Index of drugs

Treatment of chronic pain and refractory pain requiring the administration of opioid drugs.

Each transdermal patch releases 12.5 μg, 25 μg, 50 μg, 75 μg or 100 μg fentanyl per hour, respectively. Each of the patches contain 2.1 mg, 4.2 mg, 8.4 mg, 12.6 mg and 16.8 mg of fentanyl, respectively.

A transdermal system that delivers fentanyl, a potent opioid analgesic, to the systemic circulation continuously for 72 h. Fentanyl has a high affinity for opioid receptors. The main therapeutic action is analgesic and sedation. The minimum effective concentration of the drug in the serum (analgesic) in patients previously untreated with opioids is 0.3-1.5 ng / ml. The incidence of adverse reactions increases when serum fentanyl concentrations are above 2 ng / ml. Both the minimum effective concentration and the concentration at which toxicity symptoms occur, increase with increasing tolerance to the drug. The drug exhibits typical opioid activities: inhibition of the respiratory center, miosis, nausea and vomiting, slowing of gastrointestinal motility and reduced secretion and increased muscle tone within the gastrointestinal sphincter, euphoria and inhibition of coughing and effects on the cardiovascular system may occur . The patch is composed of a protective layer (outside) and two functional layers: a polyester outer layer and containing a fentanyl, polyacrylic adhesive layer. After sticking to the skin of the first patch, the concentration of fentanyl in the blood increases gradually, stabilizes between 12 and 24 h and remains relatively constant for 72 h. The obtained concentrations of fentanyl in the serum are proportional to the size of the patch used. At the end of the second 72 h of application, a steady state concentration of fentanyl is reached, which is maintained during subsequent applications of the same patch size. Fentanyl is bound to plasma proteins in approximately 84%. It is rapidly and extensively metabolised mainly with the participation of CYP3A4. The skin does not metabolize transdermally administered fentanyl - 92% of the dose provided by the transdermal patch appears as unchanged fentanyl in the body's circulation. After removal of the patch, the serum fentanyl concentration decreases gradually by approx. 50% within 17 h (13-22 h), if the patch was used for 24 h. After 72 h of application, the average T_0,5 is 20-27 h. During 72 h intravenous fentanyl administration, about 75% of the dose is excreted in the urine, mainly as metabolites, below 10% in unchanged form. Approx. 9% of the dose is excreted in the faeces, mainly in the form of metabolites.

Hypersensitivity to the active substance or to any of the excipients. acute or postoperative pain due to the inability to adjust the dose in a short time and the associated risk of severe and life-threatening respiratory disorders. Severe respiratory depression.

