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.

AQUAMEPHYTON (NDA-012223)

(PHYTONADIONE)

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

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03/07/2018 (SUPPL-41)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING – HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE

Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after INTRAVENOUS and INTRAMUSCULAR injection of AquaMEPHYTON. Reactions have occurred despite dilution to avoid rapid infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified.

4 Contraindications

Additions and/or revisions underlined:

Hypersensitivity to phytonadione or any other component of this medication.

5 Warnings and Precautions

Addition of the following subsection:

5.1 Hypersensitivity Reactions

Fatal and severe hypersensitivity reactions, including anaphylaxis, have occurred with intravenous or intramuscular administration of AquaMEPHYTON. Reactions have occurred despite dilution to avoid rapid intravenous infusion and upon first dose. These reactions have included shock, cardiorespiratory arrest, flushing, diaphoresis, chest pain, tachycardia, cyanosis, weakness, and dyspnea. Administer AquaMEPHYTON subcutaneously whenever feasible. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified.

Additions and/or revisions underlined:

5.2 Risk of Serious Adverse Reaction in Infants due to Benzyl Alcohol Preservative

Use benzyl alcohol-free formulations in neonates and infants, if available …

When prescribing AquaMEPHYTON in infants, consider the combined daily metabolic …

5.3 Cutaneous Reactions

Parenteral administration of vitamin K replacements (including AquaMEPHYTON) may cause cutaneous reactions. Reactions have included eczematous reactions, scleroderma-like patches, urticaria, and delayed-type hypersensitivity reactions. Time of onset ranged from 1 day to a year after parenteral administration. Discontinue AquaMEPHYTON for skin reactions and institute medical management.

6 Adverse Reactions

Addition of the following to this section:

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

Hypersensitivity Reactions
Cutaneous Reactions

6.3 Clinical Trials and Post-Marketing Experience

The following adverse reactions associated with the use of AquaMEPHYTON were identified in clinical studies or postmarketing reports. Because some of these reactions were 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.

Cardiac Disorders: Tachycardia, hypotension.

General disorders and administration site conditions: Generalized flushing; pain, swelling, and tenderness at injection site.

Hepatobiliary Disorders: Hyperbilirubinemia

Immune System Disorders: Fatal hypersensitivity reactions, anaphylactic reactions. Neurologic: Dysgeusia, dizziness.

Pulmonary: Dyspnea.

Skin and Subcutaneous Tissue Disorders: Erythema, pruritic plaques, scleroderma-like lesions, erythema perstans.

Vascular: Cyanosis.

7 Drug Interactions

Additions and/or revisions underlined:

Anticoagulants

AquaMEPHYTON may induce temporary resistance to prothrombin-depressing anticoagulants, especially when larger doses of AquaMEPHYTON are used. Should this occur, higher doses of anticoagulant therapy may be needed when resuming anticoagulant therapy, or a change in therapy to a different class of anticoagulant may be necessary (i.e., heparin sodium).

AquaMEPHYTON does not affect the anticoagulant action of heparin.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; addition of the following information:

Risk Summary

AquaMEPHYTON contains benzyl alcohol, which has been associated with gasping syndrome in neonates. The preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants. If AquaMEPHYTON is needed during pregnancy, consider using a benzyl alcohol-free formulation.

Published studies with the use of phytonadione during pregnancy have not reported a clear association with phytonadione and adverse developmental outcomes. There are maternal and fetal risks associated with vitamin K deficiency during pregnancy. Animal reproduction studies have not been conducted with phytonadione.

The estimated background risk for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with vitamin K deficiency hypoprothrombinemia may be at an increased risk for bleeding diatheses during pregnancy and hemorrhagic events at delivery. Subclinical maternal vitamin K deficiency during pregnancy has been implicated in rare cases of fetal intracranial hemorrhage.

Data

Human Data

Phytonadione has been measured in cord blood of infants whose mothers were treated with phytonadione during pregnancy in concentrations lower than seen in maternal plasma. Administration of vitamin K1 to pregnant women shortly before delivery increased both maternal and cord blood concentrations. Published data do not report a clear association with phytonadione and adverse maternal or fetal outcomes when used during pregnancy. However, these studies cannot definitively establish the absence of any risk because of methodologic limitations including small sample size and lack of blinding.

Animal Data

In pregnant rats receiving vitamin K1 orally, fetal plasma and liver concentrations increased following administration, supporting placental transfer.

8.2 Lactation

PLLR conversion; addition of the following information:

Risk Summary

AquaMEPHYTON contains benzyl alcohol. If available, preservative-free AquaMEPHYTON is recommended when AquaMEPHYTON is needed during lactation.

Phytonadione is present in breastmilk. There are no data on the effects of AquaMEPHYTON on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the clinical need for AquaMEPHYTON and any potential adverse effects on the breastfed child from AquaMEPHYTON or from the underlying maternal condition.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of AquaMEPHYTON for prophylaxis and treatment of vitamin K deficiency have been established in neonates. Use of phytonadione injection for prophylaxis and treatment of vitamin K deficiency is based on published clinical studies.

Serious adverse reactions including fatal reactions and the “gasping syndrome” …

When prescribing AquaMEPHYTON in infants … from all sources including AquaMEPHYTON (AquaMEPHYTON contains 9 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.

Whenever possible, use preservative-free phytonadione formulations in neonates. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. Premature and low-birth weight infants may be more likely to develop toxicity.

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

PATIENT COUNSELING INFORMATION

Newly added information:

Inform the patient of the following important risks of AquaMEPHYTON:

Serious Hypersensitivity Reactions

Advise the patient and caregivers to immediately report signs of hypersensitivity after receiving AquaMEPHYTON.

Risk of Gasping Syndrome Due to Benzyl Alcohol

Advise the patient and caregivers of the risk of gasping syndrome associated with the use of products that contain benzyl alcohol (including AquaMEPHYTON) in neonates, infants, and pregnant women.

Cutaneous Reactions

Advise the patient and caregivers to report the occurrence of new rashes after receiving AquaMEPHYTON. These reactions may be delayed for up to a year after treatment.

05/25/2017 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

… dose should not be exceeded …

Addition of the following:

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the intensive care unit who received drugs containing benzyl alcohol as a preservative. 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 0.61to 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 AquaMEPHYTON in infants consider the combined daily metabolic load of benzyl alcohol from all sources including AquaMEPHYTON (AquaMEPHYTON contains 9 mg of benzyl alcohol) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

WARNINGS

Addition of the following:

Use benzyl alcohol-free formulations in neonates and infants, if available. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including AquaMEPHYTON. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

When prescribing AquaMEPHYTON in infants, consider the combined daily metabolic load of benzyl alcohol from all sources including AquaMEPHYTON (contains 9 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.