GlaxoSmithKline (GSK) began distributing a changed formulation of Eltroxin tablets in New Zealand, in June 2007. Subsequently, the Centre for Adverse Reactions Monitoring (CARM) received an increase in adverse reaction reports associated with the new formulation.
In the interests of transparency, Medsafe is providing a comprehensive description of the change in formulation, the evaluation process, and the actions taken in response to the increase in adverse reaction reports.
The information provided in this document includes:
- a timeline detailing the entire regulatory process, from receiving GSK's application to the approval of alternative brands. The attachments include documents relevant to the specific action
- a question and answer section providing detailed information on Medsafe's evaluation process and information pertaining specifically to the Eltroxin application.
Eltroxin Questions and Answers
When did GSK inform Medsafe of their intention to change the formulation of Eltroxin tablets?
The manufacturer of Eltroxin tablets, GlaxoSmithKline (GSK), notified Medsafe of the reformulation of Eltroxin tablets in a letter dated 17 March 2004. The letter accompanied an application requesting approval of the new formulation.
The application was processed in accordance with the steps outlined in Section 5.3.2 of the New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth Edition, October 2001 (refer to www.medsafe.govt.nz/downloads/vol1.doc).
Assessment of the application involved evaluation, peer review and quality assurance processes. Additional information was required from the applicant and, as is common for this type of application, there were several cycles of additional information requested, provided and evaluated. When the assessment of the application was complete, a recommendation to consent the medicine was made to the Minister's delegate who formally approved the distribution of the product in New Zealand.
When was the new formulation approved?
The new formulation was approved for use in New Zealand on 16 November 2006.
When was the new formulation introduced to the New Zealand market?
The new formulation of Eltroxin was introduced to the New Zealand market in July 2007. Although the change occurred in July 2007, supplies of the old formulation were slowly used up by pharmacies meaning patients may not have been dispensed the new formulation until the end of 2007 or even early 2008.
Why did the formulation of Eltroxin change?
GSK made the decision to change the formulation. This was not due to a request from Medsafe or PHARMAC.
The reasons provided by GSK for the change in formulation were firstly that the new formulation will become the standard formulation marketed globally and secondly to improve stability of the product.
What information was assessed by Medsafe prior to approval of the new formulation of Eltroxin?
The application for the new formulation of Eltroxin consisted of administrative information, quality information and a bioequivalence study.
Data requirements for New Medicine Applications depend on whether the medicine meets the criteria for a new higher-risk medicine, new intermediate-risk medicine or new lower-risk medicine (refer to Section 3.3 of the New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth Edition, October 2001 available at www.medsafe.govt.nz/downloads/vol1.doc.
The new formulation of Eltroxin met the criteria for a new intermediate-risk medicine as the active ingredient and dose form had been previously approved by the Minister of Health.
Although the new formulation was to replace the innovator product marketed at that time, it was appropriate to evaluate the application against the Standard Requirements for New Multi-source (Generic) Prescription Medicines. These requirements are outlined in Section 8.3 of the New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth Edition, October 2001 available at www.medsafe.govt.nz/downloads/vol1.doc.
Medsafe currently accepts new intermediate-risk medicine applications that are presented in the internationally recognised Common Technical Document (CTD) format. The CTD format consists of Module 1 (administrative data), Module 2 (Overviews and Summaries of the Quality, Non-clinical and Clinical data), Module 3 (Quality), and, if relevant, Module 4 (Non-clinical study data) and Module 5 (Clinical Study Reports). Further information regarding the CTD format is available at http://www.ich.org/cache/compo/276-254-1.html.
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) stipulates that specific information is included in Modules 1, 2, 3 and 5 of a New Medicine Application as summarised in Table 1.
Table 1: Summary of Modules 1, 2, 3 and 5 of a New Medicine Application
|Module 1 Administrative information||Documents specific to each region; for example, application forms or the proposed label for use in the region.
