Fentanyl Transdermal Patch Application Sites

English: 2D structure of fentanyl (Photo credit: Wikipedia)

We know that fentanyl patches should be applied to dry, noninflamed, non-irradiated, hairless skin. Body hair may be trimmed but not shaved. Be sure to press the patch firmly in place for 60 seconds or more. If problems with adherence, use Tegaderm or Micropore.

Fact or Fiction From Medscape:

Q: Is it true that fentanyl patches infuse more quickly in patients with very little subcutaneous fat?

A: No. The amount of fentanyl absorbed is proportional to the surface area of the patch. The absorption rate does not vary to any clinically significant extent between the chest, abdomen, and thigh.^[5] Fentanyl is released from the patch into top layers of the skin (stratum corneum and epidermis), and it accumulates within these layers to form a depot. The drug is released slowly into the systemic circulation via small blood vessels within the dermis. Fat tissue should not impair release, as the drug is released directly from the skin into the blood supply.^[2,5]

Furthermore, fentanyl exhibits wide tissue distribution to the lungs, kidneys, heart, spleen, brain, muscles, and body fat -- indicating a high extravascular volume of distribution (3-8 L/kg). It takes about 6 days to reach steady-state plasma concentrations after initiating fentanyl patch therapy.^[5]

^{Reference 5:} 

• Muijsers BBR, Wagstaff AJ. Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control. Drugs. 2001;61:2289-2307. Abstract

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FDA Okays Fentanyl Nasal Spray for Ca Pain - in Public Health & Policy, FDA General from MedPage Today

Medical News: FDA Okays Nasal Spray for Ca Pain - in Public Health & Policy, FDA General from MedPage Today

By Cole Petrochko, Associate Staff Writer, MedPage TodayPublished:

July 02, 2011 WASHINGTO -- The FDA has approved a nasal spray formulation of the drug fentanyl (Lazanda) to manage breakthrough pain in cancer patients ages 18 and older who are already using opioid therapy. The drug comes in 100 mcg- and 400 mcg-spray doses.

Drug efficacy was established in a double-blind study that found fentanyl nasal spray outperformed placebo at the primary endpoint of sum of pain intensity difference at 30 minutes.

The nasal spray formulation is not equivalent to other fentanyl products for breakthrough pain on a microgram-per-microgram basis. Healthcare professionals prescribing Lazanda should not convert from other fentanyl products. A dosage conversion guide is not available at this time.

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Fentanyl Citrate Sublingual Dosing And Stability

Fentanyl S/L:

- Use: incident pain


- Onset of action: 5-15 minutes

- Peak effect: within 20 minutes

- Duration of action: maximum 45minutes

- Supplied: 100mcg/2ml ampoules (Sublimaze®) – glass ampoules.

* Needs special authorization for Alberta Blue Cross

- Note: decreased saliva production can delay absorption of sublingual fentanyl

- If administered sublingually, the drugs have to remain there for at least 5 minutes.
- Oral bioavailability of fentanyl is negligible and therefore this medication cannot be taken orally.
- Patients are generally unable to keep more than 1.5ml to 2ml under the tongue before it dribbles into the mouth, rendering it inactive.

Counseling:

- Determine the maximum amount of liquid that can be held under the tongue using the cold water technique (pt should be able to feel cold water trickling down throat).

o Max 1.5 ml – 2ml (CHR long term care formulary)

o Max 0.5 ml – 1ml (cold water test)

- Fentanyl must remain under the tongue for at least 5 minutes to be absorbed.

o Oral bioavailability of fentanyl is negligible and therefore this medication cannot be taken orally.

- Any remaining/extra fentanyl in the amp should be drawn up to a syringe and kept in the fridge.


CHR Incident Pain Protocol*

Step 1: Fentanyl 12.5mcg (0.25ml)

Step 2: Fentanyl 25 mcg (0.5ml)

Step 3: Fentanyl 50 mcg (1ml)

Step 4: Fentanyl 100 mcg (2ml)

- Opioid naïve pt: start at Step 1.

- If the pt is opioid tolerant, then start at Step 2.

- If pt unable to tolerate the volume in a single dose then the volume may be given in 2 doses at an interval of 5-10minutes apart. (ie: 2ml – take 1ml twice 5 minutes apart).

- After 10-15 minutes, if the initial dose appears to be insufficient, then the same dose may be repeated up to 2 further doses, at 10-15 minute intervals.

- Consider moving to the next step of the protocol if the maximum number of doses (3) is required to achieve comfort. One may move to the next step of the protocol after one hour of the last dose of fentanyl.

- The Incident Pain Protocol may be used up to q1h.

Side Effects:

Drowsiness, sedation, nausea and vomiting. Respiratory depression is dose dependent, it could potentially occur with an initial fentanyl dose greater than 200mcg IV.

Stabilty:

Undiluted fentanyl citrate 50 mcg/mL was tested for stability in polypropylene syringes. The fentanyl citrate injection was filled into polypropylene syringes that were then capped off. The samples were stored for 28 days under refrigeration at 5 °C and at room temperature of 22 °C exposed to light. No change in color or clarity occurred. No loss of fentanyl citrate at either set of storage conditions occurred when evaluated using stability-indicating HPLC analysis.

