Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

SEROQUEL XR (NDA-022047)

(QUETIAPINE FUMARATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/27/2022 (SUPPL-46)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions were identified during post approval use of SEROQUEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, drug reaction with eosinophilia and systemic symptoms (DRESS), hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), decreased platelet count, serious liver reactions (including hepatitis, liver necrosis, and hepatic failure), agranulocytosis, intestinal obstruction, ileus, colon ischemia, sleep apnea, urinary retention, acute generalized exanthematous pustulosis (AGEP), confusional state and cutaneous vasculitis. Bezoar observed in overdosage [see Overdosage (10)].

09/18/2020 (SUPPL-41)

5 Warnings and Precautions

5.5 Metabolic Changes

(Extensive changes; please refer to label)

5.9 Increases in Blood Pressure

(Additions and/or revisions underlined)

In placebo-controlled trials in children and adolescents with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of increases at any time in systolic blood pressure (greater than or equal to 20 mmHg) was 15.2% (51/335) for SEROQUEL and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (greater than or equal to 10 mmHg) was 40.6% (136/335) for SEROQUEL and 24.5% (40/163) for placebo. In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis. Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.

In a placebo-controlled SEROQUEL XR clinical trial (8 weeks duration) in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (greater than or equal to 20 mmHg) was 6.5% (6/92) for SEROQUEL XR and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (greater than or equal to 10 mmHg) was 46.7% (43/92) for SEROQUEL XR and 36.0% (36/100) for placebo.

6 Adverse Reactions

6.1 Clinical Studies Experience

(Extensive changes to table; please refer to label)

6.2 Postmarketing Experience

(Additions underlined)

…

Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, drug reaction with eosinophilia and systemic symptoms (DRESS), hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), decreased platelet count, serious liver reactions (including hepatitis, liver necrosis, and hepatic failure), agranulocytosis, intestinal obstruction, ileus, colon ischemia, sleep apnea, urinary retention, and acute generalized exanthematous pustulosis (AGEP). Bezoar observed in overdosage [see Ov erdosage (10)].

7 Drug Interactions

7.1 Effect of Other Drugs on Quetiapine

(Additions and/or revisions underlined)

Anticholinergic Drugs:

Concomitant treatment with quetiapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. SEROQUEL should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions (5.20)].

8 Use in Specific Populations

8.4 Pediatric Use

(Extensive changes to table; please refer to label)

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the approximately 3700 patients in clinical studies with SEROQUEL, 7% (232) were 65 years of age or over. In general, there was no indication of any different tolerability of SEROQUEL in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to SEROQUEL, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of SEROQUEL was reduced by 30% to 50% in elderly patients when compared to younger patients [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)].

09/18/2020 (SUPPL-44)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effect of Othe r Drugs on Quetiapine

(Additions underlined)

…

Anticholinergic Drugs:

…

02/05/2020 (SUPPL-43)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, drug reaction with eosinophilia and systemic symptoms (DRESS), hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), decreased platelet count, serious liver reactions (including hepatitis, liver necrosis, and hepatic failure), agranulocytosis, intestinal obstruction, ileus, colon ischemia, sleep apnea, urinary retention, and acute generalized exanthematous pustulosis (AGEP).

08/26/2019 (SUPPL-40)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion with extensive changes; please refer to labeling for complete information)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Risk Summary

Limited data from published literature report the presence of quetiapine in human breast milk at relative infant dose of <1% of the maternal weight-adjusted dosage. There are no consistent adverse events that have been reported in infants exposed to quetiapine through breast milk. There is no information on the effects of quetiapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SEROQUEL XR and any potential adverse effects on the breastfed child from SEROQUEL XR or from the mother’s underlying condition.

