THOUSAND OAKS, Calif.,
June 8, 2018 /PRNewswire/
-- Amgen (NASDAQ:AMGN) today announced that the European
Commission (EC) has approved a new indication
for Prolia® (denosumab) for the treatment of bone
loss associated with long-term systemic glucocorticoid therapy in
adult patients at increased risk of fracture. The EC approval
is based on the positive results of a Phase 3 study that
evaluated the safety and efficacy of Prolia compared with
risedronate in patients receiving glucocorticoid
treatment.1
"We are pleased that today's EC approval provides physicians
with a new treatment option for bone loss associated with the use
of glucocorticoid medications," said Sean
E. Harper, M.D., executive vice president of Research and
Development at Amgen. "As a leader in bone health with more than 20
years of osteoporosis research experience, we believe that Prolia
can address a critical treatment need for patients with
glucocorticoid-induced osteoporosis in Europe and globally."
"Long-term glucocorticoid therapy is associated with a rapid and
early decline in bone mineral density and increase in fracture
risk," said Professor Dr. Willem F.
Lems, researcher and rheumatologist, VU University Medical
Centre, Amsterdam. "This approval
provides a new treatment option to effectively counter the
detrimental effects of glucocorticoid therapy on bone in patients
at increased risk of fracture."
The EC approval is supported by a Phase 3 randomized,
double-blind, double-dummy, active-controlled study evaluating the
safety and efficacy of Prolia compared with risedronate in patients
receiving glucocorticoid treatment.1 The study included
two patient groups: those on sustained glucocorticoid therapy and
those newly initiating glucocorticoid therapy. The study met the
primary endpoint (percent change from baseline in lumbar spine bone
mass density [BMD] at 12 months, assessing non-inferiority) and all
secondary endpoints (the percent changes from baseline in lumbar
spine and total hip BMD at 12 and 24 months, assessing
superiority).
In the glucocorticoid-continuing subpopulation, Prolia
demonstrated a greater increase in lumbar spine BMD compared to
risedronate at one year (Prolia 3.6 percent, risedronate 2.0
percent; p<0.001) and two years (Prolia 4.5 percent,
risedronate 2.2 percent; p<0.001). In the
glucocorticoid-initiating subpopulation, Prolia demonstrated a
greater increase in lumbar spine BMD compared to risedronate at one
year (Prolia 3.1 percent, risedronate 0.8 percent;
p<0.001) and two years (Prolia 4.6 percent, risedronate
1.5 percent; p<0.001).
In addition, compared with risedronate, Prolia demonstrated
significantly greater mean percent increases in BMD from baseline
at one and two years at the total hip, femoral
neck and trochanter in both the
glucocorticoid-continuing and glucocorticoid-initiating
subpopulations. Adverse events and serious adverse events were
similar between treatment groups and consistent with the known
safety profile of Prolia. No serious adverse events were reported
with a subject incidence of two percent or greater in either
treatment group.
The U.S. Food and Drug Administration (FDA) approved the
expanded indication of Prolia for the treatment of osteoporosis
associated with newly initiating or sustained systemic
glucocorticoid therapy in men and women at high risk of fracture on
May 18, 2018.
About Glucocorticoid-Induced Osteoporosis (GIOP)
GIOP
is the most common form of secondary
osteoporosis.2 However, the proportion of patients
that qualify for GIOP diagnosis and intervention is small and
depends on the level of exposure to glucocorticoid
medications.3,4 In addition, a significant proportion of
the patients treated long-term with glucocorticoid medications are
already diagnosed with postmenopausal osteoporosis or treated with
osteoporosis medications. Importantly, at similar levels of BMD,
postmenopausal women taking glucocorticoids have considerably
higher risk of fracture compared with postmenopausal nonusers of
glucocorticoids.5 The most frequent chronic
inflammatory diseases associated with long-term glucocorticoid use
are chronic obstructive pulmonary disorder (COPD), asthma and
rheumatoid arthritis.6 In an European Union (EU)
study, 30 to 40 percent of patients on long-term glucocorticoid
treatment had radiographic evidence of vertebral
fractures.6
About Prolia® (denosumab)
Prolia is
the first approved therapy that specifically targets RANK Ligand,
an essential regulator of bone-removing cells (osteoclasts). Prolia
is approved and marketed in over 80 countries worldwide.
