Drugs Xagena
Denosumab ( Prolia ) is a monoclonal antibody against receptor activator of nuclear factor-kappa B ligand ( RANKL ).
The following safety issues associated with Denosumab exposure have been identified in clinical trials: occurrence of serious infection, development of new malignancies, potential for tumor progression in patients with cancer, bone histomorphometry findings that suggest suppression of bone remodeling which may lead to complications such as delayed fracture healing, osteonecrosis of the jaw, or atypical fracture with long-term use, and dermatologic adverse events.
Deaths
There were a total of 354 deaths in the Denosumab clinical development program; 169 in subjects with low bone mass or osteoporosis and 185 in subjects with underlying cancer.
The number of subjects who died during the PMO fracture trial 20030216 was not higher in Denosumab ( 70 ) compared to placebo ( 90 ) groups. There were no deaths in the PMO prevention trial 20040132.
Serious adverse events were slightly higher in the Denosumab group compared to placebo. Likewise, the number of subjects who died during the key Hormone Ablation studies was not higher in Denosumab ( 45 ) compared to placebo ( 47 ) groups.
Infections
Overall, subjects in the Denosumab group had a slightly increased incidence of serious infections. There were more serious infections of the skin, ear, abdominal system and urinary tract. Also, endocarditis, infected arthritis and skin ulcers occurred more commonly in denosumab subjects.
There were 4 cases of endocarditis in the Denosumab group ( including 3 cases in Study 20030216 ). One case in the placebo group occurred during Study 20040138.
Streptococcal infections occurred more frequently among Denosumab subjects.
There were 3 Denosumab subjects in Phase I studies who developed pneumonia requiring hospitalization following a single dose of Denosumab.
There did not appear to be an increase in opportunistic infections in Denosumab subjects.
Malignancy
No carcinogenicity studies were performed due to lack of an appropriate animal model because Denosumab is not pharmacologically active in rodent species. Three relatively healthy subjects receiving a high dose of Denosumab in the dose-finding study ( Study 20010223 ) died of a new malignancy; all subjects received Denosumab 100 mg Q6 months.
Overall, subjects in the Denosumab group in the Primary PMO safety population had a slightly increased incidence of breast cancer, pancreatic cancer, gastrointestinal cancer and reproductive cancers.
Breast cancer was the most common adverse event that led to discontinuation of investigational product in the Primary PMO safety population, with 20 Denosumab ( 0.5% ) and 10 placebo ( 0.3% ) subjects discontinuing due to breast cancer.
Skin and soft tissue disorder
Overall, subjects in the Denosumab group were more likely to develop skin and soft tissue related adverse events, which were statistically significant.
There were more bullous conditions, pruritic conditions, skin rashes, dermatitis and eczema related adverse events in the denosumab group compared to placebo.
Bone biopsy histomorphometry
Bone histomorphometry results raise concerns about the degree of bone remodeling suppression. The Denosumab group had markedly suppressed osteoclast and osteoblast counts compared to placebo and Alendronate.
Dynamic bone formation parameters such as activation frequency, bone formation rate and mineralizing surface were also markedly suppressed.
This raises a concern that with long term use, suppression of bone remodeling may lead to complications such as delayed fracture healing, osteonecrosis of the jaw, or atypical fracture.
Hypocalcemia
Hypocalcemia is a known class effect of antiresorptive drugs. Denosumab-induced hypocalcemia appears to be transient ( nadir at day 8-11 ) with spontaneous resolution without any serious sequelae observed in this study.
Outside of the controlled clinical trial environment, more patients may experience hypocalcemia.
It has been proposed hypocalcemia being a contraindication and in the Warnings and Precautions section of the label.
Osteonecrosis of the jaw
No cases of osteonecrosis of the jaw have been positively adjuducated in the PMO and Hormone Ablation trials under review. However, at least one confirmed case of osteonecrosis of the jaw has been reported in other trials conducted in patients with multiple myeloma and metastatic cancer.
Cardiovascular
In the entire ISS population, cardiovascular adverse effects were similarly distributed between the two groups. Adjudicated serious cardiovascular events were similar between the two treatment groups in trials 20030216 and 20040135.
No differences were found in aortic calcification scores at 3 years between treatment arms.
Clinical laboratory evaluation
There were no clinically relevant changes seen in the laboratory safety parameters. There was no indication that treatment with Denosumab 60mg Q6M SC led to decreases in renal or hepatic function.
Source: FDA, 2009
XagenaMedicine_2009
