public assessment report - gov.uk · pdf filepar levothyroxine 25, 50 and 100micrograms/5ml...

PAR Levothyroxine 25, 50 and 100micrograms/5ml Oral Solution

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Public Assessment Report

Decentralised Procedure

Levothyroxine 25micrograms/5ml Oral Solution Levothyroxine 50micrograms/5ml Oral Solution

Levothyroxine 100micrograms/5ml Oral Solution

(Levothyroxine sodium)

Procedure No: UK/H/5477/002-04/DC

UK Licence No: PL 29831/0493-495

Wockhardt UK Ltd.


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LAY SUMMARY

Levothyroxine 25micrograms/5ml Oral Solution Levothyroxine 50micrograms/5ml Oral Solution Levothyroxine 100micrograms/5ml Oral Solution

(levothyroxine sodium, oral solution, 25,50 or 100micrograms (mcg)/5ml)

This is a summary of the Public Assessment Report (PAR) for Levothyroxine 25, 50 and 100micrograms/5ml Oral Solution (PL 29831/0493-495; UK/H/5477/002-4/DC). It explains how Levothyroxine 25, 50 and 100micrograms/5ml Oral Solution were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Levothyroxine 25, 50 and 100micrograms/5ml Oral Solution. The products will be collectively referred to as Levothyroxine Oral Solution throughout the remainder of this PAR. For practical information about using Levothyroxine Oral Solution, patients should read the package leaflet or contact their doctor or pharmacist. What is Levothyroxine Oral Solution and what is it used for? Levothyroxine Oral Solution is a ‘generic medicine’. This means that Levothyroxine Oral Solution is similar to ‘reference medicines’ already authorised in the European Union (EU) called Eltroxin 25, 50 and 100 micrograms per 5ml Oral Solution (Mercury Pharmaceuticals Ltd). Levothyroxine Oral Solution is used to treat hypothyroidism, a condition in which the thyroid gland is underactive and so does not make enough thyroxine for the body's needs. Levothyroxine Oral Solution is also used to treat thyroid cancer and diffuse non-toxic goitre or Hashimoto's thyroiditis, conditions in which the thyroid gland becomes enlarged causing a swelling in the front of the neck. Levothyroxine Oral Solution in this formulation is not

suitable for children under five years of age due to the amount of the ingredient propylene glycol in this medicine (100 mg/5ml). Alternative formulations of this medicine exist with a different ingredient content, that are more suitable for children under five years of age.

How does Levothyroxine Oral Solution work? Levothyroxine sodium (the active ingredient in this medicine) belongs to a group of medicines called thyroid hormones. Levothyroxine is the same as the hormone thyroxine, which is produced naturally by the thyroid gland. The thyroid gland produces and releases two thyroid hormones: thyroxine (T4) and tri-iodothyronine (T3). T3 is the more active thyroid hormone, and thyroxine is converted into T3 in various parts of the body. These hormones are responsible for maintaining a normal rate of metabolism in the body. When the thyroid gland is unable to produce normal amounts of thyroxine, the level of both thyroid hormones in the blood decreases (hypothyroidism). This results in a reduced rate of metabolism, leading to symptoms such as weight gain, intolerance to cold and tiredness. This medicine is given to replace the thyroxine that would normally be produced naturally by the thyroid gland to return the levels of T3 and T4 to normal.


