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
Cubicin Side Effects, and Drug Interactions - Daptomycin
Cubicin Side Effects, and Drug Interactions - Daptomycin
SIDE EFFECTS
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice. The adverse reaction information
from clinical trials does, however, provide a basis for identifying the adverse
events that appear to be related to drug use and for approximating rates.
Clinical studies sponsored by Cubist enrolled 1409 patients
treated with daptomycin and 1185 treated with comparator. Most adverse events
reported in these clinical studies were described as mild or moderate in intensity.
In Phase 3 cSSSI trials, daptomycin was discontinued in 15/534 (2.8%) patients
due to an adverse event while comparator was discontinued in 17/558 (3.0%) patients.
The rates of most common adverse events, organized by body
system, observed in cSSSI patients are displayed in Table 5.
|
Table 5 Incidence (%) of Adverse Events that Occurred
in ³ 2% of Patients in Either Daptomycin
or Comparator Treatment Groups in Phase 3 cSSSI Studies
|
|
Adverse Event
|
Daptomycin (N=534)
|
Comparator* (N=558)
|
|
Gastrointestinal disorders
|
|
Constipation
|
6.2%
|
6.8%
|
|
Nausea
|
5.8%
|
9.5%
|
|
Diarrhea
|
5.2%
|
4.3%
|
|
Vomiting
|
3.2%
|
3.8%
|
|
Dyspepsia
|
0.9%
|
2.5%
|
|
General disorders
|
|
Injection site reactions
|
5.8%
|
7.7%
|
|
Fever
|
1.9%
|
2.5%
|
|
Nervous system disorders
|
|
Headache
|
5.4%
|
5.4%
|
|
Insomnia
|
4.5%
|
5.4%
|
|
Dizziness
|
2.2%
|
2.0%
|
|
Skin/subcutaneous disorders
|
|
Rash
|
4.3%
|
3.8%
|
|
Pruritis
|
2.8%
|
3.8%
|
|
Diagnostic investigations
|
|
Abnormal liver function tests
|
3.0%
|
1.6%
|
|
Elevated CPK
|
2.8%
|
1.8%
|
|
Infections
|
|
Fungal infections
|
2.6%
|
3.2%
|
|
Urinary tract infections
|
2.4%
|
0.5%
|
|
Vascular disorders
|
|
Hypotension
|
2.4%
|
1.4%
|
|
Hypertension
|
1.1%
|
2.0%
|
|
Renal/urinary disorders
|
|
Renal failure
|
2.2%
|
2.7%
|
|
Blood/lymphatic disorders
|
|
Anemia
|
2.1%
|
2.3%
|
|
Respiratory disorders
|
|
Dyspnea
|
2.1%
|
1.6%
|
|
Musculoskeletal disorders
|
|
Limb pain
|
1.5%
|
2.0%
|
|
Arthralgia
|
0.9%
|
2.2%
|
|
* Comparators included vancomycin (1 g IV q12h) and semi-synthetic
penicillins (ie, nafcillin, oxacillin, cloxacillin, flucloxacillin; 4-12
g/day in divided doses)
|
In Phase 3 studies of community-acquired pneumonia (CAP), the
death rate and rates of serious cardiorespiratory adverse events were higher
in daptomycin-treated patients than in comparator-treated patients. These differences
due to lack of therapeutic effectiveness of daptomycin in the treatment of CAP
in patients experiencing these events (see INDICATIONS
AND USAGE). Additional adverse events that occurred in 1-2% of patients
in daptomycin- or comparator-treatment groups in the cSSSI studies are as follows:
edema, cellulitis, hypoglycemia, ele vated alkaline phosphatase, cough, back
pain, abdominal pain, hypokalemia, hyperglycemia, decreased appetite, anxi ety,
chest pain, sore throat, cardiac failure, confusion, and Candida infections.
These events occurred at rates from 0.2-1.7% in daptomycin-treated patients
and at rates of 0.4-1.8% in comparator-treated patients.