The preparation can not be used to treat acute or post-operative pain due to the inability to adjust the dose in a short time and the associated risk of severe and life-threatening respiratory problems. Patients who have experienced serious adverse events should be monitored for 24 h after removal of the patch, as the concentration of fentanyl in serum decreases gradually by approximately 50% within 17 h (range 13-22 h). When changing from one transdermal patch to another fentanyl patch, continuing analgesia and patient safety requires additional medical supervision and a detailed explanation of the patient's use (as with the first clinical dose). In very rare cases, the use of the preparation as an initiating therapy with opioids (even at the lowest available dose) in patients not previously treated with opioids was associated with the occurrence of clinically significant respiratory and / or death depression. It is recommended that the preparation be used in patients who have shown tolerance to opioids.Patients should be monitored for respiratory disorder. Depression of the respiratory center may persist after removal of the patch. The likelihood of developing respiratory depression increases with a higher dose. Drugs acting on o.u.n. may increase depression of the respiratory center. Co-administration with CYP3A4 inhibitors (eg ritonavir, ketoconazole, Itraconazole, troleandomycin, Clarithromycin, nelfinavir, nefazodone, Verapamil, diltiazem and amiodarone) may result in increased plasma fentanyl concentrations which may increase or prolong both therapeutic effect and undesirable and may also cause severe depression of the respiratory center. In such situations, it is recommended to provide the patient with special care and careful observation of the patient's condition. Co-administration of CYP3A4 inhibitors and transdermal fentanyl is not recommended, unless it is possible to closely monitor the patient's condition for symptoms of respiratory depression, and adjust the medication if necessary. Patients with COPD or other lung diseases may have more severe side effects. In such patients, drugs in this group may inhibit the activity of the respiratory center and increase resistance in the airways. In the case of repeated use of opioids, such as fentanyl, tolerance to the drug and physical and psychological dependence may develop. The risk of developing pathological behaviors associated with the use of the drug was higher in patients without cancer with chronic pain than in patients with chronic pain caused by cancer. Iatrogenic addiction after using opioids is rare. Patients with an earlier addiction to drugs or alcohol have a higher risk of developing addiction or opioid abuse. Patients at increased risk of opioid abuse may still be adequately treated with opioid forms with a modified release of the active substance, although they will require monitoring of signs and symptoms of misuse, abuse or dependence on the substance. Fentanyl can be overdosed, as are other opioid receptor agonists. Abuse or intentional misuse of the preparation may result in overdose and / or death. The product should be used with extreme caution in patients who may be particularly sensitive to the central effects of CO-retention₂, e.g. in patients with increased intracranial pressure, with consciousness disorders or in a coma. Special care should be taken in patients with brain tumors. The preparation should be used with caution in patients with bradyarrhythmias. Opioids may induce hypotension, especially in patients with severe hypovolaemia. Before starting fentanyl in the form of transdermal patches, symptomatic hypotension and / or hypovolaemia should be corrected. Patients with impaired hepatic function or renal impairment should be monitored for signs of fentanyl toxicity and the dose should be reduced as necessary. If the skin temperature rises to 40 ° C, the concentration of fentanyl in the serum may increase by 1/3. Therefore, patients who develop fever should be monitored for the occurrence of opioid-type adverse events and adjusted if necessary for the dose of the preparation. There is a possibility of a temperature-dependent increased release of fentanyl from the transdermal patch, resulting in a possible overdose and death. Applying heat to the Durogesic transdermal patch resulted in a 120% increase in AUC and mean C values_max by 61%. Avoid excessive exposure of the adhesive patch to external heat sources such as heated cushions, hot water bottles (hot water bottles), electrically heated blankets, heated water beds, warming or tanning lamps, long hot baths, sauna, hot spring baths, or intense tanning. Elderly patients should be closely monitored for signs of fentanyl toxicity, and their dose should be reduced if necessary. Do not use the preparation in children who have not used opioids before. The risk of severe or life-threatening hypoventilation exists regardless of the applied dose of the transdermal patch.There were no studies with the preparation in children under 2 years of age; the preparation should only be given to children who are 2 years or more tolerant to opioids. In children, to avoid accidental ingestion by a child, care should be taken when choosing the application site and check that the transdermal patch adheres closely to the skin. Caution should be exercised when using the preparation in patients with myasthenia because non-epileptic myoclonic reactions may occur. Concomitant use of opioids with a mixed, agonist-antagonistic mechanism of action (buprenorphine, nalbuphine, pentazocine) with the preparation is not recommended. Caution should be exercised when using the preparation with drugs affecting the serotonergic neurotransmitter system (SSRI serotonin reuptake inhibitors, SNRI reuptake inhibitors and noradrenaline, drugs that disturb serotonin metabolism, including MAO inhibitors), due to the possibility of serotonin syndrome (if suspected the onset of this fentanyl syndrome should be discontinued).

Do not use during pregnancy unless clearly necessary. There have been reports of the occurrence of opioid-induced withdrawal syndrome in newborns of mothers who have been chronically using the preparation during pregnancy. The preparation is not recommended during the perinatal period, as it should not be used to control acute post-operative pain. In addition, due to the fact that fentanyl crosses the placenta, application in the perinatal period may cause respiratory depression in the newborn. Fentanyl passes into breast milk and may cause sedation and / or respiratory depression in a breast-fed child - do not breast-feed during treatment and for at least 72 hours after removing the patch.

