration- [may use 
dose in place of concentration as appropriate] 
dependent [see Warnings and Precautions (5.x)]. 
 
103  a No clinically significant QTc interval prolongation is concluded when the mean difference in placebo-corrected 
104  QTc interval change from baseline (QTc) is less than 10 ms in a conventional TQT study15 or substitute study 
105  (see Section 5.1 of the ICH E14 Q&A (R3) guidance), or when the integrated nonclinical and clinical risk 
106  assessments are used.  
107  b The upper bound of the two-sided 90% confidence interval around the estimated maximal effect on QTc is less 
108  than 10 ms but no positive control was included in the alternative QTc study, the treatment is unlikely to have an 
109  actual mean effect as large as 20 ms (see Section 6.1 of the ICH E14 Q&A (R3) guidance). 
 
14 See footnote 9.  
 
15 See footnote 9.    
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
110  For drugs that do not need a QTc interval assessment (e.g., most monoclonal antibodies), the 
111  Cardiac Electrophysiology heading and related information may be omitted from this 
112  subsection.16 
113   
114   
115  IV.  QTc INTERVAL PROLONGATION INFORMATION IN THE DRUG 
116  INTERACTIONS SECTION 
117   
118  If there are clinically significant drug interactions of the subject drug with other prescription or 
119  over-the-counter (OTC) drugs, classes of drugs, or foods that result in, or that increase risk of 
120  QTc interval prolongation, this information must be included in the DRUG INTERACTIONS 
121  section.17 If drug interactions related to QT interval prolongation are described in 
122  CONTRAINDICATIONS or in WARNINGS AND PRECAUTIONS section(s), then this 
123  interaction must be discussed in more detail in the DRUG INTERACTIONS section.18 
124   
125  The DRUG INTERACTIONS section must also briefly describe the mechanism of these 
126  clinically significant drug interactions (if known); must include specific practical instructions for 
127  preventing or managing these clinically significant interactions.19 The DRUG INTERACTIONS 
128  section should include the clinical effect(s) of these clinically significant interactions. 
129   
130  A.  Use With Other Products Known or Suspected to Prolong the QTc Interval 
131   
132  If the subject drug is known or suspected to prolong the QTc interval, then concomitant use of 
133  other products that are also known or suspected to prolong the QT interval, could further increase 
134  the risk of clinically significant adverse reactions associated with QTc interval prolongation. In 
135  this scenario, FDA generally recommends that clinically significant drug interactions regarding 
136  QTc interval prolongation be placed in a separate subsection in the DRUG INTERACTIONS 
137  section. For example: 
138   
139  7  DRUG INTERACTIONS 
140  ... 
141  7.X   Drugs that Prolong the QTc Interval 
142  Avoid concomitant use of DRUG-X with other product(s) with a known potential to 
143  prolong the QTc interval. If concomitant use cannot be avoided, obtain ECGs when 
144  initiating, during concomitant use, and as clinically indicated [see Warnings and 
 
16 Under 21 CFR 201.56(d)(4), [o]mit clearly inapplicable sections, subsections, or specific information. For 
additional information on omitting information in labeling, see the guidance for industry Labeling for Human 
Prescription Drug and Biological Products  Implementing the PLR Content and Format Requirements (February 
2013). 
 
