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Actiq (Fentanyl Citrate Oral Transmucosal) - Description and Clinical Pharmacology



Actiq (oral transmucosal fentanyl citrate) is a solid formulation of fentanyl citrate, a potent opioid analgesic, intended for oral transmucosal administration. Actiq is formulated as a white to off-white solid drug matrix on a handle that is radiopaque and is fracture resistant (ABS plastic) under normal conditions when used as directed.

Actiq is designed to be dissolved slowly in the mouth in a manner to facilitate transmucosal absorption. The handle allows the Actiq unit to be removed from the mouth if signs of excessive opioid effects appear during administration.

Active Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula:

Actiq is available in six strengths equivalent to 200, 400, 600, 800, 1200, or 1600 mcg fentanyl base that is identified by the text on the solid drug matrix, the dosage unit handle tag, the blister package, and the shelf carton.

Inactive Ingredients: Hydrated dextrates, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, modified food starch, and confectioner's sugar.



Fentanyl, a pure opioid agonist, acts primarily through interaction with opioid mu-receptors located in the brain, spinal cord and smooth muscle. The primary site of therapeutic action is the central nervous system (CNS). The most clinically useful pharmacologic effects of the interaction of fentanyl with mu-receptors are analgesia and sedation.

Other opioid effects may include somnolence, hypoventilation, bradycardia, postural hypotension, pruritus, dizziness, nausea, diaphoresis, flushing, euphoria and confusion or difficulty in concentrating at clinically relevant doses.



The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3-to-5-minute half-life). In opioid non-tolerant individuals, fentanyl provides effects ranging from analgesia at blood levels of 1 to 2 ng/mL, all the way to surgical anesthesia and profound respiratory depression at levels of 10-20 ng/mL.

In general, the minimum effective concentration and the concentration at which toxicity occurs rise with increasing tolerance to any and all opioids. The rate of development of tolerance varies widely among individuals. As a result, the dose of Actiq should be individually titrated to achieve the desired effect (see DOSAGE AND ADMINISTRATION).


Opioids increase the tone and decrease contractions of the smooth muscle of the gastrointestinal (GI) tract. This results in prolongation in GI transit time and may be responsible for the constipating effect of opioids. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening of pain.

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


All opioid mu-receptor agonists, including fentanyl, produce dose dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. During the titration phase of the clinical trials, somnolence, which may be a precursor to respiratory depression, did increase in patients who were treated with higher doses of Actiq. In studies of opioid non-tolerant subjects, respiratory rate and oxygen saturation typically decrease as fentanyl blood concentration increases. Typically, peak respiratory depressive effects (decrease in respiratory rate) are seen 15 to 30 minutes from the start of oral transmucosal fentanyl citrate (OTFC®) administration and may persist for several hours.

Serious or fatal respiratory depression can occur, even at recommended doses, in vulnerable individuals. As with other potent opioids, fentanyl has been associated with cases of serious and fatal respiratory depression in opioid non-tolerant individuals.

Fentanyl depresses the cough reflex as a result of its CNS activity. Although not observed with Actiq in clinical trials, fentanyl given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration. Therefore, physicians and other healthcare providers should be aware of this potential complication. (See BOX WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE for additional information on hypoventilation.)



The absorption pharmacokinetics of fentanyl from the oral transmucosal dosage form is a combination of an initial rapid absorption from the buccal mucosa and a more prolonged absorption of swallowed fentanyl from the GI tract. Both the blood fentanyl profile and the bioavailability of fentanyl will vary depending on the fraction of the dose that is absorbed through the oral mucosa and the fraction swallowed.

Absolute bioavailability, as determined by area under the concentration-time curve, of 15 mcg/kg in 12 adult males was 50% compared to intravenous fentanyl.

Normally, approximately 25% of the total dose of Actiq is rapidly absorbed from the buccal mucosa and becomes systemically available. The remaining 75% of the total dose is swallowed with the saliva and then is slowly absorbed from the GI tract. About 1/3 of this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. Thus, the generally observed 50% bioavailability of Actiq is divided equally between rapid transmucosal and slower GI absorption. Therefore, a unit dose of Actiq, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed.

Dose proportionality among four of the available strengths of Actiq (200, 400, 800, and 1600 mcg) has been demonstrated in a balanced crossover design in adult subjects. Mean serum fentanyl levels following these four doses of Actiq are shown in Figure 1. The curves for each dose level are similar in shape with increasing dose levels producing increasing serum fentanyl levels. Cmax and AUC0->(infinity) increased in a dose-dependent manner that is approximately proportional to the Actiq administered.

