Copper Histidinate

1 INDICATIONS AND USAGE 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.

12.1 Mechanism of Action 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.

2 DOSAGE AND ADMINISTRATION Before initiating ZYCUBO, obtain baseline serum copper and ceruloplasmin levels, serum electrolytes, kidney and liver function, and complete blood count. ( 2.1 ) The recommended dosage of ZYCUBO in pediatric patients: Less than 1 year of age is 1.45 mg twice daily (8-12 hours between injections). ( 2.2 ) 1 year of age to less than 17 years of age is 1.45 mg once daily. ( 2.2 ) Monitor serum copper and ceruloplasmin levels, serum electrolytes, kidney and liver function, and complete blood count (CBC). ( 2.3 ) Reconstitute ZYCUBO and administer subcutaneously. ( 2.4 , 2.6 ) See Full Prescribing Information for additional preparation, storage, and administration instructions. ( 2.4 , 2.5 , 2.6 ) 2.1 Recommended Testing Before Initiating ZYCUBO Before initiating ZYCUBO, obtain baseline serum copper and ceruloplasmin levels, serum electrolytes, kidney and liver function, and complete blood count (CBC) [see Warnings and Precautions ( 5.1 )] . 2.2 Recommended Dosage and Administration The recommended dosage of ZYCUBO in pediatric patients: Less than 1 year of age is 1.45 mg administered subcutaneously twice daily (8-12 hours between injections). 1 year of age to less than 17 years of age is 1.45 mg administered subcutaneously once daily. 2.3 Dosage and Administration Modifications and Monitoring Monitor serum copper and ceruloplasmin levels, serum electrolytes, kidney and liver function, and complete blood count (CBC) 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 evaluation when resuming a dosage as clinically indicated [see Warnings and Precautions ( 5.1 )] . 2.4 Preparation Instructions Preparation Use aseptic technique during preparation. Reconstitute ZYCUBO using a sterile disposable 3 mL syringe and 1 inch needle (between 16 to 22 gauge) ( see Instructions for Use ). Remove 1 ZYCUBO vial from the refrigerator and set aside for approximately 30 minutes to allow the vial to come to room temperature [20°C to 25°C (68°F to 77°F)] before use. Reconstitute ZYCUBO by tilting the vial and slowly injecting 1 mL of 0.9% Sodium Chloride Injection, USP down the inside wall of the vial. Gently swirl the vial continuously until the powder is completely dissolved. Do not shake the vial. Each vial will yield a concentration of 2.9 mg/mL. Visually inspect the reconstituted solution in the vial for particulate matter and discoloration. The solution should be blue. Discard if particles are present or the solution is discolored (not blue) or cloudy. Do not mix with other medications. 2.5 Storage of Reconstituted Solution If the reconstituted ZYCUBO vial is not used immediately, store the vial refrigerated at 2°C to 8°C (36° to 46°F) for up to 24 hours or at controlled room temperature at 20°C to 25°C (68°F to 77°F) for up to 4 hours. Discard the reconstituted ZYCUBO vial if not used within 24 hours of refrigeration or within 4 hours at room temperature. 2.6 Administration Instructions A caregiver may administer ZYCUBO to patients after proper training in subcutaneous injection technique if a healthcare provider determines that it is appropriate ( see Instructions for Use ). Administer ZYCUBO using a sterile disposable 1 mL syringe and 1/2 inch injection needle (between 23 to 27 gauge). Slowly withdraw 0.5 mL of reconstituted ZYCUBO solution from the vial and inject subcutaneously. Administer ZYCUBO by subcutaneous injection at separate sites in the abdominal area (2 inches from the navel), buttocks, and the outer lateral aspect of the upper arm or thigh. Rotate injection sites with each injection to reduce the risk of lipodystrophy. Do not give injections into areas where the skin is scarred, tender, bruised, red, or hard. Discard u

6 ADVERSE REACTIONS 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)

5 WARNINGS AND PRECAUTIONS 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 )].

4 CONTRAINDICATIONS None. None ( 4 )