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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.
ERIVEDGE (NDA-203388)
(VISMODEGIB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
03/27/2023 (SUPPL-17)
5 Warnings and Precautions
5.3 Musculoskeletal Adverse Reactions
(Newly added subsection)
Musculoskeletal adverse reactions, which may be accompanied by serum creatine phosphokinase (CPK) elevations, have occurred with ERIVEDGE and other drugs which inhibit the hedgehog (Hh) pathway. In the pooled safety population in clinical trials of ERIVEDGE, musculoskeletal and connective tissue adverse reactions occurred in 78% of patients treated, with 7% (9/138) reported as Grade 3. The most frequent manifestations of musculoskeletal and connective tissue adverse reactions (all grades) reported were muscle spasms (72%) and arthralgias (16%). In a post-approval clinical trial of 1232 patients, Grade 3 or 4 elevations in serum CPK laboratory values occurred in 2.4% of the 453 patients who had any CPK measurement [see Adverse Reactions (6.1)].
Obtain baseline serum creatine phosphokinase (CPK) and creatinine levels and as clinically indicated (e.g., if muscle symptoms are reported). Depending on the severity of symptoms, temporary dose interruption or discontinuation may be required for musculoskeletal adverse reactions or serum CPK elevation [see Dosage and Administration (2.3)].
6 Adverse Reactions
(Additions and/or revisions underlined)
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)]
- Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
- Musculoskeletal Adverse Reactions [see Warnings and Precautions (5.3)]
- Premature Fusion of the Epiphyses [see Warnings and Precautions (5.4)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
Muscle-related adverse reactions
- Advise patients starting therapy with ERIVEDGE of the risk of muscle-related adverse reactions. Advise patients to contact their healthcare provider immediately for any new unexplained muscle pain, tenderness, or weakness occurring during treatment or that persists after discontinuing ERIVEDGE [see Warnings and Precautions (5.3)]
07/31/2020 (SUPPL-16)
5 Warnings and Precautions
Newly added subsection:
5.2 Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with ERIVEDGE [see Adverse Reactions (6.2)].
Permanently discontinue ERIVEDGE in patients with these reactions [see Dosage and Administration (2.3)].
6 Adverse Reactions
Newly added information:
The following clinically significant adverse reactions are described elsewhere in the labeling:
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
Premature Fusion of the Epiphyses [see Warnings and Precautions (5.3)]
6.2 Postmarketing Experience
Newly added information:
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [see Warnings and Precautions (5.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
What are the possible side effects of ERIVEDGE?
ERIVEDGE can cause serious side effects, including:
See “What is the most important information I should know about ERIVEDGE?”
Severe skin reactions. Severe skin reactions have happened in some people taking ERIVEDGE. You may need to be treated in a hospital because these severe skin reactions can be life threatening or lead to death.
Tell your healthcare provider right away if you develop any of the following signs or
symptoms of a severe skin reaction, including:
blisters or peeling of your skin
high fever or flu-like symptoms
blisters on your lip, or around your mouth or eyes
enlarged lymph nodes
mouth sores or genital sores
skin pain and burning
Your healthcare provider may permanently stop ERIVEDGE if you develop a severe skin reaction.
Newly added information following Lactation:
Severe Cutaneous Reactions
Inform patients of the signs and symptoms of severe cutaneous reactions. Advise patients to contact their healthcare provider immediately for signs and symptoms of severe cutaneous reactions [see Warnings and Precautions (5.2)].
03/26/2019 (SUPPL-14)
6 Adverse Reactions
Newly added subsection:
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of ERIVEDGE. 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.
Hepatobiliary disorders: Drug-induced liver injury
01/18/2019 (SUPPL-12)
5 Warnings and Precautions
5.1 Embryo-Fetal Toxicity(Additions and/or revisions are underlined)
Based on its mechanism of action, ERIVEDGE can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. In animal reproduction studies, vismodegib was embryotoxic, fetotoxic, and teratogenic at maternal exposures lower than the human exposures at the recommended dose of 150 mg once daily.
Females of Reproductive Potential
Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating ERIVEDGE. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with ERIVEDGE and for 24 months after the final dose.
Males
Vismodegib is present in semen. It is not known if the amount of vismodegib in semen can cause embryo-fetal harm. Advise males to use condoms, even after a vasectomy, to avoid potential drug exposure in pregnant partners and female partners of reproductive potential during therapy and for 3 months after the final dose of ERIVEDGE. Advise male patients not to donate semen during and for 3 months after the final dose of ERIVEDGE.
(Additions and/or revisions are underlined)
Premature fusion of the epiphyses has been reported in pediatric patients exposed to ERIVEDGE. In some cases, fusion progressed after drug. ERIVEDGE is not indicated for pediatric patients.
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
The safety data described below reflect exposure to ERIVEDGE in 138 patients with advanced basal cell carcinoma (BCC) who received ERIVEDGE at doses greater than or equal to 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials [Study SHH3925g, SHH4437g, SHH4476g and SHH4610g]. The median age of these patients was 61 years (range 21 to 101 years), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (range 21 days to 36 months); 111 patients received ERIVEDGE for 6 months or longer.
Amenorrhea:
Among patients from the clinical trials included in the pooled safety data analysis, 30% of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE.
Laboratory Abnormalities
Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia (4%), azotemia (2%) and hypokalemia (1%).
Additionally, in a post-approval clinical trial conducted in 1232 patients with locally advanced or metastatic BCC treated with ERIVEDGE, a subset of 29 patients had baseline values for blood creatine phosphokinase (CPK) reported. Within this subset of patients, 38% had a shift from baseline, including Grade 3 (3%) increased CPK. Grade 3 or 4 increased CPK occurred in 2.4% of the 453 patients across the entire study population with any CPK measurement.
