Page 1 Biorphen 0.1 mg/ml 1.3.1 Patient Information Leaflet

Package Leaflet: Information for the User BIORPHEN Biorphen 0,1 mg/ml SOLUTION FOR INJECTION/ INFUSION Kommentiert [PC1]: Modified over the whole document hydrochloride according to Day 30 Comments from the CMS SI Kommentiert [PC2]: Modified over the whole document Read all of this leaflet carefully before you are given this medicine because it contains important according to Day 30 Comments from the CMS FI information for you.  Keep this leaflet. You may need to read it again  If you have any further questions, ask your doctor or nurse  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. Kommentiert [VR3]: Comment form Slovenia: Latest Q RD  If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not should be followed: See section 4. listed in this leaflet. See section 4. Kommentiert [VR4R3]: Modified accordingly If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.

What is in this leaflet: 1.What BiorphenBIORPHEN is and what it is used for 2.What you need to know before you are given BiorphenBIORPHEN 3.How BiorphenBIORPHEN will be given 4.Possible side effects 5.How to store BiorphenBIORPHEN 6.Contents of the pack and further information

1. WHAT BIO RPHEN IS AND WHAT IT IS USED FO R BiorphenBIORPHEN contains phenylephrine hydrochloride, which belongs to a group of medicines known as cardiac stimulants. It raises blood pressure by constricting blood vessels. BiorphenBIORPHEN is used in adults to treat low blood pressure during spinal, epidural and general Kommentiert [VR5]: Modified according to Day 30 Comments anaesthesia. from the CMS SI Kommentiert [PC6]: Modified in line with the amendment to the 2. WHAT YO U NEED TO KNOW BEFO RE YOU ARE GIVEN BIO RPHEN SmPC following to Day 30 Comments from the CMS NL

Do not give BiorphenBIORPHEN should not administered to you: Kommentiert [VR7]: Applicant’s reply to NL comment VAR DE/H/4407/001-002/008: modified accordingly - if you are allergic (hypersensitive) to phenylephrine hydrochloride or any of the other ingredients Kommentiert [PC8]: Modified according to Day 30 Comments (listed in section 6) from the CMS SI - if you suffer from high blood pressure or peripheral vascular disease (poor blood circulation) - if you have an overactive thyroid nd - if you are taking Monoamine Oxidase Inhibitors (MAOIs) used to treat depression (such as Kommentiert [VR9]: Applicant’s reply to RMS 2 updated FVAR: the sentence corresponding to information included in the iproniazide, nialamide), or have taken them in the last 14 days SmPC (In combination with indirectly acting sympathomimetic - if you are taking indirect stimulators of the sympathetic nervous system: risk of blood vessels agents: risk of and / or hypertensive crisis) has been constriction or severe increase in blood pressure added in a patient’s friendly language - If you are taking direct stimulators of alpha receptors of the sympathetic nervous system (oral Kommentiert [VR10]: Modified according to Day 30 and/or nasal use) that are used to treat or nasal congestion: risk of blood vessels Comments from the CMS SE nd constriction or severe increase in blood pressure. Kommentiert [VR11]: Applicant’s reply to RMS 2 updated FVAR: the sentence corresponding to information included in the - SmPC (In combination with alpha-sympathomimetic agents (oral and / or nasal use): risk of vasoconstriction and / or hypertensive crisis) has been added in a patient’s friendly language Page 2 Biorphen 0.1 mg/ml 1.3.1 Patient Information Leaflet

- If you are taking Alpha-sympathomimetic agents (etylefrine, , , , etc.): risk of vasoconstriction or hypertensive crisis. Kommentiert [VR12]: Applicant’s reply to NL comment VAR Warnings and precautions DE/H/4407/001-002/008: modified accordingly Talk to your doctor before giving BiorphenBIORPHEN is administered to you, if you have: Kommentiert [VR13]: Modified according to Day 30 - any heart problems or disease, including chronic heart conditions, peripheral vascular Comments from the CMS SE insufficiency, arrhythmias, tachycardia (high heart rate) or angina a disease of your blood vessels, Kommentiert [VR14]: Applicant’s reply to NL comment VAR such as arteriosclerosis DE/H/4407/001-002/008: modified accordingly - diabetes mellitus Kommentiert [VR15]: Comment form Slovenia:Please delete the sentence. Arteriosclerosis is mentioned twice in section - an uncontrolled overactive thyroid Warnings and precautions (marked in y ellow) - bradycardia Kommentiert [VR16R15]: Deleted accordingly - partial heart block - arterial hypertension - blood vessel disease, such as arteriosclerosis (hardening and thickening of the walls of the blood vessels - a poor blood circulation in the brain - a closed angle glaucoma (a rare eye disease).

