EVENITY 105mg 90mg / ml injection solution in pre-filled syringe medication leaflet

Each pre-filled pen contains 105 mg of romosozumab in 1.17 ml of solution (90 mg/ml).

Each pre-filled syringe contains 105 mg of romosozumab in 1.17 ml of solution (90 mg/ml).

Romosozumab is a humanized IgG2 monoclonal antibody produced using recombinant DNAtechnology in Chinese hamster ovary (CHO) cells.

Each pre-filled pen and each pre-filled syringe contains 0.07 mg polysorbate 20.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear to opalescent, colorless to light yellow solution.

EVENITY is indicated in treatment of severe osteoporosis in postmenopausal women at high risk offracture (see section 5.1).

Treatment should be initiated and supervised by specialist physicians experienced in the managementof osteoporosis.

The recommended dose is 210 mg romosozumab (administered as two subcutaneous injections of105 mg each) once monthly for 12 months.

Patients should be adequately supplemented with calcium and vitamin D before and during treatment(see sections 4.3 and 4.4).

Patients treated with EVENITY should be given the package leaflet and the patient alert card.

Following completion of romosozumab therapy, transition to antiresorptive therapy is recommendedin order to extend the benefit achieved with romosozumab beyond 12 months.

If the romosozumab dose is missed, it should be administered as soon as it can be feasible. Thereafter,the next romosozumab dose should not be given earlier than one month after the last dose.

No dose adjustment is necessary in elderly patients (see also section 5.2).

No dose adjustment is required in patients with renal impairment (see section 5.2). Serum calciumshould be monitored in patients with severe renal impairment or receiving dialysis (see section 4.4).

No clinical trials have been conducted to evaluate the effect of hepatic impairment (see section 5.2).

The safety and efficacy of romosozumab in paediatric patients (age <18 years) have not yet beenestablished. No data are available.

Subcutaneous use

To administer the 210 mg dose, 2 subcutaneous injections of romosozumab should be given into theabdomen, thigh, or upper arm. The second injection should be given immediately after the first one,but at a different injection site. Draft

Administration should be performed by an individual who has been trained in injection techniques.

For instructions on handling and disposal see section 6.6.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1(see section 4.4)

- Hypocalcaemia (see section 4.4)

- History of myocardial infarction or stroke (see section 4.4)

In randomised controlled studies, an increase in serious cardiovascular events (myocardial infarctionand 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 section4.3).

When determining whether to use romosozumab for an individual patient, consideration should begiven 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, severerenal impairment, age). Romosozumab should only be used if the prescriber and patient agree that thebenefit outweighs the risk. If a patient experiences a myocardial infarction or stroke during therapy,treatment with romosozumab should be discontinued.

Transient hypocalcaemia has been observed in patients receiving romosozumab.

Hypocalcaemia should be corrected prior to initiating therapy with romosozumab and patients shouldbe monitored for signs and symptoms of hypocalcaemia. If any patient presents with suspectedsymptoms 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 to29 ml/min/1.73 m2) or receiving dialysis are at greater risk of developing hypocalcaemia and thesafety data for these patients is limited. Calcium levels should be monitored in these patients.

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

Osteonecrosis of the jaw (ONJ), has been reported rarely in patients receiving romosozumab. Thefollowing 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 theantiresorptive 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 tohead and neck. Draft

- 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 ofsores or discharge during treatment with romosozumab.

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

Atypical low-energy or low trauma fracture of the femoral shaft, which can occur spontaneously, hasbeen reported rarely in patients receiving romosozumab. Any patient who presents with new orunusual thigh, hip, or groin pain should be suspected of having an atypical fracture and should beevaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fractureshould also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption ofromosozumab therapy should be considered, based on an individual benefit-risk assessment.

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 essentiallysodium-free.

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

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 withromosozumab in rats (see section 5.3). A risk for malformations of developing digits in the humanfoetus is low following romosozumab exposure due to the timing of digit formation in the firsttrimester in humans, a period when placental transfer of immunoglobulins is limited.

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 beexcreted in breast milk during the first few days after birth, which is decreasing to low concentrationssoon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this shortperiod.

No data are available on the effect of romosozumabDraft on human fertility. Animal studies in female andmale 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.

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). Inrandomised controlled studies, an increase in serious cardiovascular events (myocardial infarction andstroke) has been observed in romosozumab treated patients compared to controls (see section 4.4 andinformation below).

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 systemorgan class, adverse reactions are presented in order of decreasing seriousness.

