Active ingredients: Fentanyl
Effentora 100 micrograms buccal tablets
Effentora 200 micrograms buccal tablets
Effentora 400 micrograms buccal tablets
Effentora 600 micrograms buccal tablets
Effentora 800 micrograms buccal tablets
Why is Effentora used? What is it for?
The active ingredient in Effentora is fentanyl citrate. Effentora is a pain reliever known as an opioid, which is used to treat breakthrough pain in adult cancer patients who are already being treated with another opioid for chronic persistent (24 hours a day) pain due to cancer.
Breakthrough pain is sudden, additional pain that occurs even after you have taken your usual opioid painkillers.
Contraindications When Effentora should not be used
Do not use Effentora:
- If you have not used a prescription opioid medicine (e.g. codeine, fentanyl, hydromorphone, morphine, oxycodone, pethidine) daily and regularly for at least one week to control persistent pain. If you do not use these medicines you should not use Effentora as this could increase the risk of your breathing becoming dangerously slow and / or shallow, or even becoming blocked.
- If you are allergic to fentanyl or any of the other ingredients of this medicine (listed in section 6).
- If you have severe breathing problems or severe obstructive pulmonary disease.
- If you suffer from short-term pain other than breakthrough pain.
Precautions for use What you need to know before taking Effentora
Talk to your doctor or pharmacist before using Effentora.
During treatment with Effentora, continue to use the opioid pain reliever you are taking for your persistent (24 hour) cancer pain.
Do not use any other fentanyl-based therapies previously prescribed for your breakthrough pain while you are taking Effentora. If you still have any of these therapies at home, contact your pharmacist to find out how to dispose of them.
Before treatment with Effentora, tell your doctor or pharmacist if you have any of the following conditions:
- A definitive dosage has not yet been found for the other opioid she takes for her persistent (lasting all day) pain from cancer.
- If you have any condition that affects your respiratory function (such as asthma, wheezing, breathlessness).
- If you have a head injury.
- If you have an exceptionally low heart rate or other heart problems.
- If you have any liver or kidney problems, as these organs affect the way the medicine is broken down.
- If you have a low amount of fluid in your circulation or low blood pressure.
- If you have heart problems, especially a slow heartbeat.
- If you are taking antidepressants or antipsychotics, please refer to the section Other medicines and Effentora.
What to do if someone accidentally takes Effentora
If you think someone has accidentally taken Effentora, call a doctor immediately.
Try to keep the person awake until medical help arrives.
If you take Effentora accidentally, you may have the same side effects as described in section 3 "If you use more Effentora than you should".
Children and adolescents
Do not give this medicine to children between the ages of 0 and 18.
Interactions Which drugs or foods may change the effect of Effentora
Before starting to use Effentora tell your doctor or pharmacist if you are taking, have recently taken or might take any of the following medicines:
- Any medicine that could normally cause drowsiness (i.e. has a sedative effect) such as sleeping pills, anxiolytics, antihistamines or tranquilizers.
- Any medicine that could affect the way your body processes Effentora, such as ritonavir, nelfinavir, amprenavir, and fosamprenavir (medicines to help control HIV infection) or other so-called CYP3A4 inhibitors such as ketoconazole, itraconazole, or fluconazole (medicines used to treat fungal infections), troleandomycin, clarithromycin, or erythromycin (medicines used to treat bacterial infections), aprepitant (medicine used in severe nausea) and diltiazem and verapamil (medicines used to treat hypertension or heart failure)
- Medicines called monoamine oxidase (MAO) inhibitors (used in severe depression) taken in the last two weeks.
- Some types of pain relievers, called partial agonists / antagonists, eg. buprenorphine, nalbuphine and pentazocine (medicines to treat pain). You may experience withdrawal symptoms (nausea, vomiting, diarrhea, anxiety, chills, tremors and sweating) while using these medicines.
- The risk of side effects increases if you are taking medicines such as certain antidepressants or antipsychotics. Effentora may interact with these medicines and mental status changes (e.g. agitation, hallucinations, coma) and other effects, such as a body temperature above 38 ° C, rapid heart rate, unstable blood pressure and excessive reflexes, stiffness, may occur. muscle, lack of coordination and / or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea). Your doctor will tell you if Effentora is suitable for you.
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Effentora with food, drink and alcohol
- Effentora can be used before or after, but not during meals. Before using Effentora, you can drink some water to moisten your mouth, but you should not eat or drink while you are taking it.
- You should not drink grapefruit juice while using Effentora, as this can affect the way your body processes the medicine.