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions are underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ERIVEDGE during pregnancy. Report pregnancies to Genentech at 1-888-835-2555.
Risk Summary
Based on its mechanism of action and findings from animal reproduction studies, ERIVEDGE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of vismodegib during organogenesis at doses below the 150 mg clinical dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats. There are no human data on the use of ERIVEDGE in pregnant women. Advise pregnant women of the potential risk to a fetus.
Data
Animal Data
In an embryo-fetal toxicity study, pregnant rats were administered vismodegib orally at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of 60 mg/kg/day [approximately 2 times the human exposure at the 150 mg clinical dose based on area under the curve (AUC)], which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day [approximately 0.2 times the human exposure (AUC) at the recommended 150 mg clinical dose] resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws).
(Additions and/or revisions are underlined)
Females
Advise females of reproductive potential to use effective contraception during therapy with ERIVEDGE and for 24 months after the final dose.
(Additions and/or revisions are underlined)
The safety and effectiveness of ERIVEDGE have not been established in pediatric patients.
Premature fusion of the epiphyses and precocious puberty have been reported in pediatric patients exposed to ERIVEDGE. In some cases, epiphyseal fusion progressed after drug discontinuation.
Juvenile Animal Toxicity Data
In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at greater than or equal to 50 mg/kg/day (approximately greater than or equal to 0.4 times the human exposure (AUC) at the 150 mg clinical dose). Abnormalities in growing incisor teeth (including degeneration/necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at greater than or equal to 15 mg/kg/day (approximately greater than or equal to 0.2 times the human exposure (AUC) at the 150 mg clinical dose).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Extensive changes; please refer to labeling)
(Additions and/or revisions are underlined)
Pregnancy Exposure Registry:
There is a Pregnancy Exposure Registry for females taking ERIVEDGE who become pregnant. The purpose of this registry is to monitor the health of you and your unborn baby. If you think that you or your female partner may have been exposed to ERIVEDGE during pregnancy, talk to your healthcare provider right away. If you become pregnant during treatment with ERIVEDGE, you or your healthcare provider should report your pregnancy to Genentech at 1-888-835-2555.
08/01/2017 (SUPPL-11)
8 Use in Specific Populations
8.1 PregnancyAnimal Data
All greater than or equal to symbols have been changed to epsilon symbols
All greater than or equal to symbols have been changed to epsilon symbols
11/02/2016 (SUPPL-10)
5 Warnings and Precautions
5.1 Embryo-Fetal Toxicity…Advise females of reproductive potential to use effective contraception during therapy with ERIVEDGE and for 24 months after the final dose…
Advise patients not to donate blood or blood products while receiving ERIVEDGE and for 24 months after the final dose of ERIVEDGE.
Premature fusion of the epiphyses has been reported in pediatric patients exposed to ERIVEDGE. In some cases, fusion progressed after drug discontinuation.
6 Adverse Reactions
6.1 Clinical Trials ExperienceLaboratory Abnormalities:
Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%).
Additionally, in a post-approval clinical trial conducted in 1232 patients with locally advanced or metastatic BCC treated with ERIVEDGE, a subset of 29 patients had baseline values for CPK reported. Within the subset of patients, 38% had a shift from baseline, and one of the patients had a Grade 3 value. The prevalence of Grade 3/4 CPK elevation across the entire study population with any CPK measurement was 2.4% (11 out of 453 patients).
The following adverse reactions have been identified during post-approval use of ERIVEDGE. 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.
Musculoskeletal and connective tissue disorders: Premature fusion of the epiphyses.
Investigations: blood creatine phosphokinase increased8 Use in Specific Populations
8.1 PregnancyData
Animal Data
All epsilon symbols in this section have been replaced with greater than or equal to symbols.
…Because of the potential for serious adverse reactions in breastfed infants from ERIVEDGE, advise a nursing woman that breastfeeding is not recommended during therapy with ERIVEDGE and for 24 months after the final dose.
Contraception
Females
…Advise females of reproductive potential to use effective contraception during therapy and for 24 months after the final dose of ERIVEDGE.
The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. Premature fusion of the epiphyses has been reported in pediatric patients exposed to ERIVEDGE. In some cases, fusion progressed after drug discontinuation.
All epsilon symbols in this section have been replaced with greater than or equal to symbols.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEWhat is the most important information I should know about ERIVEDGE?
In order to avoid pregnancy, you should use birth control during treatment and for 24 months after your final dose of ERIVEDGE.
See “What is the most important information I should know about ERIVEDGE?”
are breastfeeding or plan to breastfeed. It is not known if ERIVEDGE passes into your breast milk. You should not breastfeed during treatment and for 24 months after your final dose of ERIVEDGE…
What should I avoid while taking ERIVEDGE?
Do not donate blood or blood products while you are taking ERIVEDGE and for 24 months after your final dose.
See “What is the most important information I should know about ERIVEDGE?”
Bone growth problems. Bone growth problems have happened in children who have been exposed to ERIVEDGE. These problems may continue even after stopping treatment with ERIVEDGE.
Advise females of reproductive potential to use effective contraception during therapy with and for 24 months after the final dose of ERIVEDGE.
Lactation
Advise women that breastfeeding is not recommended during therapy with ERIVEDGE and for 24 months after the final dose.
Blood Donation
Advise patients not to donate blood or blood products while taking ERIVEDGE and for 24 months after the final dose of ERIVEDGE.
Premature Fusion of the Epiphyses
Advise patients and caregivers that premature fusion of the epiphyses has been reported in pediatric patients exposed to ERIVEDGE. In some cases, fusion progressed after drug discontinuation.