EVENITY Solution for injection Ref.[112433] Active ingredients: Romosozumab

Myocardial infarction and stroke

In randomised controlled studies, an increase in serious cardiovascular events (myocardial infarction and stroke) has been observed in romosozumab treated patients compared to controls (see section 4.8).

Romosozumab is contraindicated in patients with previous myocardial infarction or stroke (see section 4.3).

When determining whether to use romosozumab for an individual patient, consideration should be given to her fracture risk over the next year and her cardiovascular risk based on risk factors (e.g. established cardiovascular disease, hypertension, hyperlipidaemia, diabetes mellitus, smoking, severe renal impairment, age). Romosozumab should only be used if the prescriber and patient agree that the benefit outweighs the risk. If a patient experiences a myocardial infarction or stroke during therapy, treatment with romosozumab should be discontinued.

Hypocalcaemia

Transient hypocalcaemia has been observed in patients receiving romosozumab. Hypocalcaemia should be corrected prior to initiating therapy with romosozumab and patients should be monitored for signs and symptoms of hypocalcaemia. If any patient presents with suspected symptoms of hypocalcaemia during treatment (see section 4.8), calcium levels should be measured. Patients should be adequately supplemented with calcium and vitamin D (see sections 4.3 and 4.8).

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 hypocalcaemia and the safety data for these patients is limited. Calcium levels should be monitored in these patients.

Hypersensitivity

Clinically significant hypersensitivity reactions, including angioedema, erythema multiforme, and urticaria occurred in the romosozumab group in clinical trials. If an anaphylactic or other clinically significant allergic reaction occurs, appropriate therapy should be initiated and use of romosozumab should be discontinued (see sections 4.3 and 4.8).

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ), has been reported rarely in patients receiving romosozumab. 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 (the risk increases with the antiresorptive potency of the compound), and cumulative dose of antiresorptive 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 romosozumab.

Patients who are suspected of having or who develop ONJ while on romosozumab should receive care by a dentist or an oral surgeon with expertise in ONJ. Discontinuation of romosozumab therapy should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Atypical femoral fractures

Atypical low-energy or low trauma fracture of the femoral shaft, which can occur spontaneously, has been reported rarely in patients receiving romosozumab. Any patient who presents with new or unusual thigh, hip, 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 romosozumab therapy should be considered, based on an individual benefit-risk assessment.

Excipients

This medicine contains 0.070 mg of polysorbate 20 in each pre-filled pen and each pre-filled syringe. Polysorbates may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially sodium-free.

No drug interaction studies have been performed with romosozumab. No pharmacokinetic drug interactions are expected with romosozumab.

Pregnancy

Romosozumab is not indicated for use in women of child-bearing potential or in pregnant women. There are no data from the use of romosozumab in pregnant women. Skeletal malformations (including syndactyly and polydactyly) were observed at a low incidence in a single study with romosozumab in rats (see section 5.3). A risk for malformations of developing digits in the human foetus is low following romosozumab exposure due to the timing of digit formation in the first trimester in humans, a period when placental transfer of immunoglobulins is limited.

Breast-feeding

Romosozumab is not indicated for use in breast-feeding women.

No data are available on excretion of romosozumab in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period.

Fertility

No data are available on the effect of romosozumab on human fertility. Animal studies in female and male rats did not show any effects on fertility endpoints (see section 5.3).

Romosozumab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions were nasopharyngitis (13.6%) and arthralgia (12.4%). Hypersensitivity-related reactions occurred in 6.7% of patients treated with romosozumab. Hypocalcaemia was reported uncommonly (0.4% of patients treated with romosozumab). In randomised controlled studies, an increase in serious cardiovascular events (myocardial infarction and stroke) has been observed in romosozumab treated patients compared to controls (see section 4.4 and information below).

Tabulated list of adverse reactions

The following convention has been used for the classification of the adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness.

^a See sections 4.3 and 4.4.
^b Defined as albumin adjusted serum calcium that was below the lower limit of normal. See sections 4.3 and 4.4.
^c See section “Myocardial infarction and stroke” below.
^d Most frequent injection site reactions were pain and erythema.

Description of selected adverse reactions

Immunogenicity

In postmenopausal women dosed with monthly romosozumab, the incidence of anti-romosozumab antibodies was 18.6% (1162 of 6244) for binding antibodies and 0.9% (58 of 6244) for neutralizing antibodies. The earliest onset of anti-romosozumab antibodies was 3 months after first dosing. The majority of antibody responses were transient.

The presence of anti-romosozumab binding antibodies decreased romosozumab exposure by up to 25%. No impact on the efficacy of romosozumab was observed in the presence of antiromosozumab antibodies. Limited safety data show that the incidence of injection site reactions was numerically higher in female patients with neutralizing antibodies.

Myocardial infarction, stroke and mortality

In the active-controlled trial of romosozumab for the treatment of severe osteoporosis in postmenopausal women during the 12-month double-blind romosozumab treatment phase, 16 women (0.8%) had myocardial infarction in the romosozumab arm versus 5 women (0.2%) in the alendronate arm and 13 women (0.6%) had stroke in the romosozumab arm versus 7 women (0.3%) in the alendronate arm. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 women (0.8%) in the romosozumab group and 12 (0.6%) women in the alendronate group. The number of women with major adverse cardiac events (MACE = positively adjudicated cardiovascular death, myocardial infarction or stroke) was 41 (2.0%) in the romosozumab group and 22 (1.1%) in the alendronate group, yielding a hazard ratio of 1.87 (95% confidence interval [1.11, 3.14]) for romosozumab compared to alendronate. All-cause death occurred in 30 women (1.5%) in the romosozumab group and 22 (1.1%) women in the alendronate group.

In the placebo-controlled trial of romosozumab for the treatment of osteoporosis in postmenopausal women (including women with severe and less severe osteoporosis) during the 12-month double-blind romosozumab treatment phase, there was no difference in positively adjudicated MACE; 30 (0.8%) occurred in the romosozumab group and 29 (0.8%) in the placebo group. All-cause death occurred in 29 women (0.8%) in the romosozumab group and 24 (0.7%) women in the placebo group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.