What Factors Affect a Sufficient Fentanyl Dose?

Fentanyl transdermal patch is an indication for the treatment of moderate to severe chronic pain and difficult-to-remove pain that can only be treated with opioid analgesics.

Drug Name: Fentanyl transdermal patch
Drug type: Prescription drugs, topical drugs, medical insurance workers' injuries

Special medicine: Narcotic drugs, stimulants
Use classification: Analgesics

Fentanyl transdermal patch ingredients

Main ingredients: Fentanyl Chemical name: N- [1- (2-phenethyl) -4-piperidinyl] -N-phenyl-propionamide Chemical structural formula:

Molecular formula: C ₂₂ H ₂₈ N ₂ O
Molecular weight: 336.46

Fentanyl transdermal patch properties

This product should be a rounded rectangular translucent film patch with the product name and release rate printed on the back.

Fentanyl transdermal patch indications

This product is used for the treatment of moderate to severe chronic pain and those difficult to eliminate pain that can only be treated with opioid analgesics.

Fentanyl transdermal patch specifications

This product has 4 specifications:
12 g / hour, 2.1 mg / paste 25 g / h, 4.2 mg / paste 50 g / h, 8.4 mg / paste 75 g / h, 12.6 mg / paste fentanyl release rate patch size fentanyl content ( g / hour) (cm2) (mg)
12.5 5.25 2.1
25 10.5 4.2
50 21 8.4
75 31.5 12.6

