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
Photofrin Side Effects, and Drug Interactions - Porfimer Sodium
Photofrin Side Effects, and Drug Interactions - Porfimer Sodium
SIDE EFFECTS
Systemically induced effects associated with PDT with PHOTOFRIN®
consist of photosensitivity and mild constipation. All patients who receive
PHOTOFRIN® will be photosensitive and must observe precautions
to avoid sunlight and bright indoor light (see PRECAUTIONS).
Photosensitivity reactions occurred in approximately 20% of patients treated
with PHOTOFRIN® in clinical studies. Typically these reactions
were mostly mild to moderate erythema but they also included swelling,
itching, burning sensations, feeling hot, or blisters. In a single study
of 24 healthy subjects, some evidence of photosensitivity reactions occurred
in all subjects. Other less common skin manifestations were also reported
in areas where sensitivity reactions had occurred, such as increased hair
growth, skin discoloration, skin nodules, increased wrinkles and increased
skin fragility. These manifestations may be attributable to a pseudoporphytria
state (temporary drug-induced cutaneous porphyria).
Most toxicities associated with this therapy are local effects seen in
the region of illumination and occasionally in surrounding tissues. The
local adverse reactions are characteristic of an inflammatory response
induced by the photodynamic effect.
Esophageal Carcinoma
The following adverse events were reported over the entire follow-up
period in at least 5% of patients treated with PHOTOFRIN®
PDT, who had completely or partially obstructing esophageal cancer. Table
5 presents data from 88 patients who received the currently marketed formulation.
The relationship of many of these adverse events to PDT with PHOTOFRIN®
is uncertain.
| TABLE 5. Adverse Events Reported in
5% or More of Patientsa with Obstructing Esophageal Cancer |
BODY SYSTEM/
Adverse Event |
Number (%) of Patients |
| n=88 |
| Patients with at Least One Adverse Event |
84 |
(95%) |
| AUTONOMIC NERVOUS SYSTEM |
| Hypertension |
5 |
(6%) |
| Hypotension |
6 |
(7%) |
| BODY AS A WHOLE |
| Asthenia |
5 |
(6%) |
| Back pain |
10 |
(11%) |
| Chest pain |
19 |
(22%) |
| Chest pain (substernal) |
4 |
(5%) |
| Edema generalized |
4 |
(5%) |
| Edema peripheral |
6 |
(7%) |
| Fever |
27 |
(31%) |
| Pain |
19 |
(22%) |
| Surgical complication |
4 |
(5%) |
| CARDIOVASCULAR |
| Cardiac failure |
6 |
(7%) |
| GASTROINTESTINAL |
| Abdominal pain |
18 |
(20%) |
| Constipation |
21 |
(24%) |
| Diarrhea |
4 |
(5%) |
| Dyspepsia |
5 |
(6%) |
| Dysphagia |
9 |
(10%) |
| Eructation |
4 |
(5%) |
| Esophageal edema |
7 |
(8%) |
| Esophageal tumor bleeding |
7 |
(8%) |
| Esophageal stricture |
5 |
(6%) |
| Esophagitis |
4 |
(5%) |
| Hematemesis |
7 |
(8%) |
| Melena |
4 |
(5%) |
| Nausea |
21 |
(24%) |
| Vomiting |
15 |
(17%) |
| HEART RATE/RHYTHM |
| Atrial fibrillation |
9 |
(10%) |
| Tachycardia |
5 |
(6%) |
| METABOLIC & NUTRITIONAL |
| Dehydration |
6 |
(7%) |
| Weight decrease |
8 |
(9%) |
| PSYCHIATRIC |
|
|
| Anorexia |
7 |
(8%) |
| Anxiety |
6 |
(7%) |
| Confusion |
7 |
(8%) |
| Insomnia |
12 |
(14%) |
| RED BLOOD CELL |
| Anemia |
28 |
(32%) |
| RESISTANCE MECHANISM |
| Moniliasis |
8 |
(9%) |
| RESPIRATORY |
| Coughing |
6 |
(7%) |
| Dyspnea |
18 |
(20%) |
| Pharyngitis |
10 |
(11%) |
| Pleural effusion |
28 |
(32%) |
| Pneumonia |
16 |
(18%) |
| Respiratory insufficiency |
9 |
(10%) |
| Tracheoesophageal fistula |
5 |
(6%) |
| SKIN & APPENDAGES |
| Photosensitivity reaction |
17 |
(19%) |
| URINARY |
| Urinary tract infection |
6 |
(7%) |
a Based on adverse events reported at any time during the entire
period of follow-up.
Location of the tumor was a prognostic factor for three adverse events:
upper-third of the esophagus (esophageal edema), middle-third (atrial
fibrillation), and lower-third, the most vascular region (anemia). Also,
patients with large tumors (> 10 cm) were more likely to experience anemia.
Two of 17 patients with complete esophageal obstruction from tumor experienced
esophageal perforations which were considered to be possibly treatment
associated; these perforations occurred during subsequent endoscopies.