MedDRA System Organ Class Adverse reaction Frequencycategory

Infections and infestations Nasopharyngitis Very common

Sinusitis Common

Hypersensitivitya Common

Rash Common

Immune system disorders Dermatitis Common

Urticaria Uncommon

Angioedema Rare

Erythema multiforme Rare

Metabolism and nutrition disorders Hypocalcaemiab Uncommon

Nervous system disorders Headache Common

Strokec Uncommon

Eye disorders Cataract Uncommon

Cardiac disorders Myocardial infarctionc Uncommon

Musculoskeletal and connective tissue Arthralgia Very commondisorders Neck pain Common

Muscle spasms Common

General disorders and administration site dconditions Injection site reactions Common

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.

Draft

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

The presence of anti-romosozumab binding antibodies decreased romosozumab exposure by up to25%. No impact on the efficacy of romosozumab was observed in the presence of antiromosozumabantibodies. Limited safety data show that the incidence of injection site reactions was numericallyhigher in female patients with neutralizing antibodies.

In the active-controlled trial of romosozumab for the treatment of severe osteoporosis inpostmenopausal 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 alendronatearm and 13 women (0.6%) had stroke in the romosozumab arm versus 7 women (0.3%) in thealendronate arm. These events occurred in patients with and without a history of myocardial infarctionor 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 deathoccurred in 30 women (1.5%) in the romosozumab group and 22 (1.1%) women in the alendronategroup.

In the placebo-controlled trial of romosozumab for the treatment of osteoporosis in postmenopausalwomen (including women with severe and less severe osteoporosis) during the 12-month double-blindromosozumab 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 in29 women (0.8%) in the romosozumab group and 24 (0.7%) women in the placebo group.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience with overdose in clinical trials. There is no known antidote to romosozumab orspecific treatment for overdose. In case of overdose, it is recommended that patients are monitoredclosely and given appropriate treatment.

Pharmacotherapeutic group: Drugs for treatment of bone diseases, drugs affecting bone structure andmineralization, ATC code: M05BX06.

Romosozumab is a humanized monoclonal antibody (IgG2) that binds and inhibits sclerostin, therebyincreasing bone formation due to the activation of bone lining cells, increasing bone matrix productionby osteoblasts, and recruitment of osteoprogenitor cells. Additionally, romosozumab results in changesto expression of osteoclast mediators, thereby decreasing bone resorption. Together, this dual effect ofincreasing bone formation and decreasing bone resorption results in rapid increases in trabecular andcortical bone mass, improvements in bone structureDra,ft and strength.

In postmenopausal women with osteoporosis, romosozumab increased the bone formation markerprocollagen Type 1 N terminal propeptide (P1NP) early in treatment, with a peak increase ofapproximately 145% relative to placebo 2 weeks after initiating treatment, followed by a return toplacebo levels at month 9 and a decline to approximately 15% below placebo at month 12.

Romosozumab decreased the bone resorption marker type-1 collagen C-telopeptide (CTX) with amaximal reduction of approximately 55% relative to placebo 2 weeks after initiating treatment. CTXlevels remained below placebo and were approximately 25% below placebo at month 12.

After discontinuation of romosozumab therapy in postmenopausal women with osteoporosis, P1NPlevels returned to baseline within 12 months; CTX increased above baseline levels within 3 monthsand returned toward baseline levels by month 12, reflecting reversibility of effect. Upon retreatmentwith romosozumab (in a limited number of patients) after 12 months placebo treatment, the levels ofincrease in P1NP and decrease in CTX by romosozumab were similar to that observed during theinitial treatment.

Clinical trial efficacy

Efficacy and safety of romosozumab was assessed in two pivotal studies, an alendronate-controlled(ARCH) and a placebo-controlled study (FRAME).

The efficacy and safety of romosozumab in the treatment of osteoporosis in postmenopausal womenwas evaluated in a multicenter, multinational, randomized, double-blind, alendronate-controlled,superiority study of 4,093 postmenopausal women aged 55 to 90 years (mean age of 74.3 years) withprevious fragility fractures.

Enrolled women had either a BMD (Bone Mineral Density) T-score at the total hip or femoral neck of≤ −2.50, and either at least 1 moderate or severe vertebral fracture; or at least 2 mild vertebralfractures; or a BMD T-score at the total hip or femoral neck of ≤ -2.00, and either at least 2 moderateor severe vertebral fractures; or a fracture of the proximal femur that occurred within 3 to 24 monthsprior to randomization.

