Evenity (Romosozumab) Travel & Timezone-Shift Protocols

Does crossing time zones change the schedule?

Romosozumab is given once a month for 12 monthly doses, so the schedule is set by calendar dates rather than clock times [1]. The label says that if a dose is missed, it should be administered as soon as it can be rescheduled, and thereafter Evenity can be scheduled every month from the date of the last dose [1]. A flight that moves the clock a few hours forward or back does not change a monthly date.

For reference, after a single 210 mg dose the median time to maximum concentration is 5 days, steady state is reached by month 3 of monthly dosing, and the mean effective half-life is about 12.8 days at 3 mg/kg every 4 weeks [1].

Who gives the injection when you are away from home

The label calls for two separate 105 mg/1.17 mL prefilled syringes injected one after the other for a 210 mg dose, into the abdomen, thigh or upper arm, once every month for 12 doses, and states that Evenity should be administered by a healthcare provider [1]. A trip that spans a dose date therefore means arranging that dose with a qualified provider.

In the European Union the product is a 105 mg prefilled syringe or pen, with two injections at different body sites for 210 mg once a month for 12 months, and treatment should be started and supervised by a specialist doctor with experience in treating osteoporosis [2].

The prescribing information says to let the syringes sit at room temperature for at least 30 minutes before injection and not to warm them any other way [1].

If the trip makes the scheduled date impossible

For a missed dose, the label says to administer it as soon as it can be rescheduled, then schedule monthly doses from the date of that dose [1]. Treatment is limited to 12 monthly doses [1].

Timing of the 12th dose and what comes next

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

In the ARCH trial, women who received romosozumab for 12 months and then alendronate had new vertebral fractures in 6.2% versus 11.9% on alendronate throughout, a 48% lower risk at 24 months [3].

What to watch for while you are away

Evenity carries a boxed warning that it may increase the risk of myocardial infarction, stroke and cardiovascular death, and it should not be initiated in patients who have had an MI or stroke in the preceding year; in patients with other cardiovascular risk factors the benefits and risks should be weighed, and the drug should be discontinued if an MI or stroke occurs during therapy [1]. The label also says to monitor for signs and symptoms of MI and stroke and to seek prompt medical attention if they occur [1].

The size of that signal differed by comparator. In the alendronate-controlled ARCH trial, adjudicated major adverse cardiac events occurred in 2.0% (41 of 2,040) on Evenity versus 1.1% (22 of 2,014) on alendronate, hazard ratio 1.87 (95% CI 1.11 to 3.14) [1]. In the placebo-controlled FRAME trial the rates were 0.8% (30) versus 0.8% (29), hazard ratio 1.03 (95% CI 0.62 to 1.72) [1].

Other label points:

• Hypocalcemia is a contraindication, and pre-existing hypocalcemia must be corrected before starting; patients should be adequately supplemented with calcium and vitamin D during treatment, and 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 on dialysis are at greater risk and need serum calcium monitoring [1].
• Hypersensitivity reactions including angioedema, erythema multiforme, dermatitis, rash and urticaria have occurred, and the label says to discontinue Evenity if a clinically significant allergic reaction occurs; across both trials these reactions were reported in 6.5% of Evenity-treated and 6.5% of control patients [1].
• Osteonecrosis of the jaw and atypical femoral fractures have been reported; new or unusual thigh, hip or groin pain should be evaluated to rule out an incomplete femur fracture [1].
• Injection site reactions (pain, erythema) occurred in 4.9% on Evenity versus 2.8% in controls across the two trials, leading to discontinuation in 0.1% [1].