A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Aredia Side Effects, and Drug Interactions - Pamidronate Disodium
Aredia Side Effects, and Drug Interactions - Pamidronate Disodium
SIDE EFFECTS
Clinical Studies
Hypercalcemia of Malignancy: Transient mild elevation
of temperature by at least 1° C was noted 24 to 48 hours after administration
of Aredia in 34% of patients in clinical
trials. In the saline
trial, 18% of patients had a temperature
elevation of at least 1°
C 24 to 48 hours after treatment. Drug-related local
soft-tissue symptoms (redness, swelling or induration
and pain on palpation) at the
site of catheter
insertion were most common (18%) in patients treated with 90 mg
of Aredia. When all on-therapy events are considered, that rate
rises to 41%. Symptomatic treatment resulted in rapid resolution
in all patients.
Rare cases of uveitis, iritis, scleritis, and episcleritis
have been reported, including one case
of scleritis, and one case of
uveitis upon separate rechallenges.
Five of 231 patients (2%) who received Aredia during the three U. S.
controlled hypercalcemia
clinical studies were reported
to have had seizures, 2 of whom had preexisting seizure
disorders. None of the seizures were considered to be drug-related by
the investigators. However, a possible relationship between the drug
and the occurrence of seizures cannot be ruled out. It should be noted
that in the saline arm
1 patient (4%) had a seizure.
There are no controlled clinical trials comparing the efficacy and safety of 90 mg Aredia over 24
hours to 2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from
separate clinical trials suggests that the overall safety profile in patients who received 90 mg
Aredia over 24 hours is similar to those who received 90 mg Aredia over 2 hours. The only
notable differences observed were an increase in the proportion of patients in the Aredia
24 hour group who experienced fluid overload and electrolyte/mineral abnormalities.
At least 15% of patients treated with Aredia for hypercalcemia
of malignancy also experienced the following adverse events during a clinical
trial:
General: Fluid overload, generalized pain
Cardiovascular: Hypertension
Gastrointestinal: Abdominal pain,
anorexia, constipation,
nausea, vomiting
Genitourinary: Urinary tract
infection
Musculoskeletal: Bone pain
Laboratory abnormality: Anemia, hypokalemia,
hypomagnesemia, hypophosphatemia
Many of these adverse experiences may have been related to the underlying
disease state. The following table
lists the adverse experiences considered to be treatment-related during
comparative, controlled U. S. trials.
Table 6.
|
Treatment-Related Adverse Experiences Reported
in Three U. S. Controlled Clinical Trials
|
| |
Percent of Patients
|
|
Aredia
|
Didronel
|
Saline
|
| |
60 mg
over 4 hr
n=23
|
60 mg
over 24 hr
n=73
|
90 mg
over 24 hr
n=17
|
7.5 mg/kg
x 3 days
n=35
|
n=23
|
| General |
Edema
|
0
|
1
|
0
|
0
|
0
|
Fatigue
|
0
|
0
|
12
|
0
|
0
|
Fever
|
26
|
19
|
18
|
9
|
0
|
Fluid overload
|
0
|
0
|
0
|
6
|
0
|
Infusion-site reaction
|
0
|
4
|
18
|
0
|
0
|
Moniliasis
|
0
|
0
|
6
|
0
|
0
|
Rigors
|
0
|
0
|
0
|
0
|
4
|
| Gastrointestinal |
Abdominal pain
|
0
|
1
|
0
|
0
|
0
|
Anorexia
|
4
|
1
|
12
|
0
|
0
|
Constipation
|
4
|
0
|
6
|
3
|
0
|
Diarrhea
|
0
|
1
|
0
|
0
|
0
|
Dyspepsia
|
4
|
0
|
0
|
0
|
0
|
Gastrointestinal hemorrhage
|
0
|
0
|
6
|
0
|
0
|
Nausea
|
4
|
0
|
18
|
6
|
0
|
Stomatitis
|
0
|
1
|
0
|
3
|
0
|
Vomiting
|
4
|
0
|
0
|
0
|
0
|
| Respiratory |
Dyspnea
|
0
|
0
|
0
|
3
|
0
|
Rales
|
0
|
0
|
6
|
0
|
0
|
Rhinitis
|
0
|
0
|
6
|
0
|
0
|
Upper respiratory
infection
|
0
|
3
|
0
|
0
|
0
|
| CNS |
Anxiety
|
0
|
0
|
0
|
0
|
4
|
Convulsions
|
0
|
0
|
0
|
3
|
0
|
Insomnia
|
0
|
1
|
0
|
0
|
0
|
Nervousness
|
0
|
0
|
0
|
0
|
4
|
Psychosis
|
4
|
0
|
0
|
0
|
0
|
Somnolence
|
0
|
1
|
6
|
0
|
0
|
Taste perversion
|
0
|
0
|
0
|
3
|
0
|
| Cardiovascular |
Atrial fibrillation
|
0
|
0
|
6
|
0
|
4
|
Atrial flutter
|
0
|
1
|
0
|
0
|
0
|
Cardiac failure
|
0
|
1
|
0
|
0
|
0
|
Hypertension
|
0
|
0
|
6
|
0
|
4
|
Syncope
|
0
|
0
|
6
|
0
|
0
|
Tachycardia
|
0
|
0
|
6
|
0
|
4
|
| Endocrine |
Hypothyroidism
|
0
|
0
|
6
|
0
|
0
|
| Hemic and Lymphatic |
Anemia
|
0
|
0
|
6
|
0
|
0
|
Leukopenia
|
4
|
0
|
0
|
0
|
0
|
Neutropenia
|
0
|
1
|
0
|
0
|
0
|
Thrombocytopenia
|
0
|
1
|
0
|
0
|
0
|
| Musculoskeletal |
Myalgia
|
0
|
1
|
0
|
0
|
0
|
| Urogenital |
Uremia
|
4
|
0
|
0
|
0
|
0
|
| Laboratory Abnormalities |
Hypocalcemia
|
0
|
1
|
12
|
0
|
0
|
Hypokalemia
|
4
|
4
|
18
|
0
|
0
|
Hypomagnesemia
|
4
|
10
|
12
|
3
|
4
|
Hypophosphatemia
|
0
|
9
|
18
|
3
|
0
|
Abnormal liver function
|
0
|
0
|
0
|
3
|
0
|
Paget's Disease Transient mild elevation of temperature
>1 ° C above pretreatment
baseline was noted within
48 hours after completion of treatment
in 21% of the patients treated with 90 mg
of Aredia in clinical trials.
