Page 1 Biorphen 10 mg/ml 1.3.1 Summary of Product Characteristics (SmPC) SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Biorphen 10 mg/ml, solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml of solution for injection contains 10 mg of phenylephrine hydrochloride corresponding to 8.2 mg of phenylephrine. Kommentiert [VR1]: Modified according to Day 30 Comments from the CMS FI 1 ampoule of 1 ml contains 10 mg of phenylephrine hydrochloride corresponding to 8.2 mg of Day 30 Comments from the CMS SE Kommentiert [VR2R1]: Applicant’s reply to NL and SE phenylephrine. comment VAR DE/H/4407/001-002/008: already modified at day 60 of the RUP procedure Excipients with known effect: Kommentiert [VR3]: Comment from Slovenia: Latest Q RD should be followed: 1 ampoule of 1 ml contains 0.103 mmol (or 2.36 mg) sodium. Excipient(s) with known effect Kommentiert [VR4R3]: Modified accordingly For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection. A clear colourless solution free from visible particles. Kommentiert [PC5]: Modified according to Day 30 Comments from the CMS the RO and according to section 3.2.P.5.1 pH 3.0-5.0. Specification Osmolarity: 270 to 300 mOsm/l. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Biorphen is indicated in adults for treatment of hypotension during spinal, epidural or general Kommentiert [VR6]: Modified according to Day 30 Comments from the CMS the SI anaesthesia. Kommentiert [VR7]: Modified according to Day 30 Comments from the CMS the NL 4.2 Posology and method of administration Route of Administration: 4.44.2 Biorphen 10 mg/ml, solution for injection, for subcutaneous or intramuscular. Biorphen 10 mg/ml, solution for injection, should only be administered by healthcare professionals with appropriate training and relevant experience. Posology: Adults Biorphen 10 mg/ml injection may be administered subcutaneously or intramuscularly in a dosage of 2 to 5 mg with further doses of 1 to 10 mg if necessary according to response, or in a dose of 100 to 500 Kommentiert [VR8]: Modified according to Day 60 from the RMS. 1 Page 2 Biorphen 10 mg/ml 1.3.1 Summary of Product Characteristics (SmPC) micrograms by slow intravenous injection as a 0.1% solution, repeated as necessary after at least 15 minutes. Biorphen 10 mg/ml injections may be administered subcutaneously or intramuscularly in a Kommentiert [VR9]: Modified according to Day 30 Comments from the CMS Sweden. Dosage information are proposed in dosage at doses of 2 to 5 mg phenylephrine and, if necessary and depending on the response, at further accordance with the reference product ‘Phenylephrine Injection BP 10 mg/ml’ (rev. date Nov. 2018) of the present procedure. doses of 1 to 10 mg. Alternatively, 10 8.2 mg of phenylephrine (1ml of Biorphen 10 mg/ml injection) diluted in 500 ml of glucose 50 mg/ml (5%) injection or sodium chloride 9 mg/ml (0.9%) injection may be infused intravenously., initially at a rate ofup to 180 micrograms per minute, reduced according to response Kommentiert [VR10]: Applicants reply to Day 30 Comments from the CMS Sweden between 25 and 100 µg/min.reduced according to response to 30-60 µg/min. Doses between 25 and The maximum dose of 180 µg/min is in line with information reported in the leaflet of the reference product Phenylephrine 100 µg/min has been deemed effective.The initial dose is 25 to 50 µg/min phenylephrine., up to 180 Injection BP 10 mg/ml’ (rev. date Nov. 2018) The applicant would like to maintain the maximum dose of 180 µg/min as additional µg/min. The doses may be increased or decreased to maintain systolic blood pressure near the normal safety measure in order to avoid administration of excessive doses which could lead to overdose episodes and would like to maintain value. Doses between 25 and 100 µg/min has been deemed effective. dosage indications in line with those reported in the SmPC of the reference product. Kommentiert [VR11R10]: The Applicant acknowledges the comments received at Day 30 from SE and Day 48 from RMS. Therefore, in order to align the recommended dosage for intravenous infusions between the two products, the same dosage instruction has been reported. The applicant however would like to maintain the Patients with renal impairment maximum dosage of 180 mcg/min as included in the most updated pheny lephrine injection SmPCs available on the market. Lower doses of Biorphen may be required in patients with renal impairment. Kommentiert [VR12R10]: Applicant’s reply to RMS’s PVAR DE/H/4407/001-002/008: the proposed posology has already been Patients with hepatic impairment: proposed in the frame of RUP procedure at Day 60. The Applicant’s in fact proposed the following change: ‘Initial dose is 25 to 50 Higher