- Do not drink alcohol while using Effentora. This may increase the risk of dangerous side effects.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Effentora should not be used during pregnancy unless you have discussed this with your doctor. Effentora should not be used during delivery as fentanyl can cause respiratory depression in the newborn.
Fentanyl can pass into breast milk and may cause side effects in the breastfed infant. Do not use Effentora if you are breast-feeding. You should not start breastfeeding until at least 5 days after your last dose of Effentora.
Driving and using machines
You should discuss with your doctor whether it is safe for you to drive or use machines after taking Effentora. Do not drive or use machines if: you feel drowsy or dizzy; have blurred or double vision; or has difficulty concentrating. It is important that you know how you react to Effentora before driving or using machines.
Effentora contains sodium
Each Effentora 100 microgram tablet contains 10 mg of sodium. Each tablet of Effentora 200 micrograms, Effentora 400 micrograms, Effentora 600 micrograms and Effentora 800 micrograms contains 20 mg of sodium. This should be borne in mind if you are on a low-sodium diet, so you should ask your doctor for advice.
Dose, Method and Time of Administration How to use Effentora: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Dosage and frequency of administration
When you start using Effentora for the first time, your doctor will work with you to find the optimal dose to relieve your breakthrough pain. It is very important that you use Effentora exactly as your doctor has told you. The starting dose is 100 micrograms. When determining the right dosage for you, your doctor may instruct you to take more than one tablet per episode. If your breakthrough pain episode is not relieved after 30 minutes, use only 1 more Effentora tablet at this point during the titration phase.
Once your doctor has determined the right dose, generally use 1 tablet per episode of severe pain. In subsequent courses of therapy, your need for analgesic therapy may vary. Higher dosages may be necessary. If your pain is not relieved after 30 minutes, then take another Effentora tablet alone during the dose adjustment phase.
Contact your doctor if your right dose of Effentora does not relieve your breakthrough pain. Your doctor will decide if your dose needs to be changed.
Before treating another episode of severe pain with Effentora, wait at least 4 hours.
If you use Effentora more than four times a day, you should tell your doctor immediately, as he may change the medicine for your persistent pain. Once your persistent pain has been checked, your doctor may need to change your Effentora dosage. For more effective pain relief, tell your doctor about your pain and how Effentora works for you, so the dosage can be changed if needed.
Do not change the dose of Effentora or any other pain reliever on your own. Any change in dosage should be prescribed and monitored by the physician.
If you are not sure what the right dosage is or if you have any other questions about how to take this medicine, please contact your doctor.
Method of administration
Effentora buccal tablets are for oromucosal use (through the oral mucosa). When you put a tablet in your mouth, it dissolves and the medicine is absorbed into your blood system through the lining of your mouth. Taking the medicine in this way causes it to be absorbed quickly to relieve your breakthrough pain.
Taking the medicine
- Only open the blister when you are ready to use the tablet. The tablet should be used immediately after taking it out of the blister.
- Separate one of the units from the entire blister by tearing along the perforated line.
- Fold the unit along the indicated line.
- To remove the tablet, remove the foil on the back of the blister. DO NOT try to push the tablet through the foil, as this could damage it.
- Remove the tablet from the unit and immediately place the entire tablet next to a molar tooth, between the gum and cheek (as shown in the picture). Sometimes, your doctor may tell you to place the tablet under your tongue instead.
- Do not try to crush or break the tablet.
- Do not bite, suck, chew or swallow the tablet, as this will cause less pain relief than when the tablet is taken as directed.
- The tablet should be held between the cheek and the gum until it is completely dissolved, which will take 14 to 25 minutes.
- You may feel a slight fizzing sensation between your cheek and gum as the tablet dissolves.
- In case of irritation, the position of the tablet on the gum can change.
- After 30 minutes, if there are still remnants of the tablet left in the mouth, they can be swallowed with a glass of water.
If you forget to use Effentora
If the pain exacerbation episode is still ongoing, you can take Effentora as prescribed by your doctor. If the pain has already stopped, do not take Effentora until your next painful episode.
If you stop taking Effentora
You should stop using Effentora when you no longer experience breakthrough pain.
You should continue to take your usual analgesic opioid to treat persistent cancer pain as directed by your doctor. When you stop taking Effentora you may experience withdrawal symptoms similar to the possible side effects of Effentora. If you experience withdrawal symptoms or are concerned about pain relief, talk to your doctor. He will consider whether medicines are needed to reduce or eliminate withdrawal symptoms.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Effentora
If you use more Effentora than you should
- The most common side effects are sleepiness, nausea or dizziness. If, before the tablet has dissolved completely, you begin to feel particularly drowsy or drowsy, rinse your mouth with water and completely expel the remaining tablet into a washbasin or toilet.
