Fentanyl Novaplus Patch

9.1 Controlled Substance

Fentanyl transdermal system 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. Fentanyl transdermal system can be abused and is subject to criminal diversion [see Warnings and Precautions (5.1)]. 

9.2 Abuse

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 fentanyl transdermal system 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.

9.3 Dependence

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 (2.3)].

10.1 Clinical Presentation

Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The pharmacokinetic characteristics of fentanyl transdermal system must also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects. Deaths due to overdose have been reported with abuse and misuse of fentanyl transdermal system. 

10.2 Treatment

Give primary attention to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Remove all fentanyl transdermal system systems.

The pure opioid antagonists, such as naloxone, are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal is expected to be less than the duration of action of fentanyl, carefully monitor the patient until spontaneous respiration is reliably reestablished. After fentanyl transdermal system system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20 to 27 hours. Therefore, management of an overdose must be monitored accordingly, at least 72 to 96 hours beyond the overdose.

Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including fentanyl transdermal system, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

12.1 Mechanism of Action

Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.

12.2 Pharmacodynamics

Central Nervous System Effects
Fentanyl exerts its principal pharmacologic effects on the central nervous system. Central nervous system effects increase with increasing serum fentanyl concentrations. In addition to analgesia, alterations in mood, euphoria, dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Analgesic blood concentrations of fentanyl may cause nausea and vomiting directly by stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more common in ambulatory than in recumbent patients, as is postural syncope.

Ventilatory Effects
In clinical trials of 357 non-opioid tolerant subjects treated with fentanyl transdermal system, 13 subjects experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing less than 63 kg (9 of 13). Although subjects with prior impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with fentanyl transdermal system.

Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation. The use of fentanyl transdermal system is contraindicated in patients who are not tolerant to opioid therapy.

Gastrointestinal Tract and Other Smooth Muscle
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening rather than relief of pain.

While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination.

Cardiovascular Effects
Fentanyl may cause orthostatic hypotension and fainting. Fentanyl may infrequently produce bradycardia. The incidence of bradycardia in clinical trials with fentanyl transdermal system was less than 1%.

Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50 mcg/kg.

12.3 Pharmacokinetics

Absorption
Fentanyl transdermal system releases fentanyl from the reservoir at a nearly constant amount per unit time. The concentration gradient existing between the saturated solution of drug in the reservoir and the lower concentration in the skin drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the copolymer release membrane and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.

While there is variation in dose delivered among patients, the nominal flux of the systems (25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient.

Following fentanyl transdermal system application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial fentanyl transdermal system application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 24 and 72 hours after initial application (see Table 6). Serum fentanyl concentrations achieved are proportional to the fentanyl transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first few system applications. After several sequential 72-hour applications, patients reach and maintain a steady state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl (see figure 1).

The kinetics of fentanyl in normal subjects following application of a 100 mcg/hr fentanyl transdermal system patch were bioequivalent with or without a Bioclusive™ overlay (polyurethane film dressing).

After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 17 (range 13 to 22) hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3-12) hours.

A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal system system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.

NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 17 hours.

+Estimated

NOTE: Information on volume of distribution and half-life not available for renally impaired patients.

Distribution
Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3-8; N=8). 

Metabolism
Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. 

Excretion
Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.

Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.

Hepatic Impairment
Information on the effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of fentanyl transdermal system delivering 50 mcg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), Cmax and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively.

Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of fentanyl transdermal system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosing and Administration (2.2), Warnings and Precautions (5.12) and Use in Specific Populations (8.6)]. 

Renal Impairment
Information on the effect of renal impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of intravenous injection of 25 mcg/kg fentanyl was evaluated in patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found.

Because there is in-vivo evidence of renal contribution to the elimination of fentanyl transdermal system, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.13) and Use in Specific Populations (8.7)].

Pediatric Use
In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to [see Dosage and Administration (2.2)]. 

Geriatric Use
Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. In this study, a single fentanyl transdermal system 100 mcg/hour patch was applied to a skin site on the upper outer arm in a group of healthy elderly Caucasians ≥65 years old (n=21, mean age 71 years) and worn for 72 hours. The mean Cmax and AUC∞ values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC∞ was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%, respectively). The mean half-life value was longer in subjects ≥65 years old than in subjects 18 to 45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5)]. 

Drug Interactions
The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg tid on Day 1 and 300 mg tid on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%-420%) increase in fentanyl AUC0-∞. Coadministration of ritonavir in patients receiving fentanyl transdermal system has not been studied; however, an increase in fentanyl AUC is expected [see Box Warning and Warnings and Precautions (5.7) and Drug Interactions (7.1)].

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore, potential interactions may occur when fentanyl transdermal system is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, 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 potentially fatal respiratory depression. Carefully monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and adjust the dosage if warranted [see Box Warning and Warnings and Precautions (5.7)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 mcg/kg/day in males or 100 mcg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/h patch based on AUC0-24h comparison).

Mutagenesis
There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays.

Impairment of Fertility
The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.