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How is Levothyroxine Oral Solution used? The pharmaceutical form of Levothyroxine Oral Solution is an oral solution and the route of administration is via the mouth (oral). The patient must take this medicine exactly as their doctor has told them. The patient should check with their doctor or pharmacist if they are not sure. The patient’s doctor will have decided what dose the patient should take each day depending on the patient’s age and condition. The patient’s doctor will take blood samples at regular intervals to monitor their response to treatment. If the patient is switching from the oral solution to the tablet version of levothyroxine or from the tablet version to the oral solution of thyroxine, the patient’s doctor will monitor them more closely. The patient should take this medicine on an empty stomach, usually before breakfast. The patient must use the oral syringe provided with this medicine to deliver their specific dose. Instructions on how to use the syringe are included in section 3 the package leaflet. Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment. The duration of treatment is usually for life if the patient is being treated for hypothyroidism, non-toxic diffuse goite or Hashitmoto’s thyroiditis. Levothyroxine Oral Solution can only be obtained with a prescription. What benefits of Levothyroxine Oral Solution have been shown in studies? Because Levothyroxine Oral Solution is a generic medicine, studies in patients have been limited to tests to determine that this medicine is bioequivalent to the reference medicine Eltroxin 25, 50 and 100 micrograms per 5ml Oral Solution (Mercury Pharmaceuticals Ltd). Two medicines are bioequivalent when they produce the same levels of the active substance in the body. What are the possible side effects of Levothyroxine Oral Solution? Because Levothyroxine Oral Solution is a generic medicine, its benefits and possible side effects are taken as being the same as the reference medicine. For the full list of restrictions, see the package leaflet. For the full list of all side effects reported with Levothyroxine Oral Solution, see section 4 of the package leaflet available on the MHRA website. Why was Levothyroxine Oral Solution approved? It was concluded that, in accordance with EU requirements, Levothyroxine Oral Solution has been shown to have comparable quality and to be bioequivalent to Eltroxin 25, 50 and 100 micrograms per 5ml Oral Solution (Mercury Pharmaceuticals Ltd). Therefore, the MHRA decided that, as for Eltroxin 25, 50 and 100 micrograms per 5ml Oral Solution (Mercury Pharmaceuticals Ltd), the benefits are greater than their risk and recommended that it can be approved for use.


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What measures are being taken to ensure the safe and effective use of Levothyroxine Oral Solution? A risk management plan (RMP) has been developed to ensure that Levothyroxine Oral Solution 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 Levothyroxine Oral Solution including the appropriate precautions to be followed by healthcare professionals and patients. It includes information stating that Levothyroxine Oral Solution in this formulation is not suitable for children under five years of age due to some of the ingredients it contains e.g. propylene glycol (100 mg/5ml). Alternative formulations of this medicine exist with a different ingredient content, that are more suitable for children under five years of age. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously. Other information about Levothyroxine Oral Solution Ireland and the UK agreed to grant Marketing Authorisations for Levothyroxine Oral Solution on 27 January 2016. Marketing Authorisations were granted in the UK on 18 February 2016. The full PAR for Levothyroxine Oral Solution follows this summary. For more information about treatment with Levothyroxine Oral Solution read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in April 2016.


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TABLE OF CONTENTS

I Introduction Page 6 II Quality aspects Page 8 III Non-clinical aspects Page 10 IV Clinical aspects Page 10 V User consultation Page 15 VI Overall conclusion, benefit/risk assessment and

recommendation Page 15


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I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the applications for Levothyroxine Oral Solution (PL 29831/0493-495; UK/H/5477/002-4/DC) could be approved. The products are prescription-only medicines (POM) indicated for:

• Hypothyroidism (congenital or acquired) • Diffuse non-toxic goitre • Goitre associated with Hashimoto’s thyroiditis • Suppression therapy in thyroid carcinoma

