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
Actiq Side Effects, and Drug Interactions - Fentanyl Citrate
Actiq Side Effects, and Drug Interactions - Fentanyl Citrate
SIDE EFFECTS
Pre-Marketing Clinical Trial Experience
The safety of Actiq has been evaluated in 257 opioid tolerant
chronic cancer pain patients. The duration of Actiq use varied
during the open-label study. Some patients were followed for over 21 months.
The average duration of therapy in the open-label study was 129 days.
The adverse events seen with Actiq are typical opioid side effects.
Frequently, these adverse events will cease or decrease in intensity with
continued use of Actiq as the patient is titrated to the proper
dose. Opioid side effects should be expected and managed accordingly.
The most serious adverse effects associated with all opioids are respiratory
depression (potentially leading to apnea or respiratory arrest), circulatory
depression, hypotension, and shock. All patients should be followed for
symptoms of respiratory depression.
Because the clinical trials of Actiq were designed to evaluate
safety and efficacy in treating breakthrough cancer pain, all patients
were also taking concomitant opioids, such as sustained-release morphine
or transdermal fentanyl, for their persistent cancer pain. The adverse
event data presented here reflect the actual percentage of patients experiencing
each adverse effect among patients who received Actiq for breakthrough
cancer pain along with a concomitant opioid for persistent cancer pain.
There has been no attempt to correct for concomitant use of other opioids,
duration of Actiq therapy, or cancer-related symptoms. Adverse
events are included regardless of causality or severity.
Three short-term clinical trials with similar titration schemes were
conducted in 257 patients with malignancy and breakthrough cancer pain.
Data are available for 254 of these patients. The goal of titration in
these trials was to find the dose of Actiq that provided adequate
analgesia with acceptable side effects (successful dose). Patients were
titrated from a low dose to a successful dose in a manner similar to current
titration dosing guidelines. Table 3 lists by dose groups, adverse events
with an overall frequency of 1% or greater that occurred during titration
and are commonly associated with opioid administration or are of particular
clinical interest. The ability to assign a dose-response relationship
to these adverse events is limited by the titration schemes used in these
studies. Adverse events are listed in descending order of frequency within
each body system.
Table 3.
Percent of Patients with Specific Adverse Events Commonly Associated
with Opioid Administration or of Particular Clinical Interest Which
Occurred During Titration (Events in 1% or More of Patients) |
| Dose Group |
200-600 µg |
800-1400 µg |
1600 µg |
> 1600 µg |
Any |
| Number of Patients |
230 |
138 |
54 |
41 |
254 |
|
Body As A Whole
|
| Asthenia |
6 |
4 |
0 |
7 |
9 |
| Headache |
3 |
4 |
6 |
5 |
6 |
| Accidental Injury |
1 |
1 |
4 |
0 |
2 |
| Digestive |
| Nausea |
16 |
15 |
11 |
22 |
23 |
| Vomiting |
7 |
6 |
6 |
15 |
12 |
| Constipation |
1 |
4 |
2 |
0 |
4 |
| Nervous |
| Dizziness |
10 |
16 |
6 |
15 |
17 |
| Somnolence |
9 |
9 |
11 |
20 |
17 |
| Confusion |
1 |
6 |
2 |
0 |
4 |
| Anxiety |
3 |
0 |
2 |
0 |
3 |
| Abnormal Gait |
0 |
1 |
4 |
0 |
2 |
| Dry Mouth |
1 |
1 |
2 |
0 |
2 |
| Nervousness |
1 |
1 |
0 |
0 |
2 |
| Vasodilatation |
2 |
0 |
2 |
0 |
2 |
| Hallucinations |
0 |
1 |
2 |
2 |
1 |
| Insomnia |
0 |
1 |
2 |
0 |
1 |
| Thinking Abnormal |
0 |
1 |
2 |
0 |
1 |
| Vertigo |
1 |
0 |
0 |
0 |
1 |
| Respiratory |
| Dyspnea |
2 |
3 |
6 |
5 |
4 |
| Skin |
| Pruritus |
1 |
0 |
0 |
5 |
2 |
| Rash |
1 |
1 |
0 |
2 |
2 |
| Sweating |
1 |
1 |
2 |
2 |
2 |
| Special Senses |
| Abnormal Vision |
1 |
0 |
2 |
0 |
2 |
The following adverse events not reflected in Table 3 occurred during
titration with an overall frequency of 1% or greater and are listed in
descending order of frequency within each body system.
Body as a Whole: Pain, fever, abdominal pain, chills, back pain,
chest pain, infection.
Cardiovascular: Migraine.
Digestive: Diarrhea, dyspepsia, flatulence.
Metabolic and Nutritional: Peripheral edema, dehydration.
Nervous: Hypesthesia.
Respiratory: Pharyngitis, cough increased.
The following events occurred during titration with an overall frequency
of less than 1% and are listed in descending order of frequency within
each body system.
Body as a Whole: Flu syndrome, abscess, bone pain.
