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.

TRALEMENT (NDA-209376)

(CUPRIC SULFATE; MANGANESE SULFATE; SELENIOUS ACID; ZINC SULFATE)

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

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06/30/2021 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Neurologic Toxicity with Manganese

(Additions and/or revisions are underlined)

Pediatric patients on long-term parenteral nutrition receiving manganese at higher than recommended dosages and pediatric patients with cholestatic liver disease have experienced manganese accumulation in the basal ganglia. Some adult patients with brain MRI findings reportedly experienced neuropsychiatric symptoms, including changes in mood or memory, seizures and/or parkinsonian-like tremors, dysarthria, mask-face, and halting gait. Some pediatric patients experienced dystonic movements or seizures. Brain MRI findings and clinical symptoms have also been observed in patients who received manganese at or below the recommended dosage and with normal blood manganese concentrations. Regression of symptoms and brain MRI findings have occurred over weeks to months following discontinuation of manganese in most patients but have not always completely resolved.

Monitor patients receiving long-term parenteral nutrition solutions containing Multrys for neurologic signs and symptoms and routinely monitor whole blood manganese concentrations and liver function tests. In case of suspected manganese toxicity or new neuro-psychiatric manifestations, temporarily discontinue Multrys, check manganese whole blood concentrations, and consider brain MRI evaluation.

Monitor patients receiving Multrys for cholestasis or other biliary liver disease. Consider individual trace element products as an alternative to Multrys in patients with hepatobiliary disease [see Warnings and Precautions (5.4)].

5.4 Hepatic Accumulation of Copper and Manganese

(Additions and/or revisions are underlined)

Copper is primarily eliminated in the bile and excretion is decreased in patients with cholestasis and/or cirrhosis. Hepatic accumulation of copper and manganese have been reported in autopsies of patients receiving long-term parenteral nutrition containing copper and manganese at dosages higher than recommended.

Patients with cholestasis and/or cirrhosis receiving parenteral nutrition are at increased risk of manganese brain deposition and neurotoxicity [see Warnings and Precautions (5.3)].

Administration of copper to patients with cholestasis and/or cirrhosis may cause hepatic accumulation of copper. Administration of copper to patients with Wilson disease, an inborn error of copper metabolism with a defect in hepatocellular copper transport, may cause both increased hepatic accumulation of copper and aggravation of the underlying hepatocellular degeneration.

If a patient develops signs or symptoms of hepatobiliary disease during the use of Multrys, obtain serum concentrations of copper and ceruloplasmin as well as manganese whole blood concentrations; consider using individual trace element products in these patients [see Use in Specific Populations (8.6)].

5.5 Aluminum Toxicity

(Additions and/or revisions are underlined)

Research indicates that patients with impaired kidney function, including preterm infants and premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration or lower daily amounts. Exposure to aluminum from Multrys is not more than 0.45 mcg/kg/day. When prescribing Multrys for use in parenteral nutrition containing other small volume parenteral products, the total daily patient exposure to aluminum from the admixture should be considered and maintained at no more than 5 mcg/kg/day.

5.6 Monitoring and Laboratory Tests

(Additions and/or revisions are underlined)

Monitor zinc, copper, and selenium serum concentrations, manganese whole blood concentration, fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count, and coagulation parameters during use of parenteral nutrition containing Multrys [see Dosage and Administration (2.4)].

5.7 Hypersensitivity Reactions with Zinc and Copper

(Additions and/or revisions are underlined)

Postmarket safety reporting has identified zinc hypersensitivity in patients receiving zinc-containing insulin products and copper hypersensitivity in women receiving copper-containing intrauterine devices, providing evidence that patients may experience hypersensitivity reactions when exposed to these metals. If hypersensitivity reactions (e.g., pruritis, angioedema, dyspnea, rash, urticaria) occur in patients receiving Multrys in parenteral nutrition, discontinue Multrys, and initiate appropriate medical treatment [see Contraindications (4)].

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Multrys is approved for use in neonatal and pediatric patients weighing less than 10 kg as a source of zinc, copper, manganese, and selenium for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Safety and dosing recommendations in pediatric patients less than 10 kg are based on published literature describing controlled studies of products containing zinc, copper, manganese, and selenium [see Dosage and Administration (2.5)].

8.6 Hepatic Impairment

(Additions and/or revisions are underlined)

Copper is primarily excreted in the bile. Excretion is decreased in patients with cholestasis and/or cirrhosis. Manganese is presumed to be excreted in bile [see Clinical Pharmacology (12.3)]. Hepatic accumulation of copper and manganese has been reported with long-term administration of parenteral nutrition at dosages higher than recommended [see Warnings and Precautions (5.4)].

For patients with cholestasis or cirrhosis, monitor hepatic and biliary function during long-term administration of Multrys.

If a patient develops signs or symptoms of hepatobiliary disease during use of Multrys, obtain serum concentrations of copper and ceruloplasmin as well as manganese whole blood concentrations; consider using individual trace element products in these patients.

Other

Other: The name “Tralement” revised to read “Multrys” throughout the prescribing information.