In patients with serious heart failure, phenylephrine may worsen the heart failure as a consequence of blood vessel constriction. The blood pressure in your arteries will be monitored during treatment. If you have heart disease, additional monitoring of vital functions will be performed.

Children and adolescents Kommentiert [VR17]: Modified according to Day 30 This medicine is not recommended for use in children due to insufficient data on efficacy, safety and Comments from the CMS SI dosage recommendations.

O ther medicines and BiorphenBIORPHEN Please tell your doctor or nurse if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. In particular, the following medicines may affect or be affected by concomitant use: - certain (iproniazide, nialamide, moclobemide, toloxatone, , , minalcipram, venlafaxine) - , , methylergotamine, methylsergide (for migraine) - linezolid (an antibiotic) - , , , (for Parkinson’s disease) - medicine used to inhibit the production of an hormone responsible of lactation (cabergoline) - medicine used as an appetite suppressant (sibutramine) Kommentiert [VR18]: Comment from Slovenia: Clinical assessor of the applicant should consider if mentioning sibutramine is - medicines used to treat high blood pressure () still relevant (obsolete). - medicines known as alpha blockers or beta blockers (used to treat heart conditions or reduce blood Kommentiert [VR19R18]: Deleted accordingly pressure) - medicines given orally and via nose that causes blood vessels to contract (, midodrine, naphazoline, oxymetazoline, , ,, ) - anaesthetics that are inhaled (desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane) - medicines used to treat heart failure and certain irregular heartbeats (cardiac glycosides) Page 3 Biorphen 0.1 mg/ml 1.3.1 Patient Information Leaflet

- medicine used to treat abnormal heart rhythm () - medicine used during labour (oxytocin).

Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.Tell your doctor or nurse if you are pregnant or breast- feeding. Kommentiert [PC20]: Modified according to Day 55 The safety of phenylephrine during pregnancy and breast-feeding has not been established. Comments from the CMS SI Giving phenylephrine in late pregnancy or labour may reduce the fetal heart rate and oxygen levels.

Driving and using machines Kommentiert [VR21]: Modified according to Day 30 No adverse effect known Comments from the CMS SE Biorphen 0.1 mg/ml has minor influence on the ability to drive and use machines. Kommentiert [VR22]: Applicant’s reply to NL comment VAR Not relevant. DE/H/4407/001-002/008: already modified, the following sentence was proposed in the frame of D60 reply of the RUP procedure Kommentiert [VR23]: Modified according to Day 30 Biorphen contains Sodium Comments from the CMS SE and to Day 48 Comments from the This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium- RMS. free’.This medicine contains 3.54 mg sodium (main component of cooking/table salt) in each ml. This is Kommentiert [VR24]: Modified as per NL request equivalent to 0.2% of the recommended maximum daily dietary intake of sodium for an adult. Kommentiert [PC25]: Modified according to Day 55 Comments from the CMS SI 3. HOW BIORPHEN WILL BE GIVEN You will normally be given BiorphenBIORPHEN in a hospital or clinic. BiorphenBIORPHEN 0.1 mg/ml injection/iInfusion can be given by slow injection or infusion (drip) into a vein.

Dose for adults, including the elderly: When given by slow injection into a vein, the bolus dose of Biorphen 0.1 mg/ml injection/infusion is 50 to 100 micrograms phenylephrine, which can be repeated as necessary. Alternatively, Biorphen 0.1 mg/ml injection/infusion can be administered as venous drip infusion, with the dose being adjusted between 25 to 100 µg/min phenylephrine depending on the response.may be infused Kommentiert [VR26]: Applicant’s reply to PVAR: modified into a vein (drip), and the dose adjusted according to the response can be 25 to 180 µg/min. accordingly Kommentiert [VR27]: Modified according to the SmPC Use in patients with impaired renal function (kidney not functioning well): Lower doses of phenylephrine may be needed in patients with impaired renal function.

Use patients with impaired liver function (liver not functioning well): Higher doses of phenylephrine may be needed in patients with impaired liver function.

Use in children and adolescents: Kommentiert [VR28]: Modified according to Day 30 This medicine is not recommended for use in children due to insufficient data on efficacy, safety and dose Comments from the CMS SI recommendations.

If you are given more BIORPHEN than you should You may have the following symptoms: palpitation, cardiac rhythm disorders, tachycardia. As you will be given BiorphenBIORPHEN in a hospital or clinic by a qualified healthcare professional, this will be unlikely. If you have any further questions on the use of this product, ask your doctor or nurse.

