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.
TEMIXYS (NDA-211284)
(LAMIVUDINE; TENOFOVIR DISOPROXIL FUMARATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/29/2019 (SUPPL-2)
5 Warnings and Precautions
5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV(additions underlined)
…, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
…
additions underlined)
…
Prior to initiation and during use of TEMIXYS, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.
…
(additions underlined)
…
Clinical trials
evaluating TDF-containing regimens in pediatric subjects were conducted. Under
normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1
infected pediatric subjects less than 18 years of age, bone effects were
similar to those observed in adult subjects and suggest increased bone
turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected
pediatric subjects as compared to the control groups. In all pediatric trials,
normal skeletal growth (height) was not affected for the duration of the
clinical trials.
The effects of
TDF-associated changes in BMD and biochemical markers on long-term bone health
and future fracture risk are unknown. The long-term effect of lower spine
and total body BMD on skeletal growth in pediatric patients, and in particular,
the effects of long-duration exposure in younger children is unknown.
Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial.
…
(new subsection added)
The concomitant use of TEMIXYS and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs .
See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TEMIXYS; review concomitant medications during therapy with TEMIXYS; and monitor for adverse reactions associated with the concomitant drugs.
6 Adverse Reactions
(additions underlined)
The following adverse reactions are discussed in other sections of the labeling:
…
Bone Loss and Mineralization Defects
…
8 Use in Specific Populations
8.1 Pregnancy(subsection revised, additions underlined)
…
Tenofovir Disoproxil Fumarate: Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for tenofovir disoproxil fumarate (TDF) (2.1%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%.
In animal reproduction studies, no adverse developmental effects were observed when TDF was administered at doses/exposures greater than or equal to 14 (TDF) and 2.7 (tenofovir) times those of the recommended daily dose of TDF (see Data).
…
Tenofovir Disoproxil Fumarate: Based on prospective reports from the APR exposures to TDF-containing regimens during pregnancy resulting in live births (including 3,342 exposed in the first trimester and 1,475 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.8%) with first trimester exposure to TDF- containing regimens, and 2.1% (95% CI: 1.4% to 3.0%) with the second/third trimester exposure to TDF- containing regimens.
Prospective reports from the APR of overall major birth defects in pregnancies exposed to TDF are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.
…
Tenofovir Disoproxil Fumarate: TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of TDF.
(subsection revised, additions underlined)
…
Because of the potential for 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TEMIXYS.
…
Tenofovir Disoproxil Fumarate: Based on published data, tenofovir has been shown to be present in human breast milk. It is not known if tenofovir affects milk production or has effects on the breastfed child.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
…
Bone Loss and Mineralization Defects
Inform patients that decreases in bone mineral density have been observed with the use of lamivudine and tenofovir disoproxil fumarate. Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia.
…
Drug Interactions
Advise patients that TEMIXYS may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other medication, including other HIV drugs and drugs for treatment of hepatitis C virus.
Do not administer TEMIXYS with HEPSERA.
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