In controlled and uncontrolled studies, the safety of IONSYSÃ? 40 mcg was evaluated in a total of 2114 patients with acute postoperative pain requiring opioid analgesia.

The most common adverse events (≥ 2%) in the placebo-controlled studies, regardless of relationship to study medication, are listed in Table 6.

Adverse Events Reported including All Studies in Patients Treated With IONSYSÃ? (40 mcg/dose: n= 2114 in 3 Placebo-Controlled Trials and 4 Active Comparator Trials vs. IV PCA morphine)

The most common (>10%) adverse events reported regardless of relationship to IONSYSÃ? use were nausea, vomiting, application site reaction-erythema, fever, and headache. Other adverse events reported for IONSYSÃ? were:

Body as a whole: abdominal pain**, back pain**, extremity pain**, pain**, injection site reaction*, chills*, internal postoperative bleeding*, chest pain*, infection*, injection site edema*, injection site pain*, immune system disorder*, abdomen enlarged*, asthenia*, neck pain*, abscess*, and hypothermia*, Cardiovascular System: hypotension**, tachycardia**, hypertension**, syncope*, postural hypotension*, pulmonary embolus*, atrial fibrillation*, bradycardia*, migraine*, myocardial infarct*, vasodilation*, hemorrhage*, deep thrombophlebitis*, bigeminy*, and arrhythmia*, Digestive System: constipation**, flatulence**, dyspepsia**, ileus**, gastrointestinal disorder*, dry mouth*, diarrhea*, and gastrointestinal hemorrhage*, Hemic and Lymphatic System: anemia**, and leukocytosis*, and Metabolic and Nutritional System: hypokalemia**, peripheral edema*, hypomagnesemia*, hypocalcemia*, hyponatremia*, hyperglycemia*, healing abnormal*, hypoglycemia*, hypophosphatemia*, edema*, and dehydration*, Musculoskeletal System: leg cramps* and myalgia*, Nervous System: dizziness**, insomnia**, anxiety**, hypertonia**, somnolence**, confusion*, paresthesia*, hypesthesia*, nervousness*, agitation*, abnormal dreams*, and tremor*, Respiratory System: hypoxia**, pharyngitis**, hypoventilation*, dyspnea*, apnea*, cough increased*, lung disorder*, asthma*, hiccup*, pneumonia*, atelectasis*, upper respiratory tract infection*, rhinitis*, sinusitis*, and hyperventilation*, Skin System: pruritus**, application site reaction (ASR)-itching**, ASR-vesicles**, ASR-edema**, ASR-other**, sweating**, wound site oozing/bleeding**, wound site inflammation/erythema*, rash*, ASR-dry and flaky*, ASR-papules/pustules*, vesiculobullous rash*, ASR-pain*, ASR-burning*, Special Senses: abnormal vision-blurred vision*, and ear pain*, Urogenital System: urinary retention**, urination impaired*, oliguria*, urogenital disorder*, hematuria*, urinary tract infection*, urinary urgency*, and dysuria*.

The level of current (62 microA/cm²) provided by IONSYSÃ? is generally imperceptible to the patient.

Scheduled observation of the skin approximately 24 hours after system removal was included in several studies. Some redness at the skin sites was observed in approximately 60% of patients at this observation. The skin findings included erythema, edema, and papules. The majority of these events were categorized as mild. Two patients were noted to have hyperpigmentation lasting 2-3 weeks at the application site. Three patients from another study noted a rectangular mark at the application site, which persisted for up to 3 months after study completion.

IONSYSÃ? contains fentanyl, a Schedule II controlled substance.

IONSYSÃ? contains a high concentration of a potent Schedule II controlled opioid agonist, fentanyl. Schedule II opioid substances, which include fentanyl, morphine, oxycodone, oxymorphone, hydromorphone, and methadone, have the highest potential for abuse. These drugs also have a risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high drug content and concentrated formulation of fentanyl in IONSYSÃ? may be a particular target for abuse and diversion and may add to the risk of adverse outcomes from abuse. After the maximum dosage administration, a significant amount of fentanyl remains in the device.

Access to abusable drugs such as IONSYSÃ? presents a risk for abuse and diversion in the health care community. Implementation of effective accounting procedures in addition to routine procedures for handling controlled substances may minimize these risks.

Tolerance and physical and psychological dependence may develop upon repeated administration of opioids. Iatrogenic addiction following opioid administration is relatively rare. Physicians should not let concerns of physical dependence deter them from using adequate amounts of opioids in the management of acute post-operative pain when such use is indicated.

The concomitant use of other central nervous system depressants, including other opioids, sedatives, hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, or alcoholic beverages, may produce additive depressant effects. Hypoventilation, hypotension, profound sedation, coma, or death may occur. Therefore, use of concomitant CNS depressants requires individual adjustment of dosage of the concomitant medication and observation of a given patient.

Fentanyl is metabolized mainly via the cytochrome P450 3A4 enzyme (CYP3A4). Therefore, drug interactions may occur when IONSYSÃ? is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce CYP3A4 activity, such as rifampin, carbamazepine, phenytoin, and Saint Johns Wort may cause increased clearance of fentanyl and reduce the efficacy of IONSYSÃ?. The concomitant use of fentanyl with CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin), azole antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g. ritonavir) may result in a decrease in fentanyl clearance, which could increase or prolong adverse drug effects including serious respiratory depression. In this situation, special patient care and observation are appropriate.

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