Page 4 Biorphen 0.1 mg/ml 1.3.1 Patient Information Leaflet

4. PO SSIBLE SIDE EFFECTS

Like all medicines, this medicine BIORPHEN can cause side effects, although not everybody gets them. Kommentiert [PC29]: Modified according to Day 30 Comments Some side effects may be serious. Tell your doctor or nurse straight away if you have any of the from the CMS SI following side effects:  an irregular heartbeat (arrhythmias)  chest pain or pain due to angina  feeling the heart pumping in the chest  bleeding in the brain (speech disorder, dizziness, paralysis of one side of the body)  psychosis (loosing contact with reality)

O ther side effects (unknown frequency not known (cannot be estimated from available Kommentiert [VR30]: Modified according to Day 30 data)frequencies are not known) Comments from the CMS SI  reaction of hypersensitivity (allergy) Kommentiert [PC31]: Modified according to Day 55 Comments from the CMS SI  excessive dilation of the pupils  increased pressure in the eye (aggravation of glaucoma)  excitability (excessive sensitivity of an organ or body part)  agitation (restlessness)  anxiety  confusion  headache  nervousness  insomnia (difficulty falling or staying asleep)  shaking (tremor)  burning of the skin  prickling of the skin  itching or tingling skin sensation (paresthesia)  slow or high heart rate  high blood pressure  difficulty in breathing  fluids in the lung  nausea  vomiting  sweating  pallor or skin blanching (pale colour of the skin)  goose flesh  tissue damage at the site of the injection  muscle weakness  difficulty in passing urine or urine retention.  excessive production of saliva  altered metabolism including glucose metabolism.

Page 5 Biorphen 0.1 mg/ml 1.3.1 Patient Information Leaflet

Reporting of side effects If you get any side effects, talk to your doctor or nurse. 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.

5. HOW TO STORE BIORPHEN Keep this medicine out of the sight and reach of children. Do not refrigerate or freeze.This medicinal product does not require any special temperature Kommentiert [VR32]: Applicant’s reply to RMS’s PVAR storage conditions. DE/H/4407/001-002/008: Modified accordingly , please refer to Quality reply document Use immediately after first openingThis medicinal product does not require any special storage conditions. Kommentiert [VR33]: Modified according to Day 30 Comments from the CMS SE Do not use after the expiry date, which is stated on the carton and ampoule. The expiry date refers to the last day of that month. Kommentiert [VR34]: Modified according to Day 30 Comments from the CMS SI 6. CONTENTS O F THE PACK AND OTHER INFO RMATIO N Kommentiert [PC35]: Modified according to Day 55 Comments from the CMS SE What BiorphenBIORPHEN Infusion contains The active substance is phenylephrine. 1 ml contains 0.1 mg of phenylephrine hydrochloride Kommentiert [PC36]: Modified according to Day 30 corresponding to 0.08 mg of phenylephrine. Comments from the CMS SI The other ingredients are sodium chloride, hydrochloric acid (for pH adjustment) and water for injections. Kommentiert [VR37]: In line with the SmPC Kommentiert [PC38]: Modified according to Day 30 What BIORPHEN looks like and contents of the pack Comments from the CMS SI BiorphenBIORPHEN 0.1 mg/ml injection/iInfusion is a clear, colourless, sterile solution in a 5 ml glass ampoule, available in packs of 10 ampoules.

Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: Sintetica GmbH Albersloher Weg 11 48155 Münster Germany

Manufacturer: Sintetica GmbH Albersloher Weg 11 48155 Münster Germany

Sirton Pharmaceuticals Spa Piazza XX Settembre, 2 22079 Villa Guardia (CO) Italy

This medicinal product is authorised in the Member States of the EEA under the following names: Member State Product name Page 6 Biorphen 0.1 mg/ml 1.3.1 Patient Information Leaflet

Austria Biorphen 0.1 mg/ml Injektions-/Infusionslösungsolution for infusion

Germany Biorphen 0.1 mg/ml Injektions-/Infusionslösungsolution for infusion Kommentiert [VR39]: Adapted in line with the German name

