Actonel®
Risedronate Sodium Hemi-pentahydrate
Bone Metabolism Regulator
Procter & Gamble Pharmaceuticals
http://www.pg.com/en_US/index.jhtml
actonel Monograph PDF download here.
CPS:PIS_m006550
Date of Preparation: August 4, 1999
Date of Revision: July 9, 2004
Pharmacology
Actonel (risedronate sodium), a
pyridinylbisphosphonate in the form of hemi-pentahydrate with small amounts of
monohydrate, inhibits osteoclast bone resorption and modulates bone metabolism.
Actonel has a high affinity for hydroxyapatite crystals in bone and is a potent
antiresorptive agent. At the cellular level, Actonel inhibits osteoclasts. The
osteoclasts adhere normally to the bone surface, but show evidence of reduced
active resorption (e.g., lack of ruffled border). Histomorphometry in rats,
dogs, and minipigs showed that Actonel treatment reduces bone turnover (i.e.,
activation frequency, the rate at which bone remodelling sites are activated)
and bone resorption at remodeling sites.
Pharmacokinetics
Absorption: Absorption after an oral dose is
relatively rapid (tmax approximately 1 hour), and occurs throughout
the upper gastrointestinal tract. Absorption is independent of dose over the
range studied (single dose, 2.5 to 30 mg; multiple dose, 2.5 to 5 mg daily; and
multiple dose, 35 and 50 mg weekly). Steady-state conditions in the serum are
observed within 57 days of daily dosing. Mean oral bioavailability of the
tablet is 0.63% and is bioequivalent to a solution. Extent of absorption when
administered 30 minutes before breakfast is reduced by 55% compared to dosing
in the fasting state (i.e., no food or drink for 10 hours prior to or 4 hours
after dosing). Dosing 1 hour prior to breakfast reduces extent of absorption by
30% compared to dosing in the fasting state. Dosing either 30 minutes prior to
breakfast or 2 hours after a meal results in a similar extent of absorption.
Distribution: The mean steady-state volume of
distribution is 6.3 L/kg in humans. Human plasma protein binding of drug
is about 24%. Preclinical studies in rats and dogs dosed i.v. with single doses
of [14C] Actonel indicate that approximately 60% of the dose is distributed
to bone. The remainder of the dose is excreted in the urine. After multiple
oral dosing in rats, the uptake of Actonel in soft tissues was found to be
minimal (in the range of 0.001% to 0.01%), with drug levels quickly decreasing
after the final dose.
Metabolism: There is no evidence that Actonel is
systemically metabolized.
Elimination: Approximately half of the absorbed
dose is excreted in urine within 24 hours, and 85% of an i.v. dose is recovered
in the urine over 28 days. Mean renal clearance is 105 mL/min (CV=34%) and mean
total clearance is 122 mL/min (CV=19%), with the difference primarily
reflecting nonrenal clearance or clearance due to adsorption to bone. The renal
clearance is not concentration dependent, and there is a linear relationship
between renal clearance and creatinine clearance. Unabsorbed drug is eliminated
unchanged in feces. Once Actonel is absorbed, the serum concentration-time
profile is multiphasic with an initial half-life of about 1.5 hours and a
terminal exponential half-life of 480 hours. Although the elimination rate of
bisphosphonates from human bone is unknown, the 480-hour half-life is
hypothesized to represent the dissociation of Actonel from the surface of bone.
Special Populations: Children: Actonel
pharmacokinetics have not been studied in patients <18 years of age.
Gender: Bioavailability and disposition
following oral administration are similar in men and women.
Geriatric: Bioavailability and disposition are
similar in elderly (≥ 65 years of age) and younger subjects. No
dosage adjustments are necessary (see Precautions, Geriatrics).
Race: Pharmacokinetic differences due to race
have not been studied.
Renal Insufficiency: Actonel is excreted intact
primarily via the kidney. Patients with mild-to-moderate renal impairment
(creatinine clearance ≥ 30 mL/min) do not require a dosage adjustment.
Exposure to Actonel was estimated to increase by 44% in patients with
creatinine clearance of 20 mL/min. Actonel is not recommended for use in
patients with severe renal impairment (creatinine clearance <30 mL/min)
because of lack of clinical experience.
