Effentora · 4.4 Special warnings and precautions for use · 1

HOS-154280 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Typical opioid adverse reactions are to be expected with Effentora. Frequently, these will cease or decrease in intensity with continued use of the medicinal product, as the patient is titrated to the most appropriate dose. However, the most serious adverse reactions are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patients should be closely monitored for these. The clinical studies of Effentora were designed to evaluate safety and efficacy in treating BTP and all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent pain. Therefore it is not possible to definitively separate the effects of Effentora alone. Tabulated list of adverse reactions The following adverse reactions have been reported with Effentora and/or other fentanyl-containing compounds during clinical studies and post marketing experience. Adverse reactions are listed below as MedDRA preferred term by system organ class and frequency (frequencies are defined as: very common ≥1/10, common ≥1/100 to <1/10, uncommon ≥ 1/1,000 to <1/100, rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data); within each frequency group, undesirable effects are presented in order of decreasing seriousness: Very common Common Uncommon Rare Not known Infections and Oral candidiasis Pharyngitis Oral pustule infestations Blood and Anaemia Thrombocyto- lymphatic Neutropenia penia system disorders Immune Hypersensitivit system y* disorders Endocrine Hypogonadism Adrenal disorders insufficiency Androgen deficiency Metabolism Anorexia and nutrition disorders 10  Very common Common

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HOS-154276 · has-contraindication-information · PDF-Seite 6

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Patients without maintenance opioid therapy as there is an increased risk of respiratory depression. • Severe respiratory depression or severe obstructive lung conditions. • Treatment of acute pain other than breakthrough pain. • Patients being treated with medicinal products containing sodium oxybate.

HOS-154275 · has-indication-information · PDF-Seite 3

Effentora is indicated for the treatment of breakthrough pain (BTP) in adults with cancer who are already receiving maintenance opioid therapy for chronic cancer pain. BTP is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain. Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25 micrograms of transdermal fentanyl per 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.

HOS-154278 · has-interaction-information · PDF-Seite 8

Agents that affect CYP3A4 activity Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when Effentora is given concurrently with agents that affect CYP3A4 activity. CYP3A4 inducers Co-administration with agents that induce 3A4 activity may reduce the efficacy of Effentora. CYP3A4 inhibitors The concomitant use of Effentora with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, and nelfinavir) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and 8 verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug reactions including fatal respiratory depression. Patients receiving Effentora concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done with caution. Agents that can increase CNS depressant effects Co-administration of fentanyl with other central nervous system depressants, including other opioids, sedatives or hypnotics, (including benzodiazepines), general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines, gabapentinoids (gabapentin and pregabalin) and alcohol can produce additive depressant effects which may result in respiratory depression, hypotension, profound sedation, coma or a fatal outcome (see section 4.4). Sedative medicines such as benzodiazepines or related drugs The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4). Partial opioid agonists/antagonists The concomitant use of partial opioid agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependant patients. Serotoninergic agents Co-administration of fentanyl with a serotoninergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-u

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HOS-154279 · has-pregnancy-information · PDF-Seite 9

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 in pregnancy unless clearly necessary. With long-term use of fentanyl during pregnancy, there is a risk of neonatal opioid withdrawal syndrome which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see section 4.8). It is advised not to use fentanyl during labour and delivery (including caesarean section) because fentanyl passes through the placenta and may cause respiratory depression in the foetus. If Effentora is administered, an antidote for the child should be readily available. Breast-feeding Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breast-fed child. Fentanyl should not be used by breastfeeding women and breastfeeding should not be restarted until at least 5 days after the last administration of fentanyl. 9 Fertility There are no human data on fertility available. In animal studies, male fertility was impaired (See Section 5.3).

HOS-154277 · has-warning-information · PDF-Seite 6

Because of the risks, including fatal outcome, associated with accidental exposure, misuse, and abuse, patients and their carers must be advised to keep Effentora in a safe and secure place, not accessible by others. Accidental use in children Patients and their carers must be instructed that Effentora contains an active substance in an amount that can be fatal, especially to a child. Therefore they must keep all tablets out of the sight and reach of children. Monitoring In order to minimise the risks of opioid-related undesirable effects and to identify the effective dose, it is imperative that patients be monitored closely by health professionals during the titration process. Maintenance opioid treatment It is important that the maintenance opioid treatment used to treat the patient’s persistent pain has been stabilised before Effentora therapy begins and that the patient continues to be treated with the maintenance opioid treatment whilst taking Effentora. The product must not be given to patients without maintenance opioid therapy as there is an increased risk of respiratory depression and death. Respiratory depression As with all opioids, there is a risk of clinically significant respiratory depression associated with the use of fentanyl. Improper patient selection (e.g., use in patients without maintenance opioid therapy) and/or improper dosing have resulted in fatal outcome with Effentora as well as with other fentanyl products. Effentora should only be used for conditions specified in section 4.1. Chronic obstructive pulmonary disease Particular caution should be used when titrating Effentora 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 drive to the point of respiratory failure. Sleep-related breathing disorders Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep- related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage. Alcohol The concomitant use of alcohol with fentanyl can produce increased depressant effects which may result in a fatal outcome (see section 4.5). 6 Risks of concomitant administration with benzodiazepines or related drugs Concomitant use of opio

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