Cardiovascular: Deep thrombophlebitis, hypertension, hypotension.
Digestive: Anorexia, eructation, esophageal stenosis, fecal impaction,
gum hemorrhage, mouth ulceration, oral moniliasis.
Hemic and Lymphatic: Anemia, leukopenia.
Metabolic and Nutritional: Edema, hypercalcemia, weight loss.
Musculoskeletal: Myalgia, pathological fracture, myasthenia.
Nervous: Abnormal dream, urinary retention, agitation, amnesia,
emotional lability, euphoria, incoordination, libido decreased, neuropathy,
paresthesia, speech disorder.
Respiratory: Hemoptysis, pleural effusion, rhinitis, asthma, hiccup,
pneumonia, respiratory insufficiency, sputum increased.
Skin and Appendages: Alopecia, exfoliative dermatitis.
Special Senses: Taste perversion.
Urogenital: Vaginal hemorrhage, dysuria, hematuria, urinary incontinence,
urinary tract infection.
A long-term extension study was conducted in 156 patients with malignancy
and breakthrough cancer pain who were treated for an average of 129 days.
Data are available for 152 of these patients. Table 4 lists by dose groups,
adverse events with an overall frequency of 1% or greater that occurred
during the long-term extension study and are commonly associated with
opioid administration or are of particular clinical interest. Adverse
events are listed in descending order of frequency within each body system.
Table 4.
Percent of Patients with Adverse Events Commonly Associated with Opioid
Administration or of Particular Clinical Interest
Which Occurred During Long Term Treatment (Events in 1% or More of
Patients) |
| Dose Group |
200-600 µg |
800-1400 µg |
1600 µg |
> 1600 µg |
Any |
| Number of Patients |
98 |
83 |
53 |
27 |
152 |
|
Body As A Whole
|
| Asthenia |
26 |
30 |
17 |
15 |
38 |
| Headache |
12 |
17 |
13 |
4 |
20 |
| Accidental Injury |
4 |
6 |
4 |
7 |
9 |
| Hypertension |
2 |
2 |
2 |
0 |
3 |
| Digestive |
| Nausea |
31 |
36 |
25 |
26 |
45 |
| Vomiting |
21 |
28 |
15 |
7 |
31 |
| Constipation |
14 |
11 |
13 |
4 |
20 |
| Intestinal Obstruction |
0 |
2 |
4 |
7 |
3 |
| Cardiovascular |
| Hypertension |
1 |
1 |
0 |
0 |
1 |
| Nervous |
| Dizziness |
12 |
10 |
9 |
0 |
16 |
| Anxiety |
9 |
8 |
8 |
7 |
15 |
| Somnolence |
8 |
13 |
8 |
7 |
15 |
| Confusion |
2 |
5 |
13 |
7 |
10 |
| Depression |
9 |
4 |
2 |
7 |
9 |
| Insomnia |
5 |
1 |
8 |
4 |
7 |
| Abnormal Gait |
5 |
1 |
0 |
0 |
4 |
| Dry Mouth |
3 |
1 |
2 |
4 |
4 |
| Nervousness |
2 |
2 |
2 |
4 |
3 |
| Stupor |
4 |
1 |
0 |
0 |
3 |
| Vasodilatation |
1 |
1 |
4 |
0 |
3 |
| Thinking Abnormal |
2 |
1 |
0 |
0 |
2 |
| Abnormal Dreams |
1 |
1 |
0 |
0 |
1 |
| Convulsions |
0 |
1 |
2 |
0 |
1 |
| Myoclonus |
0 |
0 |
4 |
0 |
1 |
| Tremor |
0 |
1 |
2 |
0 |
1 |
| Vertigo |
0 |
0 |
4 |
0 |
1 |
| Respiratory |
| Dyspnea |
15 |
16 |
8 |
7 |
2 |
| Skin |
| Rash |
3 |
5 |
8 |
4 |
8 |
| Sweating |
3 |
2 |
2 |
0 |
4 |
| Pruritus |
2 |
0 |
2 |
0 |
2 |
| Special Senses |
| Abnormal Vision |
2 |
2 |
0 |
0 |
3 |
| Urogenital |
| Urinary Retention |
1 |
2 |
0 |
0 |
2 |
The following events not reflected in Table 4 occurred with an overall
frequency of 1% or greater in the long-term extension study and are listed
in descending order of frequency within each body system.
Body as a Whole: Pain, fever, back pain, abdominal pain, chest
pain, flu syndrome, chills, infection, abdomen enlarged, bone pain, ascites,
sepsis, neck pain, viral infection, fungal infection, cachexia, cellulitis,
malaise, pelvic pain.
Cardiovascular: Deep thrombophlebitis, migraine, palpitation, vascular
disorder.
Digestive: Diarrhea, anorexia, dyspepsia, dysphagia, oral moniliasis,
mouth ulceration, rectal disorder, stomatitis, flatulence, gastrointestinal
hemorrhage, gingivitis, jaundice, periodontal abscess, eructation, glossitis,
rectal hemorrhage.