17 See 21 CFR 201.57(c)(8)(i). 
 
18 Ibid.  
 
19 See 21 CFR 201.57(c)(8)(i). This recommendation may be adjusted based on the indication for use, duration of 
use, and patient risk factors.  
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
145  Precautions (5.x)]. Withhold DRUG-X if the QTc interval is > 500 ms or the change 
146  from baseline is > 60 ms [see Dosage and Administration (2.x)].  
147   
148  Drugozide-x causes QTc interval prolongation [see Clinical Pharmacology (12.2)]. 
149  Concomitant use of DRUG-X with other products that prolong the QTc interval may 
150  result in a greater increase in the QTc interval and adverse reactions associated with QTc 
151  interval prolongation, including Torsade de pointes, other serious arrythmias, and sudden 
152  death [see Warnings and Precautions (5.x)].  
153   
154  B.  Use With Other Products That Affect the Pharmacokinetics (PK) of the Subject 
155  Drug 
156   
157  If DRUG-X is associated with concentration-dependent QTc prolongation, then concomitant use 
158  with other product(s) that can increase its concentrations may increase the risk of a clinically 
159  significant QTc interval prolongation and adverse reactions associated with QTc interval 
160  prolongation. For example: 
161   
162  7   DRUG INTERACTIONS 
163  ... 
164  7.X   Effect of Other Drugs on DRUG-X 
165   
166  Strong CYP3A Inhibitors  
167  Avoid concomitant use of DRUG-X with strong CYP3A inhibitors.  
168    
169  Drugazide-x is metabolized by CYP3A. Concomitant use of DRUG-X with a strong 
170  CYP3A inhibitor may increase drugozide-x concentrations [see Clinical Pharmacology 
171  (12.3)], which may increase the incidence and severity of adverse reactions, including 
172  QTc interval prolongation. Prolongation of the QTc interval increases the risk of Torsade 
173  de pointes, other serious arrythmias, and sudden death [see Warnings and Precautions 
174  (5.x)]. 
175   
176   
177  V.  QTc INTERVAL PROLONGATION INFORMATION IN THE WARNINGS AND 
178  PRECAUTIONS SECTION 
179   
180  When QTc interval prolongation information has implications for prescribing decisions or 
181  patient management, the WARNINGS AND PRECAUTIONS should generally describe the 
182  risks of, or clinically significant adverse reactions from QTc interval prolongation in patients 
183  taking the drug.20  
184   
185  Some factors that support including a QTc interval prolongation warning in the WARNINGS 
186  AND PRECAUTIONS section include: 
187   
 
20 See the guidance for industry Warnings and Precautions, Contraindications, and Boxed Warning Sections of 
Labeling for Human Prescription Drug and Biological Products  Content and Format (October 2011).   
 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
188    An increased rate of potential proarrhythmic effects, such as TdP, ventricular tachycardia, 
189  ventricular fibrillation and flutter, syncope, seizure, or sudden death, or;21  
190   
191    Results from studies that demonstrate the drug causes a clinically significant QTc interval 
192  prolongation, particularly when proarrhythmic activity is consistent with the 
193  pharmacology of the drug or related drugs (e.g., human ether-a-go-go-related gene 
194  (hERG) positive at low concentrations or in vivo nonclinical QT study that are strongly 
195  positive). 
196   
197  When describing the clinically significant risks of QTc interval prolongation in this section, FDA 
198  recommends including the following information, as applicable: 
199   
200    A succinct description of the clinically significant adverse reactions related to QTc 
201  interval prolongation that have occurred in patients, including sudden death, TdP, or 
202  other clinically significant ventricular arrythmias.  
203   
204    A description of pertinent exclusion criteria in the clinical trial(s) in which these adverse 
205  reactions were observed (such as exclusion of patients with clinically significant active 
206  cardiovascular disease or recent myocardial infarction). 
207   
208    The percentage of patients who developed an absolute QTc interval value of greater than 
209  500 ms over a specific treatment duration.  
210   
211    The percentage of patients with a greater than 60 ms increase in the QTc interval from 
212  baseline over a specific treatment duration. 
213   
214    A summary of the relationship of dose or concentration to increases in the QTc interval 
215  (e.g., DRUG-X causes an dose- or concentration-dependent QTc interval 
216  prolongation).  
217   
218    A description of the risk of increased QTc interval prolongation with concomitant use of 
219  other products (e.g., prescription drugs, OTC drugs, or nutritional supplements), when 
220  serious or otherwise clinically significant outcomes related to increases in the QTc 
221  interval are reasonably associated with concomitant use. Include cross-reference(s) to 
222  more detailed information in the DOSAGE AND ADMINISTRATION, DRUG 
223  INTERACTIONS, or CLINICAL PHARMACOLOGY sections, as applicable. See 
224  Section IV of this guidance for more information. 
225   
226  The warning should provide steps to take to prevent or mitigate clinically significant adverse 
227  reactions or risks associated with QTc interval prolongation.22 Some steps that may be taken to 
228  prevent or mitigate the risk of such clinically significant adverse reactions include: 
229   
 
21 See the guidance for industry Adverse Reactions Section of Labeling for Human Prescription Drug and Biological 
Products  Content and Format (January 2006).  
 