Levothyroxine 25, 50 and 100micrograms/5ml Oral Solution in this formulation is not suitable for children under the age of five years due to the excipient content (see section 4.4 of the SmPC). Alternative formulations of Levothyroxine 25, 50 and 100micrograms/5ml Oral Solution exist, with a different excipient content, that are more suitable for the paediatric population under five years of age. The applications were submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Ireland as Concerned Member State (CMS). The applications were submitted under Article 10.1 of Directive 2001/83/EC, as amended, as a generic application. The reference medicinal products for these applications are Eltroxin 25, 50 and 100 micrograms per 5ml Oral Solution (PL 12762/0459, PL 12762/0461 and PL 12762/0462), which were granted in the UK on 16 May 2012 via an incoming decentralised procedure (DE/H/3013/01-03/DC) with the UK as a CMS. The reference products were submitted under Article 10(a), as bibliographic applications and are considered as full dossiers but not in principle entitled to a new period of data exclusivity. They may therefore be cited as a reference product in an application under Article 10 and are considered part of the same global marketing authorisation as the Eltroxin tablet forms. The legal basis is satisfactory. Thyroxine (T4) is a naturally occurring hormone containing iodine, produced by the thyroid gland. It is converted to its more active principle tri-iodothyronine (T3) in the peripheral tissues. Receptors for T3 are found on cell membranes, mitochondria and cell nuclei. Thyroid hormones are required for normal growth and development of the body, especially the nervous system. They increase the basal metabolic rate of the whole body and have stimulatory effects on the heart, skeletal muscle, liver and kidney. The synthetic levothyroxine contained in Levothyroxine Oral Solution is identical in effect with the naturally occurring thyroxine secreted by the thyroid. No new non-clinical studies were conducted for these applications, which is acceptable given that the applications were based on being a generic medicinal product of an originator product that contains an active ingredient of well-established use. As the excipient compositions of the applicant’s products are different to the reference products (including the excipient maltitol which can affect gastrointestinal transit), the applicant submitted a bioequivalence study (conducted under fasting conditions). The applicant has stated that the bioequivalence study was conducted in accordance with the International Conference on Harmonisation (ICH), Harmonised Tripartite Guideline for Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place at all sites responsible for the manufacture, assembly and batch release of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.


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The RMS and CMS considered that the applications could be approved at the end of procedure on 27 January 2016. After a subsequent national phase, a licence was granted in the UK on 18 February 2016.


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II QUALITY ASPECTS II.1 Introduction Each 5 ml of oral solution contains 25, 50 or 100micrograms of levothyroxine sodium. Other ingredients consist of the following pharmaceutical excipients citric acid monohydrate, sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, propylene glycol, liquid maltitol, sodium hydroxide, hydrochloric acid and purified water. The finished product is packed into conventional amber soda glass (Type III) bottles fitted with 28mm child resistant tamper evident caps. A 5ml oral dosing pipette is provided. A pipette adaptor will be fitted to the bottle neck in order to allow the dosing device to be used. All strengths of the finished product are available in 100ml and 150ml bottle sizes. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. II.2. Drug Substance INN: Levothyroxine sodium Chemical names: Sodium (2S)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-

diiodophenyl]propanoate. Structural formula:

(anhydrous substance)

Molecular formula: C15H10I4NNaO4,xH2O (x≈5) Molecular mass: 799 g/mol Appearance: Almost white or slightly brownish-yellow, fine, slightly hygroscopic, crystalline

powder. Solubility: Very slightly soluble in water, slightly soluble in ethanol (96 per cent). It dissolves

in dilute solutions of alkali hydroxides. Levothyroxine sodium is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance, levothyroxine sodium, are covered by the European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificates of Suitability. II.3. Medicinal Product Pharmaceutical Development The objective of the development programme was to formulate a safe, efficacious, oral solution containing 25, 50 or 100micrograms of levothyroxine sodium per 5 ml of oral solution that was comparable in performance to the originator products Eltroxin 25, 50 and 100 micrograms per 5ml Oral Solution (Mercury Pharmaceuticals Ltd). A satisfactory account of the pharmaceutical development has been provided.


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All excipients comply with their respective European Pharmacopoeia monographs with the exception of sodium hydroxide and hydrochloric acid which are controlled to suitable in-house specifications. Satisfactory Certificates of Analysis have been provided for all excipients. Suitable batch analysis data have been provided for each excipient. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Manufacture of the products Satisfactory batch formulae have been provided for the manufacture of the products, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at pilot scale batch size and has shown satisfactory results. The process validation protocol to be followed for full-scale production batches has been provided and is satisfactory. Finished Product Specifications The finished product specifications proposed are acceptable. Test methods have been described that have been adequately validated. Batch data have been provided that comply with the release specifications. Certificates of Analysis have been provided for all working standards used. Stability of the Product Finished product stability studies were performed in accordance with current guidelines on batches of finished product in the packaging proposed for marketing. The data from these studies support a shelf-life of 2 years for the unopened bottle with the storage conditions ‘Do not store above 25°C.’ The in-use shelf life of the product is 3 months after first opening. Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. II.4 Discussion on chemical, pharmaceutical and biological aspects There are no objections to the approval of these applications from a pharmaceutical viewpoint.