Prolia is approved in the U.S. for the treatment of
postmenopausal women with osteoporosis 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. In the U.S., Prolia is
also approved for treatment to increase bone mass in men with
osteoporosis 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. Prolia is also indicated as a treatment
to increase bone mass in women at high risk for fracture receiving
adjuvant aromatase inhibitor therapy for breast cancer and in men
at high risk for fracture receiving androgen deprivation therapy
for non-metastatic prostate cancer in the U.S. Prolia was approved
by the FDA on May 18, 2018, as a treatment for patients with
glucocorticoid-induced osteoporosis in men and women at high risk
of fracture who are either initiating or continuing systemic
glucocorticoids in a daily dosage equivalent to 7.5 mg or greater
of prednisone and expected to remain on glucocorticoids for at
least six months. High risk of fracture is defined as a
history of osteoporotic fracture, multiple risk factors for
fracture, or patients who have failed or are intolerant to other
available osteoporosis therapy.
Prolia is approved in the EU for the treatment of osteoporosis
in postmenopausal women and in men at increased risk of fractures.
In postmenopausal women, Prolia significantly reduces the risk of
vertebral, non-vertebral and hip fractures.
In the EU, Prolia is also approved for the treatment of bone
loss associated with hormone ablation in men with prostate cancer
at increased risk of fractures. In men with prostate cancer
receiving hormone ablation, Prolia significantly reduces the risk
of vertebral fractures.
Prolia is also approved in the EU for the treatment of bone loss
associated with long-term systemic glucocorticoid therapy in adult
patients at increased risk of fracture.
Prolia is administered as a single subcutaneous injection of 60
mg once every six months. Please see the Important Safety
Information below.
EU Important EU Product Information
Calcium and Vitamin D supplementation
Adequate intake of calcium and vitamin D is important in all
patients.
Precautions for use
Hypocalcaemia
It is important to identify patients at
risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate
intake of calcium and vitamin D before initiating therapy. Clinical
monitoring of calcium levels is recommended before each dose and,
in patients predisposed to hypocalcaemia within two weeks after the
initial dose. If any patient presents with suspected symptoms of
hypocalcaemia during treatment (see section 4.8 for symptoms)
calcium levels should be measured. Patients should be encouraged to
report symptoms indicative of hypocalcaemia.
In the post-marketing setting, severe symptomatic hypocalcaemia
has been reported (see section 4.8), with most cases occurring in
the first weeks of initiating therapy, but it can occur later.
Skin infections
Patients receiving Prolia®
may develop skin infections (predominantly cellulitis) leading to
hospitalisation (see section 4.8). Patients should be advised to
seek prompt medical attention if they develop signs or symptoms of
cellulitis.
Osteonecrosis of the Jaw (ONJ)
ONJ has been reported
rarely in patients receiving Prolia® for osteoporosis
(see section 4.8).
The start of treatment/new treatment course should be delayed in
patients with unhealed open soft tissue lesions in the mouth. A
dental examination with preventive dentistry and an individual
benefit-risk assessment is recommended prior to treatment with
denosumab in patients with concomitant risk factors.
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
(higher risk for highly potent compounds), route of administration
(higher risk for parenteral administration) and cumulative dose of
bone resorption 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 denosumab. While on
treatment, invasive dental procedures should be performed only
after careful consideration and be avoided in close proximity to
Prolia® administration.
The management plan of the patients who develop ONJ should be
set up in close collaboration between the treating physician and a
dentist or oral surgeon with expertise in ONJ. Temporary
interruption of treatment should be considered until the condition
resolves and contributing risk factors are mitigated where
possible.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with
denosumab. Possible risk factors for osteonecrosis of the external
auditory canal include steroid use and chemotherapy and/or local
risk factors such as infection or trauma. The possibility of
osteonecrosis of the external auditory canal should be considered
in patients receiving denosumab who present with ear symptoms
including chronic ear infections.
Atypical fractures of the femur
Atypical femoral fractures have been reported in patients receiving
denosumab (see section 4.8). Atypical femoral fractures may occur
with little or no trauma in the subtrochanteric and diaphyseal
regions of the femur. Specific radiographic findings characterise
these events. Atypical femoral fractures have also been reported in
patients with certain co-morbid conditions (e.g. vitamin D
deficiency, rheumatoid arthritis, hypophosphatasia) and with use of
certain pharmaceutical agents (e.g. bisphosphonates,
glucocorticoids, proton pump inhibitors). These events have also
occurred without antiresorptive therapy. Similar fractures reported
in association with bisphosphonates are often bilateral; therefore
the contralateral femur should be examined in denosumab-treated
patients who have sustained a femoral shaft fracture.
