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Guide
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.
VERSACLOZ (NDA-203479)
(CLOZAPINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
04/26/2023 (SUPPL-21)
Boxed Warning
Orthostatic Hypotension, Bradycardia, Syncope
Additions and/or revisions underlined:
Orthostatic 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, with doses as low as 12.5 mg per day, or when restarting patients who have had even a brief interruption in treatment with Versacloz. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use VERSACLOZ 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, 2.6), Warnings and Precautions (5.3)].
5 Warnings and Precautions
5.3 Orthostatic Hypotension, Bradycardia, and Syncope
Additions and/or revisions underlined:
…
Consider reducing the dose if hypotension occurs. When restarting VERSACLOZ in patients who have had even a brief interruption in treatment with VERSACLOZ, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Dosage and Administration (2.6)].
…
5.8 Gastrointestinal Hypomotility and Severe Complications
Additions and/or revisions underlined:
Severe gastrointestinal adverse reactions have occurred with the use of VERSACLOZ, 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, which can result in, fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis [see Adverse Reaction (6.2)].
…
6 Adverse Reactions
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…
Gastrointestinal System
Acute pancreatitis, dysphagia, salivary gland swelling, megacolon, and intestinal ischemia, infarction, perforation, ulceration or necrosis.
…
07/29/2020 (SUPPL-12)
5 Warnings and Precautions
5.6 Myocarditis, Cardiomyopathy and Mitral Valve Incompetence(Subsection title revised; Additions and/or revisions underlined)
Myocarditis and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue VERSACLOZ and obtain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with VERSACLOZ. However, if the benefit of VERSACLOZ treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with VERSACLOZ in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.
Consider the possibility of myocarditis or cardiomyopathy in patients receiving VERSACLOZ who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression). Myocarditis most frequently presents within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis and cardiomyopathy can occur at any period during treatment with VERSACLOZ. It is common for nonspecific flu- like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure. Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP). Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction. In patients who are diagnosed with cardiomyopathy while taking clozapine 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 underlined)
The following adverse reactions are discussed in more detail in other sections of the labeling:
Severe Neutropenia [see Warnings and Precautions (5.1)].
Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.3)].
Falls [see Warnings and Precautions (5.4)].
Seizures [see Warnings and Precautions (5.5)].
Myocarditis, Cardiomyopathy and Mitral Valve Incompetence [see Warnings and Precautions (5.6)].
Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.7)].
Gastrointestinal Hypomotility and Severe Complications [see Warnings and Precautions (5.8)].
Eosinophilia [see Warnings and Precautions (5.9)].
QT Interval Prolongation [see Warnings and Precautions (5.10)].
Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.11)].
Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.12)].
Hepatotoxicity [see Warnings and Precautions (5.13)].
Fever [see Warnings and Precautions (5.14)].
Pulmonary Embolism [see Warnings and Precautions (5.15)].
Anticholinergic Toxicity [see Warnings and Precautions (5.16)].
Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.17)].
Tardive Dyskinesia [see Warnings and Precautions (5.18)].
Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.19)].
Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.20)].
(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, 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, and periorbital edema.
Endocrine System Pseudopheochromocytoma. Gastrointestinal System
Acute pancreatitis, dysphagia, salivary gland swelling, 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.
Miscellaneous
Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion; please refer to label)
(PLLR conversion)
Risk Summary
Clozapine is present in human milk. There are reports of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk (see Clinical Considerations). There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for VERSACLOZ and any potential adverse effects on the breastfed-child from VERSACLOZ or from the underlying maternal condition.
Clinical Considerations
Infants exposed to VERSACLOZ should be monitored for excess sedation.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
…
Pregnancy: Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with VERSACLOZ. Advise patients that VERSACLOZ 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 exposure registry that monitors pregnancy outcomes in women exposed to clozapine during pregnancy [see Use in Specific Populations (8.1)].
Lactation: Advise breastfeeding women using VERSACLOZ to monitor infants for excess sedation and to seek medical care if they notice this sign [see Use in Specific Populations (8.2)].
…
(Additions and/or revisions underlined)
…
are pregnant or plan to become pregnant. It is not known if VERSACLOZ will harm your unborn baby. Talk to your healthcare provider if you become pregnant while taking VERSACLOZ.
- If you become pregnant while receiving clozapine, 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/
…
What are the possible side effects of VERSACLOZ?
VERSACLOZ may cause serious side effects, including:
- See "What is the most important information I should know about VERSACLOZ?"
- severe constipation and bowel problems. You may not feel or be aware of constipation symptoms. Contact your healthcare provider if you are having bowel movements at less than your normal frequency, especially if it is less than three times a week, you have hard or dry stools, or you have difficulty passing gas. Talk with your healthcare provider about ways to prevent constipation. Other symptoms associated with bowel problems include nausea, bloating or stomach swelling, stomach pain, and vomiting.
…
04/14/2020 (SUPPL-14)
5 Warnings and Precautions
5.16 Anticholinergic Toxicity(Additions and/or revisions underlined)
VERSACLOZ has potent anticholinergic effects. Treatment with VERSACLOZ 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.
(Newly added subsection)
Severe gastrointestinal adverse reactions have occurred with the use of VERSACLOZ, 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 for 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 VERSACLOZ, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in VERSACLOZ 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 and Cardiomyopathy
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Gastrointestinal Hypomotility and Severe Complications
Eosinophilia
QT Interval Prolongation
Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)
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
(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, and post-discontinuation cholinergic rebound adverse reactions.
Cardiovascular System
Atrial or ventricular fibrillation, ventricular tachycardia, QT interval prolongation, Torsades de Pointes, myocardial infarction, cardiac arrest, and periorbital edema.
Endocrine System
Pseudopheochromocytoma.
Gastrointestinal System
Acute pancreatitis, dysphagia, salivary gland swelling, 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, and renal failure.
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.
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.
Miscellaneous
Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.
7 Drug Interactions
7.1 Potential for Other Drugs to Affect VERSACLOZ(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 VERSACLOZ with anticholinergic drugs when possible.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Discuss the following issues with patients and caregivers:
…
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-10)
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 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.
(Newly added subsection)
VERSACLOZ may cause somnolence, postural hypotension, and 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 treatment.
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
• Falls: Inform patients of the risk of falls, which may lead to fractures or other injuries.
• Hepatotoxicity: Instruct patients to immediately report to their physician any symptoms or signs of potential liver injury (e.g. fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy).
What are the possible side effects of VERSACLOZ? VERSACLOZ may cause serious side effects, including:
• falls, which may lead to fractures or other injuries
• liver problems. Call your healthcare provider right away if you have any of these symptoms:
• nausea
• vomiting
• loss of appetite
• feel tired
• pain on the right side of your stomach (abdomen)
• yellowing of your skin or the whites of your eyes