22 See footnote 9.  
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
230    Assessing the QTc interval via an ECG at baseline and during treatment as clinically 
231  indicated;  
232   
233    Obtaining serum electrolytes (including potassium, calcium, phosphorous, and 
234  magnesium) at baseline, during treatment as clinically indicated, and correcting 
235  electrolyte abnormalities; 
236   
237    Avoiding the concomitant use of products that may increase the risk of the QTc interval 
238  prolongation or may increase concentrations of the drug (if QTc interval prolongation 
239  appears concentration-dependent);  
240   
241    Avoiding concomitant use or contraindicating the use of the drug in patients who are at 
242  significant risk of developing TdP, including those with congenital long QT syndrome, 
243  uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, 
244  unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree 
245  atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism; and  
246   
247    Recommending dosage modification(s) based on increases in the QTc interval or 
248  development of clinically significant adverse reactions associated with QTc interval 
249  prolongation. The specific recommendations to modify the dosage or administration of 
250  the drug based on increases in the QTc interval should be included in the DOSAGE AND 
251  ADMINISTRATION section, rather than in the WARNINGS AND PRECAUTIONS 
252  section.23 
253   
254   
255  VI.  QTc INTERVAL PROLONGATION INFORMATION IN OTHER SECTIONS OF 
256  LABELING 
257   
258  A.  BOXED WARNING Section 
259   
260  A BOXED WARNING for QTc interval prolongation is recommended when there is reasonable 
261  evidence of a causal association between the drug and any of the following:24 
262   
263    Cardiac death with QTc interval prolongation 
264   
265    TdP 
266   
267    Polymorphic ventricular tachycardia or signs or symptoms of serious or life-threatening 
268  arrythmias 
 
23 See the draft guidance for industry Dosage and Administration Section of Labeling for Human Prescription Drug 
and Biological Products  Content and Format (January 2023). When final, this guidance will represent FDAs 
thinking on this topic. 
 
24 When there is a BOXED WARNING for QTc interval prolongation, there must be more detailed information on 
QTc interval prolongation in the CONTRAINDICATIONS section or in the WARNINGS AND PRECAUTIONS 
sections. See 21 CFR 201.57(c)(1). 
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
269   
270    Other life-threatening cardiac adverse reactions with QTc interval prolongation 
271   
272  B.  DOSAGE AND ADMINISTRATION Section  
273   
274  If there are recommended dosage modifications (e.g., dosage reduction, dosage interruption, or 
275  permanent discontinuation) to reduce the risk of QTc interval prolongation or clinically relevant 
276  adverse reactions associated with QTc interval prolongation, this information as well as 
277  information on the recommended frequency of QTc interval assessment (ECGs) should be 
278  included in the DOSAGE AND ADMINISTRATION section.25  
279   
280  If the only dosage modification information for a drug is related to QTc interval prolongation 
281  (i.e., there are no other dosage modification recommendations for other adverse reactions), 
282  consider presenting the recommendations in a subsection entitled 2.x Dosage Modifications for 
283  QTc Interval Prolongation in the DOSAGE AND ADMINISTRATION section. For example:  
284   
285  2 DOSAGE AND ADMINISTRATION 
286  ... 
287  2.x Dosage Modifications for QTc Interval Prolongation 
288  Table 2 provides recommended dosage modifications for QTc interval prolongation. 
289   
290  Table 2: Recommended DRUG-X Dosage Modifications for QTc Interval 
291  Prolongation 
292   
Adverse  Severity  Monitoring and Dosage 
Reaction  Modifications for DRUG-X 
     
QTc Interval  Torsade de pointes, polymorphic  Permanently discontinue DRUG-X. 
Prolongation  ventricular tachycardia, or signs or 
[see Warnings and  symptoms of serious or life-threatening 
Precautions (5.x)]  arrythmia 
 
   
QTc interval absolute value greater    Withhold DRUG-X until QTc 
than XXX ms   interval is less than XXX ms, then 
  resume DRUG-X at [same or 
or   reduced dosage]. 
   
