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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.
EQUETRO (NDA-021710)
(CARBAMAZEPINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/14/2022 (SUPPL-18)
5 Warnings and Precautions
5.5 Embryofetal ToxicityPLLR conversion
Additions and revisions underlined:
EQUETRO can cause fetal harm when administered to a pregnant female [see Use in Specific Populations (8.1)]. Pregnancy registries and epidemiological data suggest a potential association between the use of carbamazepine during pregnancy and major congenital malformations, including neural tube defects and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations). These available data suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.
In animal studies, administration of carbamazepine at clinically relevant doses during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations.
Inform females who may become pregnant about the potential increased risk of major congenital malformations with EQUETRO use during pregnancy. Assess the risks and benefits of EQUETRO and discuss with the patient to determine if an alternative treatment should be considered. EQUETRO can reduce the effectiveness of hormonal contraceptives. Females of reproductive potential should be counseled on the consistent use of effective nonhormonal contraception or barrier methods during treatment with EQUETRO [see Drug Interactions (7.2) and Use in Specific Populations (8.1, 8.3)].
7 Drug Interactions
7.2 Pharmacokinetic Effects of EQUETRO on other DrugsAdditions and revisions underlined:
Hormonal Contraceptives (CYP3A4 Substrates)
EQUETRO is a strong inducer of CYP3A4. EQUETRO can increase the metabolism of certain hormonal contraceptives (through CYP3A4 induction) such as oral and subdermal implant contraceptives, leading to significantly lower plasma concentrations of hormones. This can cause contraceptive failure or breakthrough bleeding. Consider alternatives to oral and subdermal implant contraceptives that are significantly affected by induction of CYP3A4; or consider alternatives to EQUETRO [see Warnings and Precautions (5.5) and Use in Specific Populations (8.3)].
8 Use in Specific Populations
8.1 PregnancyPLLR conversion; please refer to label
PLLR conversion; please refer to label
Additions and revisions underlined:
Bipolar Disorder and Pain of Trigeminal Neuralgia
The safety and effectiveness of EQUETRO have not been established in pediatric patients.
Epilepsy
Safety and effectiveness of EQUETRO in pediatric patients for the treatment of partial seizures, generalized tonic-clonic seizures, and mixed seizure patterns have been established [see Indications and Usage (1.3) and Dosage and Administration (2.4)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideAdditions and revisions underlined:
If you become pregnant while taking EQUETRO, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
are breastfeeding or plan to breastfeed. EQUETRO can pass into breast milk.
Talk to your healthcare provider about the best way to feed your baby while you take EQUETRO.
. . .
EQUETRO may cause fertility problems in males. This may affect your ability to father a child while you are taking EQUETRO. Talk to your healthcare provider if this is a concern for you.
. . .
To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-982-5438 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Additions and revisions underlined:
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Embryofetal Toxicity
EQUETRO may cause fetal harm. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy. [see Warning and Precautions (5.5) and Use in Specific Populations (8.1)].
Pregnancy
Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to EQUETRO during pregnancy [see Use in Specific Populations (8.1)].
Decreased Effectiveness of Hormonal Contraceptives
Inform patients that EQUETRO can significantly decrease the effectiveness of hormonal contraceptives, such as oral contraceptives and subdermal implants. This can cause contraceptive failure or breakthrough bleeding [see Drug Interactions (7.2) and Use in Specific Populations (8.3)].
Infertility
Advise males of reproductive potential that EQUETRO may impair fertility [see Use in Specific Populations (8.3)].
09/23/2016 (SUPPL-11)
4 Contraindications
Concomitant use of delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates for CYP3A4. (addition underlined)
5 Warnings and Precautions
5.10 Liver DamageHepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported. In some cases, hepatic effects may progress despite discontinuation of the drug. In addition rare instances of vanishing bile duct syndrome have been reported. This syndrome consists of a cholestatic process with a variable clinical course ranging from fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts. Some, but not all, cases are associated with features that overlap with other immunoallergenic syndromes such as serious dermatologic reactions and Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur. The drug should be discontinued immediately in cases of aggravated liver dysfunction or active liver disease.
AV heart block, including second and third degree block, have been reported following carbamazepine treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances.
hypoxia and threat to life … However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. (addition underlined)
6 Adverse Reactions
The following serious adverse reactions are discussed in more detail in other sections of the labeling:
Liver Damage (addition)
AV Heart Block (addition)
Laboratory Tests: thyroid function tests (T3, T4)- decreased values (addition)
The following is a list of additional adverse reactions identified in clinical trials or postmarketing reports of other forms of carbamazepine and not reported above for EQUETRO. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
Nervous System: Isolated cases of neuroleptic malignant syndrome have been reported in carbamazepine use both with and without concomitant use of other psychotropic drugs.
Skin: onychomadesis, acute generalized exanthematous pustulosis (AGEP).
To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-9VALIDUS(1-866-982-5438) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7 Drug Interactions
7.1 Pharmacokinetic Effects of other Drugs on EQUETRODrugs that Inhibit Cytochrome P450 3A4 (CYP3A4)
Acetazolamide, azole antifungals (e.g., ketoconazole, itraconazole, fluconazole, voriconazole), cimetidine, ciprofloxacin, clarithromycin, dalfopristin, danazol, dantrolene, delavirdine, diltiazem, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, ibuprofen, isoniazid, loratadine, nefazodone, niacinamide, nicotinamide, olanzapine, omeprazole, oxybutynin, quinine, quinupristin, ticlopidine, troleandomycin, valproate, verapamil, zileuton. (additions underlined)
Drugs that Inhibit Epoxide Hydrolase and CYP3A4
Clarithromycin, erythromycin, loxapine, quetiapine, and valproate also inhibit epoxide hydrolase, resulting in increased levels of the active metabolite carbamazepine-10,11-epoxide.