Very common: drowsiness, pain and dizziness, nausea, vomiting, constipation. Common: hypersensitivity, anorexia, insomnia, depression, anxiety, confusion, hallucinations, tremor, paresthesias, palpitation, tachycardia, hypertension, dyspnoea, diarrhea, dry mouth, abdominal pain, epigastric pain, indigestion, excessive sweating, pruritus, rash, erythema, muscle cramps, urinary retention, fatigue, peripheral edema, weakness, malaise, cold feeling. Uncommon: agitation, confusion, euphoric mood, hypoaesthesia, fits (including clonic seizures and grand mal seizures), amnesia, decreased level of consciousness, loss of consciousness, blurred vision, bradycardia, cyanosis, hypotension, respiratory depression, disorder syndrome respiratory tract, intestinal obstruction, eczema, allergic dermatitis, skin diseases, dermatitis, contact dermatitis, muscle twitching, erectile dysfunction, sexual dysfunction, injection site reaction, flu-like symptoms, feeling of body temperature changes, fever, hypersensitivity at the application site , withdrawal syndrome. Rare: pupillary constriction, apnea, hypoventilation, partial bowel obstruction, dermatitis or eczema at the injection site. Frequency unknown: anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, slow breathing rhythm. As with other opioid analgesics, drug tolerance and physical and psychological dependence may develop for repeated use. It is also possible for some patients to have withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety and chills) after replacing the previously used opioids with the preparation or if the treatment has been discontinued abruptly. There are very rare reports that the newborn mothers who chronically used the preparation during pregnancy had a withdrawal syndrome characteristic of them. The profile of side effects in children and adolescents treated with the product is similar to that seen in adults. In the child population, no risk factors other than those associated with the use of opioids have been identified to reduce pain associated with severe disease. Very common side effects observed in clinical studies in children were fever, vomiting and nausea.

