Evenity

Romosozumab.

EVENITY solution for injection in pre-filled syringe 105 mg: Each pre-filled syringe contains 105 mg romosozumab in 1.17 mL (90 mg/mL) solution.
EVENITY (romosozumab) is a humanised monoclonal antibody (IgG2) with high affinity and specificity for sclerostin. Romosozumab has an approximate molecular weight of 145 kDa and is produced in a mammalian cell line (Chinese hamster ovary) by recombinant DNA technology.
EVENITY is a sterile, preservative-free, clear to opalescent, colourless to light yellow solution, pH 5.2.
Excipients/Inactive Ingredients: 0.61 mg calcium, 3.8 mg acetate, 70 mg sucrose, 0.07 mg polysorbate 20, Water for Injection, Sodium hydroxide to pH of 5.2.

Pharmacotherapeutic group: Other drugs affecting bone structure and mineralisation. ATC code: M05BX06.
Pharmacology: Pharmacodynamics: Mechanism of Action: Romosozumab is a humanised monoclonal antibody (IgG2) that binds and inhibits sclerostin. Romosozumab has a dual effect on bone, increasing bone formation and decreasing bone resorption. Romosozumab stimulates new bone formation on trabecular and endocortical bone surfaces by stimulating osteoblastic activity resulting in increases in trabecular and cortical bone mass and improvements in bone structure and strength.
Pharmacodynamic Effects: EVENITY has a dual effect on bone, increasing bone formation and decreasing bone resorption. In postmenopausal women with osteoporosis, EVENITY increased the bone formation marker procollagen type 1 N-terminal propeptide (P1NP) early in treatment, with a peak increase of approximately 145% relative to placebo 2 weeks after initiating treatment, followed by a return to placebo levels at month 9 and a decline to approximately 15% below placebo at month 12. EVENITY decreased the bone resorption marker type 1 collagen C-telopeptide (CTX) with a maximal reduction of approximately 55% relative to placebo 2 weeks after initiating treatment. CTX levels remained below placebo and were approximately 25% below placebo at month 12.
After discontinuation of EVENITY therapy in postmenopausal women with osteoporosis, P1NP levels returned to baseline within 12 months; CTX increased above baseline levels within 3 months and returned toward baseline levels by month 12, reflecting reversibility of effect. Upon retreatment with EVENITY after 12 months off treatment, the level of increase in P1NP and decrease in CTX by EVENITY was similar to that observed during the initial treatment.
In women transitioning from oral alendronate, EVENITY also increased bone formation and decreased bone resorption.
Clinical Data: Treatment of Osteoporosis in Postmenopausal Women: Study 1 (ARCH, alendronate-controlled) was a randomised, double blind, alendronate-controlled study of 4093 postmenopausal women aged 55 to 90 years (mean age of 74.3 years), with a median follow-up of 33 months.
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 99.8% of women had a previous fracture. Women were randomised (1:1) to receive either monthly subcutaneous injections of EVENITY (N = 2046) or oral weekly alendronate (N = 2047) for 12 months, with daily supplementation of calcium and vitamin D. After the 12-month treatment period, women in both arms transitioned to open-label alendronate while remaining blinded to their initial treatment. The primary analysis was performed when all women had completed the month 24 study visit and clinical fracture events were confirmed for at least 330 women, which occurred after a median of 33 months on study.
The primary efficacy endpoints were the incidence of new vertebral fracture through month 24 and the incidence of clinical fracture (defined as the composite of nonvertebral fracture and clinical vertebral fracture) at primary analysis. Secondary efficacy endpoints included the incidence of nonvertebral fractures, hip fractures, and major nonvertebral fractures at the primary analysis, and percent change from baseline in BMD at the lumbar spine, total hip, and femoral neck at month 12 and month 24.
Effect on New Vertebral and Clinical Fractures: EVENITY reduced the incidence of new vertebral fracture at 24 months and clinical fracture after a median of 33 months. The number of patients who experienced vertebral and clinical fracture was consistently lower in the EVENITY arm at prespecified time points. See Table 1 for full data. (See Table 1.)

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EVENITY for 12 months followed by alendronate for 12 months demonstrated a persistent effect in reducing the incidence of new vertebral fractures (see Figure 1).

