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
Exosurf Side Effects, and Drug Interactions - Colfosceril Palmitate, Cetyl Alcohol, Tyloxapol (Suspension)
Exosurf Side Effects, and Drug Interactions - Colfosceril Palmitate, Cetyl Alcohol, Tyloxapol (Suspension)
SIDE EFFECTS
General
Premature birth is associated with a high incidence of morbidity and
mortality. Despite significant reductions in overall mortality associated
with EXOSURF NEONATAL, some infants who received EXOSURF NEONATAL developed
severe complications and either survived with permanent handicaps or died.
In controlled clinical studies evaluating the safety and efficacy of
EXOSURF NEONATAL, numerous safety assessments were made. In infants receiving
EXOSURF NEONATAL, pulmonary hemorrhage, apnea, and use of methylxanthines
were increased. A number of other adverse events were significantly reduced
in the group receiving EXOSURF NEONATAL, particularly various forms of
pulmonary air leak and use of pancuronium (see CLINICAL
PHARMACOLOGY Clinical Studies: Clinical Results). Tables
3 and 4 summarize the results of the major safety evaluations from the
controlled clinical studies.
| Table 3: Safety Assessments*
Prophylactic Treatment |
Number of Doses:
Birth Weight Range: |
Single Dose
500 to 700 g |
Single Dose
700 to 1350 g |
Single Dose
700 to 1100 g |
1 vs 3 Doses
700 to 1100 g |
| Treatment Group: |
Placebo
(Air) |
EXOSURF |
Placebo
(Air) |
EXOSURF |
Placebo
(Air) |
EXOSURF |
EXOSURF |
EXOSURF |
| 1 Dose |
3 Doses |
| Number of Infants: |
n = 108 |
n = 107 |
n= 193 |
n=192 |
n=222 |
n=224 |
n=356 |
n=360 |
| |
% of Infants |
% of Infants |
% of Infants |
% of Infants
|
| Intraventricular hemorrhage
(IVH) |
| Overall |
51
|
57 |
31 |
27 |
36 |
36 |
38 |
35 |
| Severe IVH |
26 |
25 |
10 |
8 |
13 |
14 |
9 |
9 |
| Pulmonary air leak (PAL) |
| Overall |
52 |
48 |
16 |
11 |
32 |
25 |
29 |
27 |
| Pneumothorax |
23 |
10 |
5 |
6 |
19 |
11 |
14 |
12 |
| Pneumopericardium |
1 |
4 |
2 |
0 |
<1 |
1 |
1 |
1 |
| Pneumomediastinum |
2 |
1 |
2 |
3 |
7 |
1 |
3 |
2 |
Pulmonary interstitial
emphysema |
43 |
44 |
13 |
7 |
26 |
20 |
23 |
22 |
| Death from PAL |
4 |
6 |
<1 |
<1 |
2 |
1 |
2 |
1 |
| Patent ductus arteriosus |
49 |
53 |
66 |
70 |
50 |
55 |
59 |
57 |
| Necrotizing enterocolitis |
2 |
4 |
11 |
13 |
3 |
4 |
6 |
2 |
| Pulmonary hemorrhage |
2 |
10 |
2 |
4 |
1 |
4 |
4 |
6 |
| Congenital pneumonia |
4 |
4 |
2 |
4 |
2 |
2 |
1 |
1 |
| Nosocomial pneumonia |
10 |
10 |
2 |
4 |
4 |
7 |
14 |
15 |
| Nonpulmonary infections |
33 |
35 |
34 |
39 |
28 |
29 |
35 |
34 |
| Sepsis |
30 |
34 |
30 |
34 |
23 |
24 |
30 |
27 |
| Death from sepsis |
4 |
4 |
3 |
3 |
1 |
2 |
3 |
2 |
| Meningitis |
4 |
6 |
3 |
1 |
2 |
3 |
1 |
2 |
| Other infections |
7 |
4 |
5 |
3 |
6 |
10 |
10 |
11 |
| Major anomalies |
3 |
1 |
2 |
4 |
7 |
4 |
4 |
4 |
| Hypotension |
70 |
77 |
52 |
47 |
59 |
62 |
54 |
50 |
| Hyperbilirubinemia |
22 |
21 |
63 |
61 |
27 |
31 |
20 |
21 |
| Exchange transfusion |
4 |
3 |
1 |
2 |
2 |
2 |
3 |
1 |
| Thrombocytopenia§ |
21 |
25 |
not available |
9 |
8 |
12 |
10 |
| Persistent fetal circulation |
0 |
1 |
1 |
1 |
0 |
2 |
1 |
<1 |
| Seizures |
11 |
8 |
2 |
2 |
11 |
9 |
6 |
5 |
| Apnea |
34 |
33 |
76 |
73 |
55 |
65 |
62 |
68 |
| Drug therapy |
| Antibiotics |
96 |
99 |
98 |
96 |
98 |
99 |
>99 |
99 |
| Diuretics |
55 |
60 |
39 |
37 |
59 |
63 |
64 |
65 |
| Anticonvulsants |
14 |
18 |
23 |
24 |
20 |
16 |
9 |
8 |
| Inotropes |
46 |
40 |
20 |
20 |
26 |
20 |
28 |
27 |
| Sedatives |
62 |
71 |
65 |
64 |
63 |
57 |
52 |
52 |
| Pancuronium |
19 |
11 |
22 |
14 |
19 |
13 |
15 |
11 |
| Methylxanthines |
38 |
43 |
77 |
77 |
61 |
72 |
75 |
82 |
*All parameters were examined with as- treated analyses.
