SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCTS Piritramide [MAH] 7.5 mg/ml solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml solution for injection contains 7.5 mg piritramide. 1 ampoule of 1 ml solution for injection contains 7.5 mg piritramide. 1 ampoule of 2 ml solution for injection contains 15 mg piritramide. 1 ampoule of 6 ml solution for injection contains 45 mg piritramide. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection The product is a clear and colourless solution with a pH of 3.6 - 4.3. 4. CLINICAL PARTICULARS 4.1. Therapeutic indications Severe to strongest pain 4.2. Posology and method of administration Posology and duration of administration Adults Intramuscular or subcutaneous use: A single dose of 15-30 mg is recommended. Intravenous administration (when a particularly rapid effect is required): Slow intravenous administration (10 mg per minute): Single doses of 7.5-22.5 mg are recommended. Special patient groups In elderly patients, patients with impaired liver function and patients with poor general health the dose should be reduced. Paediatric population Intramuscular or subcutaneous use: A single dose of 0.05-0.2 mg per kg body weight for children is recommended. 1 Intravenous administration (when a particularly rapid effect is required): A single dose for children is 0.05-0.1 mg per kg body weight. Further information on small children currently available is detailed in Section 5.2. Method of administration Piritramide can be used for single and repeated intramuscular, subcutaneous and intravenous administration. Intramuscular, subcutaneous and intravenous single doses can usually be repeated after 6-8 hours if the effect is fading. For instructions on dilution of the medicinal product before administration, see Section 6.6. Piritramide [MAH] is for single use only. Any unused solution from opened ampoules should be discarded. Note: The dosage recommendations should serve as a general guidance for administration. In extreme pain states (e.g. tumour pain) the dose can be adjusted. Generally the dose should be sufficiently high and at the same time the smallest analgesic effective dose for the individual patient should be aimed for. For the therapy of chronic pain administration should preferably be performed according to a defined time schedule. 4.3. Contraindications Hypersensitivity to piritramide or to any of the excipients listed in section 6.1 Respiratory depression Comatose states 4.4. Special warnings and precautions for use As with other opioids, patients on piritramide may experience depression of the CNS or respiratory depression including respiratory arrest and respiratory insufficiency. An µ-opioid antagonist, e.g. naloxone, should be available at all times. Due to the long duration of action of piritramide repeated administration of the antagonist may be necessary. After administering piritramide there may be a fall in blood pressure. This effect may exceed the norm in hypovolaemic patients or in the presence of additionally administered sedatives. Piritramide should only be used with special care with: - acute alcohol intoxication, - convulsions, - head injuries and conditions involving increased intracerebral pressure. Care is recommended with hypothyroidism, adrenal cortex insufficiency, 2 prostatic hypertrophy and shock or if the patient has taken substances depressing the CNS (e.g. alcohol, barbiturates, hypnotics, certain benzodiazepines etc.). Caution is also indicated with elderly patients, patients with impaired liver function, impaired respiratory function or with an impaired general condition (see also Section 4.2). As with other opioids, patients can develop a physical and psychological dependence of piritramide (see Section 4.8). The risk of dependence usually increases with the length of use and with increasing doses. Over time, a higher dose may be required to achieve the same analgesic effect (tolerance). Discontinuing the drug, substituting a less potent opioid or administering an antagonist may trigger withdrawal symptoms such as balance disorders, tremor, anxiety, vomiting, diarrhoea and/or high blood pressure. Like other opioids, piritramide should be used with caution with: biliary disorders, obstructive and inflammatory bowel diseases, pheochromocytoma, pancreatitis and children aged under 1 year. Intubation and ventilation equipment should be available when administering high doses. 