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Effect on Other Fracture Types/Groups: EVENITY significantly reduced the incidence of nonvertebral fracture after a median follow up of 33 months. EVENITY reduced the number of patients who experienced nonvertebral fracture, hip fracture, and major nonvertebral fractures compared to alendronate consistently at prespecified time points. See Table 2 for full data. (See Table 2.)

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The Kaplan-Meier estimates of the cumulative incidence of clinical fracture, nonvertebral fracture and hip fracture over time are shown in Figure 2 as follows. (See Figure 2).

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Effect on Bone Mineral Density (BMD): EVENITY significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with alendronate at month 12. At month 24, 12-month treatment with EVENITY followed by 12-month treatment with alendronate significantly increased BMD compared with alendronate alone for 24 months at the lumbar spine, total hip, and femoral neck. The BMD increase with EVENITY over alendronate observed at month 12 was maintained at month 24 (see Table 3).

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A total of 167 subjects participated in the imaging component (as measured by DXA) of the Imaging and PK/BTM/Biomarker Substudy. EVENITY resulted in progressive increases from baseline in BMD beginning at month 6. Treatment differences in BMD between EVENITY and alendronate groups continued to increase at month 12. After transitioning to alendronate after 12-month treatment with EVENITY, treatment differences in BMD between the EVENITY-alendronate and alendronate-alendronate groups continued to increase at month 18 and were maintained at month 24 (see Figure 3).
Consistent effects on BMD were observed regardless of baseline age, baseline BMD, and geographic region at the lumbar spine, total hip, and femoral neck.
Treatment differences in BMD at 6 months were 7.6% at the lumbar spine, 2.2% at the total hip, and 2.9% at the femoral neck. At 12 months, the treatment differences were 8.9% at the lumbar spine, 3.7% at the total hip, and 4.1% at the femoral neck. At 18 months, after transitioning to alendronate after 12 months of EVENITY treatment, the treatment differences between the EVENITY-alendronate and alendronate-alendronate groups were 9.3% at the lumbar spine, 4.3% at the total hip, and 5.4% at the femoral neck. At 24 months, the EVENITY-alendronate group maintained gains in BMD compared to on the alendronate-alendronate group, with treatment differences of 9.4% at the lumbar spine, 4.3% at the total hip, and 5.3% at the femoral neck. (See Figure 3.)

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Study 2 (FRAME, placebo-controlled) was a randomised, double blind, placebo-controlled study of 7180 postmenopausal women aged 55 to 90 years (mean age of 70.9 years). The mean baseline lumbar spine, total hip, and femoral neck BMD T-scores were -2.72, -2.47, and -2.75, respectively, and 18.3% of women had a vertebral fracture at baseline.
Women were randomised to receive subcutaneous injections of either EVENITY (N = 3589) or placebo (N = 3591) once every month for 12 months with daily supplementation of calcium and vitamin D. After the 12-month treatment period, women in both arms transitioned to open-label denosumab 60 mg subcutaneous every 6 months for 12 months while remaining blinded to initial treatment.
The co-primary efficacy endpoints were the incidence of new vertebral fractures through month 12 and through month 24. Secondary efficacy endpoints included the incidence of clinical fractures (all symptomatic fractures including nonvertebral and painful vertebral fractures), nonvertebral fractures, new or worsening vertebral fractures, major nonvertebral fractures, hip fractures, and percent change from baseline in BMD at the lumbar spine, total hip, and femoral neck, and were evaluated though 24 months.
Effect on New Vertebral and Clinical Fractures: EVENITY significantly reduced the incidence of new vertebral fractures through month 12 (p < 0.001), as shown in Table 4. The reduction in fracture risk persisted through the second year in women who received EVENITY during the first year and transitioned to denosumab compared to those who transitioned from placebo to denosumab (month 24; p < 0.001).
EVENITY also significantly reduced the incidence of clinical fractures through month 12 (see Table 4 and Figure 4 for time to first clinical fracture). (See Table 4 and Figures 4 and 5.)

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Effect on Other Fracture Types/Groups: See Table 5 for effect of EVENITY on other Fracture Types/Groups through month 24. (See Table 5).