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III NON-CLINICAL ASPECTS III.1 Introduction As the pharmacodynamic, pharmacokinetic and toxicological properties of levothyroxine sodium are well-known, no new non-clinical studies are required and none have been provided. An overview based on the literature review is, thus, appropriate. The MAH’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. III.2 Pharmacology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.3 Pharmacokinetics Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.4 Toxicology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.5 Ecotoxicity/environmental risk assessment (ERA) Since Levothyroxine Oral Solution is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.6 Discussion on the non-clinical aspects There are no objections to the approval of these applications from a non-clinical viewpoint. IV CLINICAL ASPECTS IV.1 Introduction The clinical pharmacology of levothyroxine sodium is well-known. With the exception of data from the bioequivalence study detailed below, no new pharmacodynamics or pharmacokinetic data are provided or are required for these applications. No new efficacy or safety studies have been performed and none are required for this type of application. A comprehensive review of the published literature has been provided by the applicant, citing the well-established clinical pharmacology, efficacy and safety of levothyroxine sodium. Based on the data provided, Levothyroxine Oral Solution can be considered bioequivalent to Eltroxin 25, 50 and 100 micrograms per 5ml Oral Solution (Mercury Pharmaceuticals Ltd). IV.2 Pharmacokinetics The pharmacokinetics of levothyroxine sodium are well known and are supported by published references. Arising from concerns over differences in the excipient composition of the test and reference products, including the excipient maltitol which can affect gastrointestinal transit, the applicant submitted the following bioequivalence study to support these applications: STUDY An open-label, randomised, two-period, two-sequence, single dose, crossover bioequivalence study of the applicant’s test product Levothyroxine 50micrograms/5ml Oral Solution (Wockhardt UK Ltd) versus


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the reference product Eltroxin 100 micrograms per 5ml Oral Solution (Mercury Pharmaceuticals Ltd) in healthy, adult, subjects under fasting conditions. Subjects were administered a single, supra-therapeutic dose (600 micrograms) of the test or the reference product under fasting conditions. Blood samples were collected for measurement of thyroxine concentrations before dosing and up to and including 72 hours after each administration. The washout period between the treatment phases was 35 days. The pharmacokinetic results are presented below: Table: Summary of pharmacokinetic parameters for thyroxine (T4) [baseline adjusted] following 600 micrograms Levothyroxine 50micrograms/5ml Oral Solution (Test IMP) and 600 micrograms Eltroxin 100 micrograms per 5ml Oral Solution (reference IMP): (IMP=investigational medicinal product).

AUC0-t area under the plasma concentration-time curve from zero to t hours AUC0-inf area under the plasma concentration-time curve from time zero to infinity Tmax Time taken to reach maximum plasma concentration Cmax maximum plasma concentration Conclusion The 90% confidence intervals of the test/reference ratio for AUC and Cmax values for T4 for the 50micrograms/5ml strength test product strength lie within the acceptable limits of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the applicant’s test product Levothyroxine 50micrograms/5ml Oral Solution (Wockhardt UK Ltd) is bioequivalent to the reference product Eltroxin 100 micrograms per 5ml Oral Solution (Mercury Pharmaceuticals Ltd). As the 25, 50 and 100micrograms/5ml strength test products meet the biowaiver criteria specified in the current bioequivalence guidance, the results and conclusions of the bioequivalence study with the 50micrograms/5ml oral solution strength can be extrapolated to the 25 and 100micrograms/5ml strength. Whilst the products can be concluded to have equivalent efficacy from the demonstration of equivalent systemic bioavailability of the active substance, they cannot be considered to have equivalent safety due to the presence of excipients including propylene glycol and parabens in the proposed but not in the reference product. Clinical interchangeability therefore cannot be concluded from the bioequivalence study.


