Actiq (Fentanyl Citrate Oral Transmucosal) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

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.

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 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 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.

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 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

POST-MARKETING EXPERIENCE

The following adverse reactions have been identified during postapproval use of Actiq. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to Actiq.

Digestive: Dental decay of varying severity including dental caries, tooth loss, and gum line erosion

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).

REPORTS OF SUSPECTED ACTIQ SIDE EFFECTS / ADVERSE REACTIONS

Possible Actiq side effects / adverse reactions in 42 year old female

Reported by a physician from United States on 2011-10-10

Patient: 42 year old female weighing 70.3 kg (154.7 pounds)

Reactions: Overdose, Toxicity TO Various Agents

Adverse event resulted in: death

Suspect drug(s):
Carisoprodol
    Dosage: every six hours

Fentanyl-100
    Dosage: changes patches q2d
    Indication: Pain
    End date: 2007-06-17

Alprazolam
    Administration route: Oral

Actiq
    Dosage: every 12 hours
    Administration route: Oral
    Indication: Breakthrough Pain

Other drugs received by patient: Strattera; Dextroamphetamine; Lyrica; Promethazine; Lunesta

Possible Actiq side effects / adverse reactions in 89 year old female

Reported by a physician from France on 2011-10-24

Patient: 89 year old female

Reactions: Decubitus Ulcer, Bradypnoea, Somnolence, Drug Prescribing Error

Adverse event resulted in: death

Suspect drug(s):
Actiq

Other drugs received by patient: Previscan

Possible Actiq side effects / adverse reactions in 57 year old female

Reported by a health professional (non-physician/pharmacist) from Spain on 2011-10-26

Patient: 57 year old female

Reactions: Drug Dependence, Drug Abuse

Suspect drug(s):
Actiq