Drug-related musculoskeletal
pain and nervous
system symptoms (dizziness, headache,
paresthesia, increased
sweating) were more common in patients with Paget's disease
treated with 90 mg of Aredia than
in patients with hypercalcemia
of malignancy treated with
the same dose.
Adverse experiences considered to be related to trial drug, which occurred
in at least 5% of patients with Paget's disease
treated with 90 mg of Aredia in
two U. S. clinical trials,
were fever, nausea, back pain,
and bone pain.
At least 10% of all Aredia-treated patients with Paget's disease
also experienced the following adverse experiences during clinical trials:
Cardiovascular: Hypertension
Musculoskeletal: Arthrosis, bone
pain
Nervous system: Headache
Most of these adverse experiences may have been related to the underlying
disease state.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions
of Multiple Myeloma The most commonly reported (> 15%) adverse
experiences occurred with similar frequencies in the Aredia and placebo
treatment groups, and most
of these adverse experiences may have been related to the underlying disease
state or cancer
therapy.
|
Commonly Reported Adverse Experiences in
Three U. S. Controlled Clinical Trials
|
| |
Aredia 90mg
over 4 hours
N=205
|
Placebo
N=187
|
Aredia 90mg
over 2 hours
N=367
|
Placebo
N=386
|
All Aredia 90 mg
N=572
|
Placebo
N=573
|
| General |
Asthenia
|
16.1
|
17.1
|
25.6
|
19.2
|
22.2
|
18.5
|
Fatigue
|
31.7
|
28.3
|
40.3
|
28.8
|
37.2
|
29.0
|
Fever
|
38.5
|
38.0
|
38.1
|
32.1
|
38.5
|
34.0
|
Metastases
|
1.0
|
3.0
|
31.3
|
24.4
|
20.5
|
17.5
|
Pain
|
13.2
|
11.8
|
15.0
|
18.1
|
14.3
|
16.1
|
| Digestive System |
Anorexia
|
17.1
|
17.1
|
31.1
|
24.9
|
26.0
|
22.3
|
Constipation
|
28.3
|
31.7
|
36.0
|
38.6
|
33.2
|
35.1
|
Diarrhea
|
26.8
|
26.8
|
29.4
|
30.6
|
28.5
|
29.7
|
Dyspepsia
|
17.6
|
13.4
|
18.3
|
15.0
|
22.6
|
17.5
|
Nausea
|
35.6
|
37.4
|
63.5
|
59.1
|
53.5
|
51.8
|
Pain Abdominal
|
19.5
|
16.0
|
24.3
|
18.1
|
22.6
|
17.5
|
Vomiting
|
16.6
|
19.8
|
46.3
|
39.1
|
35.7
|
32.8
|
| Hemic and Lymphatic |
Anemia
|
47.8
|
41.7
|
39.5
|
36.8
|
42.5
|
38.4
|
Granulocytopenia
|
20.5
|
15.5
|
19.3
|
20.5
|
19.8
|
18.8
|
Thrombocytopenia
|
16.6
|
17.1
|
12.5
|
14.0
|
14.0
|
15.0
|
| Musculo-skeletal System |
Arthralgias
|
10.7
|
7.0
|
15.3
|
12.7
|
13.6
|
10.8
|
Myalgia
|
25.4
|
15.0
|
26.4
|
22.5
|
26.0
|
20.1
|
Skeletal Pain
|
61.0
|
71.7
|
70.0
|
75.4
|
66.8
|
74.0
|
| CNS |
Anxiety
|
7.8
|
9.1
|
18.0
|
16.8
|
14.3
|
14.3
|
Headache
|
24.4
|
19.8
|
27.2
|
23.6
|
26.2
|
22.3
|
Insomnia
|
17.1
|
17.2
|
25.1
|
19.4
|
22.2
|
19.0
|
| Respiratory System |
Coughing
|
26.3
|
22.5
|
25.3
|
19.7
|
25.7
|
20.6
|
Dyspnea
|
22.0
|
21.4
|
35.1
|
24.4
|
30.4
|
23.4
|
Pleural Effusion
|
2.9
|
4.3
|
15.0
|
9.1
|
10.7
|
7.5
|
Sinusitis
|
14.6
|
16.6
|
16.1
|
10.4
|
15.6
|
12.0
|
Upper Resp. Tract Infection
|
32.2
|
28.3
|
19.6
|
20.2
|
24.1
|
22.9
|
| Urogenital System |
Urinary tract Infection
|
15.6
|
9.1
|
20.2
|
17.6
|
18.5
|
15.6
|
Of the toxicities commonly associated with chemotherapy, the frequency
of vomiting, anorexia,
and anemia were slightly more
common in the Aredia patients whereas stomatitis
and alopecia occurred at
a frequency similar to that in placebo
patients. In the breast
cancer trials, mild elevations
of serum creatinine
occurred in 18.5% of Aredia patients and 12.3% of placebo
patients. . Mineral and electrolyte
disturbances, including hypocalcemia, were reported rarely and in similar
percentages of Aredia-treated patients compared with those in the placebo
group. The reported frequencies of hypocalcemia, hypokalemia,
hypophosphatemia, and hypomagnesemia