The mean baseline lumbar spine, total hip, and femoral neck BMD T-scores were -2.96, -2.80,and -2.90, respectively, 96.1% of women had a vertebral fracture at baseline, and 99.0% of womenhad a previous osteoporotic fracture. Women were randomized (1:1) to receive either monthlysubcutaneous injections of romosozumab or oral weekly alendronate in a blinded fashion for12 months. After the 12-month double blind study period, women in both arms transitioned toalendronate while remaining blinded to their initial treatment. The primary analysis was performedwhen all women had completed the month 24 study visit and clinical fracture events were confirmedfor at least 330 women and occurred after a median follow-up time of approximately 33 months onstudy. Women received calcium and vitamin D supplementation daily.

The primary efficacy endpoints were the incidence of new vertebral fracture through month 24 and theincidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) at primary analysis.

As shown in Table 1, romosozumab reduced the incidence of new vertebral fracture through month 24(adjusted p-value < 0.001) and the incidence of clinical fracture at primary analysis (adjusted p-value< 0.001) as well as the incidence of non vertebral fractures at primary analysis (adjusted p-value =0.040) versus treatment with alendronate alone. Table 1 also shows nonvertebral, hip and majorosteoporotic fracture risk reduction through primary analysis, month 12 and month 24.

Draft

Table 1. The Effect of romosozumab on the Iincidence and risk of new Vvertebral, clinical,nonvertebral, hip and major osteoporotic fractures in post-menopausal women withosteoporosis

Proportion of women withfracture Absolute risk Relative risk

Alendronate/ Romosozumab/ reduction reduction

Alendronate Alendronate (%) (%)(%) (%) (95% CI) (95% CI)

New vertebral

Through month 12 85/1703 (5.0) 55/1696 (3.2) 1.84 (0.51, 3.17) 36 (11, 54)

Through month 24a 147/1834 (8.0) 74/1825 (4.1) 4.03 (2.50, 5.57) 50 (34, 62)

Clinicalb

Through month 12 110/2047 (5.4) 79/2046 (3.9) 1.8 (0.5, 3.1) 28 (4, 46)

Primary analysis(median follow-up 266/2047 (13.0) 198/2046 (9.7) NAc 27 (12, 39)approx. 33 months)

Nonvertebral

Through Month 12 95/2047 (4.6) 70/2046 (3.4) 1.4 (0.1, 2.6) 26 (-1, 46)

Primary analysis(median follow-up 217/2047 (10.6) 178/2046 (8.7) NAc 19 (1, 34)approx. 33 months)

Hip

Through Month 12 22/2047 (1.1) 14/2046 (0.7) 0.3 (-0.3, 0.9) 36 (-26, 67)

Primary analysis(median follow-up 66/2047 (3.2) 41/20Draft4 6 (2.0) NAc 38 (8, 58)approx. 33 months)

Major osteoporoticd

Through Month 12 85/2047 (4.2) 61/2046 (3.0) 1.4 (0.3, 2.5) 28 (-1, 48)

Primary analysis(median follow-up 209/2047 (10.2) 146/2046 (7.1) NAc 32 (16, 45)approx. 33 months)

a. Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusted for age strata, baselinetotal hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline. Treatment comparisonsare based on adjusted logistic regression model.

b. Clinical fractures include all symptomatic fractures including nonvertebral and painful vertebral fractures. Treatmentcomparisons are based on Cox proportional hazards model.

c. NA: not available as subjects have various exposure at primary analysis.

d. Major osteoporotic fractures include hip, forearm, humerus, and clinical vertebral.

In postmenopausal women with osteoporosis, romosozumab for 12 months followed by alendronatefor 12 months increased BMD compared with alendronate alone at month 12 and 24 (p-value < 0.001)(see Table 2).

Following 12 months of treatment, romosozumab increased BMD at the lumbar spine from baseline in98% of postmenopausal women.

Table 2. Mean percent change in BMD from baseline through month 12 and month 24 in post-menopausal women with osteoporosis

Alendronate/Alendronate Romosozumab/Alendronate Treatment difference

Mean (95% CI) Mean (95% CI) from alendronate-to-

N = 2047a N = 2046a alendronate

At Month 12

Lumbar spine 5.0 (4.8, pct. 5.2) 12.4 (12.1, 12.7) 7.4b (7.0, 7.8)

Total hip 2.9 (2.7, 3.1) 5.8 (5.6, 6.1) 2.9b (2.7, 3.2)

Femoral neck 2.0 (1.8, 2.2) 4.9 (4.6, 5.1) 2.8b (2.5, 3.2)

