Effentora

Uses

Effentora is used for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least 60 mg of oral morphine/day, at least 25 mcg of transdermal Effentora/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Effentora is also used to associated treatment for these conditions: Cancer Related Pain (Breakthrough Pain), Severe, Chronic Pain, Anesthetic premedication therapy, Anesthetics Agent, General Anesthesia, Induction of anesthesia therapy, Maintenance of anesthesia therapy, Regional Anesthesia, Preanesthetic medication therapy

How Effentora works

Effentora binds to opioid receptors, especially the mu opioid receptor, which are coupled to G-proteins. Activation of opioid receptors causes GTP to be exchanged for GDP on the G-proteins which in turn down regulates adenylate cyclase, reducing concentrations of cAMP. Reduced cAMP decreases cAMP dependant influx of calcium ions into the cell. The exchange of GTP for GDP results in hyperpolarization of the cell and inhibition of nerve activity.

Dosage

Effentora dosage

Oral-

• Starting Dose:The initial dose of Effentora should be 100 mcg.
• Re-dosing patients within a single episode: Dosing may be repeated once during a single episode of breakthrough pain if pain is not adequately relieved by one Effentora dose. Re-dosing may occur 30 minutes after the start of administration of Effentora and the same dosage strength should be used.
• Increasing the dose: Titration should be initiated using multiples of the 100 mcg Effentora tablet. Patients require to titrate above 100 mcg can be instructed to use two 100 mcg tablets (one on each side of the mouth in the buccal cavity). If this dose is not successful in controlling the breakthrough pain episode, the patient may be instructed to place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate above 400 mcg by 200 mcg increments bearing in mind using more than 4 tablets simultaneously has not been studied and it is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. To reduce the risk of overdose during titration, patients should have only one strength of Effentora tablet available at any one time.
• Dosage Adjustment:Generally, the dose of Effentora should be increased when patients require more than one dose per breakthrough pain episode for several consecutive episodes.

Injection-

• Effentora injection can be administered intravenously either as a bolus or by infusion & by intramuscular route also. The dose of fentanyl should be individualized according to age, body weight, physical status, underlying pathological condition, use of other drugs and type of surgery and anesthesia.
• Doses in excess of 200mcg are for use in anesthesia only. As a premedicant, 1-2 ml fentanyl may be given intramuscularly 45 minutes before induction of anesthesia. After IV administration in unpremedicated adult patients, 2ml fentanyl may be expected to provide sufficient analgesia for 10-20 minutes in surgical procedures involving low pain intensity. 10 ml fentanyl injected as a bolus gives analgesia lasting about one hour. The analgesia produced is sufficient for surgery involving moderately painful procedures. Giving a dose of 50mcglkg fentanyl will provide intense analgesia for some four to six hours, for intensely stimulating surgery.
• Effentora may also be given as an infusion. In ventilated patients, a loading dose of fentanyl may be given as a fast infusion of approximately 1 mcg/kg/min for the first 10 minutes followed by an infusion of approximately 0.1 mcg/kg/min. Alternatively the loading dose of fentanyl may be given as a bolus. Infusion rates should be titrated to individual patient response; lower infusion rates may be adequate. Unless it is planned to ventilate post operatively, the infusion should be terminated at about 40 minutes before the end of surgery.
• Lower infusion rates, e.g. 0.05-0.08 mcg/kg/min. are necessary if spontaneous ventilation .is to be maintained. Higher infusion rates (up to 3 mcg/kg/min) have been used in cardiac surgery. Effentora is chemically incompatible with the induction agents thiopentone & methohexitone because of wide differences in pH
• Use in elderly and debilitated patients: It is wise to reduce the dosage in the elderly and debilitated patients. The effect of the initial dose should be taken into account in determining supplemental doses.