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Effect on Bone Mineral Density (BMD): EVENITY significantly increased BMD at the lumbar spine, total hip, and femoral neck compared to placebo at month 12. Following 12 months of treatment, EVENITY increased BMD at the lumbar spine from baseline in 99% of postmenopausal women. Ninety-two percent of women treated with EVENITY achieved at least a 5% increase from baseline in BMD at lumbar spine by month 12 and 68% gained 10% or more.
These effects were sustained with transition to another osteoporosis treatment; women who received EVENITY for 12 months followed by denosumab for 12 months had greater increases in BMD at the lumbar spine, total hip, and femoral neck at month 24 compared to women who received placebo for 12 months followed by denosumab for 12 months (see Table 6).
Consistent effects on BMD were observed regardless of baseline age, baseline BMD, and geographic region at the lumbar spine, total hip, and femoral neck. (See Table 6).

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Among women with BMD assessed at baseline and every 6 months, EVENITY significantly increased BMD at the lumbar spine, total hip, and femoral neck relative to placebo at 6 and 12 months. Following the transition from EVENITY to denosumab, BMD continued to increase through month 24. In women who transitioned from placebo to denosumab, BMD also increased with denosumab use. The differences in BMD achieved at month 12 between EVENITY and placebo patients were overall maintained at month 24, when comparing patients who transitioned from EVENITY to denosumab versus patients who transitioned from placebo to denosumab (see Figure 6).
Treatment differences in BMD at 6 months were 9.4% at the lumbar spine, 4.3% at the total hip, and 3.6% at the femoral neck. After 12 months, the treatment differences were 13.3% at the lumbar spine, 6.9% at the total hip, and 5.9% at the femoral neck. At 18 months, women who received EVENITY followed by denosumab maintained gains in BMD compared to women who received placebo followed by denosumab, with treatment differences of 11.8% at the lumbar spine, 6.8% at the total hip, and 6.8% at the femoral neck. At 24 months, women who received EVENITY followed by denosumab maintained gains in BMD compared to women who received placebo followed by denosumab, with treatment differences of 12.6% at the lumbar spine, 6.0% at the total hip, and 6.0% at the femoral neck. (See Figure 6.)