The pharmacokinetic parameters of the four strengths of Actiq tested in the dose-proportionality study are shown in Table 1. The mean Cmax ranged from 0.39-2.51 ng/mL. The median time of maximum plasma concentration (Tmax) across these four doses of Actiq varied from 20-40 minutes (range of 20-480 minutes) as measured after the start of administration.

Table 1.
Pharmacokinetic Parameters in Adult Subjects Receiving 200, 400, 800, and 1600 mcg Units of Actiq
Pharmacokinetic Parameter 200 mcg 400 mcg 800 mcg 1600 mcg
Tmax, minute median (range) 40 (20-120) 25 (20-240) 25 (20-120) 20 (20-480)
Cmax, ng/mL mean (% CV) 0.39 (23) 0.75 (33) 1.55 (30) 2.51 (23)
AUC0-1440, ng/mL minute mean (% CV) 102 (65) 243 (67) 573 (64) 1026 (67)
t½ , minute mean (% CV) 193 (48) 386 (115) 381 (55) 358 (45)


Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.


Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies (see PRECAUTIONS: Drug Interactions for additional information).


Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important. The total plasma clearance of fentanyl was 0.5 L/hr/kg (range 0.3-0.7 L/hr/kg). The terminal elimination half-life after OTFC administration is about 7 hours.


Elderly Patients:

Elderly patients have been shown to be twice as sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. While a formal study evaluating the safety profile of Actiq in the elderly population has not been performed, in the 257 opioid tolerant cancer patients studied with Actiq, approximately 20% were over age 65 years. No difference was noted in the safety profile in this group compared to those aged less than 65 years, though they did titrate to lower doses than younger patients (see PRECAUTIONS).

Patients with Renal or Hepatic Impairment:

Actiq should be administered with caution to patients with liver or kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs and effects on plasma-binding proteins (see PRECAUTIONS).

Although fentanyl kinetics are known to be altered in both hepatic and renal disease due to alterations in metabolic clearance and plasma proteins, individualized doses of Actiq have been used successfully for breakthrough cancer pain in patients with hepatic and renal disorders. The duration of effect for the initial dose of fentanyl is determined by redistribution of the drug, such that diminished metabolic clearance may only become significant with repeated dosing or with excessively large single doses. For these reasons, while doses titrated to clinical effect are recommended for all patients, special care should be taken in patients with severe hepatic or renal disease.


Both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain. No clinically relevant gender differences were noted either in dosage requirement or in observed adverse events.



Actiq was investigated in clinical trials involving 257 opioid tolerant adult cancer patients experiencing breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-severe pain occurring in cancer patients experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications including at least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer.

In two dose titration studies 95 of 127 patients (75%) who were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain titrated to a successful dose of Actiq to treat their breakthrough cancer pain within the dose range offered (200, 400, 600, 800, 1200 and 1600 mcg). In these studies 11% of patients withdrew due to adverse events and 14% withdrew due to other reasons. A "successful" dose was defined as a dose where one unit of Actiq could be used consistently for at least two consecutive days to treat breakthrough cancer pain without unacceptable side effects.

The successful dose of Actiq for breakthrough cancer pain was not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and is thus best determined by dose titration.

A double-blind placebo controlled crossover study was performed in cancer patients to evaluate the effectiveness of Actiq for the treatment of breakthrough cancer pain. Of 130 patients who entered the study 92 patients (71%) achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 2.

Table 2.
Successful Dose of Actiq
Following Initial Titration
Actiq Dose Total No (%)
200 mcg 13 (14)
400 mcg 19 (21)
600 mcg 14 (15)
800 mcg 18 (20)
1200 mcg 13 (14)
1600 mcg 15 (16)
Mean±SD 789±468 mcg

On average, patients over 65 years of age titrated to a mean dose that was about 200 mcg less than the mean dose to which younger adult patients were titrated.

Actiq produced statistically significantly more pain relief compared with placebo at 15, 30, 45 and 60 minutes following administration (see Figure 2).

In this same study patients also rated the performance of medication to treat their breakthrough cancer pain using a different scale ranging from "poor" to "excellent." On average, placebo was rated "fair" and Actiq was rated "good."

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