Zycubo Drug Information

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. Limitations of Use ZYCUBO is not indicated for the treatment of Occipital Horn Syndrome.

Limitations of Use ZYCUBO is not indicated for the treatment of Occipital Horn Syndrome.

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) .

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.

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 .

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 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.

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.

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.

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.

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) . 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 Viral infection 35 Respiratory failure 1 30 Cardiopulmonary failure 11 Seizure 29 Bacterial infection 26 Renal and urinary tract infection 2 12 Hemorrhage 23 Hypotension 20 Vomiting 19 Tachycardia 16 Pyrexia 16 Volume depletion 16 Fracture 16 Dyspnea 16 Transaminases elevation 13 Diarrhea 13 Fungal infection 12 Anemia 11 Local administration reaction 9

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.

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.