- A serious side effect of Effentora is slow and / or shallow breathing. This can happen if the dose of Effentora you are taking is too high or if you take too much of the medicine. In these cases it is necessary to consult a doctor immediately.
Side Effects What are the side effects of Effentora
Like all medicines, this medicine can cause side effects, although not everybody gets them. If you notice any of these side effects, please contact your doctor.
The most serious side effects consist of shallow breathing, low blood pressure and shock. Like other fentanyl products, Effentora can cause very serious breathing problems that can lead to death.
If you experience significant sleepiness and slow and / or shallow breathing, you or caregivers should contact your doctor immediately and seek urgent help.
Very common side effects (may affect more than 1 in 10 people):
- sense of heeling, headache
- nausea, vomiting
- at the site of application of the tablet: pain, ulcers, irritation, bleeding, numbness, loss of sensation, redness, swelling or blistering.
Common side effects (may affect up to 1 in 10 people):
- anxiety or confusion, depression, insomnia
- altered sense of taste, weight loss
- drowsiness, sedation, excessive tiredness, weakness, migraine, numbness, swelling in the arms or legs, drug withdrawal syndrome (may occur with the following side effects: nausea, vomiting, diarrhea, anxiety, chills, tremor and sweating), falls, chills
- constipation, stomatitis, dry mouth, diarrhea, heartburn, loss of appetite, stomach pain, stomach discomfort, indigestion, toothache, thrush
- itching, excessive sweating, rash
- shortness of breath, sore throat
- reduction in white blood cells and red blood cells, increase or decrease in blood pressure, rarely increased heart rate
- muscle aches, back pain
- fatigue
Uncommon side effects (may affect up to 1 in 100 people):
- irritation or sore throat,
- decrease in platelets
- feeling euphoric, nervous, abnormal in general, agitation or slowing down; visual or auditory hallucinations, decreased level of consciousness, change in mental status, dependence (being addicted to medicine, addiction), disorientation, lack of concentration, loss of balance, dizziness, difficulty in speaking, tinnitus, ear discomfort
- disturbance or blurring of vision, redness of the eyes
- unusually slow heart rate, feeling very hot (hot flashes)
- severe wheezing, trouble breathing during sleep
- one or more of the following mouth disorders: ulcers, loss of sensation, discomfort, discolouration, soft tissue disorders, tongue disorders, blistering pain or tongue ulcers, pain in the gums, dry lips or chapped, tooth disorders
- inflammation of the esophagus, paralysis of the intestine, gallbladder disorders
- cold sweats, swelling of the face, generalized itching, hair loss, muscle twitching, muscle weakness, feeling sick, chest discomfort, thirst, feeling cold or hot, difficulty urinating
- sickness
- redness
Rare side effects (may affect up to 1 in 1000 people):
- thought disorders, movement disorders
- blisters in the mouth, dry lips, collection of pus under the oral mucosa
- lack of testosterone, abnormal sensation in the eye, seeing flashes of light, brittle nails
- allergic reactions such as rash, redness, swelling of the lips and face, hives
Frequency not known:
- loss of consciousness, stopping of breathing, convulsion (fits)
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
The pain reliever ingredient contained in Effentora is very strong and could be life threatening if taken accidentally by a child. This medicine must be kept out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the blister label and carton.
- Store in the original package to protect the medicine from moisture.
- Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Effentora contains
The active ingredient is fentanyl. Each tablet contains:
- 100 micrograms of fentanyl (as citrate)
- 200 micrograms of fentanyl (as citrate)
- 400 micrograms of fentanyl (as citrate)
- 600 micrograms of fentanyl (as citrate)
- 800 micrograms of fentanyl (as citrate)
The other ingredients are mannitol, sodium starch glycolate type A, sodium bicarbonate, anhydrous sodium carbonate, anhydrous citric acid, magnesium stearate.
What Effentora looks like and contents of the pack
The buccal tablets are round, with flat surfaces and a bevelled edge, embossed with the letter "C" on one side and the number "1" for Effentora 100 micrograms, "2" for Effentora 200 micrograms, "4" for Effentora on the other. 400 micrograms, "6" for Effentora 600 micrograms and "8" for Effentora 800 micrograms.
Each blister contains 4 buccal tablets, in a carton of 4 or 28 buccal tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
EFFENTORA 100 MCG GOLD SOLUBLE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each buccal tablet contains 100 mcg of fentanyl (as citrate).
Excipient (s) with known effect: each tablet contains 8 mg of sodium.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Buccal tablet.