Hepatic Insufficiency: No studies have been
performed to assess Actonel's safety or efficacy in patients with hepatic
impairment. Actonel is not metabolized in rat, dog and human liver
preparations. Insignificant amounts (<0.1% of i.v. dose) of drug are
excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be
needed in patients with hepatic impairment.
Pharmacodynamics
Treatment and Prevention of Osteoporosis in
Postmenopausal Women
Osteoporosis is a degenerative and debilitating
bone disease characterized by decreased bone mass and increased fracture risk
at the spine, hip, and wrist. The diagnosis can be confirmed by the finding of
low bone mass, evidence of fracture on x-ray, a history of osteoporotic
fracture, or height loss or kyphosis indicative of vertebral fracture.
Osteoporosis occurs in both men and women but is more common among women
following menopause.
In healthy humans, bone
formation and resorption are closely linked; old bone is resorbed and replaced
by newly formed bone. In postmenopausal osteoporosis, bone resorption exceeds
bone formation, leading to bone loss and increased risk of bone fracture. After
menopause, the risk of fractures of the spine and hip increases dramatically;
approximately 40% of 50-year-old women will experience an osteoporosis-related
fracture of the spine, hip, or wrist during their remaining lifetimes. After
experiencing one osteoporosis-related fracture, the risk of future fracture
increases 5-fold compared to the risk among a nonfractured population.
Actonel treatment
decreases the elevated rate of bone turnover and corrects the imbalance of bone
resorption relative to bone formation that is typically seen in postmenopausal
osteoporosis. In clinical trials, administration of Actonel to postmenopausal
women resulted in dose-dependent decreases in biochemical markers of bone
turnover, including urinary markers of bone resorption and serum markers of
bone formation, at doses as low as 2.5 mg daily. At the 5 mg dose,
decreases in resorption markers were evident within 14 days of treatment.
Changes in bone formation markers were observed later than changes in
resorption markers, as expected, due to the coupled nature of bone formation
and bone resorption; decreases in bone formation of about 20% were evident
within 3 months of treatment. Bone turnover markers reached a nadir of about
40% below baseline values by the sixth month of treatment and remained stable
with continued treatment for up to 3 years.
These data demonstrate
that Actonel 5 mg administered daily to postmenopausal women produces a rapid
reduction in bone resorption without over-suppression of bone formation. Bone
turnover is decreased as early as 2 weeks and maximally within about 6 months
of treatment, with achievement of a new steady-state which more nearly
approximates the rate of bone turnover seen in premenopausal women.
In a 1-year study
comparing Actonel 35 mg once a week to Actonel 5 mg daily for the treatment of
osteoporosis in postmenopausal women, similar decreases in bone resorption
(about 60%) and formation markers (about 40%) were observed for both dosage
regimens.
As a result of the
inhibition of bone resorption, asymptomatic and usually transient decreases
from baseline in serum calcium (about 2%) and serum phosphate levels (about 5%)
and compensatory increases in serum PTH levels were observed within 6 months in
Actonel 5 mg daily-treated patients in postmenopausal osteoporosis trials. No
further decreases in serum calcium or phosphate, or increases in PTH were
observed in postmenopausal women treated for up to 3 years. In the 1-year study
comparing Actonel 35 mg once a week to Actonel 5 mg daily for the treatment of
osteoporosis in postmenopausal women, similar mean changes from baseline in
serum calcium, phosphate and PTH were found for both dosage regimes.
Consistent with the
effects of Actonel on biochemical markers of bone turnover, daily oral doses as
low as 2.5 mg produced dose dependent, significant increases in lumbar spine
bone mineral density (BMD) (2.5 mg, 3% to 3.7%; 5 mg, 4% to 4.5%) after 12
months of treatment in large-scale postmenopausal osteoporosis trials. A
dose-dependent response to treatment was also observed in the BMD of the femoral
neck over the same time (2.5 mg, 0.7% to 0.9%; 5 mg, 1.5% to 2%). In the 1-year
study comparing Actonel 35 mg once a week to Actonel 5 mg daily for the
treatment of osteoporosis in postmenopausal women, similar mean changes from
baseline in BMD of the lumbar spine, total proximal femur, femoral neck and
femoral trochanter were found for both dosage regimens.