The initial dose should be based on the patient's opioid interview, including opioid tolerance (if present) and the current general and medical assessment of the patient, including body weight, age and degree of weakness.In the case of a change from one patch to another fentanyl transdermal patch, it is recommended that for additional analgesia and patient safety, additional medical supervision and a detailed explanation of the patient's use (as with the first clinically effective dose) is recommended.Adults. Patients who have previously received opioids. To replace orally or parenterally used opioids with Durogesic, the procedure should be followedConversion of analgesic potential. Calculate the patient's need for analgesics in the last 24 hours. Replace the dose obtained with the equivalent analgesic oral dose of morphine in accordance with Table 1 from the Summary of Product Characteristics for DUROGESIC. Convert the daily requirement for morphine to the equivalent dose of the preparation.The recommended initial doses of the preparation based on the daily dose of orally administered morphine, in which there is a need to replace or switch from a different opioid administration regimen (conversion ratio of oral morphine to fentanyl in the transdermal patch is about 1: 150): at a daily oral dose of morphine (mg / day) - MF of <135, the dose is 25 μg / h; at MF = 135-224 - 50 μg / h; at MF = 225-314 - 75 μg / h; at MF = 315-404 - 100 μg / h; at MF = 405-494 - 125 μg / h; at MF = 495-584 - 150 μg / h; at MF = 585-674 - 175 μg / h; at MF = 675-764 - 200 μg / h; at MF = 765-854 - 225 μg / h; at MF = 855-944 - 250 μg / h; at MF = 945-1034 - 275 μg / h; at MF = 1035-1124 - 300 μg / h.Recommended initial doses based on the daily dose of orally administered morphine for patients on stable and well-tolerated opioid therapy (conversion ratio of oral morphine to fentanyl in the transdermal patch is about 1: 100): at a daily oral dose of morphine (mg / day) - MF of <44, the dose is 12.5 μg / h; at MF = 45-89 - 25 μg / h; at MF = 90-149 - 50 μg / h; at MF = 150-209 - 75 μg / h; at MF = 210-269 - 100 μg / h; at MF = 270-329 - 125 μg / h; at MF = 330-389 - 150 μg / h; at MF = 390-449 - 175 μg / h; at MF = 450-509 - 200 μg / h; at MF = 510-569 - 225 μg / h; at MF = 570-629 - 250 μg / h; at MF = 630-689 - 275 μg / h; at MF = 690-749 - 300 μg / h. The dosage may be increased or decreased if necessary by 12.5 μg / h or 25 μg / h to achieve the lowest effective dose of the formulation depending on the clinical response and the additional need for analgesics. Initial assessment of analgesic activity should not be carried out within 24 hours of the first patch. When sticking the first patch, gradually withdraw from the previously used analgesia until the analgesic effect is achieved with the preparation.Patients not previously taking opioids. Clinical experience in these patients is limited. If the choice of treatment with the product is considered appropriate in patients previously not taking opioids, it is recommended that in these patients low-dose, immediate-release opioids (eg: morphine, hydromorphone, oxycodone, tramadol and codeine) should be used to achieve an equianal dose corresponding to release of 25 μg / h preparation. Patients can then be switched to a 25 μg / h dose. The dosage may then be increased or decreased if necessary by 12.5 μg / h or 25 μg / h to achieve the lowest effective dose of the formulation depending on the clinical response and the additional need for analgesics.Dose escalation and maintenance treatment. The available dose of 12.5 μg / h corresponds to approximately 45 mg / day of oral morphine. It is particularly useful when you need to adjust small doses of the drug. The patch should be changed every 72 hrs. The gradual increase in dose should be individual for each patient and carried out until a balance between analgesic efficacy and tolerability is achieved. If, after using the first patch, analgesia is insufficient, the dose may be increased after 3 days. Then, subsequent changes in the dose used may take place every 3 days. At an early stage of treatment, some patients may not achieve adequate analgesic efficacy on the 3rd day of this regimen and it may be necessary to change the patches every 48 h instead of every 72 h. Shortening the application time below 72 h may result in increased plasma fentanyl concentrations.If necessary, the dose should be increased by 12.5 μg / h or 25 μg / h, although the patient's severity and the need for additional doses of analgesics should always be taken into account (morphine administered orally at 45 or 90 mg / day corresponds approximately to doses of 12.5 μg / h or 25 μg / h of preparation). If it is necessary to use the product at a dose of> 100 μg / h, more than one patch may be used. Patients may periodically require additional doses of short-acting analgesics to control breakthrough pain. If it is necessary to use the product at a dose of> 300 μg / h, the possibility of using an additional or alternative method of administering opioids should be considered.Children. The preparation should only be given to tolerant opioids to children between the ages of 2 and 16 years who currently receive an equivalent of at least 30 mg oral morphine daily. In order to convert children from opioid therapy administered orally or parenterally to treatment with the preparation, one should familiarize themselves with the principles of dose exchange of valianalgesic drugs and recommended doses based on oral morphine dose: at a daily oral dose of morphine 30-44 mg / day the dose of the preparation is 12.5 μg / h; with a daily dose of 45-134 mg / day oral morphine, the dose is 25 μg / h. Replacement of the preparation in doses greater than 25 μg / h takes place in the same way in children as in adults.Discontinuation of the preparation. If it is necessary to stop using the product, its replacement with other opioids should be gradual and start with a small, gradually increased dose. This is related to the gradual decrease in the concentration of fentanyl in the blood after removal of the patch. A 50% reduction in serum fentanyl may last for 17 hours or more. The general rule is to gradually reduce the dose of opioids to avoid withdrawal symptoms. Some patients may experience withdrawal symptoms after discontinuation of opioids following a change to another treatment or dose reduction.Way of giving. For use on skin only. The patch should be used within the non-irritated and non-irradiated skin, on flat parts of the chest or upper arms. Choose a surface devoid of hair. If hair is present in the patch area, they should be cut (not shaved) before sticking the patch. If the chosen application site requires cleaning, this should be done with clean water. Do not use soap, olives, balms or other substances that could cause skin irritation or affect its permeability. Before applying the patch, the surface of the skin should be completely drained. Do not use patches that are scored, broken or damaged. In young children, the preferred area for sticking is the upper back. The patch should be worn on the skin for 72 hours without interruption. The new patch can be glued only after removing the previous patch and in any case it must be placed elsewhere in the skin. It should take a few days to put the Next patch on the same place. Patients with sticking plaster can bathe, shower and swim. After 3 days (72 h), the patch should be removed by removing it gently from the skin. After removing the patch, immediately apply another patch to a new place on the skin.