Evenity (Romosozumab) Pre-Surgery Hold Window: What Clinicians Need to Know

Does the Evenity label require a hold before surgery?

No. The prescribing information's dosing, contraindication and warning sections give no pre-operative interval, no washout period and no instruction to delay a dose for an operation [1]. The label sets the dose at 210 mg subcutaneously once a month for 12 doses, says the drug should be administered by a healthcare provider, and defines what to do if a dose is missed [1].

So there is no number of days to count backwards from a surgical date. The label facts that bear on the perioperative period are the boxed cardiovascular warning, the 12-dose ceiling, and the missed-dose rule.

What the boxed warning actually says

The warning is titled WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION, STROKE AND CARDIOVASCULAR DEATH [1]. It states that Evenity should not be initiated in patients who have had a heart attack or stroke within the preceding year, that benefits and risks should be weighed in patients with other cardiovascular risk factors, and that Evenity should be discontinued if a patient has a heart attack or stroke during therapy [1]. The label also says to monitor for signs and symptoms of heart attack and stroke and to instruct patients to seek prompt medical attention if symptoms occur [1].

The trial numbers behind the warning

In ARCH, 4,093 postmenopausal women with osteoporosis and a fragility fracture were enrolled and randomized to monthly romosozumab 210 mg or weekly oral alendronate 70 mg. During the 12-month treatment period, 2,040 received Evenity and 2,014 received alendronate [1][2]. Positively adjudicated major adverse cardiac events over that year were 2.0% (41 of 2,040) with romosozumab versus 1.1% (22 of 2,014) with alendronate, hazard ratio 1.87 (95% CI 1.11 to 3.14); heart attack 0.8% versus 0.2%, stroke 0.6% versus 0.3%, cardiovascular death 0.8% versus 0.6% [1].

In FRAME (7,180 women enrolled) [3], 3,581 women received Evenity and 3,576 received placebo, and major adverse cardiac events were 0.8% (30) versus 0.8% (29), hazard ratio 1.03 (95% CI 0.62 to 1.72) [1]. The imbalance appeared against alendronate, not against placebo.

The label does not translate this warning into a surgical timing rule [1].

The 12-dose limit and what stopping does to bone

The label limits use to 12 monthly doses, noting that the anabolic effect wanes after 12 monthly doses; if osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered [1]. After the drug is stopped without follow-on anti-resorptive therapy, bone mineral density returns to about baseline within 12 months [1].

The formation marker P1NP rose about 145% above placebo at 2 weeks, returned to placebo level by month 9, and was about 15% below placebo by month 12; after discontinuation, P1NP returned to baseline within 12 months [1].

Missed doses

The label says that if a dose is missed, it should be administered as soon as it can be rescheduled, and that dosing can then be scheduled every month from the date of the last dose [1]. It does not create a separate rule for a dose missed around an operation.

Dental surgery: the one procedure the label discusses

Osteonecrosis of the jaw has been reported in patients receiving EVENITY, can occur spontaneously, and is generally associated with tooth extraction and/or local infection with delayed healing [1]. The label calls for a routine oral examination by the prescriber before starting treatment, and lists factors that raise the risk: chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, corticosteroids, cancer, radiotherapy, poor oral hygiene, pre-existing dental disease or infection, anemia and coagulopathy [1]. For patients requiring invasive dental procedures, the label says the clinical judgment of the treating physician and/or oral surgeon should guide the management plan for each patient based on a benefit-risk assessment [1]. Across the two trials, one romosozumab-treated patient developed osteonecrosis of the jaw during treatment [1].

Low calcium and kidney function

Hypocalcemia is a contraindication, and the label says pre-existing hypocalcemia must be corrected before starting the drug [1]. The label says patients should be adequately supplemented with calcium and vitamin D during treatment; the trials used at least 500 mg calcium and 600 international units of vitamin D daily [1]. Patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) or receiving dialysis are at greater risk of hypocalcemia, and the label says to monitor their serum calcium [1]. Across the two trials, albumin-adjusted calcium fell below 8.3 mg/dL in 0.2% of both romosozumab and control patients, none fell below 7.5 mg/dL, and the nadir came by month 1 [1].

New thigh, hip or groin pain

Atypical femoral fractures have been reported with EVENITY, and causality has not been established; one case occurred during treatment across both trials [1]. The label says patients should be advised to report new or unusual thigh, hip or groin pain during treatment, and that any patient who presents with thigh or groin pain should be evaluated to rule out an incomplete femur fracture, with the opposite leg assessed as well [1].

Who the label covers

The indication is osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy [1]. The label is not written for men or premenopausal women, and the pregnancy section states the drug is not indicated for women of reproductive potential [1].

The contraindications are hypocalcemia and a history of systemic hypersensitivity to romosozumab-aqqg or any component of the product, with reactions including angioedema, erythema multiforme and urticaria [1]. A recent heart attack or stroke sits in the boxed warning as a restriction on starting the drug, not in the contraindications section [1].