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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.
ZOLEDRONIC ACID (NDA-203231)
(ZOLEDRONIC ACID)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/27/2020 (SUPPL-15)
5 Warnings and Precautions
5.10 Embryo-Fetal Toxicity
(Newly added subsection)
Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were greater than or equal to 2.4 times the human clinical exposure based on area under the curve (AUC). Bisphosphonates, such as Zoledronic Acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and after Zoledronic Acid Injection treatment [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].
6 Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions underlined)
Hypersensitivity Reactions
There have been reports of allergic reaction with intravenous zoledronic acid including angioedema and bronchoconstriction. Cases of anaphylactic reaction/shock have also been reported. Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported.
Additional adverse reactions reported in postmarketing use include:
CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; uveitis; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchospasms, interstitial lung disease (ILD) with positive rechallenge; Renal: hematuria, proteinuria, acquired Fanconi syndrome; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia, hypocalcemia (cardiac arrhythmias and neurologic adverse events including seizures, tetany and numbness have been reported due to severe hypocalcemia).
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were greater than or equal to 2.4 times the human clinical exposure based on AUC (see Data). Bisphosphonates, such as Zoledronic Acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years.
There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.
Data
Animal Data
In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal reactions were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse reactions included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved, or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal reactions observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low- dose group at 0.1 mg/kg/day…
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
After administration of Zoledronic Acid Injection, it is not known whether zoledronic acid is present in human milk, or whether it affects milk production or the breastfed child. Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during and after Zoledronic Acid Injection treatment.
(Newly added section)
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiation of Zoledronic Acid Injection.
Contraception
Females
Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Advise females of reproductive potential to use effective contraception during and after Zoledronic Acid Injection treatment.
Infertility
Females
Based on animal studies, zoledronic acid may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Extensive changes; please refer to label)
10/27/2020 (SUPPL-16)
5 Warnings and Precautions
5.10 Embryo-Fetal Toxicity
(Newly added subsection)
Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were greater than or equal to 2.4 times the human clinical exposure based on area under the curve (AUC). Bisphosphonates, such as Zoledronic Acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and after Zoledronic Acid Injection treatment [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].
6 Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions underlined)
Hypersensitivity Reactions
There have been reports of allergic reaction with intravenous zoledronic acid including angioedema and bronchoconstriction. Cases of anaphylactic reaction/shock have also been reported. Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported.
Additional adverse reactions reported in postmarketing use include:
CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; uveitis; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchospasms, interstitial lung disease (ILD) with positive rechallenge; Renal: hematuria, proteinuria, acquired Fanconi syndrome; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia, hypocalcemia (cardiac arrhythmias and neurologic adverse events including seizures, tetany and numbness have been reported due to severe hypocalcemia).
8 Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were greater than or equal to 2.4 times the human clinical exposure based on AUC (see Data). Bisphosphonates, such as Zoledronic Acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years.
There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.
Data
Animal Data
In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal reactions were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse reactions included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved, or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal reactions observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low- dose group at 0.1 mg/kg/day…
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
After administration of Zoledronic Acid Injection, it is not known whether zoledronic acid is present in human milk, or whether it affects milk production or the breastfed child. Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during and after Zoledronic Acid Injection treatment.
8.3 Females and Males of Reproductive Potential
(Newly added section)
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiation of Zoledronic Acid Injection.
Contraception
Females
Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Advise females of reproductive potential to use effective contraception during and after Zoledronic Acid Injection treatment.
Infertility
Females
Based on animal studies, zoledronic acid may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Extensive changes; please refer to label)
10/27/2020 (SUPPL-17)
5 Warnings and Precautions
5.10 Embryo-Fetal Toxicity
(Newly added subsection)
Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were greater than or equal to 2.4 times the human clinical exposure based on area under the curve (AUC). Bisphosphonates, such as Zoledronic Acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and after Zoledronic Acid Injection treatment [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].
6 Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions underlined)
Hypersensitivity Reactions
There have been reports of allergic reaction with intravenous zoledronic acid including angioedema and bronchoconstriction. Cases of anaphylactic reaction/shock have also been reported. Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported.
Additional adverse reactions reported in postmarketing use include:
CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; uveitis; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchospasms, interstitial lung disease (ILD) with positive rechallenge; Renal: hematuria, proteinuria, acquired Fanconi syndrome; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia, hypocalcemia (cardiac arrhythmias and neurologic adverse events including seizures, tetany and numbness have been reported due to severe hypocalcemia).
8 Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
Based on findings from animal studies and its mechanism of action, Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman. [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were greater than or equal to 2.4 times the human clinical exposure based on AUC (see Data). Bisphosphonates, such as Zoledronic Acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years.
There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.
Data
Animal Data
In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal reactions were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse reactions included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved, or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal reactions observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low- dose group at 0.1 mg/kg/day…
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
After administration of Zoledronic Acid Injection, it is not known whether zoledronic acid is present in human milk, or whether it affects milk production or the breastfed child. Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during and after Zoledronic Acid Injection treatment.
8.3 Females and Males of Reproductive Potential
(Newly added section)
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiation of Zoledronic Acid Injection.
Contraception
Females
Zoledronic Acid Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Zoledronic acid binds to bone long term and may be released over periods of weeks to years. Advise females of reproductive potential to use effective contraception during and after Zoledronic Acid Injection treatment.
Infertility
Females
Based on animal studies, zoledronic acid may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Extensive changes; please refer to label)
02/02/2017 (SUPPL-13)
6 Adverse Reactions
6.2 Postmarketing ExperienceOsteonecrosis of the Jaw
Additions and/or revisions underlined:
Cases of osteonecrosis (primarily involving the jaw but also of other anatomical sites including hip, femur and external auditory canal) have been reported predominantly in cancer patients …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
- Patients should be informed of the importance of good dental hygiene, routine dental care and regular dental check-ups.
- Patients should be advised to immediately tell their doctor about any oral symptoms such as loosening of a tooth, pain, swelling, or non-healing of sores or discharge during treatment with Zoledronic Acid Injection.