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.

LIDOCAINE HYDROCHLORIDE 0.4% AND DEXTROSE 5% IN PLASTIC CONTAINER (NDA-018461)

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

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02/07/2017 (SUPPL-58)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

Hypersensitivity reactions, including anaphylactic reactions, have been reported with lidocaine. Lidocaine hydrochloride is contraindicated in patients with a history of hypersensitivity to local anesthetics of the amide type.

Lidocaine is contraindicated in patients with Stokes-Adams syndrome, Wolff-Parkinson-White syndrome, or with severe degrees of sinoatrial, atrioventricular, or intraventricular block.

5 Warnings and Precautions

PRECAUTIONS, DRUG INTERACTIONS

(section revised, additions underlined)

Digitalis derivatives: Monitor toxicity when lidocaine is used with caution in patients with digitalis toxicity accompanied by supraventricular arrhythmia and/or atrioventricular block (see Contraindications).

When lidocaine is administered with other antiarrhythmic drugs such as amiodarone, phenytoin, procainamide, propranolol or quinidine, the cardiac effects may be additive or antagonistic and toxic effects may be additive.

Coadministration of propranolol or cimetidine with lidocaine has been reported to reduce the clearance of lidocaine from the plasma and may result in toxic accumulation of the drug.

Pharmacokinetic Interactions

Concomitant treatment with drugs which are inhibitors of CYP1A2 and/or CYP3A4 has the potential to increase lidocaine plasma levels by decreasing lidocaine clearance and thereby prolonging the elimination half-life. Monitor toxicity when administering lidocaine with CYP1A2 and/or CYP3A4 inhibitors.

Concomitant use of lidocaine at steady-state concentrations of the CYP1A2 inhibitor fluvoxamine increases intravenous lidocaine plasma AUC and Cmax by 71% and 22%, and decreases MEGX AUC and Cmax by 54% and 65%. Fluvoxamine decreases the plasma clearance of lidocaine by 41%-60% and prolonged the mean half-life one hour. Monitor toxicity when coadministering these medications.

Concomitant use of lidocaine with propofol, a hypnotic agent and CYP3A4 inhibitor, may increase lidocaine plasma levels by reducing lidocaine clearanc. Monitor toxicity when coadministering lidocaine with propofol.

Concomitant treatment with drugs which are inducers of CYP1A2 and/or CYP3A4 (e.g., phenytoin) has the potential to decrease lidocaine plasma levels and higher doses may be required.

Concomitant use of lidocaine with a weak CYP1A2 and CYP3A4 inhibitor has been reported to increase lidocaine plasma levels by 24% – 75% and may result in toxic accumulation of the drug. Monitor toxicity when coadministering lidocaine with cimetidine.

Beta-adrenergic blockers (e.g. propranolol): Concomitant use of lidocaine with beta- adrenergic blockers may increase lidocaine plasma levels by decreasing hepatic blood flow and thereby decrease lidocaine clearance. Monitor for toxicity when coadministering lidocaine with drugs that decrease hepatic blood flow.

PRECAUTIONS, GENERAL

(subsection revised, additions underlined)

If malignant hyperthermia develops, discontinue administration immediately and institute therapeutic countermeasures as clinically indicated.

Lidocaine hydrochloride should not be added to blood transfusion assemblies because of the possibilities of pseudoagglutination or hemolysis.

PRECAUTIONS, NURSING MOTHERS

(section revised, additions underlined)

Lidocaine is present in human milk. Published studies have reported a range of lidocaine milk: plasma ratios between 0.4-1.1. Limited data available on lidocaine’s effects on the breastfed child have not revealed a consistent pattern of associated adverse events. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for lidocaine and any potential adverse effects on the breastfed infant from lidocaine or from the underlying maternal condition.

PRECAUTIONS, PREGNANCY

(additions underlined)

Teratogenic Effects:

Reproduction studies have been performed in rats at doses up to five times the maximum human dose and have revealed no significant findings. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, physicians should carefully consider the potential risks and benefits for each specific patient before prescribing lidocaine hydrochloride.

Lidocaine may cross the placental barrier.

WARNINGS

(subsection revised, additions underlined)

Constant monitoring with an electrocardiograph is essential to the administration of lidocaine hydrochloride intravenously. Signs of excessive depression of cardiac conductivity, such as prolongation of the PR interval, widening of the QRS interval and the appearance or aggravation of arrhythmias, should be followed by prompt cessation of the intravenous infusion of this agent. It is mandatory to have emergency resuscitative equipment and drugs immediately available to manage adverse reactions involving cardiovascular, respiratory, or central nervous systems. Central nervous system adverse reactions are associated with venous plasma levels above 6.0 ?g free base per mL (see ADVERSE REACTIONS).

Hypersensitivity, including anaphylaxis, has been reported with lidocaine-containing solutions. Stop the infusion immediately if signs of hypersensitivity develop.

In patients with sinus bradycardia or incomplete heart block, the administration of lidocaine hydrochloride intravenously for the elimination of ventricular ectopic beats without prior acceleration in heart rate (e.g., by isoproterenol or by electric pacing) may promote more frequent and serious ventricular arrhythmias or complete heart block (see Contraindications).

Because lidocaine is metabolized mainly in the liver and excreted by the kidneys, patients with renal or hepatic insufficiency may be at increased risk for toxicity.

6 Adverse Reactions

(additions underlined)

Nervous System Disorders: respiratory depression and arrest; unconsciousness; convulsions; tremors; twitching; vomiting; blurred or double vision; drowsiness; dizziness; light-headedness; tinnitus; sensation of heat, cold or numbness; euphoria; apprehension; agitation; confusional state; paresthesia; dysarthria.

Cardiovascular System: cardiovascular arrest; bradycardia which may lead to cardiac arrest; hypotension, Ventricular fibrillation, Ventricular tachycardia, Ventricular arrhythmia, Asystole.

Gastrointestinal Disorders: Hypoesthesia oral, Nausea,

Hematologic Effects: methemoglobinemia.

Psychiatric Disorders: Disorientation

7 Drug Interactions

(additions underlined)

Lidocaine is incompatible with the following due to precipitate formation (includes but is not limited to):

• Amphotericin

• Cephazolin sodium

• Phenytoin sodium

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Lidocaine must not be infused simultaneously through the same tubing with other medicinal products without first verifying their compatibility.

8 Use in Specific Populations

Hepatic Impairment

(additions underlined)

Is likely to decrease clearance and increase exposure level of lidocaine. Administer lidocaine at a

lower maintenance infusion rate with close monitoring of toxicity in patients with hepatic impairment.

Pediatrics

(additions underlined)

Clinical studies to establish pediatric dosing schedules have not been conducted. The bolus dose should be repeated if infusion is not initiated within 15 minutes of the initial bolus dose.

Renal Impairment

(additions underlined)

In patients with severe renal impairment (creatinine clearance eGFR less than 30 mL/min/1.73 m2), administer lidocaine at lower maintenance infusion rate with close toxicity monitoring of toxicity.