Drug Safety-related Labeling Changes (SrLC)

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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.

NITHIODOTE (NDA-201444)

(SODIUM NITRITE; SODIUM THIOSULFATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

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01/13/2021 (SUPPL-26)

Approved Drug Label (PDF)

8 Use in Specific Populations

Data

Animal Data

Sodium nitrite

There are no intravenous toxicology studies of sodium nitrite that evaluate the potential for reproductive and developmental toxicity. In a published study, sodium nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion … to treat cyanide poisoning (based on a body surface area comparison).

In a published study, treatment of pregnant rats via drinking water with sodium nitrite at concentrations of either 2000 or 3000 mg/L during gestation and throughout lactation resulted in severe anemia, reduced growth, and increased mortality in the offspring. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (4.7 and 6.5 times the highest clinical dose of sodium nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

In a published study, treatment of pregnant mice with approximately 243 mg/kg sodium nitrite daily (2.6 times the maximum recommended daily dose of 450 mg/day based on body surface are) via the drinking water (1000 mg/L) from Gestation Day 7-18 did not result in evidence of malformations or embryofetal toxicity or maternal toxicity.

Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to sodium nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to sodium nitrite (2000 mg/L via drinking water) demonstrated impaired discrimination …prenatal hypoxia following nitrite exposure.

No malformations or evidence of embryo-fetal toxicity were noted when pregnant mice, rats, hamsters, or rabbits were administered oral doses of sodium thiosulfate of up to 550, 400, 400, or 580 mg/kg, respectively during organogenesis (0.2, 0.3, 0.26, and 0.9 times the human dose of 12.5 g/60 kg person for cyanide poisoning based on body surface area). Published studies suggest that treatment with sodium thiosulfate ameliorates the teratogenic effects of maternal cyanide poisoning in hamsters.

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

Life-sustaining therapy should not be withheld. Cyanide poisoning is a medical emergency in pregnancy, which can be fatal for the pregnant woman and fetus if left untreated (see Clinical Considerations). Therefore, if a pregnant woman has known or suspected cyanide poisoning, Sodium Nitrite Injection for sequential use with Sodium Thiosulfate Injection is recommended [see Indications and Usage (1)]. There are no available data on NITHIODOTE use in pregnant women to establish a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. If available, consider alternative therapies not associated with methemoglobinemia.

There are no intravenous animal studies to evaluate the effect of sodium nitrite, sodium thiosulfate, or the combination on embryofetal development. In published animal studies, fetal mortality was reported when pregnant guinea pigs were subcutaneously administered sodium nitrite at 1.7 times the maximum recommended human dose (MRHD) of 450 mg sodium nitrite when maternal and fetal methemoglobin concentrations were at their peak. In other published studies, no evidence of malformations were reported in guinea pigs, mice, or rats; however, severe anemia, reduced growth, and increased pup mortality was reported when pregnant rats were treated with 4.7 times the MRHD of sodium nitrite via drinking water during gestation and throughout lactation.

In published animal studies, no evidence of embryotoxicity or malformations was reported when sodium thiosulfate was administered orally during organogenesis to pregnant mice, rats, hamsters, or rabbits at 0.2 to 0.9 times the human daily dose of 12.5 g for cyanide poisoning. The sodium thiosulfate studies did not test doses that were comparable to the human dose for cyanide poisoning (see Data).

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Cyanide readily crosses the placenta. Cyanide poisoning is a medical emergency in pregnancy, which can be fatal for the pregnant woman and fetus if left untreated. Treatment for cyanide poisoning should not be withheld because of potential concerns regarding the effects of Nithiodote on the fetus.

Fetal/neonatal adverse reactions

Sodium nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults [see Use in Specific Populations (8.4)]. Based on animal studies, prenatal exposure to sodium nitrite resulted in impaired neural development likely the result of prenatal hypoxia (see Data). If available, consider alternative therapy not known to be associated with methemoglobinemia.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are no data on the presence of sodium nitrite or sodium thiosulfate in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Cyanide and thiocyanate (which is formed when sodium thiosulfate combines with cyanide) are present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment with NITHIODOTE. There are no data to determine when breastfeeding may be safely restarted following the administration of NITHIODOTE.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

Lactation

Advise women that breastfeeding is not recommended during treatment with NITHIODOTE [see Use in Specific Populations (8.2)].