Denmark Biorphen Kommentiert [PC40]: Proposed names in the new CMSs are implemented in line with the Annex 5.19 to the Application Form. Estonia Biorphen 0.1 mg/ml Finland Fenylefrin SinteticaBiorphen 0.1 mg/ml Kommentiert [GC41]: As agreed with CMS-FI during national phase due to the bilingual pack with Swedish texts. Croatia Biorphen 0.1 mg/ml Hungary Biorphen 0.1 mg/ml Iceland Biorphen 0.1 mg/ml Lithuania Phenylephrine hydrochloride Sintetica 0,1 mg/ml infuzinis tirpalas Latvia Biorphen 0,1 mg/ml šķīdums infūzijām Netherlands Biorphen 0,1 mg/ml Norway Biorphen Poland Biorphen Sweden Fenylefrin Phenylephrine Sintetica 0.1 mg/ml Kommentiert [GC42]: In line with the suggestion of CMS- Sweden during the national phase Greece Biorphen 0.1 mg/ml Διάλυμα για έγχυση Cyprus Biorphen 0.1 mg/ml Slovenia Fenilefrin Sintetica 0,1 mg/ml raztopina za injiciranje/infundiranje Kommentiert [PC43]: Modified according to Day 55 Comments from the CMS SI Romania Biorphen 0,1 mg/ml Soluţie injectabilă/perfuzabilă Kommentiert [PC44]: Modified according to Day 55 Comments from the CMS RO

This leaflet was last approved in {MM/YYYY}. ------Package Leaflet: Information for Healthcare Professional BiorphenBIORPHEN 0.1 mg/ml Solution for Infusioninjection/infusion

The following information is intended for medical or healthcare professionals only:

Q ualitative and quantitative composition Phenylephrine hydrochloride Ph.Eur. 1.0% w/v. Each 1 ml contains 0.1 mg of phenylephrine hydrochloride corresponding to 0.08 mg of phenylephrine.. Kommentiert [VR45]: According to Day 30 Comments from Each 5 ml ampoule contains 0.5 mg of phenylephrine hydrochloride corresponding to 0.4 mg of the CMS FI, phenylephrine. Day 30 Comments from the CMS SE Kommentiert [VR46R45]: Applicant’s reply to NL and SE comment VAR DE/H/4407/001-002/008: already modified at day 60 Therapeutic indications of the RUP procedure Biorphen is indicated in adults for treatment of hypotension during spinal, epidural or general anaesthesia.For the treatment of hypotensive states, e.g. circulatory failure, during spinal anaesthesia or Kommentiert [VR47]: Indication in line with those proposed in drug-induced hypotension. the SmPC

Posology and method of administration Inspect visually for particulate matter and discolouration prior to administration. Kommentiert [VR48]: Modified according to Day 30 The solution should be free from visible particles. Comments from the CMS RO and according to section 3.2.P.5.1 Specification Page 7 Biorphen 0.1 mg/ml 1.3.1 Patient Information Leaflet

For single use only.

Adults: Biorphen 0.1 mg/ml, solution for injection/infusion: Intravenous bolus injection: The usual dose is 50 µg phenylephrine, which can be repeated for until the desired effect is achieved. In severe hypotension, doses may be increased without exceeding 100 µg in a bolus, but should not exceed 100 µg per bolus.

Continuous infusion: Initial dose is 25 to 50 µg/min phenylephrine, up to 180 µg/min. The doses may be increased or decreased Kommentiert [VR49]: Applicant’s reply to DE updated to maintain systolic blood pressure near the normal value. Doses between 25 and 100 µg/min are PVAR: deleted accordingly usuallyhas been deemed effective. Kommentiert [VR50]: Applicant’s reply to RMS’s PVAR DE/H/4407/001-002/008: please refer to comment in the SmPC Patient with renal impairment Kommentiert [VR51]: In line with the SmPC, modified Lower doses of BiorphenBIORPHEN may be required in patients with renal impairment. according to updated PVAR Patients with hepatic impairment: Higher doses of BiorphenBIORPHEN may be needed in patients with liver cirrhosis.

Children and adolescents: This medicine is not recommended for use in children due to insufficient data on efficacy, safety and dose recommendations.

Elderly: There is no need for dosage reduction in the elderly.

Pharmacokinetic properties: Kommentiert [VR52]: Comment from Slovenia: This strength Biorphen 0.1 mg/ml is for intravenous use only. When injected subcutaneously or intramuscularly, is only for intravenous use, this should be clarified here. phenylephrine takes 10 to 15 minutes to act. Subcutaneous injections are effective for up to one hour and Kommentiert [VR53R52]: Modified accordingly intramuscular injections for up to two hours. The duration is 20 minutes after intravenous administration.

Incompatibilities: BiorphenBIORPHEN is not compatible with alkaline solutions, iron salts and other metals, phenytoin sodium and oxidising agents.has been stated to be incompatible with alkalis, ferric salts, phenytoin sodium and oxidising agents. Kommentiert [PC54]: Modified according to Day 55 Comments from the CMS SE

For full prescribing information please refer to the Summary of Product Characteristics.