"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
The following serious adverse reactions are discussed elsewhere in the labeling:
- Abuse Potential [see WARNINGS AND PRECAUTIONS]
- Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- Accidental Exposure [see WARNINGS AND PRECAUTIONS]
- Elderly, Cachetic, and Debilitated Patients [see WARNINGS AND PRECAUTIONS]
- Chronic Pulmonary Disease [see WARNINGS AND PRECAUTIONS]
- Head Injuries and Increased Intracranial Pressure [see WARNINGS AND PRECAUTIONS]
- Interactions with Other CNS Depressants, Alcohol, and Drugs of Abuse [see WARNINGS AND PRECAUTIONS]
- Interactions with CYP3A4 Inhibitors [see WARNINGS AND PRECAUTIONS]
- Application of External Heat [see WARNINGS AND PRECAUTIONS]
- Patients with Fever [see WARNINGS AND PRECAUTIONS]
- Cardiac Disease [see WARNINGS AND PRECAUTIONS]
- Hepatic Impairment [see WARNINGS AND PRECAUTIONS]
- Renal Impairment [see WARNINGS AND PRECAUTIONS]
- Use in Pancreatic/Biliary Tract Disease [see WARNINGS AND PRECAUTIONS]
- Avoidance of Withdrawal [see WARNINGS AND PRECAUTIONS]
- Driving and Operating Machinery [see WARNINGS AND PRECAUTIONS]
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 clinical practice.
Clinical Trial Experience
The safety of DURAGESIC was evaluated in 216 patients who took at least one dose of DURAGESIC in a multicenter, double-blind, randomized, placebo-controlled clinical trial of DURAGESIC. This trial examined patients over 40 years of age with severe pain induced by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement.
The most common adverse reactions (≥5%) in a double-blind, randomized, placebo-controlled clinical trial in patients with severe pain were nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, and anorexia. Other common adverse reactions (≥5%) reported in clinical trials in patients with chronic malignant or nonmalignant pain were headache and diarrhea. Adverse reactions reported for ≥1% of DURAGESIC-treated patients and with an incidence greater than placebo-treated patients are shown in Table 3.
The most common adverse reactions that were associated with discontinuation in patients with pain (causing discontinuation in ≥1% of patients) were depression, dizziness, somnolence, headache, nausea, vomiting, constipation, hyperhidrosis, and fatigue.
Table 3: Adverse Reactions Reported by ≥1% of
DURAGESIC-treated Patients and With an Incidence Greater Than Placebo-treated
Patients in 1 Double-Blind, Placebo-Controlled Clinical Trial of DURAGESIC
|Ear and labyrinth disorders|
|Abdominal pain upper||3||2|
|General disorders and administration site conditions|
|Metabolism and nutrition disorders|
|Musculoskeletal and connective tissue disorders|
|Nervous system disorders|
|Skin and subcutaneous tissue disorders|
Adverse reactions not reported in Table 1 that were reported by ≥1% of DURAGESIC-treated adult and pediatric patients (N=1854) in 11 controlled and uncontrolled clinical trials of DURAGESIC used for the treatment of chronic malignant or nonmalignant pain are shown in Table 4.
Table 4: Adverse Reactions Reported by ≥1% of
DURAGESIC-treated Patients in 11 Clinical Trials of DURAGESIC
|Immune system disorders|
|Nervous system disorders|
|Renal and urinary disorders|
|Skin and subcutaneous tissue disorders|
The following adverse reactions occurred in adult and pediatric patients with an overall frequency of <1% and are listed in descending frequency within each System/Organ Class:
Cardiac disorders: cyanosis
Eye disorders: miosis
Gastrointestinal disorders: subileus
Musculoskeletal and connective tissue disorders: muscle twitching
Nervous system disorders: hypoesthesia
Psychiatric disorders: disorientation, euphoric mood
Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction
Respiratory, thoracic and mediastinal disorders: respiratory depression
Skin and subcutaneous tissue disorders: eczema, dermatitis allergic, dermatitis contact
The safety of DURAGESIC was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Adverse reactions reported by ≥1% of DURAGESIC-treated pediatric patients are shown in Table 5.
Table 5: Adverse Reactions Reported by ≥1% of
DURAGESIC-treated Pediatric Patients in 3 Clinical Trials of DURAGESIC
|Gastrointestinal disorders Vomiting||34|
|Abdominal pain upper||4|
|General disorders and administration site conditions Edema peripheral||5|
|Application site reaction||1|
|Immune system disorders Hypersensitivity||3|
|Metabolism and nutrition disorders Anorexia||4|
|Musculoskeletal and connective tissue disorders Muscle spasms||2|
|Nervous system disorders Headache||16|
|Psychiatric disorders Insomnia||6|
|Renal and urinary disorders Urinary retention||3|
|Respiratory, thoracic and mediastinal disorders Respiratory depression||1|
|Skin and subcutaneous tissue disorders Pruritus||13|
The following adverse reactions have been identified during post-approval use of DURAGESIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Eye Disorders: Vision blurred
General Disorders and Administration Site Conditions: Feeling of body temperature change
Immune System Disorders: Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction
Investigations: Weight decreased
Psychiatric Disorders: Agitation
Read the Duragesic (fentanyl transdermal) Side Effects Center for a complete guide to possible side effects
Agents Affecting Cytochrome P450 3A4 Isoenzyme System
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). Coadministration with agents that induce CYP3A4 activity may reduce the efficacy of DURAGESIC. The concomitant use of DURAGESIC with a CYP3A4 inhibitor (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfanivir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause fatal respiratory depression. Closely monitor patients receiving DURAGESIC and any CYP3A4 inhibitor and reduce the dosage of DURAGESIC if warranted [see CLINICAL PHARMACOLOGY].
Central Nervous System Depressants
The concomitant use of DURAGESIC with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation, or potentially result in coma or death. Monitor patients closely when central nervous system depressants are used concomitantly with DURAGESIC and reduce the dose of one or both agents.
Avoid use of DURAGESIC in the patient who would require the concomitant administration of a monoamine oxidase (MAO) inhibitor, or within 14 days of stopping such treatment because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
Drug Abuse And Dependence
DURAGESIC contains fentanyl, a potent Schedule II opioid agonist. Schedule II opioid substances, which include hydromorphone, methadone, morphine, oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. DURAGESIC can be abused and is subject to criminal diversion [see WARNINGS AND PRECAUTIONS].
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since DURAGESIC may be diverted for non-medical use, careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood concentration of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION].
Last reviewed on RxList: 10/29/2013
This monograph has been modified to include the generic and brand name in many instances.
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