Additional drug-related adverse events (possibly or probably
related) that occurred in <1% of patients receiving mycin in cSSSI trials
are as follows:
Body as a Whole: fatigue,weakness,rigors,discomfort,jitteriness,flushing,hypersensitivity
Blood/Lymphatic System: leukocytosis, thrombocytopenia,
thrombocytosis, eosinophilia, increased normalized ratio Cardiovascular System:
supraventricular arrhythmia
Dermatologic System: eczema
Digestive System: abdominal distension, flatulence,
stomatitis, jaundice, increased serum lactate dehydrogenase
Metabolic/Nutritional System: hypomagnesemia, increased
serum bicarbonate, electrolyte disturbance
Musculoskeletal System: myalgia,muscle cramps, muscle
weakness, osteomyelitis
Nervous System: vertigo, mental status change, paraesthesia
Special Senses: taste disturbance, eye irritation
Laboratory Changes
|
Table 6 Incidence (%) of Creatine Phosphokinase (CPK)
Elevations From Baseline While on Therapy in Either Daptomycin or Comparator
Treatment Groups in Phase 3 cSSSI Studies
|
| |
All patients
|
|
Patients with normal CPK at baseline
|
| |
Daptomycin
|
Comparator
|
Daptomycin
|
Comparator
|
| |
(N=430)
|
(N=459)
|
(N=374)
|
(N=392)
|
| |
n
|
%
|
n
|
%
|
n
|
%
|
n
|
%
|
|
No increase
|
90.7%
|
390
|
91.1%
|
418
|
91.2%
|
341
|
91.1%
|
357
|
|
Maximum Value >1x ULN*
|
9.3%
|
40
|
8.9%
|
41
|
8.8%
|
33
|
8.9%
|
35
|
|
>2x ULN
|
4.9%
|
21
|
4.8%
|
22
|
3.7%
|
14
|
3.1%
|
12
|
|
>4x ULN
|
1.4%
|
6
|
1.5%
|
7
|
1.1%
|
4
|
1.0%
|
4
|
|
>5x ULN
|
1.4%
|
6
|
0.4%
|
2
|
1.1%
|
4
|
0.0%
|
0
|
|
>10x ULN
|
0.5%
|
2
|
0.2%
|
1
|
0.2%
|
1
|
0.0%
|
0
|
|
* ULN (Upper Limit of Normal) is defined as 200 U/L.
|
|
Note: Elevations in CPK observed in patients treated
with daptomycin or comparator were not clinically or statistically significantly
different (P <0.05).
|
In clinical trials,0.2% of patients treated with CUBICIN had
symptoms of muscle pain or weakness associated with CPK elevations to greater
than 4 times the upper limit of normal. The symptoms resolved within 3 days
and CPK returned to normal within 7-10 days after discontinuing treatment (see
PRECAUTIONS, Skeletal Muscle).In Phase
3 comparator-controlled trials, there was no clinically or statistically significant
difference (P <0.05) in the frequency of CPK elevations between patients
treated with CUBICIN and those treated with comparator. CPK elevations in both
groups were generally related to medical conditions, for example, skin and skin
structure infection, surgical procedures, or ntramuscular injections, and were
not associated with muscle symptoms.
There were no substantial differences between CUBICIN and the
comparators in the frequency or distribution of changes in other laboratory
parameters, regardless of drug relationship.
DRUG INTERACTIONS
Warfarin Concomitant administration of daptomycin (6
mg/kg once every 24 hours for 5 days) and warfarin (25 mg single oral dose)
had no significant effect on the pharmacokinetics of either drug, and the INR
was not significantly altered. As experience with the concomitant administration
of daptomycin and warfarin is limited to volunteer studies,anticoagulant activity
in patients receiving daptomycin and warfarin should be monitored for the first
several days after initiating therapy with CUBICIN (see CLINICAL
PHARMACOLOGY, Drug-Drug Interactions).