Transdermal-

Intractable chronic pain:

• Adult:Patches deliver fentanyl in doses that range from: 12-100 mcg/hr. Doses should be individually titrated based on previous use of opioids. Opioid-naive patients: Initially, ≤25 mcg/hr; it is recommended to initially titrate w/ low doses of short-acting opioids before starting fentanyl patches. Patients receiving a strong opioid analgesic: Initial dose should be based on the previous 24-hr opioid requirements. During transfer to fentanyl patches, previous opioid treatment should be phased out gradually. If patient requires doses >100 mcg/hr, >1 patch may be used; consider alternative or additional therapy if doses >300 mcg/hr are required. Replace patch every 72 hr and apply the new patch to a different site; avoid using the same area of skin for a few days.
• Elderly:Dose reduction may be needed.

Tablet Administration: Patients should remove the tablet from the blister strip and immediately place the entire tablet in the buccal cavity (above a rear molar, between the upper cheek and gum). Patients should not attempt to split the tablet. The tablet should not be chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed. The tablet should be left between the cheek and gum until it has disintegrated, which usually takes approximately 14-25 minutes. After 30 minutes, if remnants from the tablet remain, they may be swallowed with a glass of water.

Side Effects

As with other narcotic analgesics, the most common serious adverse reactions reported to occur with Effentora are respiratory depression, apnoea, muscular rigidity, myoclonic movements, and bradycardia. Respiratory depression is more likely to occur with intravenous administration if a dose is given too rapidly and it rarely occurs with intramuscular administration.

Toxicity

Effentora has an intravenous LD₅₀ of 2.91mg/kg in rats, an oral LD₅₀ of 18mg/kg in rats and 368mg/kg in mice. The LD50 in humans is not known.

Symptoms of overdose include respiratory depression, somnolence, stupor, coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction, pulmonary edema, bradycardia, hypotension, airway obstruction, atypical snoring, and death. In case of overdose, patients should receive naloxone or nalmefene to reverse the action of the opioids as well as supportive measures to maintain the airway or advanced life support in the case of cardiac arrest.

Precaution

Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g. driving a car or operating machinery). Patients taking Effentora should be warned of these dangers and should be counseled accordingly. The use of concomitant CNS active drugs requires special patient care and observation.

Chronic pulmonary disease: Effentora should be titrated with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to respiratory depression.

Head injuries and increased intracranial pressure: Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.

Cardiac disease: Intravenous Effentora may produce bradycardia. Therefore, Effentora should be used with caution in patients with bradyarrhythmias.

Hepatic or renal disease: Effentora should be used with caution because of the hepatic metabolism and renal excretion of Effentora.

Interaction

Co-administration of different antifungals, macrolide antibiotics, CNS depressant drugs like ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazadone may enhance or prolong the effects of Effentora. The concomitant use of amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil with Effentora may also result in an increase in Effentora plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

Food Interaction

• Avoid alcohol.

[Major] GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including fentanyl.

Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills.

In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Consumption of grapefruit juice during treatment with oral transmucosal formulations of fentanyl may result in increased plasma concentrations of fentanyl, which is primarily metabolized by CYP450 3A4 isoenzyme in the liver and intestine.

Certain compounds present in grapefruit are known to inhibit CYP450 3A4 and may increase the bioavailability of swallowed fentanyl (reportedly up to 75% of a dose) and

The clinical significance is unknown.

In 12 healthy volunteers, consumption of 250 mL regular-strength grapefruit juice the night before and 100 mL double-strength grapefruit juice one hour before administration of oral transmucosal fentanyl citrate (600 or 800 mcg lozenge) did not significantly affect fentanyl pharmacokinetics, overall extent of fentanyl-induced miosis (miosis AUC), or subjective self-assessment of various clinical effects compared to control.

However, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

The possibility of significant interaction in some patients should be considered.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with fentanyl.

Any history of alcohol or illicit drug use should be considered when prescribing fentanyl, and therapy initiated at a lower dosage if necessary.

Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension.

Due to a high degree of interpatient variability with respect to grapefruit juice interactions, patients treated with fentanyl should preferably avoid the consumption of grapefruit and grapefruit juice.