White, round, flat-sided tablet with a bevelled edge, debossed with the letter "C" on one side and "1" on the other side.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Effentora is indicated for the treatment of transient exacerbations of pain (Breakthrough Pain) in cancer adults already on opioid maintenance therapy for chronic cancer pain.
"Transient exacerbation of pain" or "breakthrough pain" means a "temporary exacerbation of pain in addition to persistent underlying pain controlled with another medicine.
Patients already on opioid maintenance therapy are those patients who are taking at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oxycodone per day, at least 8 mg of hydromorphone per day, or a dose of another opioid of equal analgesic efficacy for at least one week.
04.2 Posology and method of administration -
Treatment should be initiated and maintained under the guidance of a physician experienced in the treatment of opioid therapy in cancer patients. Physicians should be aware of the abuse potential of fentanyl. Patients should be instructed not to use two different formulations of fentanyl at the same time for the treatment of DEI, and to discard any fentanyl preparations prescribed for the DEI when switching to Effentora. The number of tablet strengths available to patients at any one time should be minimized to avoid confusion and potential overdose.
Dosage
Dosage titration
The dosage of Effentora should be adjusted on a case-by-case basis until an "optimal" dose is obtained that provides "adequate analgesia and at the same time minimizes adverse reactions. In clinical studies, it was not possible to predict the optimal dose of Effentora for the BID. based on the daily maintenance opioid.
Patients should be monitored closely until the optimal dose is found.
Dosage titration in patients who do not switch to Effentora after using other fentanyl medicines
The starting dose of Effentora should be 100 mcg, with further increments as needed based on available strengths (100, 200, 400, 600 and 800 mcg tablets).
Dosage titration in patients switching to Effentora after using other fentanyl medicines
Due to their different absorption profiles, switching from one drug to another should not be done at a ratio of 1: 1. If switching from another oral fentanyl citrate preparation, independent titration of the dosage of Fentanyl Citrate is required. Effentora, as the bioavailability of the two products is significantly different. However, a starting dose greater than 100 mcg may be considered in these patients.
Method for titration of the dosage
In the course of the search for the optimal dose, if adequate analgesia is not obtained within 30 minutes from the start of the administration of a single tablet, a second tablet of Effentora of the same strength should be used.
If treatment of a BTP episode requires more than one tablet, an increase in dose using the next higher concentration of the drug should be considered for the next BTP episode.
Different combinations of tablets can be used when searching for the optimal dosage: up to four 100 mcg tablets or up to four 200 mcg tablets can be used to treat a single BTP episode during dosage titration, according to the following scheme:
• If the first 100 mcg tablet is not effective, the patient can be instructed to treat the next BTP episode with two 100 mcg tablets. It is recommended to place one tablet against each cheek. If this dose is determined to be the optimal one, treatment of subsequent episodes of BPH can be continued with a single 200 mcg tablet of Effentora.
• If a single 200mcg tablet of Effentora (or two 100mcg tablets) is not effective, the patient can be instructed to treat the next BTP episode with two 200mcg tablets (or four 100mcg tablets). It is recommended to place two tablets against each cheek. If this dose is determined to be the optimal one, treatment of subsequent episodes of BPH can be continued with a single 400 mcg tablet of Effentora.
For titration of the dosage of the 600 and 800 mcg tablets, the 200 mcg tablets should be used.
Doses above 800 mcg have not been evaluated in clinical studies.
Do not use more than two tablets to treat any single BTP episode, except for the optimal dose phase, for which up to four tablets can be used as described above.
Patients should wait at least 4 hours before treating another BTP episode with Effentora during titration.
Maintenance therapy
Once the optimal dose has been established, patients should continue with this strength using a single tablet of that strength. Episodes of transient pain exacerbation may vary in intensity over time and the dosage of Effentora needed may therefore increase due to progression of the underlying malignancy. In these cases, a second Effentora tablet of the same strength can be used. If a second Effentora tablet is needed several times in a row, the usual maintenance dose should be readjusted (as described below).
Patients should wait at least 4 hours before treating another BTP episode with Effentora during maintenance therapy.
Dose adjustment
The maintenance dose of Effentora should be increased if the patient requires more than one dose per BTP episode, for several consecutive episodes. For dose readjustment, the same principles apply as for titration (as described above).
The dose of the background opioid drug may need to be revised if the patient has more than four BTP episodes per day (24 hours).
Discontinuation of therapy
Effentora therapy should be discontinued immediately if no longer needed.
Hepatic or renal impairment:
Effentora should be administered with caution to patients with moderate or severe hepatic or renal impairment (see section 4.4).