Fentanyl transdermal patch usage dosage

The dose of this product should be determined according to the individual circumstances of the patient, and the dose should be periodically evaluated after administration.
This product should be applied on the flat surface of the trunk or upper arm that is not irritated or exposed. Hair should be cut off before use (do not shave with a razor). Before using this product, you can wash the application area with water. Do not use soap, oil, lotion or other products that may irritate the skin or change the skin's appearance. The skin should be completely dry before using this patch.
This product should be used immediately after opening the sealed bag. When using it, press firmly with the palm of your hand for 30 seconds to ensure that the patch is in full contact with the skin, especially the edges.
This product can last for 72 hours. When replacing the patch, the application site should be changed. After a few days, you can apply it repeatedly on the same area.
Initial dose selection:
The initial dose of this product should be based on the patient's current dose of opioids. This product is recommended for patients with opioid tolerance. At the same time, the current general situation and medical condition of the patient are comprehensively considered, including: body size, age, and degree of fatigue related to tolerance of opioids.
Patients who have not used opioids:
This product has limited clinical experience in such patients. When this product is used in such patients, it is recommended to use a low dose of opioids to adjust the dose until it is equivalent to the product of 25 g / hour. Then converted to this product with a specification of 25g / hour. If necessary, dose adjustment can be carried out, the adjustment range is 12 g / hour or 25 g / hour, and the dose is supplemented according to the need for analgesia to achieve the lowest suitable dose.
Patients with opioid tolerance:
To change from oral or parenteral opiate administration to the use of this product, the following steps should be followed:
Calculate the amount of analgesic used in the first 24 hours.
Use Table 1 to convert the above dosages into equivalent morphine dosages. All intramuscular and oral doses in Table 1 correspond to an equivalent analgesic dose of 10 mg of intramuscular morphine.
Table 2 lists the doses of this product, which are calculated based on the 24-hour oral morphine dose range. Based on the calculated 24-hour morphine dose, use this table to estimate the dose of this product.
If necessary, dose adjustment can be carried out, the adjustment range is 12g / hour or 25g / hour, according to the need for analgesia to make up the dose to achieve the lowest suitable dose.
Table 1 The equivalent analgesic effect of the analgesic effect reference drug name equivalent analgesic dose (mg)
Intramuscular injection * oral morphine 10 30 (if repeated) **
10 60 (if single or intermittent administration)
Hydromorphone 1.5 7.5
Methadone 10 20
Oxycodone 15 30
Levorno 2 4
Oxymorphone 1 10 (rectal)
Diacetylmorphine 5 60
Degree Ding 75-
Codeine 130 200
Buprenorphine 0.4 0.8 (sublingual)
* Based on a single intramuscular dose of the drug and the relative titer of morphine. The recommended oral dose comes from the switch from the parenteral route to the oral route.
** Based on clinical experience in the treatment of patients with chronic pain, the oral / intramuscular strength ratio of morphine.
Table 2 Recommended dosage of this product based on daily oral dosage of morphine *
24 hour oral morphine dose (mg / 24h) The dose of this product (g / h)
<135 25
135-224 50
225-314 75
315-404 100
405-494 125
495-584 150
585-674 175
675-764 200
765-854 225
855-944 250
945-1034 275
1035-1124 300
* In clinical trials, this product is converted on the basis of the daily dose range of oral morphine.
