ZYCUBO

ZYCUBO (copper histidinate) for injection is a copper replacement product. The chemical name is copper, (L-histidinato-ϰ N ,ϰ N 3,ϰO)(L-histidinato-ϰ N ,ϰO)-, ( SP -5-14-C)-. The molecular formula is C 12 H 16 CuN 6 O 4 , and the molecular weight is 371.84 g/mol. Copper histidinate is soluble in water. The chemical structure is: ZYCUBO is a sterile, preservative-free, blue lyophilized powder or cake for subcutaneous injection after reconstitution with 1 mL sterile 0.9% Sodium Chloride Injection, USP. Each single-dose vial contains 2.9 mg of copper histidinate (equivalent to 0.5 mg elemental copper). The resultant solution has a concentration of 2.9 mg/mL and a pH of 7.4. Chemical Structure

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.

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 unused portion after each single use. Do not administer more than one dose from the vial. 2.7 Missed Dose If a ZYCUBO dose is missed, administer the missed dose as soon as possible. Administer the next scheduled dose at least 6 hours after the administration of the missed dose.

None. None ( 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)