doses of Biorphen may be needed in patients with liver cirrhosis. µg/min, up to 180 µg/min. The doses may be increased or decreased to maintain systolic blood pressure near the normal value. Doses Elderly patients: between 25 and 100 µg/min has been deemed effective. (see the tracked changes) Treatment of the elderly should be made with caution. Moreover, in the frame of D60 reply , the Applicant gave also an explanation of why the maintenance of the maximum dose of 180 Paediatric population: mcg/min was suggested. Please refer to comment above in grey . The safety and efficacy of phenylephrine in children have not been established. No data are available. Kommentiert [VR13]: Applicant’s reply to DE updated PVAR: deleted accordingly Kommentiert [VR14]: Applicant’s reply to DE updated PVAR: revised accordingly Route Method of Administration: Kommentiert [VR15]: Modified according to Day 30 Comments from the CMS SI Biorphen 10 mg/ml, solution for injection, for subcutaneous or intramuscular. Biorphen 10 mg/ml, solution for injection, should only be administered by healthcare professionals with appropriate training and relevant experience. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Phenylephrine should not be given to patients with severe hypertension or peripheral vascular disease. This can lead to ischaemia with a risk of gangrene or vascular thrombosis. In combination with indirectly acting sympathomimetic agents: risk of vasoconstriction and / or hypertensive crisis (see section 4.5). 2 Page 3 Biorphen 10 mg/ml 1.3.1 Summary of Product Characteristics (SmPC) In combination with alpha-sympathomimetic agents (oral and / or nasal use): risk of vasoconstriction and / or hypertensive crisis (see section 4.5). Kommentiert [VR16]: Applicant’s reply to RMS 2nd updated FVAR: modified accordingly In combination with indirectly acting sympathomimetic agents (ephedrine, methylphenidate, pseudoephedrine): risk of vasoconstriction and / or hypertensive crisis. In combination with alpha-sympathomimetic agents (oral and / or nasal use) (etilefrine, midodrine, naphazoline, oxymetazoline, synephrine, tetryzoline, tuaminoheptane, tymazoline): risk of vasoconstriction and / or hypertensive crisis. Kommentiert [VR17]: Applicant’s reply to NL comment VAR DE/H/4407/001-002/008: modified accordingly In combination wiht with non-selective monoamine oxidase inhibitors (MAOs) (or within 2 weeks of their withdrawal) due to risk of paroxysmal hypertension and possibly fatal hyperthermia (see section 4.5). Biorphen should not be given to patients wiht severe hyperthyroidism. 4.4 Special warnings and precautions for use Arterial blood pressure should be monitored during treatment. Biorphen should be given with caution to patients with: • diabetes, • arterial hypertension, • aneurysma, • uncontrolled hyperthyroidism, • coronary heart disease and chronic heart disease, • bradycardia, • partial heart block, • tachycardia, • arrhythmias, • angina pectoris (phenylephrine can precipitate or exacerbate angina in patients with coronary artery disease and history of angina), • non-severe peripheral vascular insufficiency, • closed angle glaucoma. Biorphen may induce a decrease in cardiac output. Therefore, it should be administered with extreme caution in patients with atherosclerosis in the elderly and in patients with impaired cerebral or coronary circulation. In patients with reduced cardiac output or coronary vascular disease, vital organ functions should be closely monitored and dose reduction should be considered when systemic blood pressure is near the lower end of the target range. Kommentiert [VR18]: According to Day 30 Comments from the CMS SE., the Applicant would like to shift the sentence and modify it accordingly . 3 Page 4 Biorphen 10 mg/ml 1.3.1 Summary of Product Characteristics (SmPC) In patients with severe heart failure or cardiogenic shock, Biorphen may cause a worsening of heart failure as a result of the induced vasoconstriction (increased afterload). Patients with medical conditions such as decreased cardiac output or peripheral coronary artery disease should have frequent monitoring of vital body functions and lower systemic blood pressure boundary should be considered as a criterion for dose reduction or discontinuation of Biorphen. Particular attention should be paid to phenylephrine injection to avoid extravasation, since this may cause tissue necrosis. Lower doses may be required in patients with renal impairment. Higher doses may be required in patients with liver cirrhosis. The administration of this drug simultaneously with the following medicines is not recommended because of the risk of vasoconstriction and / or hypertensive crisis associated with