Between the first use of this product and the onset of analgesic effect, the previous analgesics should be gradually stopped.
For patients receiving opioid therapy for the first time and tolerant to opioids, the best analgesic effect cannot be evaluated within 24 hours after using this product. This is because the serum fentanyl concentration gradually increased during the first 24 hours of using the patch. For clinical reasons, patients may need short-acting analgesics. Drugs that meet this purpose are non-opioid analgesics (e.g. acetaminophen, acetylsalicylate, non-steroidal anti-inflammatory drugs) and morphine-like drugs (products with partial agonism or antagonism should be avoided .
Dose adjustment and maintenance treatment:
This patch should be replaced every 72 hours. The dosage should be adjusted according to individual circumstances until sufficient analgesic effect is achieved. If the analgesia is not sufficient after the first application, the dose can be increased after 3 days of administration. Dose adjustments were performed every 3 days thereafter. Similarly, short-acting analgesics may be needed. The dose increase is usually 12 g / hour or 25 g / hour, but other additional pain treatments (oral morphine / 45mg / day or 90mg / day 12 g / hour or 25 g / hour of the product) and the pain state of the patient should be considered at the same time. . When the dosage is more than 75 g / hour, more than one patch of this product can be used. Patients may need short-acting analgesics periodically to relieve sudden pain. When the dosage of this product exceeds 300 g / hour, some patients may need additional or change the method of opioid administration.
Termination of treatment:
After removing the patch of this product, alternative treatment of other opioids should be started gradually, starting from a low dose and slowly increasing the amount. This is because the fentanyl concentration gradually decreases after removing this patch. It takes about 17 hours or more to reduce serum fentanyl concentration by 50%. Generally, any opioid analgesics should be phased out.
Some patients may experience opioid withdrawal symptoms when changing medications or dose adjustments.

Adverse effects of fentanyl transdermal patch

Clinical trial data:
In a multicenter, randomized, double-blind, placebo-controlled clinical trial using this product (FEN-EMA-1), patients with severe pain caused by hip or knee osteoarthritis (40 years old) and waiting for joints Patients underwent a 6-week treatment trial. Safety data were evaluated in 216 patients who received this product at least once. From the initial 25 g / hour to the maximum dose of 100 g / hour, titrate in 25 g / hour to an appropriate dose to control pain. Adverse events that occurred in more than 1% of patients in this product group and reported more frequently than in the placebo group are listed in Table 3.

Dosage: 25 g / hour, 50 g / hour, 75 g / hour or 100 g / hour. In 11 clinical trials (including FEN-EMA-1 trial) of chronic cancer pain or non-cancer pain, this product group (N = 1854) Adverse drug reactions in 1% of patients are listed in Table 4. Safety data includes all patients who have received this product at least once.

In the above clinical trial data, the adverse reactions reported by patients in this product group (N = 1854) <1% are listed in Table 5.

In 3 clinical studies of pediatric patients (<18 years of age, N = 289), adverse events in 1% of patients in this product group are listed in Table 6. Although pediatric clinical trials strictly control patient enrollment and require at least 2 years of age, 2 of these clinical trials have received the first dose at 23 months of age.

Post-marketing information The adverse reactions reported spontaneously according to the following classification principles in the medication experience of all indications of this product after global marketing are listed in Table 7.