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Infertility

Females

Based on the pharmacologic action of quetiapine (D2 antagonism), treatment with SEROQUEL XR may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions are underlined)

…

Before you take SEROQUEL XR, tell your healthcare provider if you have or have had:

diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start SEROQUEL XR and also during therapy.
high levels of total cholesterol, triglycerides or LDL-cholesterol or low levels of HDL-cholesterol
low or high blood pressure
low white blood cell count
cataracts
seizures
abnormal thyroid tests
high prolactin levels
heart problems
liver problems
any other medical condition
pregnancy or plans to become pregnant. It is not known if SEROQUEL XR will harm your unborn baby.
If you become pregnant while receiving SEROQUEL XR, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/
breast-feeding or plans to breast-feed. SEROQUEL XR can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive SEROQUEL XR.
if you have or have had a condition where you cannot completely empty your bladder (urinary retention), have an enlarged prostate, or constipation, or increased pressure inside your eyes.

PATIENT COUNSELING INFORMATION

(additions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking SEROQUEL XR.

…

Pregnancy

Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with SEROQUEL XR. Advise patients that SEROQUEL XR may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to SEROQUEL XR during pregnancy.

Infertility

Advise females of reproductive potential that SEROQUEL XR may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible.

11/29/2018 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

Addition of the following:

5.10 Leukopenia, Neutropenia and Agranulocytosis

Agranulocytosis (defined as absolute neutrophil count <500/mm3) has been reported with quetiapine, including fatal cases and cases in patients without pre-existing risk factors. Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate.

5.20 Anticholinergic (antimuscarinic) Effects

Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to anticholinergic adverse reactions when SEROQUEL XR is used at therapeutic doses, taken concomitantly with other anticholinergic medications , or taken in overdose. SEROQUEL XR should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects.

Constipation was a commonly reported adverse event in patients treated with quetiapine and represents a risk factor for intestinal obstruction. Intestinal obstruction has been reported with quetiapine, including fatal reports in patients who were receiving multiple concomitant medications that decrease intestinal motility.

SEROQUEL XR should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or increased intraocular pressure.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Anticholinergic (antimuscarinic) Effects

6.2 Postmarketing Experience

Additions and/or revisions underlined:

… Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), decreased platelet count, serious liver reactions (including hepatitis, liver necrosis, and hepatic failure), agranulocytosis, intestinal obstruction, ileus, colon ischemia, sleep apnea, and urinary retention.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

Before you take SEROQUEL XR, tell your healthcare provider if you have or have had:

if you have or have had a condition where you cannot completely empty your bladder (urinary retention), have an enlarged prostate, or constipation, or increased pressure inside your eyes.
What are possible side effects of SEROQUEL XR? SEROQUEL XR can cause serious side effects, including:
low white blood cell count. Tell your healthcare provider as soon as possible if you have a fever, flu-like symptoms, or any other infection, as this could be a result of a very low white blood cell count. Your healthcare provider may check your white blood cell level to determine if further treatment or other action is needed.
The most common side effects of SEROQUEL XR include: In Adults:
disturbance in speech or language

In Children and Adolescents:

drowsiness
dizziness
fatigue
stuffy nose
increased appetite
upset stomach
vomiting
dry mouth
tachycardia
weight increased

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Leukopenia/Neutropenia

… their CBC monitored while taking SEROQUEL XR. Patients should be advised to talk to their doctor as soon as possible if they have a fever, flu-like symptoms, sore throat, or any other infection as this could be a result of a very low WBC, which may require SEROQUEL XR to be stopped and/or treatment to be given.

02/23/2017 (SUPPL-39)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Falls

(new subsection added)

Atypical antipsychotic drugs, including SEROQUEL XR, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

6 Adverse Reactions

(addition underlined)

…

• Falls

...

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(addition underlined)

What are possible side effects of SEROQUEL XR?

…

• falls can happen in some people who take SEROQUEL XR. These falls may cause serious injuries.

…

06/17/2016 (SUPPL-38)

Approved Drug Label (PDF)

6 Adverse Reactions

Post Marketing Experience

Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include (addition of)… drug reaction with eosinophilia and systemic symptoms (DRESS),...