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Bone Histology and Histomorphometry: A total of 154 transiliac crest bone biopsy specimens were obtained from 139 postmenopausal women with osteoporosis at month 2, month 12, and/or month 24. Of the biopsies obtained, 154 (100.0%) were adequate for qualitative histology and 138 (89.6%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments from those treated with EVENITY showed normal bone architecture and quality at all time points. There was no evidence of woven bone, mineralisation defects, or marrow fibrosis.
Histomorphometry assessments on biopsies at months 2 and 12 compared the effect of EVENITY with placebo (15 specimens at month 2 and 39 specimens at month 12 in the EVENITY group, 14 specimens at month 2 and 31 specimens at month 12 in the placebo group). At month 2 in women treated with EVENITY, histomorphometric indices of bone formation at trabecular and endocortical surfaces were increased due to a significant increase in modelling based formation with no significant effect on remodelling formation. These effects on bone formation were accompanied by a decrease in indices of bone resorption. At month 12, both bone formation and resorption indices were decreased with EVENITY, while bone volume and trabecular and cortical thickness were increased. Biopsies obtained at month 24 compared the effect of EVENITY for 12 months followed by denosumab for 12 months (18 specimens) with placebo followed by denosumab (21 specimens). At month 24, indices of bone remodelling were low and similar in both groups, consistent with the effects of denosumab.
Treatment of Osteoporosis in Women Transitioning from Bisphosphonate Therapy: Study 3 (STRUCTURE) was a randomised, open-label study of 436 postmenopausal women aged 56 to 90 years (mean age of 71.5 years) with osteoporosis transitioning from bisphosphonate therapy to EVENITY. This study evaluated safety and BMD changes by dual-energy X-ray absorptiometry (DXA) through 12 months of treatment with EVENITY compared with 12 months of treatment with teriparatide. The study also evaluated hip strength estimated by finite element analysis (FEA) over 12 months using quantitative computed tomography images.
Enrolled women had a mean baseline lumbar spine, total hip, and femoral neck BMD T-scores of -2.85, -2.24, and -2.46, respectively, and a history of nonvertebral fracture after age 50 or vertebral fracture at any time.
At month 12, EVENITY increased BMD from baseline by 9.8% (95% CI: 9.0, 10.5) at the lumbar spine, 2.9% (95% CI: 2.5, 3.4) at the total hip, and 3.2% (95% CI: 2.6, 3.8) at the femoral neck. Treatment differences in BMD at 12 months compared to teriparatide were 4.4% (95% CI: 3.4, 5.4) at the lumbar spine, 3.4% (95% CI: 2.8, 4.0) at the total hip, and 3.4% at the femoral neck (95% CI: 2.6, 4.2; p-value < 0.0001 for all comparisons).
At month 12, EVENITY increased estimated strength from baseline by 2.5% (95% CI: 1.7, 3.2) at the total hip. The treatment difference in estimated strength at the total hip at month 12 compared to teriparatide was 3.2% (95% CI: 2.1, 4.3; p-value < 0.0001).
Adverse reactions observed in this study were generally consistent with those seen in women not transitioning from bisphosphonate therapy (discussed in Adverse Reactions).
Pharmacokinetics: Following SC administration, romosozumab exhibits nonlinear pharmacokinetics as a result of binding to sclerostin. Dose proportional increases in exposure were observed for the doses of 140 mg and higher.
Administration of a single dose of 210 mg romosozumab in healthy male and female subjects (N = 90, age range: 21 to 65 years) resulted in a mean (standard deviation [SD]) maximum serum concentration (C_max) of 22.2 (5.8) mcg/mL and a mean area under the concentration-time curve (AUC) of 389 (127) mcg*day/mL. The median time to maximum romosozumab concentration (T_max) was 5 days (range: 2 to 7 days).
Following a 210 mg subcutaneous dose, bioavailability was 81%. After C_max, serum levels declined with a mean effective half-life of 12.8 days. Steady state was generally reached by month 3 with minimal accumulation (less than 2-fold) following monthly dosing.
The presence of anti-romosozumab binding antibodies decreased romosozumab exposure up to 22%, which was not considered clinically meaningful [see Adverse Reactions].
Based on a population pharmacokinetic analysis, age (20-89 years), gender, race, or disease state (low bone mass or osteoporosis) had no clinically meaningful effects on pharmacokinetics (< 20% change in exposure at steady state). Romosozumab exposure decreased with increasing body weight. This decrease had a minimal impact on lumbar spine BMD gain (< 15% change) based on exposure response analyses and was not considered clinically meaningful. Thus, no dose adjustment is necessary based on age, gender, race, disease state, or body weight.
The pharmacokinetics of romosozumab were similar in patients transitioning from bisphosphonate therapy.
Drug Interactions: No drug-drug interaction studies have been conducted with romosozumab.
Special Populations: Paediatrics: The pharmacokinetics of romosozumab in paediatric patients have not been assessed.
Gender: The pharmacokinetics of romosozumab were similar in postmenopausal women and in men with osteoporosis.
Geriatrics: The pharmacokinetics of romosozumab were not affected by age from 20 to 89 years.
Renal Impairment: Following a single 210 mg dose of romosozumab in a clinical study of 16 patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²) or end-stage renal disease (ESRD) requiring haemodialysis, mean C_max and AUC were 29% and 44% higher in patients with severe renal impairment as compared to healthy subjects. Mean romosozumab exposure was similar between patients with ESRD requiring haemodialysis and healthy subjects.
A population pharmacokinetic analysis indicated an increase in romosozumab exposure with increasing severity of renal impairment. However, based on both the renal impairment study and population PK analysis, this increase is not clinically meaningful and no dose adjustment is necessary in these patients [see Precautions].
Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment.
Preclinical Safety Data/Nonclinical Toxicology: Carcinogenicity: 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 to up to 98 weeks of age. These doses resulted in systemic exposures that were up to 19 times higher than the systemic exposure observed in humans following 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 at all doses. There were no effects of romosozumab on mortality or tumour incidence in male or female rats.
Mutagenicity: Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.
Impairment of Fertility: No effects on fertility were observed in male and female rats at doses up to 300 mg/kg (100 times the clinical dose). No effects were noted in reproductive organs in rats and cynomolgus monkeys dosed with romosozumab in the 6-month chronic toxicology studies at exposures up to 37 and 90 times higher, respectively, than the systemic exposure observed in humans administered 210 mg romosozumab monthly (based on AUC comparison).
Animal Toxicology and/or Pharmacology: No adverse effects were noted in rats and monkeys after 26 once weekly subcutaneous injections at doses up to 100 mg/kg and systemic exposures 37 and 90 times higher, respectively, than the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison).
In growing rats administered a rodent surrogate sclerostin antibody at pharmacologically active doses, a transient increase in longitudinal growth rate predicted to result in < 1% increase in bone length was observed. In growing rats dosed with romosozumab for 6 months resulting in exposures up to 19 times higher than the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison), there was no effect on femur length.
In bone safety studies in ovariectomised rats and monkeys, once weekly treatment with romosozumab for 12 months increased bone formation and decreased bone resorption. The resulting increase in bone mass and improvements in cortical bone geometry and cancellous bone microarchitecture was associated with increased bone strength at exposures from 0.5 to 21 times higher than the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison).
Bone tissue was of normal or improved quality with no evidence of mineralisation defects, accumulation of osteoid, or woven bone.

