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.

ATNAA (NDA-021175)

(ATROPINE; PRALIDOXIME CHLORIDE)

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

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05/22/2020 (SUPPL-41)

Approved Drug Label (PDF)

5 Warnings and Precautions

(The following subsections created to comply with PLR; please refer to the label for complete information)

5.1 Cardiovascular Risks

5.2 Heat Injury

5.3 Acute Glaucoma

5.4 Urinary Retention

5.5 Pyloric Stenosis

5.6 Exacerbation of Chronic Lung Disease

6 Adverse Reactions

(PLR conversion)

The following serious adverse reactions are described elsewhere in the labeling:

Cardiovascular Risks
Heat Injury
Acute Glaucoma
Urinary Retention
Pyloric Stenosis
Exacerbation of Chronic Lung Disease

The following adverse reactions associated with the use of atropine and pralidoxime chloride were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

6.1 Atropine

(PLR conversion; Additions and/or revisions underlined)

Because ATNAA contains pralidoxime chloride, which may potentiate the effect of atropine, signs of atropinization may occur earlier than might be expected when atropine is used alone.

Common adverse reactions of atropine can be attributed to its antimuscarinic action. These include dryness of the mouth, blurred vision, dry eyes, photophobia, confusion, headache, dizziness, tachycardia, palpitations, flushing, urinary hesitancy or retention, constipation, abdominal pain, abdominal distention, nausea and vomiting, loss of libido, and impotence. Anhidrosis may produce heat intolerance and impairment of temperature regulation in a hot environment. Dysphagia, paralytic ileus, acute angle closure glaucoma, maculopapular rash, petechial rash, and scarletiniform rash have also been reported. Adverse cardiac reactions, including arrhythmias and myocardial infarction, have been reported with atropine.

Larger doses of atropine may produce central nervous system effects such as restlessness, tremor, fatigue, locomotor difficulties, delirium, and hallucinations.

Hypersensitivity reactions will occasionally occur; these are usually seen as skin rashes, and may progress to exfoliation. Anaphylactic reaction and laryngospasm are rare.

6.2 Pralidoxime Chloride

(PLR conversion; Additions and/or revisions underlined)

Pralidoxime chloride can cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure, muscular weakness, dry mouth, emesis, rash, dry skin, hyperventilation, decreased renal function, and decreased sweating when given parenterally to normal adult volunteers who have not been exposed to anticholinesterase poisons.

In several cases of organophosphorus poisoning, excitement and manic behavior have occurred immediately following recovery of consciousness, in either the presence or absence of pralidoxime chloride administration. However, similar behavior has not been reported in subjects given pralidoxime chloride in the absence of organophosphorus poisoning.

Elevations in AST and/or ALT enzyme levels were observed in 1 of 6 normal adult volunteers given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6 adult volunteers given 1800 mg intramuscularly. Levels returned to normal in about two weeks. Transient elevations in creatine kinase were observed in all normal volunteers given the drug.

6.3 Injection Site

(PLR conversion; Newly added information)

Muscle tightness and pain may occur at the injection site.

6.4 Inadvertent Injection

(PLR conversion; Newly added information)

In cases where ATNAA is inadvertently administered to service members who are not poisoned with susceptible organophosphorus nerve agents having anticholinesterase activity, the following effects on their ability to function normally may occur.

Atropine 2 mg IM, roughly the equivalent of one ATNAA injection, when given to healthy male volunteers, is associated with minimal effects on visual, motor, and mental functions, though unsteadiness walking and difficulty concentrating may occur. Atropine reduces body sweating and increases body temperature, particularly with exercise and under hot conditions.

Atropine 4 mg IM, roughly the equivalent of two ATNAA injections, when given to healthy male volunteers, is associated with impaired visual acuity, visual near point accommodation, logical reasoning, digital recall, learning, and cognitive reaction time. Ability to read is reduced or lost. Subjects are unsteady and need to concentrate on walking. These effects begin about 15 minutes to one hour or more post-dose.

Atropine 6 mg IM, roughly the equivalent of three ATNAA injections, when given to healthy male volunteers, is associated with the effects described above plus additional central effects including poor coordination, poor attention span, and visual hallucinations (colored flashes) in many subjects. Frank visual hallucinations, auditory hallucinations, disorientation, and ataxia occur in some subjects. Skilled and labor-intense tasks are performed more slowly and less efficiently. Decision making takes longer and is sometimes impaired.

It is unclear if the above data, obtained from studies of healthy male subjects, can be extrapolated to other populations. In the elderly and individuals with co-morbid conditions, the effects of greater than or equal to 2 mg atropine on the ability to see, walk, and think properly are unstudied; effects may be greater in susceptible populations.

Service members who are mistakenly injected with ATNAA should avoid potentially dangerous overheating, avoid vigorous physical activity, and seek medical attention as soon as feasible.

7 Drug Interactions

7.1 Succinylcholine and Mivacurium

(PLR conversion; Newly added information)

Since pralidoxime chloride in ATNAA reactivates cholinesterases and succinylcholine and mivacurium are metabolized by cholinesterases, service members poisoned by susceptible organophosphorus nerve agents having anticholinesterase activity who have received ATNAA may exhibit accelerated reversal of the neuromuscular blocking effects of succinylcholine and mivacurium (relative to poisoned service member who has not received pralidoxime). Monitor for neuromuscular effects with concomitant administration.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Atropine readily crosses the placental barrier and enters fetal circulation. There are no adequate data on the developmental risk associated with the use of atropine, pralidoxime chloride, or the combination in pregnant women. Adequate animal reproduction studies have not been conducted with atropine, pralidoxime chloride, or the combination. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.

8.2 Lactation

(PLLR conversion)

Risk Summary

Atropine has been reported to be excreted in human milk. It is not known whether pralidoxime chloride is excreted in human milk. There are no data on the effects of atropine or pralidoxime chloride on the breastfed infant or the effects of the drugs on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ATNAA and any potential adverse effects on the breastfed infant from ATNAA or from the underlying maternal condition.

8.5 Geriatric Use

(PLR conversion; Newly added information)

Geriatric individuals may be more susceptible to the effects of atropine.

8.6 Renal Impairment

(PLR conversion; Newly added information)

Pralidoxime chloride can cause decreased renal function. Individuals with severe renal impairment may require less frequent doses after the initial dose.

8.7 Hepatic Impairment

(PLR conversion; Newly added information)

Individuals with severe hepatic impairment may require less frequent doses after the initial dose.

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

PATIENT COUNSELING INFORMATION

(PLR conversion; Newly added information)

Use by Military Personnel

ATNAA is intended for use by Military Personnel. See the illustrated Instruction Sheet for Military Personnel.

Seek Definitive Medical Care

If feasible and appropriate, advise service member that ATNAA is an initial emergency treatment, that they need additional care at a healthcare facility.

Avoid Overheating

If feasible and appropriate, advise the service member to avoid a hot environment and excessive physical activity since ATNAA can inhibit sweating which can lead to overheating and heat injury.

Other

(PLR conversion)