Patients with xerostomia:
Patients presenting with xerostomia are advised to drink water to moisten the oral cavity prior to administration of Effentora. If this does not result in appropriate effervescence, a different therapy may be indicated.
Use in elderly patients (over 65 years of age)
In clinical trials it was found that patients over 65 years of age tended to require a lower optimal dose than needed for younger subjects. Particular caution is recommended in finding the optimal Effentora dosage in elderly patients.
Pediatric population:
The safety and efficacy of Effentora in children aged 0-18 years have not been established. No data are available.
Method of administration
The Effentora tablet, once exposed to moisture, uses an effervescent reaction to release the active substance. Patients should therefore be instructed not to open the blister until the tablet is placed in the mouth.
Opening the blister
Patients should be instructed NOT to attempt to push the tablet through the blister as this could damage the buccal tablet. The correct way to take the tablet out of the blister is as follows:
Separate a blister unit from the blister pack by peeling it along the perforated lines. The single blister should then be folded at the line printed on the back film. Finally, to remove the tablet, the film must be removed. Patients should be warned to do not try to crush or break the tablet.
Once removed from the blister pack, the tablet must not be stored, as its integrity cannot be guaranteed, as well as the possibility of accidental exposure to it.
Administration of the tablet
Patients should take the tablet out of the blister unit and immediately place the entire Effentora tablet in the buccal cavity (close to a molar between the cheek and the gum).
Effentora tablet should not be sucked, chewed or swallowed, as this would result in lower plasma concentrations than when the tablet is taken as directed.
Effentora should be placed and held in the mouth for a sufficient period to allow the tablet to dissolve, which usually takes 14-25 minutes.
Alternatively, the tablet can be placed under the tongue (see section 5.2).
After 30 minutes, in the presence of residues of the Effentora tablet, these can be swallowed with a glass of water.
The time it takes for the tablet to completely disintegrate after oromucosal administration does not appear to affect the initial systemic exposure to fentanyl.
Patients should not take food and drinks while holding the tablet in their mouth.
In case of irritation of the oral mucosa, it is recommended to change the position of the tablet in the mouth.
04.3 Contraindications -
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients without opioid maintenance therapy (see section 4.1), as there is an increased risk of respiratory depression.
Severe respiratory depression or severe obstructive pulmonary disease.
Treatment of acute pain other than DEI (e.g., postoperative pain, headache, migraine).
04.4 Special warnings and appropriate precautions for use -
Patients and caregivers should be taught that Effentora contains a quantity of the active ingredient which can be fatal, especially to a child. Therefore, all tablets should be kept out of the sight and reach of children.
To minimize the risks of opioid-related undesirable effects and to determine the optimal dose, it is imperative that patients are closely monitored by healthcare professionals during the dose titration phase.
It is important that long-acting opioid therapy to treat the patient's persistent pain has been stabilized before initiating Effentora therapy and that the patient continues long-acting opioid therapy while taking Effentora.
Respiratory depression
As with all opioids, there is a clinically significant risk of respiratory depression associated with the use of fentanyl. maintenance therapy with opioids) and / or inappropriate administration resulted in fatal outcomes.
Effentora should only be used for the conditions specified in section 4.1.
Chronic obstructive pulmonary disease
Particular care should be taken when titrating Effentora dosage in patients with non-severe chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression, as even normally therapeutic doses of Effentora may further decrease respiratory capacity to the point to cause a "respiratory failure.
Increased intracranial pressure, alterations in the state of consciousness
Effentora should be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention, such as those showing signs of increased intracranial pressure or deterioration of consciousness. Opioids can mask the clinical course of a patient with a head injury, and should therefore only be used if there is a clinical need.
Heart disease
Intravenously administered fentanyl can cause bradycardia. In clinical studies with Effentora, there was no clear evidence of bradycardia. However, Effentora should be used with caution in patients who already have bradyarrhythmias.
Hepatic or renal impairment
Furthermore, Effentora should be administered with caution to patients with hepatic or renal insufficiency. The influence of hepatic and renal insufficiency on the pharmacokinetics of the drug has not been evaluated, but, after intravenous administration, the clearance of fentanyl was modified due to alterations in metabolic clearance and plasma proteins. After administration of Effentora, both renal and hepatic insufficiency may increase the bioavailability of ingested fentanyl and decrease its systemic clearance, which could result in an increase and prolongation of opioid effects. Consequently, special caution should be observed during the dose titration phase in patients with moderate or severe hepatic or renal insufficiency.
Particular attention should be paid to patients with hypovolemia and hypotension.