Postmenopausal Osteoporosis: EVENITY is indicated in treatment of severe osteoporosis in postmenopausal women at high risk of fracture (see Pharmacology: Pharmacodynamics under Actions).

Dosage: The recommended dose of EVENITY is 210 mg administered subcutaneously. Administer EVENITY once every month for 12 doses.
Patients should be adequately supplemented with calcium and vitamin D [see Contraindications, Precautions, and Pharmacology: Pharmacodynamics: Clinical Data under Actions].
If the EVENITY dose is missed, administer as soon as it can be rescheduled. Thereafter, EVENITY can be scheduled every month from the date of the last dose.
After completing EVENITY therapy, consider transition to an antiresorptive osteoporosis therapy [see Pharmacology: Pharmacodynamics: Clinical Data under Actions]. Treatment should be initiated and supervised by specialist physicians experienced in the management of osteoporosis. After initial training in proper subcutaneous injection technique, an individual may self-inject EVENITY if a physician determines that is appropriate and with medical follow-up as necessary.
The efficacy and safety of treatment with EVENITY for longer than 12 months has not been established.
Method of Administration: Subcutaneous use. Administration should be performed by an individual who has been trained to administer the product.
To administer the 210 mg dose, give 2 subcutaneous injections of EVENITY.
For detailed instructions on storage, handling, and administration, follow the directions provided in the Special Precautions for Disposal and Other Handling under Cautions for Usage.
Important Administration Instructions: Visually inspect EVENITY for particles and discolouration prior to administration. EVENITY is a clear to opalescent, colourless to light yellow solution. Do not use if the solution is cloudy or discoloured or contains particles.
Administer EVENITY in the abdomen, thigh, or upper arm subcutaneously. If patient wants to use the same injection site, make sure it is not the same spot on the injection site patient used for a previous injection. Do not inject into areas where the skin is tender, bruised, red, or hard.

There is no experience with overdosage in clinical trials with EVENITY.

Hypocalcaemia: EVENITY is contraindicated in patients with uncorrected hypocalcaemia [see Precautions, Adverse Reactions, and Use in Pregnancy & Lactation].
Hypersensitivity: EVENITY is contraindicated in patients with known clinically significant hypersensitivity to romosozumab or to any component of the product formulation [see Precautions and Description].

POTENTIAL RISK OF MYOCARDIAL INFARCTION, STROKE AND CARDIOVASCULAR DEATH: EVENITY may increase the risk of myocardial infarction, stroke and cardiovascular death [see Precautions]. 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 a history of MI or stroke and other cardiovascular risk factors. If a patient experiences a myocardial infarction or stroke during therapy, EVENITY should be discontinued.