Glucocorticoid-induced Osteoporosis
Chronic exposure to glucocorticoids (≥
7.5 mg/day prednisone or its equivalent) induces rapid bone loss by decreasing
bone formation and increasing bone resorption. The bone loss occurs most
rapidly during the first 6 months of therapy with persistent but slowing bone
loss for as long as glucocorticoid therapy continues.
Glucocorticoid-induced
osteoporosis is characterized by low bone mass that leads to an increased risk
of fracture (especially vertebral, hip, and rib). It occurs in both men and
women, and approximately 50% of patients on chronic glucocorticoid treatment
will experience fractures. The relative risk of a hip fracture in patients on
>7.5 mg/day prednisone is more than doubled (RR=2.27); the relative
risk of vertebral fracture is increased five-fold (RR=5.18).
Actonel treatment
decreases bone resorption without directly inhibiting bone formation. In 1-year
clinical trials in the treatment and prevention of glucocorticoid-induced
osteoporosis, Actonel 5 mg daily produced rapid and statistically
significant reductions in biochemical markers of bone turnover, similar to
those seen in postmenopausal osteoporosis. Urinary collagen cross-linked
N-Telopeptide (a marker of bone resorption) and serum bone-specific alkaline
phosphatase (a marker of bone formation) were decreased by 50% to 55% and 25%
to 30%, respectively, within 3 to 6 months after initiation of therapy. The
reduction was evident within 14 days and bone turnover markers remained
decreased throughout the duration of Actonel treatment.
Consistent with the
changes in biochemical markers of bone turnover, Actonel 5 mg provides a
beneficial effect on bone mineral density and reduces the risk of vertebral
fractures by approximately 70% when compared to placebo.
Paget's Disease of Bone
Paget's disease of bone is a chronic focal
skeletal disorder characterized by greatly increased and disordered bone
remodelling. Excessive osteoclastic bone resorption is followed by osteoblastic
new bone formation, leading to the replacement of the normal bone architecture
by disorganized, enlarged, and weakened bone structure.
Clinical manifestations
of Paget's disease range from no symptoms to severe morbidity due to bone pain,
bone deformity, pathological fractures, and neurological and other
complications. Serum alkaline phosphatase, the most frequently used biochemical
marker of disease activity, provides an objective measure of disease severity
and response to therapy.
Actonel is a
bisphosphonate that acts primarily to inhibit bone resorption. This effect is
related to its inhibitory effect on osteoclasts. In the Phase III clinical
trial, Actonel 30 daily for 2 months produced significant (p<0.001)
reductions of 81% to 88% in serum alkaline phosphatase excess, as well as
significant reductions in bone-specific serum alkaline phosphatase (Ostase, 67%
to 70%) and urinary deoxypyridinoline/creatinine (47% to 51%). Reductions were
evident as early as 1 month after the start of treatment, and progressively
increased in magnitude (following completion of the 2-month treatment) when
measured at monthly intervals over a 6-month period. Clinically meaningful
reductions in serum alkaline phosphatase were observed starting at 1 month with
levels maintained through 12 months.
Asymptomatic and mild
decreases in serum calcium and phosphorus levels have been observed in some
patients. These decreases in calcium are associated with increases in serum
intact PTH and 1,25-dihydroxy vitamin D, resulting in an increase in tubular
reabsorption of calcium.
Markers of bone
resorption (such as urinary deoxypyridinoline/creatinine or
hydroxyproline/creatinine) usually decrease before markers of bone formation
(such as serum alkaline phosphatase). This difference is indicative of the
primary antiresorptive effect of Actonel.
Bone turnover marker
levels continue to decrease when Actonel treatment is stopped. Therefore, to
assess the full effect of response, patients should be followed for at least 2
months following the 2-month treatment period.
Indications
Postmenopausal Osteoporosis
Treatment and prevention of osteoporosis in
postmenopausal women.
Treatment of Osteoporosis
In postmenopausal women with osteoporosis,
Actonel prevents vertebral and nonvertebral osteoporosis-related fractures and
increases BMD at all measured skeletal sites of clinical importance for
osteoporotic fractures, including spine, hip, and wrist.
Osteoporosis may be
confirmed by the presence or history of osteoporotic fracture, or by the
finding of low bone mass (for example, at least 2 SD below the premenopausal
mean).
Prevention of Osteoporosis
In postmenopausal patients at risk of developing
osteoporosis, Actonel preserves or increases BMD at sites of clinical
importance for osteoporosis.