Serious and other notable adverse events observed in less than 5% of
PDT-treated patients with obstructing esophageal cancer in the clinical
studies include the following; their relationship to therapy is uncertain.
In the gastrointestinal system, esophageal perforation, gastric ulcer,
ileus, jaundice, and peritonitis have occurred. Sepsis has been reported
occasionally. Cardiovascular events have included angina pectoris, bradycardia,
myocardial infarction, sick sinus syndrome, and supraventricular tachycardia.
Respiratory events of bronchitis, bronchospasm, laryngotracheal edema,
pneumonitis, pulmonary hemorrhage, pulmonary edema, respiratory failure,
and stridor have occurred. The temporal relationship of some gastrointestinal,
cardiovascular and respiratory events to the administration of light was
suggestive of mediastinal inflammation in some patients. Vision-related
events of abnormal vision, diplopia, eye pain and photophobia have been
reported.
Obstructing Endobronchial Cancer
Table 6 presents adverse events that were reported over the entire follow-up
period in at least 5% of patients with obstructing endobronchial cancers
treated with PHOTOFRIN® PDT or Nd:YAG. These data are based
on the 86 patients who received the currently marketed formulation. Since
it seems likely that most adverse events caused by these acute acting
therapies would occur within 30 days of treatment, Table 6 presents those
events occurring within 30 days of treatment procedure, as well as those
occurring over the entire follow-up period. It should be noted that follow-up
was 33% longer for the PDT group than for the Nd:YAG group, thereby introducing
a bias against PDT when adverse event rates are compared for the entire
follow-up period. The extent of follow-up in the 30-day period following
treatment was comparable between groups (only 9% more for PDT).
|
TABLE 6. Adverse Events Reported in 5% or More of Patients with
Obstructing
Endobronchial Cancers
|
| Number (%) of Patients |
| BODY SYSTEM/Adverse Event
|
Within 30 Days
of Treatment |
Entire
Follow-up Perioda |
| PDT |
Nd: YAG |
PDT |
Nd:YAG |
| n= 86 |
n= 86 |
n= 86 |
n= 86 |
| Patients with at Least One Adverse Event |
43 |
(50%) |
33 |
(38%) |
62 |
(72%) |
48 |
(56%) |
|
BODY AS A WHOLE
|
| Back pain |
3 |
(3%) |
1 |
(1%) |
3 |
(3%) |
5 |
(6%) |
| Chest pain |
6 |
(7%) |
6 |
(7%) |
7 |
(8%) |
8 |
(9%) |
| Edema peripheral |
3 |
(3%) |
3 |
(3%) |
4 |
(5%) |
3 |
(3%) |
| Fever |
7 |
(8%) |
7 |
(8%) |
14 |
(16%) |
8 |
(9%) |
| Pain |
1 |
(1%) |
4 |
(5%) |
4 |
(5%) |
8 |
(9%) |
| CENTRAL NERVOUS SYSTEM |
| Dysphonia |
3 |
(3%) |
2 |
(2%) |
4 |
(5%) |
2 |
(2%) |
| GASTROINTESTINAL |
| Constipation |
4 |
(5%) |
1 |
(1%) |
4 |
(5%) |
2 |
(2%) |
| Dyspepsia |
1 |
(1%) |
4 |
(5%) |
2 |
(2%) |
5 |
(6%) |
| PSYCHIATRIC |
| Anxiety |
3 |
(3%) |
0 |
(0%) |
5 |
(6%) |
0 |
(0%) |
| Insomnia |
4 |
(5%) |
2 |
(2%) |
4 |
(5%) |
3 |
(4%) |
| RESPIRATORY |
| Bronchitis |
9 |
(10%) |
2 |
(2%) |
9 |
(10%) |
2 |
(2%) |
| Coughing |
5 |
(6%) |
8 |
(9%) |
13 |
(15%) |
11 |
(13%) |
| Dyspnea |
15 |
(17%) |
7 |
(8%) |
26 |
(30%) |
13 |
(15%) |
| Hemoptysis |
6 |
(7%) |
5 |
(6%) |
14 |
(16%) |
7 |
(8%) |
| Pleural effusion |
0 |
(0%) |
0 |
(0%) |
4 |
(5%) |
1 |
(1%) |
| Pneumonia |
5 |
(6%) |
4 |
(5%) |
10 |
(12%) |
5 |
(6%) |
| Pneumothorax |
0 |
(0%) |
0 |
(0%) |
0 |
(0%) |
4 |
(5%) |
| Respiratory insufficiency |
0 |
(0%) |
0 |
(0%) |
5 |
(6%) |
1 |
(1%) |
| Sputum increased |
4 |
(5%) |
5 |
(6%) |
7 |
(8%) |
6 |
(7%) |
| SKIN & APPENDAGES |
| Photosensitivity reaction |
16 |
(19%) |
0 |
(0%) |
18 |
(21%) |
0 |
(0%) |
a Follow-up was 33% longer for the PDT group than for the Nd:YAG
group, introducing a bias against PDT when adverse events are compared
for the entire follow-up period.