Hypocalcaemia: Transient hypocalcaemia has been observed in patients receiving EVENITY. Correct hypocalcaemia prior to initiating therapy with EVENITY [see Contraindications, Adverse Reactions, and Use in Pregnancy & Lactation].
Monitor patients for signs and symptoms of hypocalcaemia. Patients should be adequately supplemented with calcium and vitamin D [see Pharmacology: Pharmacodynamics under Actions].
Hypersensitivity: Clinically significant hypersensitivity reactions, including angio-oedema, erythema multiforme, and urticaria occurred in the EVENITY group in clinical trials. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of EVENITY [see Contraindications and Adverse Reactions].
Myocardial Infarction, Stroke and Cardiovascular Death: In a randomised 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.
In two large, controlled fracture trials of EVENITY for the treatment of osteoporosis in postmenopausal women, cardiovascular events of myocardial infarction (MI) and stroke were prospectively adjudicated. In the active-controlled trial (N = 4054) during the 12-month double blind EVENITY treatment phase, MI occurred in 16 women (0.8%) in the EVENITY arm and 5 (0.2%) in the alendronate arm; stroke occurred in 13 women (0.6%) in the EVENITY arm and 7 (0.3%) in the alendronate arm. These events occurred in patients with and without a history of MI or stroke. In the placebo-controlled trial (N = 7157) during the 12-month double blind EVENITY treatment phase, MI occurred in 9 women (0.3%) in the EVENITY arm and 8 (0.2%) in the placebo arm; stroke occurred in 8 women (0.2%) in the EVENITY arm and 10 (0.3%) in the placebo arm. These events occurred in patients with and without a history of MI or stroke.
A causal relationship between EVENITY and these events has not been established. In both trials, most participants had common risk factors for cardiovascular disease, and within each trial, cardiovascular risk factors were balanced between treatment arms. Consider the benefit-risk in patients at increased risk for MI or stroke. Patients should be instructed to watch for symptoms of MI and stroke and to seek prompt medical attention if symptoms occur. If a patient experiences a myocardial infarction or stroke during therapy, consider discontinuation of EVENITY.
EVENITY should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Treating physician should assess patient for risk of CV before treatment.
Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing and has occurred rarely in patients receiving EVENITY in the clinical trials.
Prior to treatment, a dental examination with appropriate preventative dentistry should be considered in patients with possible risk factors. Before commencing invasive dental procedures, patients and their dentist should be advised of the risks and reports of osteonecrosis of the jaw so that dental symptoms, including toothache, developing during treatment can be fully assessed for cause before treatment of the tooth commences.
Patients who are suspected of having or who develop ONJ while on EVENITY should receive care by a dentist or an oral surgeon. Discontinuation of EVENITY therapy should be considered based on individual benefit-risk assessment.
Atypical Femoral Fracture: Atypical low-energy or low-trauma fracture of the femoral shaft, which can occur spontaneously, has occurred rarely in patients receiving EVENITY in the clinical trials. 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 EVENITY therapy should be considered based on individual benefit-risk assessment.
Effects on Ability to Drive and Use Machines: No studies on the effect on the ability to drive or use heavy machinery have been performed in patients receiving EVENITY.
Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment.
Renal Impairment: No dose adjustment is required in patients with renal impairment. There is limited experience in patients with eGFR < 30 mL/min.
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 [see Contraindications and Precautions]. Monitoring of calcium levels is highly recommended. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis.
Use in Children: The safety and efficacy of EVENITY have not been established in paediatric patients [see Pharmacology: Preclinical Safety Data/Nonclinical Toxicology under Actions].
Use in the Elderly: Of the 6525 postmenopausal women with osteoporosis treated with EVENITY in clinical studies, 5222 (80%) were ≥ 65 years old and 2385 (36.6%) were ≥ 75 years old. No overall differences in safety or efficacy were observed among these patients and younger patients.