The following rates only reflect the spontaneous reporting rate of adverse drug reactions and do not accurately evaluate the rates obtained in clinical trials and epidemiological studies.

Like other opioid analgesics, repeated use of this product may cause drug resistance, physical dependence and psychological dependence.
In some patients who have switched from previous opioid analgesics to this product or treatment has suddenly stopped, symptoms of opioid withdrawal may occur, such as: nausea, vomiting, diarrhea, anxiety and chills. In women who use this product for a long time during pregnancy, reports of neonatal withdrawal syndrome are rare in their newborns.

Fentanyl transdermal patches contraindications

This product is contraindicated in patients known to be sensitive to fentanyl or to the adhesive in this patch.
This product should not be used for the treatment of acute pain and postoperative pain, because in this case the dose of fentanyl cannot be adjusted in the short term and may cause severe or life-threatening hypoventilation.
This product is temporarily contraindicated in patients with non-cancerous chronic pain under 40 years of age (pain treatment for patients with AIDS and paraplegia is not limited by age and pain history).

Fentanyl transdermal patch precautions

Use with caution by athletes.
This product is administered in accordance with narcotic drugs.
Because serum fentanyl concentration decreases by approximately 50% 17 (13-22) hours after discontinuation of the patch, patients with severe adverse reactions should continue observation for 24 hours after discontinuation of the product.
Keep this product out of the reach of children before and after use.
Do not cut or damage the patch in any other way.
Patients who have not used opioids and opioid intolerance < br This product is used for patients who have not used opioids for the first time. Obvious respiratory depression and / or death are rare. For patients who have not used opioids at the beginning of treatment, even when the product is used at the lowest dose, such patients still have the risk of developing severe or life-threatening hypoventilation. This product is recommended for patients with opioid tolerance.
Respiratory depression < br Similar to all powerful opioids, some patients may experience significant respiratory depression when using this product. Care must be taken to observe such effects on patients. Respiratory depression may persist until you stop using this product. The incidence of respiratory depression increases with the dose of this product. Refer to the description of respiratory depression in [Drug Overdose]. Drugs acting on the central nervous system may increase the incidence of respiratory depression (see [Drug Interactions]).
Drug dependence and the possibility of abuse < br Drug resistance, physical dependence and psychological dependence may occur after repeated use of opioids. Iatrogenic addiction caused by the use of this product is extremely rare.
Fentanyl may be abused similarly to other opioids. Abuse or deliberate misuse of this product can lead to overdose and / or death. Patients at high risk for opioid abuse may be appropriately treated with limited-release opioids and monitored for signs of misuse, abuse, or addiction in such patients.
Chronic lung diseases < br br For patients with chronic obstructive or other lung diseases, this product may produce more serious adverse reactions. In these patients, opioids may reduce breathing power and increase airway resistance.
Increased intracranial pressure <br /> This product should be used with caution in patients with intracranial effects of carbon dioxide retention, such as increased intracranial pressure, impaired consciousness, or coma. Patients with brain tumors should also pay attention when using this product.
Heart disease < br Fentanyl may cause bradycardia, so patients with bradyarrhythmias should use caution when using this product.
Liver Diseases < br Because fentanyl is metabolized in the liver to inactive metabolites, liver disease can delay its clearance. Patients with liver cirrhosis do not change their pharmacokinetics even if their serum concentration tends to increase when they are used for a single time. Patients with liver damage should be carefully monitored for symptoms of fentanyl toxicity, which can be reduced if necessary.
Kidney disease Less than 10% of fentanyl is excreted by the kidney in its original form. Unlike morphine, fentanyl has no known active metabolites excreted through the kidneys. The data obtained after intravenous injection of fentanyl in patients with renal failure indicate that dialysis can change the volume of distribution of fentanyl and may affect its serum concentration. Patients with impaired renal function must carefully monitor the toxicity symptoms of fentanyl after using this product, and reduce it if necessary.
Medication for Elderly Patients <br /> Fentanyl intravenous studies have shown that clearance in elderly patients is reduced and half-life is prolonged, and they may be more sensitive to the drug than younger patients. Studies on this product have shown that, although the serum fentanyl concentration of elderly patients has a tendency to increase, there is no significant difference in pharmacokinetics with young patients. The toxic symptoms of fentanyl in elderly patients should be carefully monitored and reduced if necessary.
Other diseases < br should be used with caution: hypothyroidism, adrenal insufficiency, prostate cancer, respiratory depression, acute alcoholism, trauma to the skull and brain, and increased intracranial pressure and unexplained abdominal pain syndrome .
The effects of fever / external heat <br /> The pharmacokinetic model shows that when the skin temperature rises to 40 ° C, the serum fentanyl concentration may increase by about 1/3. Therefore, patients with fever should monitor the side effects of opioids when using this product, and the dose of this product should be adjusted if necessary. All patients should be informed: Avoid directly contacting the application site of the product with heat sources, such as: heating pads, electric blankets, heated water beds, baking lamps or sunlight, strong sunbathing, thermos bottles, long-term hot water baths, steam Baths and thermal vortex hot spring baths.
Interactions with other drugs <br /> Interactions with CYP3A4 inhibitors:
This product and cytochrome P450 3A4 (CYP3A4) inhibitors (for example: ritonavir, ketoconazole, acetamycin, clarithromycin, narfinavir, nafazodone, verapamil, amine (Iodonone) may increase the blood concentration of fentanyl, which may increase or prolong the efficacy and adverse reactions of fentanyl, which may cause severe respiratory depression. In this case, the patient should be given special care and observation. Unless closely monitored, this product is not recommended for use with P450 3A4 (CYP3A4) inhibitors. When using this product, especially when combined with P450 3A4 (CYP3A4) inhibitors, patients should be monitored for signs of respiratory depression and dose adjustments must be made.
Impact on the ability to drive and manipulate machines:
This product may affect the mental and / or physical strength required to perform potentially hazardous tasks such as driving a car or operating a machine.

