IMPORTANT SAFETY INFORMATION FOR EVENITY®
4.3 Contraindications
EVENITY is contraindicated in patients with:
• Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with EVENITY [see Special Warnings and Precautions for use (4.4), Undesirable effects (4.8) and Fertility, pregnancy & Lactation (4.6)].
• A history of systemic hypersensitivity to romosozumab or to any component of the product formulation. Reactions have included angioedema, erythema multiforme, and urticaria [see Special Warnings and Precautions for use (4.4) & Undesirable effects (4.8)].
4.4 Special Warnings and Precautions for Use
Major Adverse Cardiac Events (MACE)
In a randomized controlled trial in postmenopausal women, there was a higher rate of major adverse cardiac events (MACE), a composite endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, in patients treated with EVENITY compared to those treated with alendronate [see Undesirable effects (4.8)].
EVENITY should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the benefits outweigh the risks in patients with other cardiovascular risk factors. Monitor for signs and symptoms of myocardial infarction and stroke and instruct patients to seek prompt medical attention if symptoms occur. If a patient experiences a myocardial infarction or stroke during therapy, EVENITY should be discontinued.
Hypersensitivity Reactions
Hypersensitivity reactions, including angioedema, erythema multiforme, dermatitis, rash, and urticaria have occurred in EVENITY-treated patients. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of EVENITY [see Contraindications (4.3) and Undesirable effects (4.8)].
Hypocalcemia
Hypocalcemia has occurred in patients receiving EVENITY. Correct hypocalcemia prior to initiating EVENITY [see Contraindications (4.3), Special Warnings and Precautions for use (4.4), Undesirable effects (4.8) and Fertility, pregnancy & Lactation (4.6)].
Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D while on EVENITY [see Posology and method of administration (4.2) and Clinical Studies (5.5)].
Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) or receiving dialysis are at greater risk of developing hypocalcemia. Monitor serum calcium and adequately supplement patients who have severe renal impairment or are receiving dialysis with calcium and vitamin D. Instruct patients with severe renal impairment, including those receiving dialysis, about the symptoms of hypocalcemia and the importance of maintaining calcium levels with adequate calcium and vitamin D supplementation.
Osteonecrosis of the Jaw (ONJ)
Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients receiving EVENITY. A routine oral examination should be performed by the prescriber prior to initiation of EVENITY treatment. Concomitant administration of drugs associated with ONJ (chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, and corticosteroids) may increase the risk of developing ONJ. Other risk factors for ONJ include cancer, radiotherapy, poor oral hygiene, pre-existing dental disease or infection, anemia, and coagulopathy [see Undesirable effects (4.8)].
For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on benefit-risk assessment. Patients who are suspected of having or who develop ONJ while on EVENITY should receive care by a dentist or an oral surgeon. In these patients, dental surgery to treat ONJ may exacerbate the condition. Discontinuation of EVENITY should be considered based on benefit-risk assessment.
Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical low-energy or low trauma fractures of the femoral shaft have been reported in patients receiving EVENITY [see Undesirable effects (4.8)]. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated.
Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs.
During EVENITY treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of EVENITY therapy should be considered based on benefit-risk assessment.
Pregnancy
EVENITY is not indicated for use in women of reproductive potential.
Lactation
EVENITY is not indicated for use in women of reproductive potential.
4.8 Undesirable Effects – Key Safety Findings
Major Adverse Cardiac Events (MACE)
Study 1 (placebo-controlled):
- MACE: 30 (0.8%) EVENITY vs 29 (0.8%) placebo
- Hazard ratio: 1.03 (95% CI 0.62, 1.72)
Study 2 (alendronate-controlled):
- MACE: 41 (2.0%) EVENITY vs 22 (1.1%) alendronate
- Hazard ratio: 1.87 (95% CI 1.11, 3.14)
Most common adverse reactions (≥5%)
Hypersensitivity
- Angioedema
- Erythema multiforme
- Dermatitis
- Rash
- Urticaria
Hypocalcemia
- Albumin-adjusted calcium decreases below reference range occurred
- Nadir occurred by month 1
Injection Site Reactions
- Occurred in 4.9% EVENITY vs 2.8% control
Osteonecrosis of the Jaw
Atypical Femoral Fracture
IMPORTANT SAFETY INFORMATION FOR PROLIA®
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypocalcaemia (see section 4.4).
4.4 Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Calcium and vitamin D supplementation
Adequate intake of calcium and vitamin D is important in all patients.
Hypocalcaemia
It is important to identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia within two weeks after the initial dose. If any patient presents with suspected symptoms of hypocalcaemia during treatment (see section 4.8 for symptoms) calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcaemia.
In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported (see section 4.8), with most cases occurring in the first weeks of initiating therapy, but it can occur later.
Concomitant glucocorticoid treatment is an additional risk factor for hypocalcaemia.
Renal impairment
Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risks of developing hypocalcaemia and accompanying parathyroid hormone elevations increase with increasing degree of renal impairment. Adequate intake of calcium, severe and fatal cases have been reported. Vitamin D and regular monitoring of calcium is especially important in these patients, see above.
Skin infections
Patients receiving Prolia may develop skin infections (predominantly cellulitis) leading to hospitalisation (see section 4.8). Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.
Osteonecrosis of the jaw (ONJ)
ONJ has been reported rarely in patients receiving Prolia for osteoporosis (see section 4.8).
The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with denosumab in patients with concomitant risk factors.
The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:
- Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures (e.g. tooth extractions).
All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling or non-healing of sores or discharge during treatment with denosumab. While on-treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Prolia administration.
The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with ear symptoms including chronic ear infections.
Atypical fractures of the femur
Atypical femoral fractures have been reported in patients receiving denosumab (see section 4.8). Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterise these events. Atypical femoral fractures have also been reported in patients with certain co-morbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation of Prolia therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient based on an individual benefit/risk assessment. During denosumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.
Long-term antiresorptive treatment
Long-term antiresorptive treatment (including both denosumab and bisphosphonates) may contribute to an increased risk for adverse outcomes such as osteonecrosis of the jaw and atypical femur fractures due to significant suppression of bone remodelling (see section 4.2).
Concomitant treatment with other denosumab-containing medicinal products
Patients being treated with Prolia should not be treated concomitantly with other denosumab-containing medicinal products (for prevention of skeletal related events in adults with bone metastases from solid tumours).
Hypercalcaemia in paediatric patients
Prolia should not be used in paediatric patients (age < 18). Serious hypercalcaemia has been reported. Some clinical trial cases were complicated by acute renal injury.
Warnings for excipients
This medicine contains 47 mg sorbitol in each mL of solution. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.
This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg that is to say essentially ‘sodium-free’.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Prolia is not recommended for use in pregnant women and women of child-bearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment with Prolia. Any effects of Prolia are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
Breast-feeding
It is unknown whether denosumab is excreted in human milk.
A decision on whether to abstain from breast-feeding or to abstain from therapy with Prolia should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of Prolia therapy to the woman.
4.8 Undesirable effects (Safety Summary)
The most common side effects with Prolia (seen in more than one patient in ten) are musculoskeletal pain and pain in the extremity.
Uncommon cases of cellulitis, rare cases of hypocalcaemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures have been observed in patients taking Prolia.
Artist rendering of bone imagery for illustrative purposes only.
Artist rendering of bone imagery for illustrative purposes only.
Artist rendering of bone imagery for illustrative purposes only.