Pregnancy: Risk Summary: EVENITY is not indicated for use in women of reproductive potential. In animal reproduction studies, weekly administration of romosozumab to pregnant rats during the period of organogenesis at exposures greater than 31 times the clinical exposure produced skeletal abnormalities in the offspring. Administration of romosozumab to rats prior to mating and through to the end of lactation produced minimal to slight decreases in femoral bone mineral density and/or cortical circumferences in the offspring at 1.4 to 54 times the expected exposure in humans [see Data as follows].
Data: Animal Data: Reproductive and developmental effects of romosozumab were assessed in the rat in a preliminary and definitive embryo-foetal development study, a combined fertility and embryo-development study, and a pre- and postnatal development study.
Skeletal malformations including syndactyly and polydactyly occurred in 1 out of 75 litters across all rat reproductive toxicity studies, in the litter of a dam given weekly subcutaneous romosozumab doses of 300 mg/kg (equivalent to at least 31 times the clinical exposure observed in humans following a monthly subcutaneous dose of 210 mg, based on area under the concentration-time curve [AUC] comparison).
In the offspring of female rats given weekly romosozumab doses from 6 weeks before cohabitation through mating and lactation, femoral periosteal and endocortical circumferences were slightly decreased at 10, 60, and 300 mg/kg (equivalent to 1.4, 18, and 54 times the clinical exposure following a monthly subcutaneous dose of 210 mg, based on AUC comparison). Cortical thickness was increased at 300 mg/kg (equivalent to 54 times expected clinical exposure). Femoral metaphyseal bone mineral density was slightly decreased at 60 and 300 mg/kg (equivalent to 18 and 54 times expected clinical exposure).
Lactation: Risk Summary: EVENITY is not indicated for use in women of reproductive potential. In animal studies where pregnant rats were given weekly doses of romosozumab from 6 weeks before cohabitation through mating and lactation at 10, 60, or 300 mg/kg (equivalent to 1.4, 18 or 54 times the clinical exposure following a monthly subcutaneous dose of 210 mg, based on AUC comparison), romosozumab was dose-dependently present in the serum of offspring on postnatal day 21 at 0.01 to 2.4 times maternal exposure due to gestational and/or lactational exposure.

Summary of the Safety Profile: The adverse reactions described in the table as follows are based on 12-month pooled data from 3695 postmenopausal women with osteoporosis treated with EVENITY in Phase II and Phase III, placebo-controlled clinical trials [see Adverse Reactions]. The adverse reactions in EVENITY treated patients (N = 2040) in a double blind, Phase III active-controlled study were similar in type to those seen in the placebo-controlled trials. The most common adverse reactions (≥ 1/10) from the pooled safety data were viral upper respiratory tract infection and arthralgia.
Tabulated Summary of Adverse Reactions: Adverse reactions are displayed by system organ class and frequency as follows using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), and very rare (< 1/10,000). (See Table 7).

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Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of romosozumab has been evaluated using a screening immunoassay for the detection of binding anti-romosozumab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro assay was performed to detect neutralising antibodies.
In postmenopausal women dosed with 210 mg monthly EVENITY, the incidence of anti-romosozumab antibodies was 18.1% (1072 of 5914) for binding antibodies and 0.8% (50 of 5914) for neutralising antibodies. Across all doses studied in postmenopausal women, the pooled incidence of binding antibodies and neutralising antibodies was similar to the 210 mg monthly dose, respectively. No impact to the efficacy and safety of romosozumab was observed in the presence of anti-romosozumab antibodies.
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 as per local regulations.

No drug interaction studies have been conducted with EVENITY.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special Precautions for Disposal and Other Handling: Before administration, the solution should be inspected. Do not inject the solution if it contains particles, or is cloudy or discoloured. To avoid discomfort at the site of injection, allow the medicine to reach room temperature (up to 25°C) before injecting. Inject the entire contents.
Prior to subcutaneous administration, allow EVENITY to sit at room temperature for at least 30 minutes before injecting. Do not warm in any other way.
Visually inspect the solution for particles and discolouration. Do not use if the solution is discoloured, cloudy, or contains particles.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Comprehensive instructions for the administration of EVENITY are provided in the Important Administration Instructions under Dosage & Administration.

Refrigerate at 2°C to 8°C in the original carton.
If removed from the refrigerator, EVENITY should be kept at controlled room temperature (up to 25°C) in the original carton and must be used within 30 days.
Protect EVENITY from direct light and do not expose to temperatures above 25°C.
Do not freeze.
Do not store EVENITY in extreme heat or cold.
Do not shake.

Agents Affecting Bone Metabolism

M05BX06 - romosozumab ; Belongs to the class of other drugs affecting bone structure and mineralization. Used in the treatment of bone diseases.

B