Actonel may be
considered in postmenopausal women who are at risk of developing osteoporosis
and for whom the desired clinical outcome is to maintain bone mass and to
reduce the risk of fracture.
Factors such as family
history of osteoporosis (particularly maternal history), previous fracture,
smoking, moderately low BMD, high bone turnover, thin body frame, Caucasian or
Asian race, and early menopause are associated with an increased risk of
developing osteoporosis and fractures.
Glucocorticoid-induced Osteoporosis
Treatment and prevention of
glucocorticoid-induced osteoporosis in men and women.
Paget's Disease of Bone
For patients with Paget's disease of bone
(osteitis deformans) having alkaline phosphatase levels at least 2 times the
upper limit of normal, or who are symptomatic, or who are at risk for future
complications from their disease, to induce remission (normalization of serum alkaline
phosphatase).
Contraindications
• Known
hypersensitivity to any component of this product.
•
Hypocalcemia (see Precautions, General).
Warnings
Bisphosphonates may cause upper gastrointestinal
disorders such as dysphagia, esophagitis, esophageal ulcer, and gastric ulcer
(see Adverse Effects).
Precautions
General
Hypocalcemia and other disturbances of bone and
mineral metabolism should be effectively treated before starting Actonel
therapy.
Adequate intake of
calcium and vitamin D is important in all patients, especially in patients with
Paget's disease in whom bone turnover is significantly elevated.
Co-administration of medications containing polyvalent cations (e.g., calcium,
magnesium, aluminum and iron) can interfere with the absorption of Actonel. As
with food, such medications should therefore be administered at a different
time of the day (see Dosage).
Actonel is not
recommended for use in patients with severe renal impairment (creatinine
clearance <30 mL/min).
Since some bisphosphonates
have been associated with esophagitis and esophageal ulcerations, to facilitate
delivery to the stomach and minimize the risk of these events, patients should
take Actonel while in an upright position (i.e., sitting or standing) and with
sufficient plain water (≥ 120 mL). Patients should not lie down for at
least 30 minutes after taking the drug. Prescribers should be particularly
careful to emphasize the importance of the dosing instructions to patients with
a history of esophageal disorders (e.g., inflammation, stricture, ulcer, or
disorders of motility).
Information to Be Provided to the Patient
The patient should be informed to pay particular
attention to the dosing instructions as clinical benefits may be compromised by
failure to take the drug according to instructions. Specifically, Actonel
should be taken on an empty stomach and may be taken:
• at least
30 minutes before the first food or drink (other than plain water) of the day,
or
• at other
times during the day, at least 2 hours from any food or drink other than plain
water (i.e., nothing to eat or drink 2 hours before and 2 hours after dosing).
To facilitate delivery
to the stomach and minimize the risk of potential esophageal irritation,
patients should take Actonel while in an upright position (i.e., sitting or
standing) and with sufficient plain water (≥ 120 mL). Patients should
not lie down for at least 30 minutes after taking the medication and should not
take Actonel less than 30 minutes before bedtime (see Precautions, General).
Patients should not chew or suck on the tablet because of a potential for
oropharyngeal irritation.
Patients should receive
supplemental calcium and vitamin D if dietary intake is inadequate (see
Precautions, General). Co-administration of medications containing polyvalent
cations (e.g., calcium, magnesium, aluminum and iron) can interfere with the
absorption of Actonel. As with food, such medications should therefore be
administered at a different time of the day (see Dosage).
Patients should be
instructed that if they miss a dose of Actonel 35 mg once a week on their
regularly scheduled day, they should take 1 tablet on the day they first
remember missing their dose (see Dosage). Patients should then return to taking
1 tablet once a week as originally scheduled on their chosen day. Patients
should not take 2 tablets on the same day.
Geriatrics
No dosage adjustment is necessary in elderly
patients (see Dosage). Of the patients receiving Actonel 5 mg daily in
postmenopausal osteoporosis studies, 43% were between 65 and 75 years of age,
and 20% were over 75. The corresponding proportions were 26% and 11% in
glucocorticoid-induced osteoporosis trials. In the 1-year study comparing daily
versus weekly oral dosing regimens of Actonel in postmenopausal women, 41% of
patients receiving Actonel 35 mg once a week were between 65 and 75 years of
age and 23% were over 75.