Tolerance, dependence
After repeated administration of opioids such as fentanyl, physical and / or psychological dependence may develop. However, iatrogenic dependence after therapeutic use of opioids is rare.
Controlled sodium diet
This medicine contains 8 mg of sodium per tablet.
This should be borne in mind in patients on a low sodium diet.
04.5 Interactions with other medicinal products and other forms of interaction -
Fentanyl is metabolised primarily via the cytochrome P450 3A4 (CYP3A4) isoenzyme system, and therefore interactions may occur when Effentora is administered concomitantly with agents affecting CYP3A4 activity. Co-administration of agents that induce CYP3A4 activity may reduce the efficacy of Effentora. The concomitant use of Effentora and potent CYP3A4 inhibitors (eg, ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin and nelfinavir) or moderate (eg. Amprenavir, aprepitant, diltiazem, erythromycin, flamprenazole, fos- ) may lead to increased plasma concentrations of fentanyl, leading to possible serious adverse drug reactions, including fatal respiratory depression. Patients treated with Effentora together with both strong and moderate CYP3A4 inhibitors should be monitored closely for an extended period. "Dosage increase should be done with caution.
Co-administration of other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, musculoskeletal relaxants, sedative antihistamines and alcohol may result in additional depressant effects.
Effentora is not recommended for use in patients who have taken monoamine oxidase (MAO) inhibitors within the previous 14 days, as strong and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
The concomitant use of partial opioid agonists / antagonists (e.g., buprenorphine, nalbuphine, pentazocine) is not recommended. They have high affinity for opioid receptors and relatively low intrinsic activity, and therefore partially antagonize the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid-dependent patients.
04.6 Pregnancy and breastfeeding -
Pregnancy
There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Effentora should not be used during pregnancy. pregnancy, unless absolutely necessary.
With long-term use, fentanyl can cause withdrawal syndrome in the newborn.
It is recommended not to use fentanyl during labor and delivery (including caesarean section), as fentanyl crosses the placenta and can cause respiratory depression in the fetus. In case of administration, an antidote for the newborn should be readily available.
Feeding time
Fentanyl passes into breast milk and can cause sedation and respiratory depression in the breastfed infant. Fentanyl should not be used by breastfeeding women, and breastfeeding should not be resumed until at least 48 hours after the last administration of fentanyl.
Fertility
There are no data on fertility in humans. Male fertility was negatively affected in animal studies (see section 5.3).
04.7 Effects on ability to drive and use machines -
No studies on the ability to drive and use machines have been performed. However, opioid analgesics impair the mental and / or physical ability required to perform potentially hazardous activities (eg driving or operating machinery). Patients should be advised not to drive or use machines if drowsiness, dizziness or visual disturbances are present during therapy with Effentora, and not to drive and operate machinery until they have tested their reactions to the medicinal product.
04.8 Undesirable effects -
Summary of the safety profile
Typical adverse reactions of opioid drugs can be expected with Effentora. Often these effects disappear or lessen in intensity with continued use of the drug, once the optimal dose for the patient has been found. However, the most serious adverse reactions are respiratory depression (which can result in apnea or respiratory arrest), circulatory depression , hypotension and shock, and therefore all patients should be closely monitored for these effects.
Clinical trials of Effentora were designed to evaluate its safety and efficacy in the treatment of BPH, and all patients were taking other opioid drugs such as prolonged-release morphine or transdermal fentanyl at the same time to control chronic pain. therefore it is possible to definitively separate the effects due exclusively to Effentora.
Table of adverse reactions
The following adverse reactions have been reported with Effentora during clinical trials and post-marketing experience. Adverse reactions are listed by system organ class and frequency according to MedDRA terminology and convention. Frequencies are defined as: very common (≥1 / 10), common (≥1 / 100 and
Description of selected adverse reactions
Physical and / or psychological tolerance and dependence may develop with repeated administration of opioids such as fentanyl.
Drug withdrawal symptoms such as nausea, vomiting, diarrhea, anxiety and tremors were observed in studies with Effentora.
Loss of consciousness and respiratory arrest were observed in the context of overdose.
04.9 Overdose -
Symptoms of fentanyl overdose are predictably similar in nature to those observed for fentanyl and other intravenously administered opioids and consist of a prolongation of its pharmacological actions, with the most severe significant effects being altered mental status, loss of consciousness, hypotension, respiratory depression, respiratory distress and respiratory failure, which was followed by death.