P< 0.05.
P< 0.01.
§ Thrombocytopenia requiring platelet transfusion.
|
Table 4: Safety Assessments* Rescue Treatment
|
Number of Doses:
Birth Weight Range: |
2 Doses
700 to 1350 g |
2
Doses
1250 g and above |
| Treatment Group:
|
Placebo(Air) |
EXOSURF |
Placebo(Air) |
EXOSURF |
| Number of Infants:
|
n = 213 |
n = 206 |
n=622 |
n=615 |
| |
% of Infants |
% of Infants |
| Intraventricular
hemorrhage (IVH) |
| Overall |
48
|
52 |
23 |
18 |
| Severe IVH |
13 |
9 |
5 |
4 |
| Pulmonary air
leak (PAL) |
| Overall |
54 |
34 |
30 |
18 |
| Pneumothorax |
29 |
20 |
20 |
10 |
| Pneumopericardium |
4 |
1 |
1 |
2 |
| Pneumomediastinum |
8 |
4 |
5 |
2§ |
| Pulmonary
interstitial emphysema |
48 |
25 |
24 |
13 |
| Death from
PAL |
7 |
3 |
<1 |
1 |
| Patent ductus arteriosus |
66 |
57 |
54 |
45 |
| Necrotizing enterocolitis |
3 |
3 |
1 |
2 |
| Pulmonary hemorrhage |
3 |
1 |
<1 |
1 |
| Congenital pneumonia |
2 |
3 |
2 |
2 |
| Nosocomial pneumonia |
5 |
7 |
2 |
2 |
| Nonpulmonary infections |
19 |
22 |
13 |
13 |
| Sepsis |
15 |
17 |
8 |
8 |
| Death from sepsis |
<1 |
<1 |
1 |
<1 |
| Meningitis |
1 |
<1 |
1 |
<1 |
| Other infections |
5 |
8 |
5 |
6 |
| Major anomalies |
3 |
3 |
4 |
4 |
| Hypotension |
62 |
57 |
50 |
39§ |
| Hyperbilirubinemia |
17 |
19 |
12 |
10 |
| Exchange transfusion |
3 |
4 |
1 |
2 |
| ThrombocytopeniaII |
10 |
11 |
4 |
<1§ |
| Persistent fetal circulation |
1 |
1 |
6 |
2§ |
| Seizures |
10 |
10 |
6 |
3 |
| Apnea |
48 |
65§ |
37 |
44 |
| Drug therapy |
| Antibiotics |
100 |
99 |
98 |
98 |
| Diuretics |
60 |
65 |
45 |
34 |
| Anticonvulsants |
17 |
17 |
10 |
5§ |
| Inotropes |
36 |
31 |
27 |
16 |
| Sedatives |
72 |
68 |
76 |
64 |
| Pancuronium |
34 |
17§ |
33 |
15 |
| Methylxanthines |
62 |
74§ |
49 |
53 |
*All parameters were examined with as- treated analyses.
P< 0.05.
P< 0.001.
§ P< 0.01.
II Thrombocytopenia requiring platelet transfusion.
Pulmonary Hemorrhage
See WARNINGS.
Abnormal Laboratory Values
Abnormal laboratory values are common in critically ill, mechanically
ventilated, premature infants. A higher incidence of abnormal laboratory
values in the group receiving EXOSURF NEONATAL was not reported.
Events During Dosing
Data on events during dosing are available from more than 8800 infants
in the open, uncontrolled clinical study (Table 5).
| Table 5: Events During Dosing in the Open, Uncontrolled
Study* |
|
Treatment Type:
Number of Infants:
|
Prophylactic Treatment
n = 1127 |
Rescue Treatment
n = 7711 |
| |
% of Infants |
% of Infants |
| Reflux of EXOSURF NEONATAL |
20 |
31 |
| Drop in O2 saturation ( ³20%) |
6 |
22 |
| Rise in O2 saturation ( ³10%) |
5 |
6 |
Drop in transcutaneous
pO2 ( ³20 mm Hg) |
1 |
8 |
Rise in transcutaneous
pO2 ( ³20 mm Hg) |
2 |
5 |
Drop in transcutaneous
pCO2 ( ³20 mm Hg) |
<1 |
1 |
Rise in transcutaneous
pCO2 ( ³20 mm Hg) |
1 |
3 |
| Bradycardia (< 60 beats/ min) |
1 |
3 |
| Tachycardia (> 200 beats/ min) |
<1 |
<1 |
| Gagging |
1 |
5 |
| Mucous plugs |
<1 |
<1 |
*Infants may have experienced more than 1 event. Investigators were prohibited
from adjusting FiO2 and/or ventilator settings during dosing
unless significant clinical deterioration occurred.
Reflux: Reflux of EXOSURF NEONATAL into the endotracheal
tube during dosing has been observed and may be associated with rapid
drug administration. If reflux occurs, drug administration should be halted
and, if necessary, peak inspiratory pressure on the ventilator should
be increased by 4 to 5 cm H2O until the endotracheal tube clears.
Greater Than 20% Drop in Transcutaneous Oxygen Saturation:
If transcutaneous oxygen saturation declines during dosing, drug administration
should be halted and, if necessary, peak inspiratory pressure on the ventilator
should be increased by 4 to 5 cm H2O for 1 to 2 minutes. In
addition, increases of FiO2 may be required for 1 to 2 minutes.
Mucous Plugs: See WARNINGS.
DRUG INTERACTIONS
No information provided.
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