Based upon the above
study populations, no overall differences in efficacy or safety were observed
between these patients and younger patients (<65 years).
Children
Safety and efficacy in children and growing
adolescents have not been established.
Pregnancy
Actonel is not intended for use during
pregnancy. There are no studies of Actonel in pregnant women.
Lactation
Actonel is not intended for use with nursing
mothers. It is not known whether risedronate is excreted in human milk. Actonel
was detected in feeding pups exposed to lactating rats for a 24-hour period
post-dosing, indicating a small degree of lacteal transfer. Since many drugs
are excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from bisphosphonates, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.
Drug Interactions
Patients in the clinical trials were exposed to
a wide variety of commonly used concomitant medications (including
non-steroidal anti-inflammatory drugs, H2-blockers, proton pump
inhibitors, antacids, calcium channel blockers, β -blockers, thiazides,
glucocorticoids, anticoagulants, anticonvulsants, cardiac glycosides) without
evidence of clinically relevant interactions.
No specific drug-drug
interaction studies were performed. Animal studies have demonstrated that
risedronate is highly concentrated in bone and is retained only minimally in
soft tissue. No metabolites have been detected systemically or in bone. The
binding of risedronate to plasma proteins in humans is low (24%), resulting in
minimal potential for interference with the binding of other drugs. In an
additional animal study, there was also no evidence of hepatic microsomal
enzyme induction. In summary, Actonel is not systemically metabolized, does not
induce cytochrome P450 enzymes and has low protein binding. Actonel is
therefore not expected to interact with other drugs based on the effects of
protein binding displacement, enzyme induction or metabolism of other drugs.
Supplements/Antacids
Co-administration of medications which contain
polyvalent cations (e.g., calcium, magnesium, aluminum and iron) can interfere
with the absorption of Actonel. As with food, such medications should therefore
be administered at a different time of the day (see Dosage).
Hormone Replacement Therapy
If considered appropriate, Actonel may be used
concomitantly with hormone replacement therapy.
Acetylsalicylic Acid (ASA)
Of over 5700 patients enrolled in the Actonel
5mg daily Phase III osteoporosis studies, ASA use was reported by 31% of
patients. Among ASA users, the incidence of upper gastrointestinal adverse
experiences in Actonel-treated patients was similar to that in placebo-treated
patients. In the 1-year study comparing Actonel 35 mg once a week to Actonel 5
mg daily in postmenopausal women, ASA use was reported by 56% of patients in
the Actonel 35 mg once a week and 5 mg daily groups. Among ASA users, the
incidence of upper gastrointestinal adverse experiences was found to be similar
between the weekly- and daily-treated groups.
Other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Of over 5700 patients enrolled in the Actonel
Phase 5 mg daily Phase III osteoporosis studies, 48% used NSAIDs. Among NSAID
users, the incidence of upper gastrointestinal adverse experiences in
Actonel-treated patients was similar to that in placebo-treated patients. In
the 1-year study comparing Actonel 35 mg once a week to Actonel 5 mg daily in
postmenopausal women, 41% of patients in the Actonel 35 mg once a week and 5 mg
daily groups used NSAIDs. Among NSAID users, the incidence of upper gastrointestinal
adverse experiences was found to be similar between the weekly- and
daily-treated groups.
H2-Blockers and Proton Pump
Inhibitors (PPIs)
Of over 5700 patients enrolled in the Actonel 5
mg daily Phase III osteoporosis studies, 21% used H2-blockers
and/or PPIs. Among these patients, the incidence of upper gastrointestinal
adverse experiences in the Actonel-treated patients was similar to that in
placebo-treated patients. In the 1-year study comparing Actonel once a week and
daily dosing regimens in postmenopausal women, at least 9% of patients in the
Actonel 35 mg once a week and 5 mg daily groups used H2-blockers
and/or PPIs. Among these patients, the incidence of upper gastrointestinal
adverse experiences was found to be similar between the weekly- and
daily-treated groups.
Laboratory Test Interactions
Bisphosphonates are known to interfere with the
use of bone-imaging agents. Specific studies with Actonel have not been
performed.
