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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.
VYTORIN (NDA-021687)
(EZETIMIBE; SIMVASTATIN)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
03/28/2024 (SUPPL-66)
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions and/or revisions underlined:
…
Hepatobiliary Disorders: cholelithiasis, cholecystitis, elevations in liver transaminases including elevations more than 5 X ULN, hepatitis/jaundice, fatal and non-fatal hepatic failure
…
02/08/2024 (SUPPL-61)
8 Use in Specific Populations
8.1 Pregnancy
PLLR conversion; please refer to label for complete information
8.2 Lactation
PLLR conversion
Risk Summary
There is no information about the presence of ezetimibe or simvastatin in human breast milk, the effects of the drug on the breastfed infant or the effect of the drug on milk production. However, it has been shown that other statins pass into human milk. Statins, including VYTORIN, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breast fed infant.
Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of
action, advise patients that breastfeeding is not recommended during treatment with VYTORIN [see Use in Specific Populations (8.2) and Clinical Pharmacology (12.1)].
Data
Animal Data
Ezetimibe was present in the milk of lactating rats. The pup to maternal plasma ratio for total ezetimibe was 0.5 on lactation day 12.
02/08/2024 (SUPPL-64)
6 Adverse Reactions
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…
Skin and Subcutaneous Tissue Disorders: rash, pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome
02/08/2024 (SUPPL-65)
4 Contraindications
Additions
and/or revisions underlined:
VYTORIN is contraindicated in the following conditions:
Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti- viral medications, and nefazodone) [see Drug Interactions (7.1)].
Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti- viral medications, and nefazodone) [see Drug Interactions (7.1)].
Concomitant use of cyclosporine, danazol, or danazol [see Drug Interactions (7.1)].
Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)].
Hypersensitivity to simvastatin, ezetimibe, or any excipients in VYTORIN. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome, have been reported [see Adverse Reactions (6.2)].
5 Warnings and Precautions
5.1 Myopathy and Rhabdomyolysis
Extensive changes; please refer to label for complete information
5.2 Immune-Mediated Necrotizing Myopathy
Additions and/or revisions underlined:
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue VYTORIN if IMNM is suspected.
5.3 Hepatic Dysfunction
Section title revised
Additions and/or revisions underlined
Increases in serum transaminases have been reported with use of VYTORIN [see Adverse Reactions (6.1)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Marked persistent increases of hepatic transaminases have also occurred with VYTORIN. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including VYTORIN.
…
Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.
Consider liver enzyme testing before VYTORIN initiation and when clinically indicated thereafter. VYTORIN is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue VYTORIN.
5.4 Increases in HBA1c and Fasting Serum Glucose Levels
Section title revision
Additions and/or revisions underlined:
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including VYTORIN. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.
6 Adverse Reactions
Additions and/or revisions underlined:
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]
Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]
Hepatic Dysfunction [see Warnings and Precautions (5.3)]
Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
…
VYTORIN
In the VYTORIN (ezetimibe and simvastatin) placebo-controlled clinical trials database of 1420 patients (age range 20-83 years, 52% female, 87% White, 3% Black or African American, 3% Asians, 5% other races identified as Hispanic or Latino ethnicity) with a median treatment duration of 27 weeks, 5% of patients on VYTORIN and 2.2% of patients on placebo discontinued due to adverse reactions.
…
Simvastatin
In a clinical outcome trial in which 12,064 adult patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times (1200U/L) upper limit of normal [ULN]) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0.02% and 0.9% respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%. The incidence of myopathy and rhabdomyolysis, was highest during
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…
Nervous System Disorders: dizziness, depression, paresthesia, peripheral neuropathy, rare reports of
cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion)
associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin
discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.
7 Drug Interactions
Extensive changes; please refer to label for complete information
8 Use in Specific Populations
8.1 Pregnancy
PLLR conversion; please refer to label for complete information
8.2 Lactation
PLLR conversion
Risk Summary
There is no information about the presence of ezetimibe or simvastatin in human breast milk, the effects of the drug on the breastfed infant or the effect of the drug on milk production. However, it has been shown that other statins pass into human milk. Statins, including VYTORIN, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breast fed infant.
Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with VYTORIN [see Use in Specific Populations (8.2) and Clinical Pharmacology (12.1)].
Data
Animal Data
Ezetimibe was present in the milk of lactating rats. The pup to maternal plasma ratio for total ezetimibe was 0.5 on lactation day 12.
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of ezetimibe in combination with a statin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of VYTORIN for this indication is based on a double-blind, placebo-controlled clinical trial in 248 pediatric patients (142 males and 106 postmenarchal females) 10 years of age and older with HeFH [see Clinical Studies (14)]. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the adolescent males or females, or on menstrual cycle length in females.
The safety and effectiveness of VYTORIN have not been established in pediatric patients younger than 10 years of age with HeFH, or in pediatric patients with other types of hyperlipidemia.
8.5 Geriatric Use
Additions and/or revisions underlined:
Advanced age (?65 years) is a risk factor for VYTORIN-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving VYTORIN for the increased risk of myopathy [see Warnings and Precautions (5.1)].
Of the 10,189 patients who received VYTORIN in clinical studies, 3242 (32%) were 65 and older (this included 844 (8%) who were 75 and older). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients but greater sensitivity of some older individuals cannot be ruled out.
8.6 Renal Impairment
Additions and/or revisions underlined:
Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Doses of VYTORIN exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].
8.7 Hepatic Impairment
Additions and/or revisions underlined:
VYTORIN is contraindicated in patients with acute liver failure or decompensated cirrhosis. [See Contraindications (4) and Warnings and Precautions (5.3).]
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).
Myopathy and Rhabdomyolysis
Advise patients that VYTORIN may cause myopathy and rhabdomyolysis. Inform patients taking the 80 mg daily dose of simvastatin that they are at an increased risk. Inform patients that the risk is also increased when taking certain types of medication or consuming grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dose of an existing medication that they are taking VYTORIN. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7.1)].
Hepatic Dysfunction
Inform patients that VYTORIN may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)].
Increases in HbA1c and Fasting Serum Glucose Levels
Inform patients that increases in HbA1c and fasting serum glucose levels may occur with VYTORIN. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)].
Pregnancy
Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if VYTORIN should be discontinued [see Use in Specific Populations (8.1)].
Lactation
Advise patients that breastfeeding is not recommended during treatment with VYTORIN [see Use in Specific Populations (8.2)].
Missed Dose
Instruct patients to take VYTORIN only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose.
PATIENT INFORMATION
Extensive changes; please refer to label for complete information
09/25/2020 (SUPPL-63)
5 Warnings and Precautions
5.2 Immune-Mediated Necrotizing Myopathy(New subsection added)
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.
10/04/2019 (SUPPL-62)
5 Warnings and Precautions
5.1 Myopathy/Rhabdomyolysis(additions and/or revisions are underlined)
(addition of Daptomycin to the Interacting Agents of table; please refer to labeling for complete information)
…
Drug Interactions
The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels of simvastatin and simvastatin acid. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs that inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, and voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice. Combination of these drugs with VYTORIN is contraindicated. If short- term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with VYTORIN must be suspended during the course of treatment.
The combined use of VYTORIN with gemfibrozil, cyclosporine, or danazol is contraindicated.
Caution should be used when prescribing fenofibrates with VYTORIN, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered.
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing VYTORIN with colchicine.
The benefits of the combined use of VYTORIN with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (fenofibrates or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine.
Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products.
Cases of rhabdomyolysis have been reported with VYTORIN administered with daptomycin.
Temporarily suspend VYTORIN in patients taking daptomycin.
…
7 Drug Interactions
7.10 Daptomycin(newly added subsection)
Cases of rhabdomyolysis have been reported with VYTORIN administered with daptomycin. Both VYTORIN and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Temporarily suspend VYTORIN in patients taking daptomycin.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION(additions and/or revisions are underlined)
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Tell your doctor who prescribes VYTORIN if another doctor increases the dose of another medicine you are taking.