*Hecq JD, Boitquin LP, Venbeckbergen DF et al. Effect of freezing, long-term storage, and microwave thawing on the stability of ketorolac tromethamine. Ann Pharmacother. 2005; 39:1654-8. [PubMed 16159993]

[Accessed Feb 10/10: Handbook on Injectable Drugs - 15th Ed. (2009)]

Pharmacy On-Call (Calgary Pharmacy) will premix syringes which are stable for 1 week.

*Calgary Health Region Long Term Care Formulary: fentanyl citrate injection.

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Medications In The Pipeline: Intranasal Fentanyl Spray Versus Oral Transmucosal Fentanyl Citrate

A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: an open-label, randomised, crossover trial

Current Medical Research and Opinion, 10/08/09

“Mercadante S et al. – In this open–label, randomised, crossover trial, significantly more patients attained faster ‘meaningful’ pain relief with intranasal fentanyl spray (INFS) than oral transmucosal fentanyl citrate (OTFC), and more patients preferred INFS to OTFC.”

Results:

Among the intention-to-treat population (n ¼ 139):
• median time to onset of ‘meaningful’ pain relief was 11 minutes with INFS versus 16 minutes with OTFC; 65.7% of patients attained faster time to ‘meaningful’ pain-relief onset with INFS ( p50.001). PID was statistically significantly greater for INFS than OTFC from 5 minutes post-dosing.
• Significantly more INFS-treated breakthrough pain episodes achieved clinically important pain relief (_33% and _50% PI reduction) up to 30 minutes post-dosing.
• The proportions of episodes treated with INFS and OTFC achieving a PI reduction of _33% at 5 minutes were 25.3% versus 6.8% ( p50.001), and at 10 minutes were 51.0% versus 23.6% ( p50.001), respectively
• The proportions of episodes treated with INFS and OTFC achieving a _50% PI reduction at 5 minutes were 12.8% versus 2.1% ( p50.001), and at 10 minutes were 36.9% versus 9.7% ( p50.001), respectively.
• Both treatments were well tolerated. In the safety population (n ¼ 139), 56.8% (n ¼ 79) of patients experienced _1 AE during the trial. The only AE that occurred in _5% of patients in either treatment group was nausea. Among those patients who experienced serious AEs (13.7%, n ¼ 19), none were considered to be related to either study medication.
• There was a weak correlation between effective INFS doses and background opioid doses.

Treatment administration:
• Up to four episodes of BTP per day were treated with study medication, intranasal fentanyl spray (INFS), as described below.
• Intranasal fentanyl spray has recently received marketing authorization from the Committee for Medicinal Products for Human Use and will be launched under the trade name Instanyl (Nycomed, Denmark).
• Doses of 50, 100 and 200 mg fentanyl (using INFS solutions of 0.5 mg/ml, 1.0 mg/ml and 2.0 mg/ml, respectively) were taken as a single dose in one nostril. A second INFS dose was permitted 10 minutes after the first, if required, taken in the other nostril. Rescue analgesics were permitted 10 minutes after the second INFS administration if pain relief was still insufficient.
• The comparator medication, oral transmucosal fentanyl citrate (OTFC) (Actiq, Cephalon, USA), was used at six doses: 200, 400, 600, 800, 1200 or 1600 mg in the form of single compressed lozenges with integral oromucosal applicators. One lozenge equalled one dose. OTFC was administered according to manufacturer’s recommendations (15 minutes in the oral cavity between cheek and gum). A second OTFC dose was permitted 30 minutes after the first, if required. Rescue analgesics were allowed, as needed, 45 minutes (if a second OTFC dose was not taken) or 60 minutes (if a second OTFC dose was taken) after start of administration.

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Pain And Symptom Control Medication Highlights - Intranasal Fentanyl

Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: A phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period

Clinical Therapeutics, 08/26/09

Kress HG et al. – Intranasal fentanyl spray (INFS), at 50, 100, and 200 micrograms, was associated with an onset of activity at 10 min and effective tx of breakthrough pain compared with placebo.

Methods
Phase III, double-blind, randomized, placebo-controlled, crossover trial 120 adults with cancer receiving a stable dose of long-term opioid tx for the control of background pain. Patients were treated at home with 50, 100, or 200 micrograms of INFS or placebo for 3 weeks, followed by a 10-month, phase when they received their effective dose of INFS.

Results
The pain intensity difference at 10 minutes (PID10) with INFS was 2-fold that with placebo.
The mean response rate with all 3 doses of INFS was 51.1% vs. 20.9% with placebo.
The prevalence of AEs was 19.8% (nausea [4.5%] and vertigo [1.8%]).

Of course, Onsolis (Fentanyl Buccal Film) was approved by the FDA back in July “for the management of breakthrough pain in patients with cancer aged 18 years and older who receive around-the-clock opioid therapy and are able to safely use high doses of additional opioid agents.”

"Onsolis can provide strong pain relief to patients who are opioid tolerant. But for patients who are not opioid tolerant, it can lead to overdose, sudden serious breathing difficulties and death," said Bob Rappaport, MD, director, Division of Anesthesia, Analgesia and Rheumatology Products in the FDA's Center for Drug Evaluation and Research, in an agency news release. "For this reason, Onsolis should be prescribed only under the safeguards provided by the FDA-required [risk evaluation and mitigation strategy] and by health care professionals knowledgeable about Onsolis and the use of potent opioid medications."

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