Summary Public Assessment Report. non-generics. Folic acid Colonis Folic acid MT/H/0203/001/DC

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1 CMDh/233/2011 June 2014 Summary Public Assessment Report non-generics Folic acid Colonis Folic acid MT/H/0203/001/DC Date: 18 th November, 2016 Summary PAR non-generics 1/4

2 Summary Public Assessment Report non-generics Folic acid Colonis Folic acid This is a summary of the public assessment report (PAR) for Folic acid. It explains how Folic acid was assessed and its authorisation recommended as well as its conditions of use. It is not intended to provide practical advice on how to use Folic acid. For practical information about using Folic acid, patients should read the package leaflet or contact their doctor or pharmacist. What is Folic acid and what is it used for? Folic acid is a medicine with well-established use. This means that the medicinal use of the active substance of Folic acid is well established in the European Union for at least ten years, with recognised efficacy and an acceptable level of safety. Folic oral solution is used for the prevention and treatment of conditions caused by deficiency of folic acid: 1. Prevention of neural tube defects (abnormalities of the spine, eg. spina bifida) in babies, including if you have previously had a baby with this disorder. 2. Prevention and treatment of anaemia caused by folic acid deficiency. This may occur in the following situations. a) pregnancy b) excessive alcohol intake or poor nutrition c) effects of other drugs (eg. anticonvulsants, used to prevent fits) d) sickle cell anaemia (or other types of anaemia caused by abnormal red blood cells) e) problems with absorption of folic acid from the gut (eg. tropical sprue or coeliac disease) How does Folic acid work? <Copy the relevant information from Section 1 of the PL What X is and what is it used for. Note that the PL is directed to the patient, rewrite accordingly if necessary. If relevant, add information from Section 5.1 in the SmPC, reworded in lay terms.> How is Folic acid used? The pharmaceutical form of Folic acid is oral solution and the route of administration is oral. Please read section 3 of the PL for detailed information on dosing recommendations, the route of administration, and the duration of treatment. Summary PAR non-generics 2/4

3 Dose: Adults and Elderly people To treat folate deficiency anaemia: The recommended dose is 5 ml a day for 4 months, which may be increased up to a maximum of 15 ml a day. To prevent folate deficiency caused by some medicines: The recommended dose is 5 ml a day for 4 months, which may be increased up to a maximum of 15 ml a day. To prevent folate deficiency caused by long-term red blood cell damage or kidney dialysis: The recommended dose can vary from a minimum of 5ml every week to a maximum of 5ml every day. Your doctor will tell you what dose you should take. To prevent neural tube defects in babies, in women who have previously had an affected child: The recommended dose is 5 ml a day started before conception and continued throughout the first three months of pregnancy. To prevent neural tube defects in babies, in women who are at a lower risk of having an affected child: The recommended dose is 0.4 ml a day started before conception and continued throughout the first three months of pregnancy. Dose: Pregnancy The recommended dose during pregnancy is 5 ml a day, continued until birth in women who have previously had an affected child and 0.4 ml per day in women who are at lower risk of having an affected child. Dose: Children The usual dose is 5 to 10 ml a day. Your doctor will decide the correct dose for you, and will advise you how long to take your medicine for. The medicine can only be obtained with a prescription. What benefits of Folic acid have been shown in studies? As Folic acid is a well-known substance, and its use in the prevention of neural tube defects and in the prevention and treatment of anaemia is well established, the applicant presented data from the scientific literature. The literature provided confirmed the efficacy and safety of Folic acid in the prevention of neural tube defects and in the prevention and treatment of anaemia What are the possible side effects from X? For the full list of all side effects reported with Folic acid, see section 4 of the package leaflet. Do not take folic acid if you have a tumour or cancer. Please refer to the PL of Folic acid for a full list of situations where this medicine should not be taken. The main safety concerns identified in the Risk Management Plan are the following: Summary PAR non-generics 3/4

4 Why is Folic acid approved? Folic acid is both effective and safe when used according to the instructions detailed in the PL. In spite of the adverse effects associated with folic acid, it remains a very useful drug in a variety of patients for whom its benefit outweighs the risks. The Medicines Authority decided that Folic acid s benefits are greater than its risks and recommended that it be approved for use. What measures are being taken to ensure the safe and effective use of Folic acid? A risk management plan has been developed to ensure that Folic acid is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Folic acid, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously as well. Other information about Folic acid The marketing authorisation for Folic acid was granted on the 17 th of September, The full PAR for Folic acid can be found on the website For more information about treatment with Folic acid, read the package leaflet or contact your doctor or pharmacist. This summary was last updated in Summary PAR non-generics 4/4

5 CMDh/223/2005 February 2014 Public Assessment Report Scientific discussion Folic acid Colonis 1mg/ml oral solution Folic acid MT/H/0203/001/DC Date: 18 th November, 2016 This module reflects the scientific discussion for the approval of Folic Acid Colonis 1mg/ml oral solution. The procedure was finalised on the 17 th of September, For information on changes after this date please refer to the module Update.