Talk to your doctor before you start taking any new medicines.
Taking VYTORIN with certain other medicines may affect each other causing side effects. VYTORIN may affect the way other medicines work, and other medicines may affect how VYTORIN works.
Taking VYTORIN with certain substances can increase the risk of muscle problems. It is especially important to tell your doctor if you take:
fibric acid derivatives (such as fenofibrate)
amiodarone or dronedarone (drugs used to treat an irregular heartbeat)
verapamil, diltiazem, amlodipine, or ranolazine (drugs used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions)
grapefruit juice (which should be avoided while taking VYTORIN)
colchicine (a medicine used to treat gout)
lomitapide (a medicine used to treat a serious and rare genetic cholesterol condition)
daptomycin (a drug used to treat complicated skin and bloodstream infections)
large doses of niacin or nicotinic acid
Tell your doctor if you are taking niacin or a niacin-containing product, as this may increase your risk of muscle problems, especially if you are Chinese.
It is also important to tell your doctor if you are taking coumarin anticoagulants (drugs that prevent blood clots, such as warfarin).
Tell your doctor about all the medicines you take, including any prescription and nonprescription medicines, vitamins, and herbal supplements.
04/02/2019 (SUPPL-52)
5 Warnings and Precautions
5.1 Myopathy/Rhabdomyolysis(additions underlined)
… Chinese patients may be at increased risk for myopathy.
…
7 Drug Interactions
7.4 Niacin(additions underlined)
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products. The risk of myopathy is greater in Chinese patients. In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (greater than or equal to1 g/day) of niacin. Coadministration of VYTORIN with lipid-modifying doses (greater than or equal to1 g/day) of niacin is not recommended in Chinese patients. It is unknown if this risk applies to other Asian patients
8 Use in Specific Populations
8.8 Chinese Patients(new subsection added)
In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non- Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). The incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe and simvastatin 10/40 mg/day coadministered with extended-release niacin 2 g/day was 1.24%.
Chinese patients may be at higher risk for myopathy, monitor patients appropriately. Coadministration of VYTORIN with lipid-modifying doses (greater than or equal to1 g/day niacin) of niacin-containing products is not recommended in Chinese patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION(additions underlined)
…
What should I tell my doctor before and while taking VYTORIN? Tell your doctor if you:
…
are Chinese
…
What are the possible side effects of VYTORIN? VYTORIN may cause serious side effects, including:
Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death.
…
Your chances of getting muscle problems are higher if you:
…
are Chinese
…
02/28/2018 (SUPPL-60)
5 Warnings and Precautions
5.1 Myopathy/Rhabdomyolysis(Additions and/or revisions are underlined)
… Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. Predisposing factors for myopathy include advanced age greater than or equal to 65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
Drug Interactions
The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels of simvastatin and simvastatin acid…
(Additions and/or revisions are underlined)
In three placebo-controlled, 12-week trials, the incidence of consecutive elevations greater than or equal to 3 X ULN) in serum transaminases was 1.7% overall for patients treated with VYTORIN and appeared to be dose- related with an incidence of 2.6% for patients treated with VYTORIN 10/80. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations greater than or equal to 3 X ULN) in serum transaminases was 1.8% overall and 3.6%...
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
VYTORIN
The most commonly reported adverse reactions (incidence greater than or equal to 2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%)…
8 Use in Specific Populations
8.5 Geriatric Use(Additions and/or revisions are underlined)
… Since advanced age (greater than or equal to 65 years) is a predisposing factor for myopathy, VYTORIN should be prescribed with caution in the elderly. Because advanced age (greater than or equal to 65 years) is a predisposing factor for myopathy, including rhabdomyolysis, VYTORIN should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients greater than or equal to 65 years of age had an increased risk of myopathy…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Patient Information).