Adverse Effects
Treatment and Prevention of Postmenopausal
Osteoporosis
Actonel 5 mg daily has been studied for up to 3
years in over 5000 women enrolled in Phase III clinical trials for treatment or
prevention of postmenopausal osteoporosis. Most adverse events reported in
these trials were either mild or moderate in severity, and did not lead to
discontinuation from the study. The distribution of severe adverse events was
similar across treatment groups. In addition, the overall incidence of adverse
effects was found to be comparable amongst Actonel- and placebo-treated patients.
Table 1 lists adverse
events reported in ≥ 2% of Actonel 5 mg daily-treated patients and at an
incidence higher than in the placebo group in Phase III postmenopausal
osteoporosis trials. Adverse events are shown without attribution of causality.
Discontinuation of therapy due to serious clinical adverse events occurred in
5.5% of Actonel 5 mg daily-treated patients and 6.0% of patients treated
with placebo.
CPS:Actonel_t1Click here for Table 1
Table 1: Actonel
Adverse Events Reported in ≥ 2% of
Actonel 5 mg Daily-treated Patientsa and Occurring at ≥ 1.1
Times the Placebo Rate in Combined Phase III Postmenopausal Osteoporosis Trials
|
Adverse Event
|
Placebo Control
% (N=1744)
|
Actonel 5 mg
% (N=1742)
|
|
|
Cardiovascular
|
|
Hypertension
|
9.4
|
10.6
|
|
|
Cardiovascular Disorder
|
1.8
|
2.6
|
|
|
Digestive
|
|
Abdominal Pain
|
9.5
|
11.8
|
|
|
Hernia
|
2.6
|
3.1
|
|
|
Gastritis
|
2.4
|
2.6
|
|
|
Rectal Disorder
|
1.9
|
2.2
|
|
|
Hemic and Lymphatic
|
|
Ecchymosis
|
3.9
|
4.5
|
|
|
Anemia
|
1.9
|
2.5
|
|
|
Musculoskeletal
|
|
Joint Disorder
|
5.5
|
7.1
|
|
|
Neck Pain
|
4.6
|
5.4
|
|
|
Bone Pain
|
4.5
|
5.1
|
|
|
Bone Disorder
|
3.4
|
4.4
|
|
|
Leg Cramps
|
2.7
|
3.6
|
|
|
Tendon Disorder
|
2.5
|
3.0
|
|
|
Nervous System
|
|
Dizziness
|
5.5
|
6.7
|
|
|
Asthenia
|
4.5
|
5.1
|
|
|
Anxiety
|
2.9
|
4.6
|
|
|
Hypertonia
|
2.1
|
2.4
|
|
|
Paresthesia
|
1.9
|
2.2
|
|
|
Respiratory
|
|
Pharyngitis
|
5.2
|
6.0
|
|
|
Rhinitis
|
5.0
|
5.9
|
|
|
Dyspnea
|
3.2
|
3.7
|
|
|
Pneumonia
|
2.7
|
3.0
|
|
|
Skin and Appendages
|
|
Pruritus
|
2.2
|
2.9
|
|
|
Skin Carcinoma
|
1.8
|
2.1
|
|
|
Special Senses
|
|
Cataract
|
5.3
|
6.1
|
|
|
Conjunctivitis
|
2.7
|
3.3
|
|
|
Urogenital
|
|
Cystitis
|
3.6
|
4.3
|
|
a AEs shown are without attribution
of causality.
Once a Week Dosing
In the 1-year, double-blind, multicentre study
comparing Actonel 35 mg once a week to Actonel 5 mg daily in postmenopausal
women, the overall safety and tolerability profiles of the 2 oral dosing
regimens were similar.
Patients with active or
a history of upper gastrointestinal disorders at baseline and those taking ASA,
NSAIDs or drugs traditionally used for the treatment of peptic ulcers were not
specifically excluded from participating in the Actonel once a week dosing
study. The proportion of patients who experienced an upper gastrointestinal adverse
event and the pattern of those events were found to be similar between the
Actonel 35 mg once a week and Actonel 5 mg daily-treated groups.
Glucocorticoid-induced Osteoporosis
Actonel 5 mg daily has been studied in two
Phase III glucocorticoid-induced osteoporosis trials enrolling more than
500 patients. The adverse event profile of this population was similar to that
seen in postmenopausal osteoporosis trials.
