Zycubo Drug Information
Generic name: COPPER HISTIDINATE
Uses of Zycubo
ZYCUBO is indicated for the treatment of Menkes disease in pediatric patients. Limitations of Use ZYCUBO is not indicated for the treatment of Occipital Horn Syndrome.
Dosage & Administration of Zycubo
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. 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 ). 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.
Side Effects of Zycubo
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 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.
Table 1.
| 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) |
Warnings & Cautions for Zycubo
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).
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. 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. 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. Increased cellularity and pigmented macrophages in the spleen and increased hematological values were observed in studies conducted over 13-weeks in normal juvenile rats.
Pregnancy Safety for Zycubo
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 of Zycubo
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. 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.
Clinical Studies of Zycubo
Data from ZYCUBO-treated patients in these two trials were compared to data from an untreated contemporaneous external control cohort as collected under a protocol amendment of Trial 2. In both trials, pediatric patients: Less than 1 year of age received 1.45 mg of ZYCUBO administered subcutaneously twice daily until 1 year of age. Equal to or greater than 1 year of age received 1.45 mg of ZYCUBO subcutaneously once daily for up to 3 years.
Overall survival was evaluated in a subset of the pooled population from Trial 1 and Trial 2, referred to as the pooled efficacy population. This efficacy population included only patients with Menkes disease who carried a severe pathogenic variant of the ATP7A gene (duplication/deletion, nonsense, or a canonical splice junction variant) and were born after 1999. Patients in the pooled efficacy population were assigned to 1 of 4 cohorts as described in Table 2.
Table 2. Efficacy Results Primary Efficacy Results (Overall Survival) in the ZYCUBO-ET and EC-ET Cohorts The primary efficacy analysis compared the overall survival in patients in the ZYCUBO-ET and EC-ET cohorts. Patients in the ZYCUBO-ET cohort (patients treated with ZYCUBO) had a significant improvement in overall survival compared to patients in the EC-ET cohort, with a 78% reduction in the risk of death ( Table 3 and Figure 1 ).
In the EC-ET cohort, no patients survived >6 years. Table 3. Primary Efficacy Results: Overall Survival in ZYCUBO Early Treatment and External Control Early Treatment Cohorts with Menkes Disease 0.22 Figure 1.
Patients in the ZYCUBO-LT cohort (patients treated with ZYCUBO) had a significant improvement in overall survival compared to patients in the EC-LT cohort, with a 73% reduction in the risk of death ( Table 4 and Figure 2 ). Table 4. Secondary Efficacy Results: Overall Survival in ZYCUBO Late Treatment and External Control Late Treatment Cohorts with Menkes Disease 0.27 Figure 2.
Figure 1 Figure 2
| All values are in median (range) | ||||
| 1 Within 4 weeks of birth or within 4 weeks of birth corrected for prematurity (i.e., < 40 weeks' gestation) | ||||
| 2 After 4 weeks of birth or after 4 weeks of birth corrected for prematurity (i.e., < 40 weeks' gestation) | ||||
| Treated Cohorts | Untreated Cohorts | |||
| ZYCUBO- Early Treatment (ZYCUBO-ET) n=31 | ZYCUBO- Late Treatment (ZYCUBO-LT) n=35 | External Control-Early Treatment (EC-ET) n=17 | External Control-Late Treatment (EC-LT) n=16 | |
| Eligibility | Started ZYCUBO treatment within 4 weeks of birth [1] | Started ZYCUBO treatment after 4 weeks of birth [2] | No prior ZYCUBO or copper treatment Asymptomatic for significant neurological signs and symptoms approximately 4 weeks after birth Survived at least 4 weeks after diagnosis | Subset of the EC-ET cohort Diagnosed with Menkes disease after 4 weeks of birth Survived at least 2 weeks after diagnosis |
| Age at diagnosis (months) | 0.1 (-4.5 – 1.9) | 4.8 (0.4 – 29.4) | 4.7 (2.1 – 22.2) | 5.6 (2.1 – 22.2) |
| Age at treatment initiation (months) | 0.4 (0.1 – 1.9) | 7.1 (1.3 – 31.4) | NA | NA |
| Treatment duration (months) | 34.1 (1.1 – 36) | 20 (1.3 – 36) | NA | NA |
| CI=Confidence Interval; NE=Not estimable | ||
| Note: If death dates were unknown, patients were censored at the last known date alive. | ||
| ZYCUBO-Early Treatment (n=31) | External Control-Early Treatment (n=17) | |
| Number (%) of Patients Alive | 16 (52%) | 2 (12%) |
| Median survival time (months) (95% CI) | 177.1 (33, NE) | 17.6 (11.5, 28.6) |
| Hazard Ratio (95% CI) | 0.22 (0.10, 0.49) | |
| CI=Confidence Interval | ||
| Note: If death dates were unknown, patients were censored at the last known date alive. | ||
| ZYCUBO Late-Treatment (LT) (n=35) | External Control-Late Treatment (EC-LT) (n=16) | |
| Number of Patients Alive (%) | 12 (34%) | 2 (12%) |
| Median survival time (months) (95% CI) | 62.4 (29.6, 80.7) | 20.7 (12.6, 28.6) |
| Hazard Ratio (95% CI) | 0.27 (0.12, 0.57) | |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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