Discontinuation of Prolia® therapy in patients
suspected to have an atypical femur fracture should be considered
pending evaluation of the patient based on an individual
benefit-risk assessment. During denosumab-treatment, patients
should be advised to report new or unusual thigh, hip, or groin
pain. Patients presenting with such symptoms should be evaluated
for an incomplete femoral fracture.
Long-term antiresorptive treatment
Long-term antiresorptive treatment (including both denosumab and
bisphosphonates) may contribute to an increased risk for adverse
outcomes such as osteonecrosis of the jaw and atypical femur
fractures due to significant suppression of bone remodelling (see
section 4.2).
Concomitant treatment with other denosumab-containing
medicinal products
Patients being treated with Prolia® should not be
treated concomitantly with other denosumab-containing medicinal
products (for prevention of skeletal related events in adults with
bone metastases from solid tumours).
Renal impairment
Patients with severe renal impairment (creatinine clearance
< 30 mL/min) or receiving dialysis are at greater risk
of developing hypocalcaemia. The risks of developing hypocalcaemia
and accompanying parathyroid hormone elevations increase with
increasing degree of renal impairment. Adequate intake of calcium,
vitamin D and regular monitoring of calcium is especially important
in these patients, see above.
Dry natural rubber
The needle cover of the pre-filled syringe contains dry natural
rubber (a derivative of latex), which may cause allergic
reactions.
Warnings for excipients
This medicinal product contains sorbitol. Patients with rare
hereditary problems of fructose intolerance should not take this
medicinal product.
This medicinal product contains less than 1 mmol sodium
(23 mg) per 60 mg i.e. essentially 'sodium-free'.
U.S. Important Safety Information
Contraindications
Prolia® is
contraindicated in patients with hypocalcemia. Pre-existing
hypocalcemia must be corrected prior to initiating
Prolia®. Prolia® is contraindicated in women
who are pregnant and may cause fetal harm. In women of reproductive
potential, pregnancy testing should be performed prior to
initiating treatment with Prolia®. Prolia® is
contraindicated in patients with a history of systemic
hypersensitivity to any component of the product. Reactions have
included anaphylaxis, facial swelling and urticaria.
Same Active Ingredient
Prolia® contains the same active ingredient
(denosumab) found in XGEVA®. Patients receiving
Prolia® should not receive XGEVA®.
Hypersensitivity
Clinically significant
hypersensitivity including anaphylaxis has been reported with
Prolia®. Symptoms have included hypotension, dyspnea,
throat tightness, facial and upper airway edema, pruritus, and
urticaria. If an anaphylactic or other clinically significant
allergic reaction occurs, initiate appropriate therapy and
discontinue further use of Prolia®.
Hypocalcemia
Hypocalcemia may worsen with the use of
Prolia®, especially in patients with severe renal
impairment. In patients predisposed to hypocalcemia and
disturbances of mineral metabolism, clinical monitoring of calcium
and mineral levels is highly recommended within 14 days of
Prolia® injection. Adequately supplement all
patients with calcium and vitamin D.
Osteonecrosis of the Jaw (ONJ)
ONJ, which can occur spontaneously, is generally associated with
tooth extraction and/or local infection with delayed healing, and
has been reported in patients receiving Prolia®. An oral
exam should be performed by the prescriber prior to initiation of
Prolia®. A dental examination with appropriate
preventive dentistry is recommended prior to treatment in patients
with risk factors for ONJ such as invasive dental procedures,
diagnosis of cancer, concomitant therapies (e.g., chemotherapy,
corticosteroids, angiogenesis inhibitors), poor oral hygiene, and
co-morbid disorders. Good oral hygiene practices should be
maintained during treatment with Prolia®. The risk
of ONJ may increase with duration of exposure to
Prolia®.
For patients requiring invasive dental procedures, clinical
judgment should guide the management plan of each patient. Patients
who are suspected of having or who develop ONJ should receive care
by a dentist or an oral surgeon. Extensive dental surgery to treat
ONJ may exacerbate the condition. Discontinuation of
Prolia® should be considered based on individual
benefit-risk assessment.
Atypical Femoral Fractures
Atypical low-energy, or low trauma fractures of the shaft have been
reported in patients receiving Prolia®. Causality has
not been established as these fractures also occur in osteoporotic
patients who have not been treated with anti-resorptive agents.