for Aredia-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%, respectively,
and for placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%, respectively.
In previous hypercalcemia
of malignancy trials, patients
treated with Aredia (60 or 90 mg
over 24 hours) developed electrolyte
abnormalities more frequently (see SIDE EFFECTS,
Hypercalcemia of Malignancy).
Arthralgias and myalgias were reported slightly more frequently in the
Aredia group than in the placebo
group (13.6% and 26% vs 10.8%
and 20.1%, respectively).
In multiple myeloma
patients, there were five Aredia-related serious and unexpected adverse
experiences. Four of these were reported during the 12-month extension
of the multiple myeloma
trial. Three of the reports were of worsening renal
function developing in patients
with progressive multiple myeloma
or multiple myeloma-associated
amyloidosis. The fourth report was the adult
respiratory distress
syndrome developing in a
patient recovering from pneumonia
and acute gangrenous
cholecystitis. One Aredia-treated patient experienced an allergic
reaction characterized by
swollen and itchy eyes, runny nose, and scratchy throat
within 24 hours after the sixth infusion.
In the breast cancer
trials, there were four Aredia-related adverse experiences, all moderate
in severity, that caused a patient
to discontinue participation in the trial. One was due to interstitial
pneumonitis, another to malaise
and dyspnea. One Aredia patient
discontinued the trial due to a symptomatic
hypocalcemia. Another Aredia patient
discontinued therapy due to severe bone
pain after each infusion,
which the investigator felt was trial-drug-related.
Renal Toxicity
In a study of the safety and efficacy of Aredia 90 mg (2 hour infusion) versus Zometa 4 mg
(15 minute infusion) in bone metastases patients with multiple myeloma or breast cancer, renal
deterioration was defined as an increase in serum creatinine of 0.5 mg/dL for patients with
normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an
abnormal baseline creatinine (≥ 1.4 mg/dL). The following are data on the incidence of
renal deterioration in patients in this trial. See Table below.
Incidence of Renal Function Deterioration in Multiple
Myeloma and Breast Cancer Patients with Normal and
Abnormal Serum Creatinine at Baseline *
|
Patient Population/Baseline Creatinine
|
Aredia®
90 mg/2 hours
|
Zometa®
4 mg/15 minutes
|
|
|
n/N
|
(%)
|
n/N
|
(%)
|
|
Normal
|
20/246
|
(8.1%)
|
23/246
|
(9.3%)
|
|
Abnormal
|
2/22
|
(9.1%)
|
1/26
|
(3.8%)
|
|
Total
|
22/268
|
(8.2%)
|
24/272
|
(8.8%)
|
|
*Patients were randomized following the 15-minute infusion amendment for the Zometa arm.
|
Post-Marketing Experience Rare instances of allergic
manifestations have been reported, including hypotension,
dyspnea, or angioedema,
and very rarely, anaphylactic shock. Aredia is contraindicated in patients
with clinically significant
hypersensitivity
to Aredia or other bisphosphonates (see CONTRAINDICATIONS).
Cases of osteonecrosis (primarily of the jaws) have been reported since market introduction.
Osteonecrosis of the jaws has other well documented multiple risk factors. It is not possible
to determine if these events are related to Aredia or other bisphosphonates, to concomitant
drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), to patient's
underlying disease, or to other comorbid risk factors (e.g., anemia, infection, preexisting oral disease).
DRUG INTERACTIONS
Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of Aredia.
Caution is indicated when Aredia is used with other potentially nephrotoxic drugs.
Also see CLINICAL PHARMACOLOGY
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