At Month 24

Lumbar spine 7.2 (6.9, 7.5) 14.0 (13.6, 14.4) 6.8b (6.4, 7.3)

Total hip 3.5 (3.3, 3.7) 6.7 (6.4, 6.9) 3.2b (2.9, 3.6)

Femoral neck 2.5 (2.3, 2.8) 5.7 (5.4, 6.0) 3.2b (2.8, 3.5)

Means and confidence intervals are based on patients with available data. Based on ANCOVA model; missing values ofbaseline BMD and BMD percent change from baseline at month 12 and month 24 were imputed by control-based patternimputation.

a. Number of women randomized

b. p-value < 0.001

The significant difference in BMD achieved in the first 12 months was maintained through month 36upon transition/continuation to alendronate. Treatment differences were observed at 6 months atlumbar spine, total hip and femoral neck.

The efficacy and safety of romosozumab in the treatment of postmenopausal osteoporosis wasevaluated in a multicenter, multinational, randomize d, double-blind, placebo-controlled, parallel-group

Draftstudy of 7,180 postmenopausal women aged 55 to 90 years (mean age of 70.9 years). 40.8% ofenrolled women had severe osteoporosis with a prior fracture at baseline.

The co-primary efficacy endpoints were the incidence of new vertebral fractures through month 12and through month 24.

Romosozumab reduced the incidence of new vertebral fractures through month 12 (absolute riskreduction: 1.3% [95% CI: 0.79; 1.80], relative risk reduction: 73% [95% CI: 53; 84], adjusted p-value< 0.001) and after transition to denosumab through month 24 (absolute risk reduction: 1.89 % [95%

CI: 1.30; 2.49], relative risk reduction: 75% [95% CI: 60, 84], adjusted p-value < 0.001).

The safety and efficacy of romosozumab in postmenopausal women with severe osteoporosistransitioning from bisphosphonate therapy (92.7% in teriparatide group and 88.1% in romosozumabgroup had prior alendronate use during the last 3 years) were evaluated in a multicenter, randomized,open-label study of 436 postmenopausal women aged 56 to 90 years (mean age of 71.5 years) versusteriparatide.

The primary efficacy variable was percent change in total hip BMD from baseline at month 12.

Romosozumab significantly increased BMD at the total hip relative to teriparatide at month 12 (meantreatment difference from Teriparatide: 3.4% [95% CI: 2.8; 4.0], p-value < 0.0001). The trial was notintended to estimate the effect on fractures but there were seven fractures in the romosozumab arm andnine fractures in the teriparatide arm of the study.

In a bone histology sub-study, a total of 154 transiliac crest bone biopsy specimens were obtainedfrom 139 postmenopausal women with osteoporosis at months 2 and 12 (in FRAME study).

Qualitative histology assessments showed normal bone architecture and quality at all time points,normal lamellar bone with no evidence of mineralization defects, woven bone, marrow fibrosis, orclinically significant marrow abnormality in patients treated with romosozumab.

Histomorphometry assessments on biopsies at months 2 and 12 in women showed an increase of boneformation parameters and a decrease in bone resorption parameters while bone volume and trabecularthickness were increased in romosozumab group compared to placebo group.

The European Medicines Agency has deferred the obligation to submit the results of studies withromosozumab in one or more subsets of the paediatric population in the treatment of osteoporosis.

See section 4.2 for information on paediatric use.

The median time to maximum romosozumab concentration (tmax) was 5 days (range: 2 to 7 days).

Following a 210 mg subcutaneous dose, bioavailability was 81%.

Romosozumab is a humanized monoclonal antibody (IgG2) with high affinity and specificity forsclerostin, and therefore is cleared via a rapid saturable elimination pathway (i.e. target mediatednonlinear clearance, mediated by degradation of the romosozumab-sclerostin complex) and via a slow

Draftnonspecific elimination pathway mediated by the reticuloendothelial system.

After Cmax, serum levels declined with a mean effective half-life of 12.8 days. Steady-state wasgenerally reached by month 3 with less than 2-fold accumulation following monthly dosing.

Following subcutaneous administration, romosozumab exhibits non-linear pharmacokinetics as aresult of binding to sclerostin. Multiple doses administered ranged from 70 to 210 mg.

Following a 210 mg dose of romosozumab in a clinical trial of 16 patients with severe renalimpairment (creatinine clearance < 30 ml/min) or end-stage renal disease (ESRD) receivinghaemodialysis, mean Cmax and AUC were 29% and 44% higher in patients with severe renalimpairment as compared to healthy subjects. Mean romosozumab exposure was similar in patientswith ESRD receiving haemodialysis as compared to healthy subjects.

