ZYCUBO Solution for injection Ref.[116175] Active ingredients: Copper

5.1 Copper Accumulation and Risk of Toxicity

Impaired copper transport in patients with Menkes disease can lead to copper accumulation and organ impairment in the kidneys, liver, and hematopoietic system. Treatment with ZYCUBO may lead to further copper accumulation and related toxicity, especially in the first two years of life given renal and hepatic immaturity.

Obtain baseline serum copper and ceruloplasmin levels, serum electrolytes, kidney and liver function, and complete blood count (CBC). After initiating ZYCUBO, monitor laboratory values every 6 weeks for the first 6 months, then every 3 months for 18 months, and then every 6 months thereafter during ZYCUBO treatment. If laboratory abnormalities are detected, consider reducing the frequency of ZYCUBO administration or temporarily withholding or permanently discontinuing ZYCUBO. Return to increased frequency of laboratory monitoring when resuming a dosage as clinically indicated.

Drug-Induced Kidney Injury

Copper accumulation with ZYCUBO use has the potential to result in renal tubular toxicity in patients with Menkes disease. Routinely monitor patients starting or re-starting ZYCUBO for signs and symptoms of renal tubular toxicity. New-onset or worsening non-anion gap metabolic acidosis may be a sign of drug-related renal tubular acidosis. Increased urinary beta-2 microglobulin and/or new-onset hypophosphatemia, hyponatremia, or hypokalemia may be signs of drug-related proximal renal tubular toxicity. Provide supportive care with electrolyte repletion and supplementation as clinically indicated.

Copper accumulation with ZYCUBO use has the potential to result in glomerular injury, leading to decreased kidney function or new-onset proteinuria.

Liver Dysfunction

Copper accumulation with ZYCUBO can result in liver dysfunction. Elevations of liver transaminases have been reported in patients taking ZYCUBO for Menkes disease [see Adverse Reactions (6.1)]. Single cell necrosis, inflammation, and fibrosis, along with increased liver transaminases and bilirubin were observed in studies conducted over 13-weeks in juvenile rats with normal baseline copper levels [see Use in Specific Populations (8.4)].

Hematological Abnormalities

Copper accumulation with ZYCUBO can result in spleen and bone marrow dysfunction as well as interference with iron metabolism. Anemia has been reported in patients taking ZYCUBO for Menkes disease [see Adverse Reactions (6.1)]. Increased cellularity and pigmented macrophages in the spleen and increased hematological values were observed in studies conducted over 13-weeks in normal juvenile rats [see Use in Specific Populations (8.4)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Copper Accumulation and Risk of Toxicity: Drug-Induced Kidney Injury, Liver Dysfunction, Hematological Abnormalities [see Warnings and Precautions (5.1)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety analysis from 2 open-label, single-arm clinical trials included a total of 129 ZYCUBO-treated patients with an age range from 0 to 48 months. Patients less than 1 year of age received ZYCUBO 1.45 mg twice daily, and patients 1 year of age and older received ZYCUBO 1.45 mg once daily. The median exposure duration was 24 months (range: 1 to 39 months) [see Clinical Studies (14)].

Serious Adverse Reactions

Serious adverse reactions reported in ≥5% of ZYCUBO-treated pediatric patients with Menkes disease were pneumonia, dehydration, seizure, respiratory distress, respiratory syncytial virus infection, cardiopulmonary failure, upper respiratory tract infection, respiratory failure, and vomiting.

Common Adverse Reactions

Table 1 lists the most common adverse reactions that occurred in ≥7% of patients in the pooled safety analysis during an observation period ranging from 1 to 39 months.

Table 1. Adverse Reactions Occurring in ≥7% Patients with Menkes Disease (Trial 1 and Trial 2):

¹ Respiratory failure consists of multiple similar terms including cardiopulmonary failure.
² Bacterial infection consists of multiple similar terms including renal and urinary tract infection.

Risk Summary

There are no available data on ZYCUBO use during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with ZYCUBO.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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.

Risk Summary

There are no data on the presence of copper histidinate and its metabolites in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZYCUBO and any potential adverse effects on the breastfed infant from ZYCUBO or from the underlying maternal condition.

The safety and effectiveness of ZYCUBO for the treatment of Menkes disease have been established in pediatric patients, and the information on this use is discussed throughout the labeling.

Juvenile Animal Toxicity Data

Juvenile rats with normal baseline copper levels were administered copper histidinate from postnatal day (PND) 10 (the equivalent of a human newborn) to PND 100 (the equivalent of a human adult) subcutaneously twice daily for 13 weeks at 1, 2, and 5 mg/kg. Histopathological findings were observed in the kidney (tubular necrosis, eosinophilic globules), liver (single cell necrosis, inflammation, fibrosis), and spleen (increased cellularity and pigmented macrophages), in addition to increased liver transaminases (ALT, AST) and bilirubin, and decreased red blood cells, hemoglobin and hematocrit at 5 mg/kg (10-fold the human plasma concentration at the recommended dose of ZYCUBO (based on C_max)). Changes in liver (necrosis, inflammation, ALT, AST) and kidney (eosinophilic globules) were also noted as low as 1 mg/kg (equivalent to human plasma concentration at the recommended dose of ZYCUBO (based on C_max)). A no-observed-adverse-effect-level (NOAEL) in juvenile rats could not be determined. Proportional increases in copper and ceruloplasmin levels occurred with increasing dose levels.

Menkes disease is a disease of pediatric patients. Clinical trials of ZYCUBO did not include patients 65 years of age and older.