6 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Folic acid Colonis 1mg/ml oral solution, from Colonis Pharma Limited. The product is indicated: 1. For the prophylaxis of neural tube defects in case of a positive history of previous neural tube defects (NTD). 2. For the prophylaxis of NTDs with no previous history of foetal neural tube defect and no other predisposing factors 3. For the treatment of folate deficiency: a. Folate deficient megaloblastic anaemia (in pregnancy, associated with alcoholism, drug intake such as anticonvulsants). For the prevention of megaloblastic anaemia, the cobalamin status should be established before initiation of folic acid therapy. b. Impaired utilization of folate i.e. use of concomitant drugs, in liver disease, inadequate intake (e.g. alcoholism, malnutrition etc.) c. Increased excretion of folate (e.g. alcoholism, haemolytic states). 4. Folate deficiency / megaloblastic anaemia associated with haemolytic anaemia (e.g. sickle cell anaemia) 5. Treatment of folate deficiency in malabsorption syndromes (parenteral administration of folic acid may need to be considered if oral treatment is not effective) (e.g.: tropical sprue. tropical sprue responds to folate supplements in the early stages of the disease but cobalamin status must also be checked, particularly later; coeliac disease in which case the necessity of supplementation with folate ceases once a gluten free diet is introduced; non-tropical sprue; in congenital folate malabsorption (oral treatment may not be effective and parental folate may therefore be required). Cobalamin status needs to be established in all megaloblastic states (not only in pregnancy). A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation for Folic Acid Colonis has been granted in accordance with Article 10a of Directive 2001/83/EC as amended. The active substance has a well-established use within the European Community for at least 10 years, with recognised efficacy and an acceptable level of safety. The CMSes in this procedure were CY, EL and UK. This product is subject to a medical prescription. II. II.1 QUALITY ASPECTS Introduction PAR Scientific discussion 2/7

7 Each 1 ml of oral solution contains 1 mg of folic acid. The excipients are the following: Sodium Methyl Parahydroxybenzoate (E219) Disodium Edetate (E385) Mannitol (E421) Hydrochloric Acid, Concentrated (E507) Water, Purified Folic acid oral solution 1mg/ml is packed in an amber (Type III) glass bottle of 150 ml with a child-resistant, tamper-evident screw cap with an LDPE liner, a 5ml graduated oral dosing syringe and a press-in syringe/bottle adaptor (PIBA). II.2 Drug Substance The active substance Folic acid is described in the European Pharmacopoeia, reference 07/2010:0067. For the drug substance a Certificate of Suitability issued by EDQM was included in this Marketing Authorisation submission (MAA). Folic acid is a crystalline, yellow to yellow-orange practically odourless powder. It is described as very slightly soluble in water, insoluble in alcohol, acetone, ether and chloroform and readily soluble in solutions of alkali hydroxides and carbonates. The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Folic acid is of sufficient quality in view of the present European regulatory requirements. The control tests and specifications for drug substance product are adequately drawn up. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period of 3 years if stored in polyethylene bags laminated with aluminium foil is justified. II.3 Medicinal Product The applicant has adequately addressed questions regarding the development of the product and the choice of excipeints included in the formulation. No novel excipients were included in the formulation. Preservative efficacy trials have been performed and reports have demonstrated proof of efficacy of the preservative at the concentrations chosen. The manufacturing process is a simple and conventional manufacturing process for an oral solution. The manufacturing process is adequately described and has been appropriately validated. The critical parameters chosen (such as mixing time, mixing speeds, ph and temperature) in the manufacturing process were adequately discussed. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on three batches. The batch analysis results show that the finished product meet the specifications proposed. The proposed packaging is an amber (Type III) glass bottle, with child-resistant, tamperevident screw cap with an LDPE liner, a 5ml graduated oral dosing syringe and a press-in syringe/bottle adaptor. The exterior container is a carton box containing one bottle, one oral syringe, one bottle adaptor and one leaflet. PAR Scientific discussion 3/7

8 The conditions used in the stability studies are according to the ICH stability guideline. The control tests and most of the specifications for the drug product are adequately drawn up. The shelf life and storage conditions requested can be granted as follows: Shelf life: 18 months. After first opening do not store above 25 C and use within 3 months. Storage conditions: Do not store above 25 C. Keep bottle in the outer carton. On the outer packaging the following statement will also be included: Date of first opening: III. III.1 NON-CLINICAL ASPECTS Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of folic acid are well known. As folic acid is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required because the application concerning it is being made in accordance with Article 10(a) of Directive 2001/83/EC as amended as a medicinal product the active substance of which has a well-established use within the European Community for at least 10 years, with recognised efficacy and an acceptable level of safety All non-clinical and clinical documentation presented in modules 4 and 5 for this application, consisted of publications. The applicant did not provide data from own tests. The submission of bibliographical nonclinical and clinical data is justified. The non-clinical overview refers 37 publications in the literature up to year The data in this overview has not raised any new concerns. The Non-Clinical Overview on the pre-clinical pharmacology, pharmacokinetics and toxicology based on literature review is, thus, appropriate. III.2 Ecotoxicity/environmental risk assessment (ERA) Given that Folic acid, known as folate in its natural form, is one of the B-group vitamins, it occurs in its natural form in the environment (broccoli, brussels sprouts, liver, spinach, asparagus, peas, chickpeas, fortified breakfast cereals etc). Therefore, it is exempt from the requirement of an ERA in line with the Guideline on the Environmental Risk Assessment of the medicinal products for human use (EMEA/CHMP/SWP/4447/00). III.3 Discussion on the non-clinical aspects The application is made under reference to article 10(a) of Directive 2001/83/EC as amended. Such applications avoid the need for repetitive tests on animals and humans. IV. IV.1 CLINICAL ASPECTS Introduction PAR Scientific discussion 4/7