Transient inflammatory reactions in PDT-treated patients occur in about
10% of patients and manifest as fever, bronchitis, chest pain and dyspnea.
The incidences of bronchitis and dyspnea were higher with PDT than with
Nd:YAG. Most cases of bronchitis occurred within 1 week of treatment and
all but one were mild or moderate in intensity. The events usually resolved
within 10 days with antibiotic therapy. Treatment-related worsening of
dyspnea is generally transient and self-limiting. Debridement of the treated
area is mandatory to remove exudate and necrotic tissue. Life-threatening
respiratory insufficiency likely due to therapy occurred in 3% of PDT-treated
patients and 2% of Nd:YAG-treated patients (see WARNINGS
and PRECAUTIONS).
There was a trend toward a higher rate of fatal hemoptysis (FMH) occurring
on the PDT arm (10%) versus the Nd:YAG arm (5%), however, the rate of
FMH occurring within 30 days of treatment was the same for PDT and Nd:YAG
(4% total events, 3% treatment-associated events). Patients who have received
radiation therapy have a higher incidence of FMH after treatment with
PDT and after other forms of local therapy than patients who have not
received radiation therapy, but analyses suggest that this increased risk
may be due to associated prognostic factors such as having a centrally
located tumor. The incidence of FMH in patients previously treated with
radiotherapy was 21% (6/29) in the PDT group and 10% (3/29) in the Nd:YAG
group. In patients with no prior radiotherapy, the overall incidence of
FMH was less than 1%. Characteristics of patients at high risk for FMH
are described in WARNINGS and
CONTRAINDICATIONS.
Other serious or notable adverse events were observed in less than 5%
of PDT-treated patients with endobronchial cancer; their relationship
to therapy is uncertain. In the respiratory system, pulmonary thrombosis,
pulmonary embolism and lung abscess have occurred. Cardiac failure, sepsis
and possible cerebrovascular accident have also been reported in one patient
each.
Superficial Endobronchial Tumors
The following adverse events were reported over the entire follow-up
period in at least 5% of patients with superficial tumors (microinvasive
or carcinoma in situ) who received the currently marketed formulation.
| TABLE 7. Adverse Events
Reported in 5% or More of Patientsa with Superficial
Endobronchial Tumors |
| Adverse Event |
Number (%) of Patients
n=90 |
| Patients with at Least One Adverse Event |
44 |
(49%) |
| Photosensitivity reaction |
20 |
(22%) |
| Coughing |
8 |
(9%) |
| Dyspnea |
6 |
(7%) |
| Edema |
16 |
(18%) |
| Exudate |
20 |
(22%) |
| Obstruction |
19 |
(21%) |
| Stricture |
10 |
(11%) |
| Ulceration |
8 |
(9%) |
a Based on adverse events reported at any time during the entire
period of follow-up.
In patients with superficial endobronchial tumors, 44 of 90 patients
(49%) experienced an adverse event, two-thirds of which were related to
the respiratory system. The most common reaction to therapy was a mucositis
reaction in one-fifth of the patients which manifested as edema, exudate,
and obstruction. The obstruction (mucus plug) is easily removed with suction
or forceps. Mucositis can be minimized by avoiding exposure of normal
tissue to excessive light (see PRECAUTIONS).
Three patients experienced life-threatening dyspnea: one was given a double
dose of light, one was treated concurrently in both mainstem bronchi and
the other had had prior pneumonectomy and was treated in the sole remaining
main airway (see WARNINGS). Stent
placement was required in 3% of the patients due to endobronchial stricture.
Fatal hemoptysis occurred within 30 days of treatment in one patient with
superficial tumors (1%).
Laboratory Abnormalities
In patients with esophageal cancer, PDT with PHOTOFRIN®
may result in anemia due to tumor bleeding. No consistent effects were
observed for other parameters or in patients with endobronchial carcinoma.
DRUG INTERACTIONS
There have been no formal interaction studies of PHOTOFRIN®
and any other drugs. However, it is possible that concomitant use of other
photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines,
sulfonylurea hypoglycemia agents, thiazide diuretics, and griseofulvin)
could increase the photosensitivity reaction.
PHOTOFRIN® PDT causes direct intracellular damage by initiating
radical chain reactions that damage intracellular membranes and mitochondria.
Tissue damage also results from ischemia secondary to vasoconstriction,
platelet activation and aggregation and clotting. Research in animals
and in cell culture has suggested that many drugs could influence the
effects of PDT, possible examples of which are described below. There
are no human data that support or rebut these possibilities.
Compounds that quench active oxygen species or scavenge radicals, such
as dimethyl sufloxide, b-carotene, ethanol, formate and mannitol would
be expected to decrease PDT activity. Preclinical data also suggest that
tissue ischemia, allopurinol, calcium channel blockers and some prostaglandin
synthesis inhibitors could interfere with PHOTOFRIN® PDT.
Drugs that decrease clotting, vasoconstriction or platelet aggregation,
e.g., thromboxane A2 inhibitors, could decrease the efficacy
of PDT. Glucocorticoid hormones given before or concomitant with PDT may
decrease the efficacy of the treatment.
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