Fentanyl transdermal patch for pregnant and lactating women

Pregnancy < br Safety data on the possible side effects of fentanyl on fetal development have not been established. There have been reports of neonatal withdrawal syndrome in newborns whose mothers have used this product for a long time during pregnancy. Therefore, this product cannot be used in pregnant women, unless its potential benefits outweigh its harms in the judgment of a doctor.
This product is not recommended for use during childbirth as it should not be used for acute or postoperative pain management (see the [Contraindications] section). In addition, fentanyl passes through the placenta and may cause respiratory depression in newborns.
Breastfeeding < br Fentanyl can be secreted into human milk, so this product is not recommended for breastfeeding women.

Fentanyl transdermal patch for children

The effectiveness and safety of this product for use in children has not been established.

Fentanyl transdermal patch for elderly

Fentanyl intravenous studies have shown that clearance is reduced in older patients, and half-life is prolonged, and they may be more sensitive to the drug than younger patients. Studies on this product have shown that, although the serum fentanyl concentration of elderly patients has a tendency to increase, there is no significant difference in pharmacokinetics with young patients. The toxic symptoms of fentanyl in elderly patients should be carefully monitored and reduced if necessary.

Fentanyl transdermal patch drug interactions

Concurrent application of other central nervous system inhibitors, including opioids, sedatives, hypnotics, general anesthetics, phenothiazines, tranquilizers, muscle relaxants, sedative antihistamines and alcoholic beverages, can produce additional Inhibition. Hypoventilation, hypotension, and deep sedation or coma may occur. Therefore, patients should be given special care and observation when using the above drugs in combination.
Fentanyl is a high clearance drug that is rapidly and extensively metabolized primarily by CYP3A4. Combining fentanyl transdermal patches with CYP3A4 inhibitors will increase fentanyl plasma concentrations, thereby enhancing or prolonging the therapeutic effects and adverse reactions of fentanyl, and may also cause severe respiratory depression. In this case, the patient should be given special care and observation. Fentanyl transdermal patches can only be used in combination with CYP3A4 inhibitors under close monitoring.
Monoamine oxidase inhibitor (MOAI)
Some patients receiving monoamine oxidase inhibitors experience severe adverse reactions when given an intravenous anesthetic. Some reports indicate that there is no problem with concurrent use of monoamine oxidase inhibitors and intravenous fentanyl. However, due to the limited number of patients, it is uncertain. Therefore, all patients treated with monoamine oxidase inhibitors are considered a high-risk population for using anesthetics, including fentanyl. This product is not recommended for patients requiring monoamine oxidase inhibitors. Serious drug interactions with monoamine oxidase inhibitors have been reported, including aggravated opioid effects and serotonergic effects. Therefore, this product should not be used within 14 days after discontinuing use of a monoamine oxidase inhibitor.

Fentanyl transdermal patch overdose

Symptoms < br When fentanyl is overdose, it appears as an extension of its pharmacological effect, and the most serious effect is respiratory depression.
Treatment < br Immediate measures should be taken to treat respiratory depression, including the removal of dorigid patches and physical or verbal stimulation of the patient. Subsequently, specific opioid antagonists such as naloxone can be used. Respiratory depression caused by overdose may last longer than opioid antagonists. The interval between intravenous injections of antagonists should be carefully determined to avoid the possibility of recurrence of opioid overdose after removal of the patch. Repeated injections or intravenous drips of naloxone may be required. Antagonism may cause acute episodes of pain and release of catecholamines.
If clinical conditions permit, an artificial airway should be established and maintained. Oropharyngeal airway or tracheal intubation can be used with oxygen and assisted or controlled breathing. Maintain body temperature and ensure fluid intake. In the event of severe or persistent hypotension, consideration should be given to hypovolemia and appropriate infusion therapy.

Fentanyl transdermal patch pharmacology and toxicology

Pharmacological effects < br Drug classification: Opioids: Phenylpiperidine derivatives. ATC-No .: N02A B03.
Analgesic fentanyl is an opioid or central analgesic and is mainly related to the interaction of -opioid receptors. The main therapeutic activity is pain and sedation. For patients using opioids for the first time, the minimum analgesic serum concentration of fentanyl ranges from 0.3 to 1.5 ng / ml: the incidence of side effects increases at serum concentrations above 2 ng / ml. When the tolerance increased, the minimum effective plasma concentration and the toxic plasma concentration increased, and there were individual differences in tolerance.
Respiratory depression Respiratory depression includes decreased breathing frequency and decreased carbon dioxide sensitivity. Despite individual differences, clinically significant reductions in minute ventilation are rarely seen when plasma concentrations are below 3 ng / ml.
This effect is not drug-resistant. Therefore, this phenomenon is considered a diagnostic sign of fentanyl saturation.
Nausea and vomiting stimulate the chemoreceptor trigger zone and may cause nausea and vomiting.
Other central effects In addition to analgesia, fentanyl's main effect is sedation. Hypnosis can be determined by changes in EEG. Fentanyl may produce euphoria and cough suppression.
Gastrointestinal effects can be summarized to include slow gastrointestinal sphincter motility, decreased secretion, and increased muscle tone (even spasms).
Cardiovascular effects The low-dose (cholinergic) excitatory effects of the vagus nerve may cause slight bradycardia and a slight decrease in systemic vascular resistance, but without a significant decrease in blood pressure. A direct effect on myocardial function was observed. Fentanyl does not cause histamine release (as opposed to morphine and pethidine).
Toxicology studies <br In vitro studies of mammalian cell culture analysis have found that fentanyl exhibits the same mutagenic effects as other opioid analgesics only at cytotoxic concentrations and conditions associated with metabolic activation. In rodent in vivo studies and bacterial analysis, there is no evidence that fentanyl is mutagenic. In a two-year study of carcinogenicity in rats, the subcutaneous injection doses of male and female rats reached a maximum of 33 g / kg / day and 100 g / kg / day, respectively. The patch had a daily exposure dose of 0.16 and 0.39 times), and no correlation was observed between fentanyl and increased tumor incidence.
Several tests on female rats have shown that fentanyl causes reduced fertility and embryonic death. These findings are related to the toxicity of the drug to the mother, but the drug has no direct effect on developing embryos. No evidence of teratogenicity.

