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.

CLOZARIL (NDA-019758)

(CLOZAPINE)

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

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05/19/2023 (SUPPL-103)

Approved Drug Label (PDF)

Boxed Warning

Orthostatic Hypotension, Bradycardia, Syncope

(Additions and/or revisions underlined)

Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with CLOZARIL treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day, or when restarting patients who have had even a brief interruption in treatment with CLOZARIL. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use CLOZARIL cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration (2.2, 2.5), Warnings and Precautions (5.3)].

5 Warnings and Precautions

5.2 Orthostatic Hypotension, Bradycardia, and Syncope

(Additions and/or revisions underlined)

Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).

Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration (2.2)]. Consider reducing the dose if hypotension occurs. When restarting CLOZARIL in patients who have had even a brief interruption in treatment with CLOZARIL, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Dosage and Administration (2.5)].

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

· Orthostatic Hypotension, Bradycardia, and Syncope: Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration. Instruct them to strictly follow the clinician’s instructions for dosage and administration [see Dosage and Administraton (2.2, 2.5)]. Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia [see Warnings and Precautions (5.3)].

12/19/2022 (SUPPL-101)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Gastrointestinal Hypomotility with Severe Complications

Additions and/or revisions underlined:

… In post marketing experience, reported effects range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, which can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration or necrosis [see Adverse Reaction (6.2)]. These reactions have resulted in hospitalization, surgery, and death …

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Gastrointestinal System

Acute pancreatitis, dysphagia, salivary gland swelling, colitis, megacolon, and intestinal ischemia, infarction, perforation, ulceration or necrosis.

02/11/2021 (SUPPL-88)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of clozapine. 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.

Central Nervous System

Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, restless leg syndrome, and post-discontinuation cholinergic rebound adverse reactions.

Cardiovascular System

Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction, cardiac arrest, myocarditis, and periorbital edema.

Vision Disorders Narrow-angle glaucoma.

Narrow-angle glaucoma.

Miscellaneous

Creatine phosphokinase elevation, hyperuricemia, hyponatremia, polyserositis, and weight loss.

04/14/2020 (SUPPL-95)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.16 Anticholinergic Toxicity

(Additions and/or revisions underlined)

CLOZARIL has potent anticholinergic effects. Treatment with CLOZARIL can result in CNS and peripheral anticholinergic toxicity, especially at higher dosages, or in overdose situations. Use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. When possible, avoid concomitant use, with other anticholinergic medications because the risk for anticholinergic toxicity or severe gastrointestinal adverse reactions is increased.

5.8 Gastrointestinal Hypomotility with Severe Complications

(Newly added subsection)

Severe gastrointestinal adverse reactions have occurred with the use of CLOZARIL, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, resulting in intestinal obstruction, fecal impaction, megacolon and intestinal ischemia or infarction. These reactions have resulted in hospitalization, surgery, and death. The risk of severe adverse reactions is further increased with anticholinergic medications (and other medications that decrease gastrointestinal peristalsis); therefore, concomitant use should be avoided when possible.

Prior to initiating CLOZARIL, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in CLOZARIL treated patients. Therefore, reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements, as well as signs and symptoms of complications of hypomotility (e.g., nausea, vomiting, abdominal distension, abdominal pain).

If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are discussed in more detail in other sections of the labeling:

Severe Neutropenia
Orthostatic Hypotension, Bradycardia, and Syncope
Falls
Seizures
Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Gastrointestinal Hypomotility with Severe Complications
Eosinophilia
QT Interval Prolongation
Metabolic Changes
Neuroleptic Malignant Syndrome
Hepatotoxicity
Fever
Pulmonary Embolism
Anticholinergic Toxicity
Interference with Cognitive and Motor Performance
Tardive Dyskinesia
Cerebrovascular Adverse Reactions

Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

Central Nervous System

Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, pleurothotonus, restless legs syndrome and post-discontinuation cholinergic rebound adverse reactions.

Cardiovascular System

Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction sometimes fatal, cardiac arrest, myocarditis sometimes fatal and periorbital edema.

Endocrine System

Pseudopheochromocytoma

Gastrointestinal System

Acute pancreatitis, dysphagia, salivary gland swelling, colitis, megacolon, intestinal ischemia or infarction.

Hepatobiliary System

Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.

Immune System Disorders

Angioedema, leukocytoclastic vasculitis.

Urogenital System

Acute interstitial nephritis, nocturnal enuresis, priapism, renal failure, and retrograde ejaculation.

Skin and Subcutaneous Tissue Disorders

Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens- Johnson Syndrome.

Musculoskeletal System and Connective Tissue Disorders

Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus.

Respiratory System

Aspiration, pleural effusion, pneumonia, lower respiratory tract infection, sleep apnea.

Hemic and Lymphatic System

Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.

Vision Disorders

Narrow-angle glaucoma.

Metabolic Changes

Obesity

Miscellaneous

Creatine phosphokinase elevation, hyperuricemia, hyponatremia, polyserositis and weight loss.

7 Drug Interactions

7.1 Potential for Other Drugs to Affect CLOZARIL

(Additions and/or revisions underlined)

…

Anticholinergic Drugs

Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of CLOZARIL with anticholinergic drugs when possible.

…

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Gastrointestinal Hypomotility with Severe Complications: Educate patients and caregivers on the risks, prevention and treatment of clozapine-induced constipation, including medications to avoid when possible (e.g., drugs with anticholinergic activity). Encourage appropriate hydration, physical activity, and fiber intake and emphasize that prompt attention and treatment to the development of constipation or other gastrointestinal symptoms is critical in preventing severe complications. Advise patients and caregivers to contact their health care provider if they experience symptoms of constipation (e.g., difficulty passing stools, incomplete passage of stool, decreased bowel movement frequency) or other symptoms associated with gastrointestinal hypomotility (e.g., nausea, abdominal distension or pain, vomiting).

…

02/23/2017 (SUPPL-84)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Hepatotoxicity

(Newly added subsection)

Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported in post marketing studies in patients treated with clozapine. Monitor for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine.

5.4 Falls

(Newly added subsection)

Clozaril 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

(Additions and/or revisions are underlined)

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Falls.

• Hepatotoxicity.

01/26/2017 (SUPPL-81)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Respiratory System

Aspiration, pleural effusion, pneumonia, lower respiratory tract infection, sleep apnea.

12/20/2016 (SUPPL-80)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined in WARNING section title)

Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence

Fatal myocarditis and cardiomyopathy have occurred with CLOZARIL treatment…

5 Warnings and Precautions

5.5 Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence

(Additions and/or revisions are underlined)

In patients who are diagnosed with cardiomyopathy while taking CLOZARIL mitral valve incompetence has been reported . These cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography In patients with suspected cardiomyopathy, consider a 2D-echo Doppler examination to identify mitral valve incompetence.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following adverse reactions are discussed in more detail in other sections of the labeling:

Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Cardiovascular System

Gastrointestinal System

Acute pancreatitis, dysphagia, salivary gland swelling, colitis.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Severe Neutropenia:

…Provide patients (and caregivers) with website information and the telephone number on how to obtain the product (www.clozapinerems.com or 1-844-267-8678)

Nursing: Advise patients and caregivers that the patient should not breastfeed…