Immediate treatment of opioid overdose consists of removing the Effentora buccal tablet if still in the mouth, ensuring that the airways are clear, verbal and physical stimulation of the patient, assessing the level of consciousness, ventilatory and circulatory status, and in assisted ventilation (ventilatory support), if needed.
For the treatment of overdose (accidental ingestion) in people who have never used opioids, it is necessary to obtain an intravenous access and treat with naloxone or another opioid antagonist, according to clinical indications. The duration of respiratory depression after drug overdose may be longer than the effects of the opioid antagonist (eg the half-life of naloxone ranges from 30 to 81 minutes), and therefore it may need to be repeated. Refer to the Summary of Product Characteristics of the individual opioid antagonist for information regarding its use in this circumstance.
For the treatment of overdose in patients already treated with opioids, intravenous access should be obtained. Judicious use of naloxone or another opioid antagonist may be justified in some cases, but this is associated with the risk of causing acute withdrawal syndrome.
Although muscle stiffness such as to interfere with breathing has not been observed after use of Effentora, this is possible with fentanyl and other opioids. In this case, this will need to be treated with assisted ventilation, an opioid antagonist and, as last alternative, with a neuromuscular blocker.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: analgesics; opioids; ATC code N02AB03.
Fentanyl is an opioid analgesic, which interacts primarily with the µ-receptor for opioids. Its main therapeutic actions are analgesia and sedation. The secondary pharmacological effects are: respiratory depression, bradycardia, hypothermia, constipation, myosis, dependence and euphoria.
The analgesic effects of fentanyl are related to its plasma levels. In general, effective concentration and toxic concentration increase with increased tolerance to opioids. The rate at which tolerance develops varies greatly from one subject to another. Consequently, the dose of Effentora should be titrated for each individual subject to achieve the desired effect (see section 4.2).
All opioid µ-receptor agonists, including fentanyl, cause respiratory depression that is dose-dependent. The risk of respiratory depression is lower in patients on chronic opioid therapy, as these patients will develop a tolerance to the drug responsible for the respiratory depression.
The safety and efficacy of Effentora have been evaluated in patients taking the medicine at the onset of an episode of pain exacerbation. Preventive use of Effentora for predictable pain episodes has not been studied in clinical trials. Two double-blind, randomized, placebo-controlled cross-over studies were conducted in a total of 248 patients suffering from BPH and cancer and who had an average of 1 to 4 BPH episodes per day, while being treated with an opioid-based maintenance therapy. During an initial open-label phase, the optimal dose of Effentora was established for each patient. Patients for whom the optimal dose was found moved to the double-blind phase of the study. The main efficacy variable was the patient's assessment of pain intensity. Patients rated pain on an 11-point scale. For each episode of BTP, pain intensity was assessed both prior to administration, both at different time intervals after it.
An optimal dose could be determined for 67% of patients.
In the pivotal clinical study (study 1) the main endpoint, represented by the mean of the sums of the differences in pain intensity scores, from the time of drug administration up to and including 60 minutes later (SPID60), was statistically significant compared to placebo (P.
In the second pivotal study (study 2), the main endpoint was represented by SPID30, which was also statistically significant compared to placebo (P.
A statistically significant improvement in pain intensity differences was observed with Effentora compared to placebo as early as 10 minutes in study 1 and as early as 15 minutes (first detected interval) in study 2. These observations remained significant in each subsequent interval. in both studies.
05.2 "Pharmacokinetic properties -
General introduction
Fentanyl is highly lipophilic and can be absorbed very quickly from the oral mucosa and more slowly via the conventional gastrointestinal route. It undergoes hepatic and intestinal first pass metabolism, and its metabolites do not contribute to its therapeutic effects.
Effentora uses an active ingredient release technique that uses an effervescent reaction that enhances the speed and amount of fentanyl absorbed through the oral mucosa. Transient pH changes accompanying the effervescent reaction can optimize tablet dissolution (with lower pH) and membrane permeation (with higher pH).
The dwell time (defined as the time required for the tablet to completely disintegrate after oral administration) does not affect the precocity of general exposure to fentanyl. A comparative study between Effentora tablets 400 mcg both buccally (ie, between cheek and gum ) that sublingually met the bioequivalence criteria.
The effect of renal or hepatic impairment on Effentora pharmacokinetics has not been studied.
Absorption
Following oromucosal administration of Effentora, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of Effentora is largely the result of a rapid initial absorption from the oral mucosa, with peak plasma concentrations reached after venous withdrawal generally within one "hour of oromucosal administration. Approximately 50% of the total administered dose is rapidly absorbed through the mucosa becoming systemically available. The other 50% of the total dose is ingested and absorbed slowly through the gastrointestinal tract. About 30% of the ingested quantity (50% of the total dose) escapes first pass hepatic and intestinal elimination and becomes available systemically.