Fentanyl transdermal patch pharmacokinetics

absorb:
Fentanyl is continuously absorbed through the skin within 72 hours of application. The release rate of fentanyl remained relatively constant. Drug release is driven by the membrane release copolymer and drug diffusion in the skin. After starting to use this product, the concentration of serum fentanyl gradually increased, usually reached a steady state within 12-24 hours, and then remained relatively stable until 72 hours. The serum concentration of fentanyl is directly proportional to the size (dose) of this patch. By the end of the second dose to 72 hours, steady-state serum concentrations were reached. When the same dose of the patch was continued, the serum concentration remained stable.
A pharmacokinetic model shows that if a new patch is applied after 24 hours (72 hours recommended), the blood concentration of fentanyl will increase by 14% (range 0-26%).
distributed:
Fentanyl has a plasma protein binding rate of about 84%.
metabolism:
Fentanyl is a high clearance drug that is rapidly and extensively metabolized primarily by CYP3A4 in the liver. The main metabolite is inactive norfentanyl. Analysis of human stratum corneum cells and clinical trials found that the fentanyl prototype drug released from the drug delivery system into the systemic circulation accounted for 92% of the administered dose, proving that fentanyl was not metabolized when it penetrated the skin.
excretion:
After removing the patch after 24 hours of administration, the serum fentanyl concentration gradually decreased, and dropped to about 50% after about 17 (range: 13-22) hours. After 72 hours of administration, the average half-life was 20-27 hours. Continued absorption of fentanyl on the skin after discontinuation of the drug allows the drug to be eliminated from the bloodstream more slowly than intravenous infusion, with an apparent half-life of approximately 7 (range 3-12) hours.
Intravenous infusion of fentanyl for 72 hours, about 75% of fentanyl is excreted through the urine, mainly metabolites, and less than 10% of the original drug. About 9% of the dose is excreted from the feces in the form of metabolites.
Special population:
Seniors:
Data from fentanyl intravenous infusion studies suggest that clearance may be reduced and half-lives prolonged in older patients, who may be more sensitive to drugs than younger patients. In a study of healthy elderly and young subjects using this product, the pharmacokinetics of the two were not significantly different, but the peak plasma concentration of the elderly subjects was lower and the average half-life t _{1/2 was} prolonged by about For 34 hours. Elderly patients should closely observe the symptoms of fentanyl toxicity and reduce the dose if necessary (refer to the section [Medicine for the elderly]).
child:
This product has not been studied in children under 2 years of age. Studies in older children have found that after weight adjustment, clearance in pediatric patients is about 20% higher than in adults. These findings have been taken into account when administering doses to pediatric patients. This product should only be used by children over 2 years of age who are opioid tolerated.
Patients with liver dysfunction:
In a study of patients with liver cirrhosis, a pharmacokinetic study of this product at a single dose of 50 g / h was performed. In these patients, although the peak time (tmax) and half-life (t _1/2 ) did not change, the average maximum plasma concentrations Cmax and AUC increased by about 35% and 73%, respectively. Patients with liver dysfunction should closely observe the toxicity symptoms of fentanyl and reduce the dose if necessary (refer to the [Precautions] section).
Patients with renal dysfunction:
Data from a study of intravenous fentanyl in patients undergoing kidney transplantation show that drug clearance may be reduced in these patients. Patients with renal dysfunction should closely observe the toxicity symptoms of fentanyl and reduce the dose if necessary (refer to the [Precautions] section).

Fentanyl transdermal patch storage

Store at 15 25 in a sealed container.

Fentanyl transdermal patch packaging

Aluminum plastic composite bag, 5 stickers / box.

Fentanyl transdermal patch expiration date

24 months

Fentanyl transdermal patch implementation standards

JM20100008 ^[1]