Population pharmacokinetic analysis indicated an increase in romosozumab exposure with increasingseverity of renal impairment. However, based on an exposure-response model of BMD changes andcomparison to exposures obtained at tolerated clinical doses, no dose adjustment is recommended inthese patients. Monitoring of hypocalcemia in patients with severe renal impairment or receivingdialysis is recommended (see section 4.4).

No clinical trials have been conducted to evaluate the effect of hepatic impairment. Hepaticimpairment is not expected to impact on the pharmacokinetics of romosozumab since the liver is not amajor organ for romosozumab metabolism or excretion.

The pharmacokinetics of romosozumab were not affected by age from 20 years to 89 years.

Romosozumab exposure decreased with increasing body weight however this decrease had a minimalimpact on lumbar spine BMD gain based on exposure-response analysis and is not clinicallymeaningful. Based on population PK analyses, the expected median steady state AUC for a 61 kg and114 kg patient is 558 µg.day/ml and 276 µg.day/ml respectively following a monthly subcutaneousdose of 210 mg romosozumab.

No dose adjustment is necessary for any patient characteristics. Based on a populationpharmacokinetic analysis, gender and race (Japanese versus non-Japanese) had no clinicallymeaningful impact on the pharmacokinetics of romosozumab (< 20% change in exposure at steadystate).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, carcinogenicDr aft potential or in bone safety studies.

In a carcinogenicity study, doses up to 50 mg/kg/week were administered by subcutaneous injection to

Sprague-Dawley male and female rats from 8 weeks of age for up to 98 weeks. These doses resulted insystemic exposures that were up to 19 times higher than the systemic exposure observed in humansfollowing a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison).

Romosozumab caused a dose-dependent increase in bone mass with macroscopic bone thickening atall doses. There were no effects of romosozumab on mortality or tumor incidence in male or femalerats.

Studies in female and male rats did not show any romosozumab-related effects on mating, fertility, ormale reproductive assessments (sperm parameters or organ weights), and there were no effects onestrous cycling or any ovarian or uterine parameters at exposures around 54 times the clinicalexposure.

Skeletal malformations, including syndactyly and polydactyly, were observed at a low incidence in 1out of 75 litters at exposures around 30 times the clinical exposure following administration ofromosozumab to rats during the period of organogenesis. There were no adverse effects on postnatalgrowth and development.

Sclerostin has been suggested to have a role in digit formation, however, as digit formation in thehuman occurs in the first trimester when placental transfer of immunoglobulins is limited, the risk of asimilar finding in humans is low (see section 4.6).

Calcium acetate

Glacial acetic acid

Sodium hydroxide (for pH adjustment)

Sucrose

Polysorbate 20

Water for injections

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

3 years.

When taken out of the refrigerator for use, EVENITY should not be returned to the refrigerator but canbe kept at room temperature (up to 25°C) for up to 30 days in the original container. If not used withinthis period, the product should be discarded.

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep the pre-filled syringe or pre-filled pen in the outer carton in order to protect from light.

Draft

A single use, disposable, handheld, mechanical injection device pre-assembled with pre-filled syringecontaining 1.17 ml solution. The syringe inside the pen is made from cyclo olefin polymer plastic witha stopper (chlorobutyl) and insert molded stainless steel needle with elastomeric needle shield(synthetic rubber).

Pack size of 2 pre-filled pens.

Multipack containing 6 (3 packs of 2) pre-filled pens.

A single use, disposable, pre-filled syringe containing 1.17 ml solution. The syringe is made fromcyclo olefin polymer plastic with a stopper (chlorobutyl) and insert molded stainless steel needle andelastomeric needle shield (synthetic rubber).

Pack size of 2 pre-filled syringes.

Multipack containing 6 (3 packs of 2) pre-filled syringes.

Not all pack sizes may be marketed.

The solution should be visually inspected for particles and discoloration prior to administration.

EVENITY should not be used if the solution is discolored, cloudy, or contains particles.

Prior to subcutaneous administration, romosozumab should be allowed to sit at room temperature forat least 30 minutes before injecting. This will help make the injection more comfortable. It should notbe warmed in any other way.

Do not shake.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

UCB Pharma S.A.

Allée de la Recherche, 60

B-1070 Bruxelles

Belgium

EU/1/19/1411/001

EU/1/19/1411/002

EU/1/19/1411/003

EU/1/19/1411/004

Date of first authorisation: 09 December 2019 Draft

Date of latest renewal: 22 August 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu