Copper Histidinate

ZYCUBO is indicated for the treatment of Menkes disease in pediatric patients. ZYCUBO is a copper replacement product indicated for the treatment of Menkes disease in pediatric patients. ( 1 ) Limitations of Use ZYCUBO is not indicated for the treatment of Occipital Horn Syndrome. ( 1 ) Limitations of Use ZYCUBO is not indicated for the treatment of Occipital Horn Syndrome.

For Injection: 2.9 mg of copper histidinate (equivalent to 0.5 mg elemental copper) as a blue lyophilized powder or cake in a single-dose vial for reconstitution. For Injection: 2.9 mg of copper histidinate (equivalent to 0.5 mg elemental copper) as a lyophilized powder or cake in a single-dose vial for reconstitution. ( 3 )

None. None ( 4 )

Copper Accumulation and Risk of Toxicity : Exogenous administration of copper with ZYCUBO may lead to further copper accumulation and has the potential to result in drug-induced kidney injury, liver dysfunction, and hematological abnormalities. Monitor patients during ZYCUBO treatment. Adjust dosage if necessary. ( 2.2 , 5.1 , 6.1 )

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 )] Most common adverse reactions (incidence ≥7%) were pneumonia, viral infection, respiratory failure, seizure, bacterial infection, hemorrhage, hypotension, vomiting, tachycardia, pyrexia, volume depletion, fracture, dyspnea, transaminases elevation, diarrhea, fungal infection, anemia, and local administration reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sentynl Therapeutics, Inc. at 1-888-507-5206 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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. Adverse Reactions Menkes Disease (N = 129) N (%) Pneumonia 38 (30) Viral infection 35 (27) Respiratory failure 1 30 (23) Cardiopulmonary failure 11 (9) Seizure 29 (23) Bacterial infection 26 (20) Renal and urinary tract infection 2 12 (9) Hemorrhage 23 (18) Hypotension 20 (16) Vomiting 19 (15) Tachycardia 16 (12) Pyrexia 16 (12) Volume depletion 16 (12) Fracture 16 (12) Dyspnea 16 (12) Transaminases elevation 13 (10) Diarrhea 13 (10) Fungal infection 12 (9) Anemia 11 (9) Local administration reaction 9 (7)

8.1 Pregnancy 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.

8.2 Lactation 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.

8.4 Pediatric Use 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.

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

Menkes disease is an X-linked recessive disorder caused by pathogenic variants in the copper transport ATPase encoded by ATP7A . Patients with Menkes disease have impaired absorption of copper from their diet, impaired transport of copper across the blood-brain barrier, and dysregulation of many copper-dependent enzymes. ZYCUBO is a bioavailable copper replacement therapy that is administered as a subcutaneous injection to bypass the impaired gastrointestinal absorption observed in patients with Menkes disease.