Increase in QTc interval greater than    Obtain an ECG at least every X 
XX ms from baseline  weeks and as clinically indicated.26 
   
 
25 See footnote 23.  
 
26 This recommendation may be adjusted based on the indication for use, duration of use, pharmacokinetic 
parameters of the drug, and patient risk factors. 
  9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
293  However, if there are dosage modification recommendations for other risks in addition to those 
294  for QTc interval prolongation, consider including all such dosage modifications in a single 
295  subsection entitled 2.x Dosage Modifications for Adverse Reactions.27 
296   
297  C.  CONTRAINDICATIONS Section 
298   
299  The CONTRAINDICATIONS section must describe any situations in which the drug should not 
300  be used because the risk of use (e.g., certain potentially fatal adverse reactions) clearly outweighs 
301  any possible therapeutic benefit.28 Those situations include use of the drug in patients who have 
302  a substantial risk of being harmed by the drug and for whom no potential benefit makes the risk 
303  acceptable.29  
304   
305  For drugs in which serious adverse reactions associated with QTc interval prolongation have 
306  been observed with use of the drug, consider including a contraindication in patients with 
307  congenital long QT syndrome or uncompensated heart failure. For example,  
308   
309  4  CONTRAINDICATIONS 
310  DRUG-X is contraindicated in patients with a history of long QT syndrome or 
311  uncompensated heart failure [see Warnings and Precautions (5.x)].  
312   
313  If the concomitant use of a drug (e.g., DRUG-X) with another drug (or drug class) increases the 
314  risk of clinically significant adverse reactions related to QTc interval prolongation such that the 
315  risk of concomitant use clearly outweighs any possible therapeutic benefit, this section should 
316  contraindicate the use of DRUG-X with the other drug (or drug class). 
317   
318  For drugs used for life-threatening conditions (e.g., oncologic diseases) in which serious adverse 
319  reactions associated with QTc interval prolongation have been observed, a contraindication is 
320  generally not appropriate because the risk of use does not clearly outweigh any possible 
321  therapeutic benefit.   
322   
323  D.  ADVERSE REACTIONS Section 
324   
325  Adverse reactions associated with QTc interval prolongation (e.g., TdP or other ventricular 
326  arrythmias) must be included in the ADVERSE REACTIONS section.30 Adverse reactions 
327  associated with QTc interval prolongation that appear in the WARNINGS AND 
328  PRECAUTIONS section must also be listed in the ADVERSE REACTIONS section.31  
329   
 
27 FDA recommends discussing the specific dosage modifications for the drug with the appropriate review division. 
 
28 See 21 CFR 201.57(c)(5). 
 
29 Ibid. 
 
30 See 21 CFR 201.57(c)(7). 
 
31 See 21 CFR 201.57(c)(6) and 21 CFR 201.57(c)(7). 
  10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
330  E.  PATIENT COUNSELING INFORMATION Section  
331   
332  If a drug has a warning in the WARNINGS AND PRECAUTIONS section, the PATIENT 
333  COUNSELING INFORMATION section should generally summarize the clinically significant 
334  adverse reactions or risks associated with QTc interval prolongation (e.g., identification of these 
335  risks; the mitigation strategies that are pertinent to patients including self-monitoring 
336  information, and information on when to contact a healthcare provider, seek emergency help, or 
337  immediately discontinue the drug).32 For example,  
338   
339  17 PATIENT COUNSELING INFORMATION 
340  ... 
341  QTc Interval Prolongation 
342  Inform patients that DRUG-X causes QTc interval prolongation and may increase the risk 
343  of Torsades de pointes, other ventricular arrythmias, and sudden death. Inform patients 
344  that ECG monitoring will be obtained before and during treatment with DRUG-X. 
345  Advise patients or caregivers to seek immediate medical attention if they suspect or 
346  develop signs or symptoms associated with the clinical consequences of QTc interval 
347  prolongation [see Warnings and Precautions (5.x)].  
348   
349  Drug Interactions 
350  Advise patients to inform their healthcare provider before starting or discontinuing a 
351  prescription drug, nonprescription drug, or supplement. Instruct patients not to take other 
352  drugs that cause QT interval prolongation with DRUG-X [see Warnings and Precautions 
353  (5.x)]. 
 
32 See the guidance for industry Patient Counseling Information Section of Labeling for Human Prescription Drug 
and Biological Products  Content and Format (December 2014). 
  11