9 The formulation is an oral solution and no comparative bioavailability studies to demonstrate bioequivalence are required. For a well-established medicinal use marketing authorisation application for Folic acid Oral Solution it is possible to replace results of the pre-clinical and clinical trials by detailed references to published scientific literature (information available in the public domain). As a consequence, no special concern must be addressed and the clinical overview only mirrors and summarizes the toxicological and pharmacological well known properties of the active substance. The applicant provided a justification supporting well established use in the EU, with appropriate citations to European published literature categorised according to indication and publication type. The efficacy and safety is based on a literature review of case reviews, open label, and double-blind controlled trials for the treatment of folate-deficient megaloblastic anaemia, or for prophylaxis against folate deficiency in chronic haemolytic states and renal dialysis, or to prevent neural tube defect where there is a history of this condition in a previous child. References outside clinical trials, compassionate use and named patient supply are provided, and these are acceptable showing systematic use of Folic Acid outside clinical trials. IV.2 Clinical efficacy Available efficacy data have shown beneficial effects, with little or no evidence of adverse effects or toxicity, associated with oral folic acid supplementation, at levels up to 10 mg/day, for periods of several weeks or months. Furthermore, peri-conceptual folic acid supplementation in women is associated with a significant reduction in the incidence of neural tube defects (NTDs) in babies born to these women. The publications submitted demonstrate the beneficial effects of folic acid in the reduction of the incidence of neural tube defects if folic acid when administered to women a high risk of conceiving a child with such a defect and also that a similar reduction occurs in women with a lower risk if folic acid at a lower dose is given peri conceptually. The random controlled trials submitted also showed that folic acid supplementations associated with a reduction of serum levels of homocysteine in patients with hyperhomocysteinaemia. This can result in prevention of cardiovascular disease by effectively reducing homocysteine levels. IV.3 Clinical safety Folic acid is generally considered as safe, even at extremely high doses, as excesses of the compound are mostly excreted in the urine, rather than being stored in the tissues. The consequences of long-term excessive intakes are not, however, clearly established, and certain groups may be particularly susceptible to potential adverse effects. IV.4 Risk Management Plan The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Folic Acid Colonis. The following Safety specifications are acceptable: PAR Scientific discussion 5/7

10 The applicant included Cobalamin status needs to be established in all megaloblastic states (not only in pregnancy) as a routine measure to minimise the risks identified with Folic acid. IV.5 Discussion on the clinical aspects The application is made under reference to article 10(a) of Directive 2001/83/EC as amended. Such applications avoid the need for repetitive tests on animals and humans. V. USER CONSULTATION The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was English. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. The test did not involve a pilot test but consisted of two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Based on the review of the data and the Applicant s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS considers that the application for Folic acid Colonis 1mg/ml oral solution, in the treatment of 1. For the prophylaxis of neural tube defects in case of a positive history of previous neural tube defects (NTD). 2. For the prophylaxis of NTDs with no previous history of foetal neural tube defect and no other predisposing factors 3. For the treatment of folate deficiency: PAR Scientific discussion 6/7

11 d. Folate deficient megaloblastic anaemia (in pregnancy, associated with alcoholism, drug intake such as anticonvulsants). For the prevention of megaloblastic anaemia, the cobalamin status should be established before initiation of folic acid therapy. e. Impaired utilization of folate i.e. use of concomitant drugs, in liver disease, inadequate intake (e.g. alcoholism, malnutrition etc.) f. Increased excretion of folate (e.g. alcoholism, haemolytic states). 4. Folate deficiency / megaloblastic anaemia associated with haemolytic anaemia (e.g. sickle cell anaemia) 5. Treatment of folate deficiency in malabsorption syndromes (parenteral administration of folic acid may need to be considered if oral treatment is not effective) (e.g.: tropical sprue. tropical sprue responds to folate supplements in the early stages of the disease but cobalamin status must also be checked, particularly later; coeliac disease in which case the necessity of supplementation with folate ceases once a gluten free diet is introduced; non-tropical sprue; in congenital folate malabsorption (oral treatment may not be effective and parental folate may therefore be required). Cobalamin status needs to be established in all megaloblastic states (not only in pregnancy). is approvable. PAR Scientific discussion 7/7