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IV.3 Pharmacodynamics Levothyroxine sodium is a synthetic form of the endogenous thyroid hormone, thyroxine (T4). Thus, its actions in the human body are synonymous with those of T4. The free (non-bound) forms of T4 and T3 produce physiological effects. Most of the physiological effects are mediated by T3, approximately 80% of which is derived from T4 by de-iodination in peripheral tissues. Thyroid hormones exert widespread effects in the body. They work alone or together with other hormones to produce a general increase in carbohydrate, fat and protein metabolism. Oxygen consumption is increased and heat generated, with an increase in basal metabolic rate. They also stimulate cardiac function and have an essential role in normal growth and development, particularly of the nervous system. The applicant has not conducted any new studies on the pharmacodynamic effects of levothyroxine and this is accepted. IV.4 Clinical efficacy Levothyroxine has been used in the treatment of hypothyroidism for over 60 years and its efficacy is well established. The applicant has supplied a bioequivalence study that demonstrates equivalent systemic bioavailability of the active substance. Whilst the products can be concluded to have equivalent efficacy from this, this is not sufficient to conclude equivalent safety due to the presence of excipients including propylene glycol and parabens in the proposed but not in the reference product. Clinical interchangeability therefore cannot be concluded from the bioequivalence study. IV.5 Clinical safety The safety profile of levothyroxine sodium is well known and adverse events are generally associated with over-treatment. Decreased bone mineral density, osteoporosis and increased fracture risk, as well as atrial fibrillation and other cardiovascular effects, are examples of conditions that may result from levothyroxine over-treatment. The risks of these adverse events can be mitigated by careful titration of the dose to the individual patient and ongoing monitoring of treatment. Therefore the main concerns regarding safety of the applicant’s Levothyroxine Oral Solution centre round the proposed excipients, particularly propylene glycol. In adults the safety margin is wide and therefore there are likely to be few clinical consequences of this excipient. A published EMA evaluation EMA/CHMP/704195/2013 (20th November 2014) of propylene glycol exposure limits, in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00 Rev.1) contains the following recommendation: “..clinical data showed that in children from the age of 5 years and adult patients, up to 500 mg/kg/day of propylene glycol could generally be considered safe. In the absence of compelling data this safety threshold is decreased to 50 mg/kg/day in children less than 5 years old, and even to 1 mg/kg/day in pre-term and term neonates due to known immaturity of both metabolic and renal clearances of propylene glycol in these populations” For the applicant’s Levothyroxine Oral Solution, the recommended posology for neonates and young infants with congenital hypothyroidism (where a high initial dose is given for 3 months) would expose


