romosozumab: prescribing information – dosing, contraindications, interactions, side effects

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

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

Posology

The recommended dose is 210 mg romosozumab (administered as two subcutaneous injections of 105 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.

Draft

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

Missed doses
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.

Special populations

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

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

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

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

Method of administration

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

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)

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.

Draft

MedDRA System Organ Class
Adverse reaction
Frequency category
Infections and infestations
Nasopharyngitis
Very common
Sinusitis
Common
Immune system disorders
Hypersensitivitya
Rash
Dermatitis
Urticaria
Angioedema
Erythema multiforme
Common
Common
Common
Uncommon
Rare
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 disorders
Arthralgia
Very common
Neck pain
Common
Muscle spasms
Common
General disorders and administration site conditions
Injection site reactionsd
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.

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.

Draft

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.

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.

Draft

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.

Draft

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.

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

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

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

Pharmacodynamic effects

In postmenopausal women with osteoporosis, romosozumab 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.
Romosozumab 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 romosozumab 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 romosozumab (in a limited number of patients) after 12 months placebo treatment, the levels of increase in P1NP and decrease in CTX by romosozumab were similar to that observed during the initial treatment.

Clinical trial efficacy

Treatment of osteoporosis in postmenopausal women

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

Study 20110142 (ARCH)
The efficacy and safety of romosozumab in the treatment of osteoporosis in postmenopausal women was evaluated in a multicenter, multinational, randomized, double-blind, alendronate-controlled,

Draft

superiority study of 4,093 postmenopausal women aged 55 to 90 years (mean age of 74.3 years) with previous 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 vertebral fractures; or a BMD T-score at the total hip or femoral neck of ≤ -2.00, and either at least 2 moderate or severe vertebral fractures; or a fracture of the proximal femur that occurred within 3 to 24 months prior to randomization.

Absorption

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%.

Biotransformation

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

Elimination

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

Linearity/non-linearity

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

Renal impairment

Following a 210 mg dose of romosozumab in a clinical trial of 16 patients with severe renal impairment (creatinine clearance < 30 ml/min) or end-stage renal disease (ESRD) receiving haemodialysis, mean Cmax and AUC were 29% and 44% higher in patients with severe renal impairment as compared to healthy subjects. Mean romosozumab exposure was similar in patients with ESRD receiving haemodialysis as compared to healthy subjects.
Population pharmacokinetic analysis indicated an increase in romosozumab exposure with increasing severity of renal impairment. However, based on an exposure-response model of BMD changes and comparison to exposures obtained at tolerated clinical doses, no dose adjustment is recommended in these patients. Monitoring of hypocalcemia in patients with severe renal impairment or receiving dialysis is recommended (see section 4.4).

Draft

Hepatic impairment