The overall incidence
of adverse events was found to be comparable between the Actonel 5 mg daily and
placebo treatment groups, with the exception of back and joint pain. Back pain
was reported in 8.8% of placebo-treated patients and 17.8% of Actonel-treated
patients; joint pain occurred in 14.7% of placebo patients and 24.7% of Actonel
patients. Most adverse experiences reported were either mild or moderate in
severity, and did not lead to discontinuation from the study. Discontinuation
of therapy due to serious clinical adverse events occurred in 2.9% of Actonel
5 mg daily-treated patients and 5.3% of patients treated with placebo. The
occurrence of adverse events does not appear to be related to patient age,
gender or race.
Table 2 lists adverse
events reported as possibly or probably causally drug-related in ≥ 2% of
Actonel 5 mg daily-treated patients in the Phase III
glucocorticoid-induced osteoporosis studies.
CPS:Actonel_t2Click here for Table 2
Table 2: Actonel
Drug-relateda Adverse Events
Reported in ≥ 2% of Actonel 5 mg Daily-treated Patientsa in
the Phase III Glucocorticoid-induced Osteoporosis Trials
|
Adverse Event
|
Placebo Control
% (N=170)
|
Actonel 5 mg
% (N=174)
|
|
Body as a Whole
|
|
Abdominal Pain
|
4.7
|
4.0
|
|
Digestive System
|
|
Dyspepsia
|
2.9
|
5.7
|
|
Nausea
|
5.3
|
5.7
|
|
Constipation
|
3.5
|
2.9
|
|
Diarrhea
|
3.5
|
2.9
|
|
|
|
|
|
|
a Considered to be possibly or
probably causally related in at least 1 patient.
Endoscopic Findings
Actonel 5 mg daily clinical studies enrolled
over 5700 patients for the treatment and prevention of postmenopausal and
glucocorticoid-induced osteoporosis, many with pre-existing gastrointestinal
disease and concomitant use of NSAIDs or ASA. Investigators were
encouraged to perform endoscopies in any patients with moderate-to-severe
gastrointestinal complaints while maintaining the blind. These endoscopies were
ultimately performed on equal numbers of patients between the treated and
placebo groups (75 Actonel; 75 placebo).
Across treatment
groups, the percentage of patients with normal esophageal, gastric and duodenal
mucosa on endoscopy was similar (21% Actonel; 20% placebo). Positive findings
on endoscopy were also generally comparable across treatment groups. There was
a higher number of reports of mild duodenitis in the Actonel group; however,
there were more duodenal ulcers in the placebo group. Clinically important
findings (perforations, ulcers, or bleeding) among this symptomatic population
were similar between groups (39% Actonel; 51% placebo).
In the 1-year study
comparing Actonel 35 mg once a week to Actonel 5 mg daily in the treatment of
postmenopausal osteoporosis, endoscopies performed during the study revealed no
dose dependent pattern in the number of patients with positive endoscopic
findings nor in the anatomical location of abnormalities detected.
Paget's Disease of Bone
Actonel has been studied in over
390 patients with Paget's disease of bone. The adverse experiences
reported have usually been mild or moderate and generally have not required
discontinuation of treatment. The occurrence of adverse experiences does not
appear to be related to patient age, gender, or race.
In a Phase III clinical
study, Actonel and Didronel (etidronate disodium) showed similar adverse event
profiles: 6.6% (4/61) of the patients treated with Actonel 30 mg daily for 2
months discontinued treatment due to adverse experiences, compared with 8.2%
(5/61) of the patients treated with Didronel 400 mg daily for 6 months.
Adverse experiences
reported in ≥ 2% of Actonel 30 mg daily-treated patients in the Phase III
study are shown in Table 3.
CPS:Actonel_t3Click here for Table 3
Table 3: Actonel
Adverse Events Reported in ≥ 2% of Actonel
30 mg Daily-treated Patientsa in the Phase III Paget's Trial
|
Body System
|
30 mg/day
× 2 months
Actonel
%
(N=61)
|
400 mg/day
× 6 months
Didronel
%
(N=61)
|
|
Body as a Whole
|
|
Flu Syndrome
|
9.8
|
1.6
|
|
Chest Pain
|
6.6
|
3.3
|
|
Asthenia
|
4.9
|
0
|
|
Neoplasm
|
3.3
|
1.6
|
|
Digestive
|
|
Diarrhea
|
19.7
|
14.8
|
|
Abdominal Pain
|
11.5
|
8.2
|