During Prolia® treatment, patients should be advised
to report new or unusual thigh, hip, or groin pain. Any patient who
presents with thigh or groin pain should be evaluated to rule out
an incomplete femur fracture. Interruption of Prolia®
therapy should be considered, pending a risk/benefit assessment, on
an individual basis.
Multiple Vertebral Fractures (MVF) Following Discontinuation
of Prolia Treatment
Following discontinuation of Prolia® treatment,
fracture risk increases, including the risk of multiple vertebral
fractures. New vertebral fractures occurred as early as 7 months
(on average 19 months) after the last dose of Prolia®.
Prior vertebral fracture was a predictor of multiple vertebral
fractures after Prolia® discontinuation. Evaluate an
individual's benefit/risk before initiating treatment with
Prolia®. If Prolia® treatment is
discontinued, consider transitioning to an alternative
anti-resorptive therapy.
Serious Infections
In a clinical trial (N=7,808) in women with postmenopausal
osteoporosis, serious infections leading to hospitalization were
reported more frequently in the Prolia® group than
in the placebo group. Serious skin infections, as well as
infections of the abdomen, urinary tract and ear were more frequent
in patients treated with Prolia®.
Endocarditis was also reported more frequently in
Prolia®-treated patients. The incidence of opportunistic
infections and the overall incidence of infections were similar
between the treatment groups. Advise patients to seek prompt
medical attention if they develop signs or symptoms of severe
infection, including cellulitis.
Patients on concomitant immunosuppressant agents or with
impaired immune systems may be at increased risk for serious
infections. In patients who develop serious infections while on
Prolia®, prescribers should assess the need for
continued Prolia® therapy.
Dermatologic Adverse Reactions
In the same clinical trial in women with postmenopausal
osteoporosis, epidermal and dermal adverse events such as
dermatitis, eczema and rashes occurred at a significantly higher
rate with Prolia® compared to placebo. Most of
these events were not specific to the injection site. Consider
discontinuing Prolia® if severe symptoms develop.
Musculoskeletal Pain
Severe and occasionally incapacitating bone, joint, and/or muscle
pain has been reported in patients taking Prolia®.
Consider discontinuing use if severe symptoms develop.
Suppression of Bone Turnover
In clinical trials in women with postmenopausal osteoporosis,
Prolia® resulted in significant suppression of bone
remodeling as evidenced by markers of bone turnover and bone
histomorphometry. The significance of these findings and the effect
of long-term treatment are unknown. Monitor patients for these
consequences, including ONJ, atypical fractures, and delayed
fracture healing.
Adverse Reactions
The most common adverse reactions (>5% and more common than
placebo) in women with postmenopausal osteoporosis are back pain,
pain in extremity, musculoskeletal pain, hypercholesterolemia, and
cystitis. The most common adverse reactions (> 5% and more
common than placebo) in men with osteoporosis are back pain,
arthralgia, and nasopharyngitis. Pancreatitis has been reported
with Prolia®.
In women with postmenopausal osteoporosis, the overall incidence
of new malignancies was 4.3% in the placebo group and 4.8% in the
Prolia® group. In men with osteoporosis, new
malignancies were reported in no patients in the placebo group and
4 (3.3%) patients in the Prolia® group. A causal
relationship to drug exposure has not been established.
The most common adverse reactions (>3% and more common than
active-control group) in patients with glucocorticoid-induced
osteoporosis were: back pain, hypertension, bronchitis, and
headache. The most common (per patient incidence ≥ 10%) adverse
reactions reported with Prolia® in patients with bone
loss receiving ADT for prostate cancer or adjuvant AI therapy for
breast cancer are arthralgia and back pain. Pain in extremity and
musculoskeletal pain have also been reported in clinical trials.
Additionally, in Prolia®-treated men with nonmetastatic
prostate cancer receiving ADT, a greater incidence of cataracts was
observed.
Denosumab is a human monoclonal antibody. As with all
therapeutic proteins, there is potential for immunogenicity.
For more information, please see the Prolia®
Prescribing Information and Medication Guide.
About Amgen
Amgen is committed to unlocking the
potential of biology for patients suffering from serious illnesses
by discovering, developing, manufacturing and delivering innovative
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and dramatically improve people's lives. A biotechnology pioneer
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patients around the world and is developing a pipeline of medicines
with breakaway potential.
For more information, visit www.amgen.com and follow us on
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