Hemic and Lymphatic: Anemia, leukopenia, thrombocytopenia, ecchymosis,
lymphadenopathy, lymphedema, pancytopenia.
Metabolic and Nutritional: Peripheral edema, edema, dehydration,
weight loss, hyperglycemia, hypokalemia, hypercalcemia, hypomagnesemia.
Musculoskeletal: Myalgia, pathological fracture, joint disorder,
leg cramps, arthralgia, bone disorder.
Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech
disorder.
Respiratory: Cough increased, pharyngitis, pneumonia, rhinitis,
sinusitis, bronchitis, epistaxis, asthma, hemoptysis, sputum increased.
Skin and Appendages: Skin ulcer, alopecia.
Special Senses: Tinnitus, conjunctivitis, ear disorder, taste perversion.
Urogenital: Urinary tract infection, urinary incontinence, breast
pain, dysuria, hematuria, scrotal edema, hydronephrosis, kidney failure,
urinary urgency, urination impaired, breast neoplasm, vaginal hemorrhage,
vaginitis.
The following events occurred with a frequency of less than 1% in the
long-term extension study and are listed in descending order of frequency
within each body system.
Body as a Whole: Allergic reaction, cyst, face edema, flank pain,
granuloma, bacterial infection, injection site pain, mucous membrane disorder,
neck rigidity.
Cardiovascular: Angina pectoris, hemorrhage, hypotension, peripheral
vascular disorder, postural hypotension, tachycardia.
Digestive: Cheilitis, esophagitis, fecal incontinence, gastroenteritis,
gastrointestinal disorder, gum hemorrhage, hemorrhage of celon, hepatorenal
syndrome, liver tenderness, tooth caries, tooth disorder.
Hemic and Lymphatic: Bleeding time increased.
Metabolic and Nutritional: Acidosis, generalized edema, hypocalcemia,
hypoglycemia, hyponatremia, hypoproteinemia, thirst.
Musculoskeletal: Arthritis, muscle atrophy, myopathy, synovitis,
tendon disorder.
Nervous: Acute brain syndrome, agitation, cerebral ischemia, facial
paralysis, foot drop, hallucinations, hemiplegia, miosis, subdural hematoma.
Respiratory: Hiccup hyperventilation, lung disorder, pneumothorax,
respiratory failure, voice alteration.
Skin and Appendages: Herpes zoster, maculopapular rash, skin discoloration,
urticaria, vesiculobullous rash.
Special Senses: Ear pain, eye hemorrhage, lacrimation disorder,
partial permanent deafness, partial transitory deafness.
Urogenital: Kidney pain, nocturia, oliguria, polyuria, pyelonephritis.
DRUG ABUSE AND DEPENDENCE
Fentanyl is a mu-opioid agonist and a Schedule II controlled substance
that can produce drug dependence of the morphine type. Actiq may
be subject to misuse, abuse and addiction.
The administration of Actiq should be guided by the response of
the patient. Physical dependence, per se, is not ordinarily a concern
when one is treating a patient with chronic cancer pain and fear of tolerance
and physical dependence should not deter using doses that adequately relieve
the pain.
Opioid analgesics may cause physical dependence. Physical dependence
results in withdrawal symptoms in patients who abruptly discontinue the
drug. Withdrawal also may be precipitated through the administration of
drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed
agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine,
nalbuphine).
Physical dependence, usually does not occur to a clinically significant
degree until after several weeks of continued opioid usage. Tolerance,
in which increasingly larger doses are required in order to produce the
same degree of analgesia, is initially manifested by a shortened duration
of analgesic effect, and subsequently, by decreases in the intensity of
analgesia.
The handling of Actiq should be managed to minimize the risk of
diversion, including restriction of access and accounting procedures as
appropriate to the clinical setting and as required by law (see SAFETY
AND HANDLING).
DRUG INTERACTIONS
See WARNINGS
Fentanyl is metabolized in the liver and intestinal mucosa to norfentanyl
by the cytochrome P450 3A4 isoform. Drugs that inhibit P450 3A4 activity
may increase the bioavailability of swallowed fentanyl (by decreasing
intestinal and hepatic first pass metabolism) and may decrease the systemic
clearance of fentanyl. The expected clinical results would be increased
or prolonged opioid effects. Drugs that induce cytochrome P450 3A4 activity
may have the opposite effects. However, no in vitro or in vivo
studies have been performed to assess the impact of those potential interactions
on the administration of Actiq. Thus patients who begin or end
therapy with potent inhibitors of CYP450 3A4 such as macrolide antibiotics
(e.g., erythromycin), azole antifungal agents (e.g., ketoconazole and
itraconazole), and protease inhibitors (e.g., ritanovir) while receiving
Actiq should be monitored for a change in opioid effects and, if
warranted, the dose of Actiq should be adjusted.
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