ACTIQ (Page 5 of 13)

5.12 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.13 Severe Hypotension

ACTIQ may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of ACTIQ. In patients with circulatory shock, ACTIQ may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ACTIQ in patients with circulatory shock.

5.14 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ACTIQ may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ACTIQ.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ACTIQ in patients with impaired consciousness or coma.

5.15 Risks of Use in Patients with Gastrointestinal Conditions

ACTIQ is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The fentanyl in ACTIQ may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.16 Increased Risk of Seizures in Patients with Seizure Disorders

The fentanyl in ACTIQ may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during ACTIQ therapy.

5.17 Risks of Driving and Operating Machinery

ACTIQ may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ACTIQ and know how they will react to the medication.

5.18 Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use ACTIQ with caution in patients with bradyarrhythmias.

6 ADVERSE REACTIONS

The following serious adverse reactions are described, or described in greater detail, in other sections:

  • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
  • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2 )]
  • Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4)]
  • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.8)]
  • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.9)]
  • Serotonin Syndrome [see Warnings and Precautions (5.10)]
  • Adrenal Insufficiency [see Warnings and Precautions (5.12)]
  • Severe Hypotension [see Warnings and Precautions (5.13)]
  • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.15)]
  • Seizures [see Warnings and Precautions (5.16)]

6.1 Clinical Studies Experience

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 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 most serious adverse reactions associated with ACTIQ are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock.

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.

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. Table 1 lists, by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during titration. The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schemes used in these studies. Adverse reactions are listed in descending order of frequency within each body system.

Table 1. 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

Percentage of Patients Reporting Event

200-

600 mcg

(n=230)

800-

1400 mcg (n=138)

1600

mcg

(n=54)

>1600

mcg

(n=41)

Any

Dose*

(n=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

14

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

* Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.

The following adverse reactions not reflected in Table 1 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

Digestive: Diarrhea, dyspepsia, flatulence

Metabolic and Nutritional: Peripheral edema, dehydration

Nervous: Hypesthesia, migraine

Respiratory: Pharyngitis, cough increased

The following reactions 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: Bone pain

Cardiovascular: Deep thrombophlebitis, hypertension, hypotension

Digestive: Anorexia, eructation, 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 dreams, 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 2 lists by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during the long-term extension study. Adverse reactions are listed in descending order of frequency within each body system.

Table 2. 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

Percentage of Patients Reporting Event

200-

600 mcg

(n=98)

800-

1400 mcg

(n=83)

1600

mcg

(n=53)

>1600

mcg

(n=27)

Any

Dose*

(n=152)

Body As A Whole

Asthenia

25

30

17

15

38

Headache

12

17

13

4

20

Accidental Injury

4

6

4

7

9

Hypertonia

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

0

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

0

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

Convulsion

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

22

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

* Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.

The following reactions not reflected in Table 2 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, 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, migraine

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 reactions 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, 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 colon, 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

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