HMG-CoA Reductase Inhibitors Inhibitors of HMG-CoA reductase
may cause myopathy, which is manifested as muscle pain or weakness associated
with elevated levels of CPK.There were no reports of skeletal myopathy in a
placebo-controlled Phase I trial in which 10 healthy subjects on stable simvastatin
therapy were treated concurrently with daptomycin (4 mg/kg once every 24 hours)
for 14 days.Experience with co-administration of HMG-CoA reduc-tase inhibitors
and CUBICIN in patients is limited,therefore,consideration should be given to
temporarily suspending use of HMG-CoA reductase inhibitors in patients receiving
CUBICIN.
Drug-Laboratory Test Interactions: There are
no reported drug-laboratory test interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Long-term carcinogenicity studies in animals have not been conducted
to evaluate the carcinogenic potential of daptomycin. However, neither mutagenic
nor clastogenic potential was found in a battery of genotoxicity tests, including
the Ames assay,a mammalian cell gene mutation assay, a test for chromosomal
aberrations in Chinese hamster ovary cells, an in vivo micronucleus assay,an
in vitro DNA repair assay, and an in vivo sister chromatid exchange
assay in Chinese hamsters.
Daptomycin did not affect the fertility or reproductive performance
of male and female rats when administered intravenously at doses up to
150 mg/kg/day, which is approximately 9 times the estimated human exposure
level based upon AUCs.
Pregnancy: Teratogenic Effects: Pregnancy Category
B Reproductive and teratology studies performed in rats and rabbits
at doses of up to 75 mg/kg,3 and 6 times the human dose,respectively,
on a body surface area basis,have revealed no evidence of harm to the
fetus due to CUBICIN. There are, however, no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies are not
always predictive of human response, this drug should be used during pregnancy
only if clearly needed.
Nursing Mothers: It is not known if daptomycin
is excreted in human milk. Caution should be exercised when CUBICIN is administered
to nursing women.
Pediatric Use: Safety and efficacy of CUBICIN
in patients under the age of 18 have not been established.
Geriatric Use: Of the 534 patients treated with
CUBICIN in Phase 3 controlled clinical trials of complicated skin and skin structure
infection,27.0% were 65 years of age or older and 12.4% were 75 years or older.
In the two Phase 3 clinical studies in patients with cSSSI, lower clinical success
rates were seen in patients ³65 years of age compared
to those <65 years of age. In addition, treatment-emergent adverse events
were more common in patients ³65 years old than in
patients <65 years of age in both cSSSI studies.
ANIMAL PHARMACOLOGY
In animals, daptomycin administration has been associated with
effects on skeletal muscle with no changes in cardiac or smooth muscle. Skeletal
muscle effects were characterized by degenerative/regenerative changes and variable
elevations in CPK. No fibrosis or rhabdomyolysis was evident in repeat dose
studies up to the highest doses tested in rats (150 mg/kg/day) and dogs (100
mg/kg/day).The degree of skeletal myopathy showed no increase when treatment
was extended from 1 month to up to 6 months. Severity was dose dependent. All
muscle effects, including microscopic changes, were fully reversible within
30 days following cessation of dosing.
In adult animals, effects on peripheral nerve (characterized
by axonal degeneration and frequently accompanied by significant losses of patellar
reflex, gag reflex, and pain perception) were observed at doses higher than
those associated with skeletal myopathy. Deficits in the dogs’ patellar reflexes
were seen within 2 weeks of the start of treatment at 40 mg/kg (3.5 times the
human AUC),with some clinical improvement noted within 2 weeks of the cessation
of dos-ing. However, at 75 mg/kg daily for 1 month,7/8 dogs failed to regain
full patellar reflex responses within the duration of a 3 month recovery period.
In a separate study in dogs receiving doses of 75 and 100 mg/kg/day for 2 weeks,
min-imal residual histological changes were noted at 6 months after cessation
of dosing. However, recovery of peripheral nerve function was evident.
Tissue distribution studies in rats have shown that daptomycin
is retained in the kidney but does not appear to penetrate across the blood-brain
barrier following single and multiple doses.
top