A covering letter
A completed New Medicine Application Form
A comprehensive table of contents
Copies of proposed labeling
A draft datasheet and package insert (where applicable)
Evidence of Good Manufacturing Practice
Copies of European Certificates of Suitability (where applicable)
Letters of Access to required Drug Master Files (where applicable)
|Module 2 Overviews and summaries||Overviews and summaries of the Quality, Non-clinical and Clinical data|
|Module 3 Quality (Chemical and Pharmaceutical Data)||3.1 TABLE OF CONTENTS
3.2 BODY OF DATA
3.2.S DRUG SUBSTANCE
3.2.S.1 General Information
3.2.S.1.3 General Properties
3.2.S.2.2 Description of manufacturing process & controls
3.2.S.2.3 Control of materials
3.2.S.2.4 Controls of critical steps and intermediates
3.2.S.2.5 Process validation and/or evaluation
3.2.S.2.6 Manufacturing process development
3.2.S.3.1 Elucidation of structure and other characteristics
3.2.S.4 Control of drug substance
3.2.S.4.2 Analytical procedures
3.2.S.4.3 Validation of analytical procedures
3.2.S.4.4 Batch analyses
3.2.S.4.5 Justification of specification
3.2.S.5 Reference standards or materials
3.2.S.6 Container closure system
3.2.P DRUG PRODUCT
3.2.P.1 Description and composition of the drug product
3.2.P.2 Pharmaceutical development
3.2.P.3.2 Batch formula
3.2.P.3.3 Description of manufacturing process & controls
3.2.P.3.4 Controls of critical steps and intermediates
3.2.P.3.5 Process validation and / or evaluation
3.2.P.4 Control of excipients
3.2.P.4.2 Analytical procedures
3.2.P.4.3 Validation of analytical procedures
3.2.P.4.4 Justification of specifications
3.2.P.4.5 Excipients of human or animal origin
3.2.P.4.6 Novel excipients
3.2.P.5 Control of drug product
3.2.P.5.2 Analytical procedures
3.2.P.5.3 Validation of analytical procedures
3.2.P.5.4 Batch analyses
3.2.P.5.5 Characterisation of impurities
3.2.P.5.6 Justification of specification(s)
3.2.P.6 Reference standards or materials
3.2.P.7 Container closure system
3.2.P.8.1 Stability summary and conclusion
3.2.P.8.2 Post-approval stability protocol & committment
3.2.P.8.3 Stability data
3.2.A.1 Facilities and equipment
3.2.A.2 Adventitious agents safety evaluation
3.2.A.3 Novel excipients
3.2.R REGIONAL INFORMATION
3.3 LITERATURE REFERENCES
|Module 5 Clinical Study Reports||Human study reports (for new multi-source medicines this is generally a bioequivalence study report).|
The application for the new formulation of Eltroxin was presented in the CTD format and consisted of Module 1, Module 2, Module 3 and Module 5. Module 4 was not required as the active ingredient and dose form had been previously approved by Medsafe and the excipients in the product are commonly used in tablet formulations.
All of the information in Module 1, Module 3 and Module 5 of the application for the new formulation of Eltroxin and the additional information requested during the evaluation process were considered during the assessment. Module 2 is merely a summarised version on Module 3.
Is there any difference in the active ingredient (levothyroxine) contained in the old formulation and the active ingredient contained in the newly formulated tablets?
No. The active ingredient (levothyroxine also known as thyroxine) contained in the new formulation is identical to the active ingredient contained in the old formulation, and is sourced from the same manufacturing site, namely Sandoz GmbH, Schaftenau Plant, Biochemiestrasse 10, Langkampfen, Tyrol, Austria.
How is the active ingredient (levothyroxine) manufactured?
The method of manufacture for the active ingredient has not changed and is the same for the active ingredient contained in the new formulation and the old formulation. Manufacture is by chemical synthesis and does not involve genetic engineering (recombinant technology).
What ingredients are contained in the new formulation of Eltroxin tablets?
A comparison of the ingredients contained in the old formulation and the new formulation is presented in Table 2.
