Drug Safety-related Labeling Changes (SrLC)
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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.
BACTRIM (NDA-018374)
(SULFAMETHOXAZOLE; TRIMETHOPRIM)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/21/2025 (SUPPL-29)
05/21/2021 (SUPPL-28)
02/09/2018 (SUPPL-26)
03/04/2017 (SUPPL-25)
4 Contraindications
PLR conversion; additions and/or revisions underlined:
BACTRIM is contraindicated in the following:
- Pediatric patients less than two months of age
5 Warnings and Precautions
PLR conversion; additions and/or revisions underlined:
5.1 Embryofetal Toxicity
5.2 Hypersensitivity and Other Fatal Reactions
… Complete blood counts should be done frequently in patients receiving sulfonamides. Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.
5.3 Thrombocytopenia
… Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Monitor patients for hematologic toxicity. Thrombocytopenia usually resolves …
5.4 Streptococcal Infections and Rheumatic Fever
5.5 Clostridium difficile-Associated Diarrhea
Antibacterial replaces antibiotic throughtout subsection.
5.6 Sulfite Sensitivity
5.7 Benzyl Alcohol Toxicity in Pediatric Patients (“Gasping Syndrome”)
BACTRIM contains benzyl alcohol as a preservative. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol- preserved formulations in infusion solutions, including BACTRIM. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. BACTRIM is contraindicated in pediatric patients less than two months.
When prescribing BACTRIM in pediatric patients (two months of age and older), consider the combined daily metabolic load of benzyl alcohol from all sources including BACTRIM (contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.
5.8 Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia
5.9 Folate Deficiency
Avoid use of BACTRIM in patients with impaired renal or hepatic function, in those with possible folate deficiency.
5.10 Hemolysis
5.11 Infusion Reactions
5.12 Hypoglycemia
5.13 Impaired Phenylalanine Metabolism
Trimethoprim, component of
BACTRIM, has been noted …
5.14
Porphyria and Hypothyroidism
Like other drugs containing sulfonamides, BACTRIM can precipitate porphyria crisis and hypothyroidism. Avoid use of BACTRIM in patients with porphyria or thyroid dysfunction.
5.15 Potential
Risk in the Treatment of Pneumocystis
jirovecii Pneumonia in Patients with
Immunodeficiency Syndrome
(AIDS)
5.16 Electrolyte Abnormalities
5.17 Monitoring of Laboratory Tests
Complete blood counts should be done frequently in patients receiving BACTRIM. Discontinue BACTRIM if a significant reduction in the count of any formed blood element is noted. Perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function.
5.18 Development of Drug-Resistant Bacteria
6 Adverse Reactions
PLR conversion:
The following serious adverse reactions are described elsewhere in the labeling:
- Embryo-fetal Toxicity
- Hypersensitivity and Other Fatal Reactions
- Thrombocytopenia Clostridium difficile-Associated Diarrhea
- Sulfite Sensitivity
- Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia
- Infusion Reactions
- Hypoglycemia
- Electrolyte Abnormalities
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
… The most common adverse reactions are gastrointestinal disturbances (nausea, vomiting, and anorexia) and allergic skin reactions (such as rash and urticaria).
Local reaction, pain and slight irritation on intravenous (IV) administration are infrequent. Thrombophlebitis has been observed.
Table 3: Adverse Reactions Reported with BACTRIM
Table was previously known as Table 2; addition of Metabolic and Nutritionalto Body System; please refer to label.
7 Drug Interactions
Additions and/or revisions underlined:
Potential for BACTRIM to Affect Other Drugs
… Sulfamethoxazole is an inhibitor of CYP2C9. Avoid coadministration of BACTRIM with drugs …
Table 4: Drug Interactions with BACTRIM
Table was previously known as Table 3.
8 Use in Specific Populations
8.1 PregnancyPLLR Conversion, as below:
Risk Summary
BACTRIM may cause fetal harm if administered to a pregnant woman. Some epidemiologic studies suggest that exposure to BACTRIM during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot.
One of 3 rat studies showed cleft palate at doses approximately 5 times the recommended human dose on a body surface area basis; the other 2 studies did not show teratogenicity at similar doses. Studies in pregnant rabbits showed increased fetal loss at approximately 6 times the human dose on a body surface area basis.The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Advise pregnant women of the potential harm of BACTRIM to the fetus.
Clinical Considerations
Disease-associated Maternal and/or Embryo/Fetal Risk
Urinary tract infection in pregnancy is associated with adverse perinatal outcomes such as preterm birth, low birth weight, and pre-eclampsia, and increased mortality to the pregnant woman. P. jirovecii pneumonia in pregnancy is associated with preterm birth and increased morbidity and mortality for the pregnant woman. BACTRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Data
Human Data
While there are no large, prospective, well-controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to BACTRIM with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons.
Alternatively, other epidemiologic studies did not detect statistically significant associations between BACTRIM exposure and specific malformations. Brumfitt and Pursell,10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral trimethoprim and sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester.
In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.
Animal Data
In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.
Risk Summary
Levels of BACTRIM in breast milk are approximately 2 to 5% of the recommended daily dose for pediatric patients over two months of age. There is no information regarding the effect of BACTRIM on the breastfed infant or the effect on milk production. Because of the potential risk of bilirubin displacement and kernicterus on the breastfed child, advise women to avoid breastfeeding during treatment with BACTRIM.
Additions and/or revisions below:
BACTRIM is contraindicated in
pediatric patients younger than two months of age because of the
potential risk of bilirubin displacement and kernicterus.
Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received benzyl alcohol as a preservative in infusion solutions. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.
When prescribing BACTRIM in pediatric patients consider the combined daily metabolic load of benzyl alcohol from all sources including BACTRIM (BACTRIM contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONEmbryo–fetal Toxicity
Advise female patients of reproductive potential that BACTRIM can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.
Lactation
Advise nursing women to avoid breastfeeding during treatment with BACTRIM.
Diarrhea
Advise patients that diarrhea is a common problem …