The main pharmacokinetic parameters are shown in the table below.
Pharmacokinetic parameters * in adult subjects treated with Effentora
* Referred to venous blood (plasma) samples. Serum concentrations of fentanyl citrate were higher than plasma concentrations: in serum, AUC and Cmax were approximately 20% and 30% higher than plasma concentrations, respectively. The reason for this difference is not known.
** Tmax data presented as median (range).
In pharmacokinetic studies conducted to compare the absolute and relative bioavailability of Effentora and oral transmucosal fentanyl citrate (OTFC), the rate and extent of absorption of fentanyl in Effentora demonstrated 30% -50% higher exposure than observed for the OTFC. In case of switching from another fentanyl citrate preparation, an independent titration of the Effentora dosage should be performed, as the bioavailability of the products is significantly different. However, a posology greater than 100 micrograms may be considered in these patients.
Differences in exposure were observed in a clinical study with Effentora conducted in patients with grade 1 mucositis. Cmax and AUC0-8 were 1% and 25% higher in patients with mucositis than in those without mucositis, respectively. observed differences were not clinically significant.
Distribution
Fentanyl is highly lipophilic and readily distributes beyond the vascular system, with a large apparent volume of distribution. After oral administration of Effentora, fentanyl undergoes a rapid initial distribution, which is an expression of a balance of fentanyl between plasma and highly perfused tissues (brain, heart and lungs). Subsequently, fentanyl is redistributed between the deep tissue compartment (muscle and fat) and the plasma.
The plasma protein binding of fentanyl varies between 80% and 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins also contribute in part.The free fraction of fentanyl increases with acidosis.
Biotransformation
The metabolic pathways following oral administration of Effentora have not been characterized in clinical studies. Fentanyl is metabolised in the liver and intestinal mucosa to norfentanil by the isoform CYP3A4. In animal studies, norfentanyl is not pharmacologically active. Over 90% of the administered dose of fentanyl is eliminated after biotransformation to inactive N-dealkylated metabolites and hydroxylates.
Elimination
After intravenous administration of fentanyl, less than 7% of the administered dose is eliminated unchanged in the urine, and only about 1% in the faeces. The metabolites are eliminated mainly in the urine, while the elimination in the faeces is less important. .
After administration of Effentora, the terminal elimination phase of fentanyl is the result of redistribution between the plasma and the deep tissue compartment. This elimination phase is slow, with a mean final elimination half-life t½ of approximately 22 hours after administration. of the buccal formulation, and approximately 18 hours after intravenous administration. Total plasma clearance of fentanyl following intravenous administration is approximately 42 L / h.
Linearity / non-linearity
Dose proportionality has been demonstrated from 100 to 1000 mcg.
05.3 Preclinical safety data -
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.
Embryo-fetal developmental toxicity studies, conducted in rats and rabbits, did not reveal any malformations or changes in development induced by the administered drug during the period of organogenesis.
In a fertility and early embryonic development study conducted in rats and rabbits, a male-mediated effect was observed with high doses (300 mcg / kg /die,s.c.) and is considered secondary to the sedative effects of fentanyl in animal studies.
In pre- and postnatal developmental studies in rats, offspring survival was significantly reduced at dosages causing severe maternal toxicity. Additional findings, at doses toxic to the mothers, were retarded physical development, sensory functions, reflexes, and behavior in first-generation descendants. These effects could be indirect, due to impaired maternal care and / or reduced breastfeeding, or a direct consequence of fentanyl on the offspring.
Carcinogenicity studies (alternative dermal biological test of Tg.AC in 26-week transgenic mice; 2-year subcutaneous carcinogenicity study in rats) did not highlight any findings indicative of oncogenic potential.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Mannitol
Sodium starch glycolate type A
Sodium bicarbonate
Sodium carbonate anhydrous
Anhydrous citric acid
Magnesium stearate
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
Store in the original package to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package -
PVC laminated aluminum blister / aluminum foil / polyamide / PVC paper / polyester coating.
The blister packs are presented in cartons of 4 or 28 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
Patients and caregivers should be advised to dispose of any remaining tablets when they are no longer needed.
The medicine used or not used because it is no longer needed, and the waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
TEVA Pharma B.V.
Computerweg 10
3542DR Utrecht
Netherlands
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/08/441/001 - AIC n. 038660015
EU / 1/08/441/002 - AIC n. 038660027
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 04 April 2008
10.0 DATE OF REVISION OF THE TEXT -
February 2013