Drugs that Induce CYP3A4
Such drugs include the following:
Aminophylline, cisplatin, doxorubicin, felbamate, phosphenytoin, methsuximide, phenobarbital, phenytoin, primidone, rifampin and theophylline. (additions underlined)
EQUETRO is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with EQUETRO, monitoring of concentrations or dosage adjustment of these agents may be necessary.
Aripiprazole
When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases
should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced.
Tacrolimus
When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage
adjustments are recommended.
Temsirolimus
The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If
patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be
considered.
Lapatinib
The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient
already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the
lapatinib dose should be reduced.
HIV Protease Inhibitors
Due to strong induction of CYP3A4 caused by carbamazepine, use of EQUETRO with HIV protease inhibitors is not
recommended.
Other CYP1A2 and CYP3A4 Substrates
Cyclophosphamide
Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic co-administration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.
Isoniazid
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
Neuromuscular Blocking Agents
Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered
carbamazepine. Whether or not carbamazepine has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
8 Use in Specific Populations
8.1 PregnancyPregnancy Registry
Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAddition; please refer to label.
Decreased Effectiveness of Oral Contraceptives
Inform patients that EQUETRO can significantly decrease the effectiveness of oral contraception. This can cause contraceptive failure or breakthrough bleeding.
09/23/2016 (SUPPL-12)
4 Contraindications
Concomitant use of delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates for CYP3A4. (addition underlined)
5 Warnings and Precautions
5.10 Liver DamageHepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported. In some cases, hepatic effects may progress despite discontinuation of the drug. In addition rare instances of vanishing bile duct syndrome have been reported. This syndrome consists of a cholestatic process with a variable clinical course ranging from fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts. Some, but not all, cases are associated with features that overlap with other immunoallergenic syndromes such as serious dermatologic reactions and Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur. The drug should be discontinued immediately in cases of aggravated liver dysfunction or active liver disease.
AV heart block, including second and third degree block, have been reported following carbamazepine treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances.
hypoxia and threat to life … However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. (addition underlined)
6 Adverse Reactions
The following serious adverse reactions are discussed in more detail in other sections of the labeling:
Liver Damage (addition)
AV Heart Block (addition)
Laboratory Tests: thyroid function tests (T3, T4)- decreased values (addition)
The following is a list of additional adverse reactions identified in clinical trials or postmarketing reports of other forms of carbamazepine and not reported above for EQUETRO. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
Nervous System: Isolated cases of neuroleptic malignant syndrome have been reported in carbamazepine use both with and without concomitant use of other psychotropic drugs.
Skin: onychomadesis, acute generalized exanthematous pustulosis (AGEP).
To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-9VALIDUS(1-866-982-5438) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7 Drug Interactions
7.1 Pharmacokinetic Effects of other Drugs on EQUETRODrugs that Inhibit Cytochrome P450 3A4 (CYP3A4)
Acetazolamide, azole antifungals (e.g., ketoconazole, itraconazole, fluconazole, voriconazole), cimetidine, ciprofloxacin, clarithromycin, dalfopristin, danazol, dantrolene, delavirdine, diltiazem, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, ibuprofen, isoniazid, loratadine, nefazodone, niacinamide, nicotinamide, olanzapine, omeprazole, oxybutynin, quinine, quinupristin, ticlopidine, troleandomycin, valproate, verapamil, zileuton. (additions underlined)
Drugs that Inhibit Epoxide Hydrolase and CYP3A4
Clarithromycin, erythromycin, loxapine, quetiapine, and valproate also inhibit epoxide hydrolase, resulting in increased levels of the active metabolite carbamazepine-10,11-epoxide.
Drugs that Induce CYP3A4
Such drugs include the following:
Aminophylline, cisplatin, doxorubicin, felbamate, phosphenytoin, methsuximide, phenobarbital, phenytoin, primidone, rifampin and theophylline. (additions underlined)
EQUETRO is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with EQUETRO, monitoring of concentrations or dosage adjustment of these agents may be necessary.
Aripiprazole
When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases
should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced.
Tacrolimus
When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage
adjustments are recommended.
Temsirolimus
The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If
patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be
considered.
Lapatinib
The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient
already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the
lapatinib dose should be reduced.
HIV Protease Inhibitors
Due to strong induction of CYP3A4 caused by carbamazepine, use of EQUETRO with HIV protease inhibitors is not
recommended.
Other CYP1A2 and CYP3A4 Substrates
Cyclophosphamide
Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic co-administration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.
Isoniazid
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
Neuromuscular Blocking Agents
Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered
carbamazepine. Whether or not carbamazepine has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
8 Use in Specific Populations
8.1 PregnancyInformation about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAddition; please refer to label.
Decreased Effectiveness of Oral Contraceptives
Inform patients that EQUETRO can significantly decrease the effectiveness of oral contraception. This can cause contraceptive failure or breakthrough bleeding.