4.5 Interaction with other medicinal products and other forms of interaction In patients concurrently receiving other central nervous system depressants (e.g. barbiturates, benzodiazepines, phenothiazines, inhalation anaesthetics, other non selective hypnotics or alcohol) the undesirable effects of piritramide can be enhanced, especially respiratory depression. With the use of monoamine oxidase inhibitors (MAOIs) within 14 days priori to the opioid application life threatening interactions on the central nervous system, respiratory function and circulation with pethidine were observed and can not be excluded for piritramide. Therefore, MAOIs must be stopped at least 10 days prior to the treatment with piritramide. Pentazocine partly antagonises the effect of piritramide, e.g. the analgesic effect. 4.6 Fertility, pregnancy and lactation Pregnancy There is no data from the use of piritramide in pregnant women and only insufficient experimental studies in animals (see section 5.3). The potential risk to humans is unknown. Piritramide is therefore not recommended during pregnancy unless clearly necessary. Lactation It is not known whether piritramide passes into breast milk. However, it is known that other opioids pass into breast milk. Piritramide should not be used whilst breast-feeding unless absolutely necessary. Breast-feeding should be 3 discontinued during treatment with piritramide and only resume at least 24 hours after the last dose of piritramide. It cannot be ruled out that chronic use during pregnancy may lead to habituation and to post-partum withdrawal symptoms in the neonate. 4.7 Effects on ability to drive and use machines Although it varies widely between individuals, the sedative effect of piritramide must be borne in mind. As a precaution the patient should wait for a minimum of 6 to 8 hours after a single dose of 20 mg piritramide and for a minimum of 12 to 24 hours after repeated administration . 4.8 Undesirable effects The most commonly reported side effects in 7 clinical studies (pooled data) were (in percentage incidence) increased heart rate (15.0%), low blood pressure (13.1%) and stupor (9.9%). The frequency of undesirable effects is classified into the following categories: 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 Very rare <1/10,000 Not known cannot be estimated from the available data Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Immune system disorders Not known: Anaphylaxis, anaphylactic shock Psychiatric disorders: Uncommon: Dependence Not known: Withdrawal symptoms Nervous system disorders: Common: Stupor, vertigo (dizziness), drowsiness Uncommon: Headache Not known: Unconsciousness Eye disorders: Not known: Miosis 4 Cardiac disorders: Not known: Bradycardia, bradyarrhythmia, cyanosis Vascular disorders: Uncommon: Hypotension Respiratory, thoracic and mediastinal disorders: Not known: Respiratory arrest, respiratory insufficiency, status asthmaticus, bronchospasm, dyspnoea Gastrointestinal disorders: Common: Nausea, vomiting, retching Skin and subcutaneous tissue disorders: Common: Pallor Uncommon: Hyperhidrosis Not known: Allergic dermatitis, pruritus General disorders and symptoms at the administration site: Not known: Reactions at the administration site Investigations: Very common: Increased heart rate, low blood pressure Uncommon: Reduced respiration rate Withdrawal symptoms can be triggered by stopping the medication after repeated use, replacement with a less potent opioid or application of an opioid antagonist. A need to counteract the opioid effect was reported in 0.4% of study patients. As with other opioids, patients who are on piritramide may experience an inhibition of gastrointestinal motility which can lead to constipation. With other opioids there have also been reports of dry mouth, increased muscle tone in urinary bladder, gall bladder and pancreas and, in rare cases, difficulties in passing water. Reporting of suspected side effects Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V* 4.9 Overdose Symptoms Typical symptoms are miosis and respiratory depression ranging through to respiratory arrest. Additionally, disturbance of consciousness ranging through to coma, low blood pressure, tachycardia and dizziness can occur. The parenteral dose at which severe respiratory depression may occur is 60-80 mg 5 in non-predisposed adults and 1 mg/kg body weight in children. Therapy These effects can be neutralised with administration of an opioid antagonist (e.g. naloxone), which is given cautiously in small repeated doses, because the duration of action of the opioid antagonist is shorter than that of piritramide (e.g. 0.4 mg naloxone every 2-3 minutes for adults). Besides this,