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this population to 40 – 60 mg/kg, 20 – 30 mg/kg and 10 – 15 mg/kg of propylene glycol per day with the respective 25 microgram, 50 microgram and 100 microgram per 5ml strengths. The recommended upper limit of propylene glycol exposure of 1mg/kg/day is exceeded in neonates with all formulation strengths; and for children under 5 years (the propylene glycol limit being 50mg/kg/day), with the lowest strength only. Given that it is counterintuitive to the prescriber that higher strength solutions would be safer for young children, a possible limited exclusion of under 5 years of age, but beyond the newborn period, for the lowest strength formulation only, is considered to present too great a risk. In addition, no acceptable daily intake for propylparaben has been determined for neonates and children under 2 years of age because of uncertainty related to the maturation of enzymes that metabolise propylparaben as well as the limitation of the available animal data corresponding to the youngest children. Therefore the risk posed by propylene glycol is added to by uncertainty over safety of exposure to propylparaben. The applicant’s Levothyroxine Oral Solution contains the same qualitative and quantitative composition of active substance as the reference product. Equivalent systemic bioavailability of the active substance has been demonstrated by a bioequivalence study. The substantially different excipient composition between the proposed and the reference product, in particular with respect to the excipient propylene glycol, poses a potential risk to children under 5 years of age. This has been addressed by clear warnings in the product information that this particular formulation of oral levothyroxine solution is not suitable for children under 5 years of age and that alternative formulations should be used in this age group. Although this is permissible in principle under generic prescribing legislation, it is very important that all measures are taken to ensure that prescriber, dispenser and patient/carer are fully aware of the unsuitability of the generic product in the under 5 years age group. The applicant has made suitable amendments to the SmPC, leaflet and label, warning that the product is not recommended for children under 5 years of age. Warnings will be included on the outer packaging, to be assessed during the National phase, that the product is not suitable for the under 5 years of age group, such that a dispensing pharmacist will be alerted to this as well as the prescriber. For the purpose of clarity, the level of risk posed by the potential to exceed the daily recommended exposure to propylene glycol in the under 5 years age group is reflected not by a full contraindication (and therefore this age group is not specified as excluded in section 4.3 of the SmPC). Instead, there are clear recommendations provided in section 4.1, 4.2 and 4.4 of the SmPC that alternative formulations of oral levothyroxine solution should be used in this age group. Furthermore, in the event that this product is on occasion supplied off-label for young children – perhaps due to unavailability of an alternative formulation – it is important that appropriate dosing information – aligned with that of the reference product - is included for this age group as there would be a far greater acute risk of dosing error if this were not present in the SmPC. This combination of instructions and warnings is considered to optimise the benefit-risk. IV.6 Risk Management Plan (RMP) The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), 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 Levothyroxine Oral Solution. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below:


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Summary table of safety concerns:

Summary table of risk minimisation measures:


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IV.7 Discussion on the clinical aspects The grant of marketing authorisations is recommended for these applications. 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. VI Overall conclusion, benefit/risk assessment and recommendation The efficacy of levothyroxine in the treatment of hypothyroid states and the benefit of its use is well established. The benefit of the applicant’s Levothyroxine Oral Solution compared with other formulations of levothyroxine, namely tablets, is in patients who have difficulty swallowing tablets, mainly children and the elderly. By provision of a satisfactory bioequivalence study, the applicant has confirmed that excipients with the potential to affect gastrointestinal transit and consequently absorption of levothyroxine, have not affected bioavailability of levothyroxine compared with currently licensed products. The applicant’s Levothyroxine Oral Solution contains excipients that are not included in other currently marketed oral solutions, in particular propylene glycol and hydroxybenzoates. The concentrations of these excipients are low enough that they are unlikely to cause clinical adverse events in adults. It is well known however that young children under the age of 5 years, and neonates in particular, are at increased risk from propylene glycol exposure due to the immaturity of elimination pathways involving alcohol dehydrogenase metabolism and renal clearance also. The current EMA recommendation for the upper limit of propylene glycol exposure is 1mg/kg/day for neonates and 50 mg/kg/day for children under 5 years. The presence of propylene glycol in the applicant’s Levothyroxine Oral Solution in amounts that would lead to exposure in excess of currently recommended limits, if prescribed in accordance with the recommended posology for treatment of hypothyroidism in young children, renders the formulation unsuitable for the age group under 5 years of age. The risk posed by propylene glycol is added to by the presence of parabens in the formulation, given that the safety of parabens in the paediatric population remains uncertain.


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Levothyroxine sodium 25, 50 and 100 microgram/ 5ml Oral Solution in this formulation cannot be recommended for children under 5 years of age and the product information reflects this. Given that alternative levothyroxine formulations exist on the UK and Irish markets, which contain neither propylene glycol nor parabens, it is considered that this restriction does not present a consequential risk to this age group as alternatives are available. The quality of the products is acceptable, and no new non-clinical or other clinical safety concerns other than those highlighted above, have been identified. Extensive clinical experience with levothyroxine sodium is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive. .


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website. The approved labelling for Levothyroxine 25 and 50micrograms/5ml Oral Solution is presented below:


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The following text is the approved label text for Levothyroxine 100micrograms/5ml Oral Solution. No label mock-ups have been provided. In accordance with medicines legislation, the product shall not be marketed in the UK until approval of the label mock-ups has been obtained:


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