In addition, patients receiving transdermal formulations of fentanyl should be cautioned that drug interactions and drug effects may be observed for a prolonged period beyond removal of the patch, as significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed.

Effentora Drug Interaction

Major: zolpidem, zolpidem, lorazepam, lorazepam, duloxetine, duloxetine, hydromorphone, hydromorphone, pregabalin, pregabalin, acetaminophen / hydrocodone, acetaminophen / hydrocodone, alprazolam, alprazolam, ondansetron, ondansetronModerate: furosemide, furosemideUnknown: cholecalciferol, cholecalciferol

Effentora Disease Interaction

Major: impaired GI motility, infectious diarrhea, liver disease, prematurity, acute alcohol intoxication, drug dependence, gastrointestinal obstruction, hypotension, intracranial pressure, respiratory depressionModerate: fever, adrenal insufficiency, biliary spasm, hypothyroidism, renal dysfunction, seizure disorders, urinary retention, arrhythmias

Volume of Distribution

The intravenous volume of distribution is 4L/kg (3-8L/kg). The oral volume of distribution is 25.4L/kg. In hepatically impaired patients, the intravenous volume of distribution ranges from 0.8-8L/kg.

Effentora crosses the blood brain barrier and the placenta.

Elimination Route

Effentora sublingual tablets are 54% bioavailable, transmucosal lozenges are 50% bioavailable, buccal tablets are 65% bioavailable, sublingual spray is 76% bioavailable, and nasal spray is 20% more bioavailable than transmucosal (or approximately 64% bioavailable).

Effentora transmucosal lozenges reach a C_max of 0.4±0.1ng/mL for a 200µg dose and 2.5±0.6ng/mL for a 1600µg dose with a T_max of 20-40 minutes. The AUC was 172±96ng*min/mL for a 200µg dose and 1508±1360ng*min/mL for a 1600µg dose.

Effentora sublingual spray reached a C_max of 0.20±0.06ng/mL for a 100µg dose and 1.61±0.60ng/mL for an 800µg dose with a T_max of 0.69-1.25 hours, decreasing as the dose increased. The AUC was 1.25±0.67ng*h/mL for a 100µg dose and 10.38±3.70ng*h/mL for a 800µg dose.

Effentora transdermal systems reached a C_max of 0.24±0.20ng/mL with a T_max of 3.6±1.3h for a 25µg/h dose. The AUC was 0.42±0.35ng/mL*h.

Effentora nasal spray reaches a C_max of 815±301pg/mL with a T_max of less than 1 hour for a 200µg/100µL dose. The AUC was 3772pg*h/mL.

Half Life

The half life of fentanyl is 7 hours. The half life of fentanyl sublingual spray is 5-12 hours.

Clearance

Total plasma clearance of fentanyl is 0.5L/hr/kg (0.3-0.7L/hr/kg) or 42L/hr. Following an intravenous dose, surgical patients displayed a clearance of 27-75L/h, hepatically impaired patients displayed a clearance of 3-80L/h, and renally impaired patients displayed a clearance of 30-78L/h.

Elimination Route

Within 72 hours, 75% of a dose of fentanyl is excreted in the urine with Label,15,19

Pregnancy & Breastfeeding use

Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Effentora should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Effentora is excreted in human milk; therefore Effentora should not be used in nursing women because of the possibility of sedation and/or respiratory depression in their infants.

Contraindication

Effentora is contraindicated in the management of acute or postoperative pain. Effentora Citrate must not be used in opioid non-tolerant patients. Effentora is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug Effentora.

Acute Overdose

In insufficient overdosage, Effentora would produce narcosis, marked skeletal muscle rigidity. Cardio-respiratory depression and cyanosis may also occur. In the presence of hypoventilation or apnoea, oxygen should be administered and respiration should be assisted. A specific narcotic antagonist, such as naloxane, should be available for use as indicated to manage respiratory depression.

Storage Condition

Store between 20-25°C. Protect from light.

Innovators Monograph

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