Table 2: Ingredients contained in the old and new formulations
|Component||Old formulation||New formulation|
|Active ingredient||Levothyroxine sodium||Levothyroxine sodium|
|Excipients||Magnesium stearate||Magnesium stearate|
|Lactose monohydrate||Microcrystalline cellulose|
|Maize starch||Pre-gelatinized maize starch|
|Silicon dioxide (Colloidal anhydrous silica)|
All of the excipients in the new formulation comply with the requirements of the European Pharmacopoeia (an internationally recognised standard) and are commonly used in medicines.
The new formulation does not contain monosodium glutamate (MSG) or wheat-based products.
Who manufactures the new formulation of Eltroxin tablets?
Glaxo Wellcome GmbH & Co, Industriestrasse 32-36, Bad Oldesloe, Germany is responsible for manufacturing, packing and testing the new formulation of Eltroxin tablets.
How is the new formulation of Eltroxin manufactured?
The new formulation of Eltroxin is manufactured by blending of the ingredients (initially the levothyroxine and a portion of the microcrystalline cellulose and later the remaining ingredients), then direct compression of the blend to form tablets.
The old formulation of Eltroxin was manufactured by blending all the ingredients except for the magnesium stearate and a portion of the maize starch. The blend was wet granulated and the granules dried and blended with the magnesium stearate and remaining portion of the maize starch prior to compression into tablets.
The manufacturing processes for both the old formulation and new formulation utilise standard, internationally accepted processes.
The manufacture of the tablet does not involve any genetic engineering (recombinant technology) steps.
What quality systems are in place at the manufacturing site to ensure the quality of the product?
To ensure that products are consistently produced and controlled to appropriate quality standards, manufacturers of pharmaceutical products are required to comply with internationally accepted standards known as Good Manufacturing Practice (GMP) standards.
Good Manufacturing Practice is a set of quality requirements that must be met by a medicines manufacturer in order to ensure that medicines made meet the required quality standards and are consistently safe and effective. The requirements cover such areas as factory management, factory design and hygiene, processing operations, contamination and cross-contamination control, raw material quality, documentation and record keeping, testing and many other aspects of a manufacturer's operation. The aim is to ensure that everything is done during the manufacture of a product to ensure that a quality product is made and that it will meet the requirements before it is released for use.
Evidence of GMP compliance from a recognised authority is required for all finished product manufacturing, packing and testing sites prior to consent of a medicine by the Minister of Health. A GMP certificate, licence or report from an authority with GMP assessment systems that are compatible with internationally accepted standards is required. For details of accepted documentation refer to Section 11 of the New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, October 2001 available at www.medsafe.govt.nz/downloads/vol1.doc.
Appropriate documentation from the Therapeutic Goods Administration in Australia was accepted as evidence that the site responsible for manufacturing, packing and testing the new Eltroxin formulation complies with internationally accepted GMP standards.
As part of the quality systems in place to ensure that a medicine is of an acceptable quality, the medicine must comply, for the duration of the product shelf-life, with specifications that were agreed between the company marketing the medicine and Medsafe. These specifications are known as shelf-life specifications.
The shelf-life specifications for the new Eltroxin formulation were considered acceptable based on the ICH Guideline, Specifications: Test Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances Q6A (available at http://www.ich.org/LOB/media/MEDIA430.pdf) and are an improvement from the finished product shelf-life specifications applied for the old formulation as presented in Table 3.
Table 3: Approved finished product shelf-life specifications that the old and new Eltroxin formulations must comply with for the duration of the product shelf life
|Old formulation||New formulation|
|Description||50 mcg tablet:
A white, ¼", biconvex tablet,
with a bisecting breakline on one
face and "50" inscribed above the
breakline. The other face is plain.
|50 mcg tablet:
White to off-white, round,
biconvex tablets imprinted
GS 11E on one face and
50 on the other.
|Standard requirement for pharmaceutical products.
|100 mcg tablet:
A yellow, ¼", biconvex tablet,
with a bisecting breakline on one
face and "100" inscribed above the
breakline. The other face is plain.
|100 mcg tablet:
White to off-white, round,
biconvex tablets imprinted
GS 21C on one face and
100 on the other.
|Identification of levothyroxine sodium|
|By HPLC||No specification||The retention time of the principal peak in the sample chromatogram corresponds with that of the principal peak in the levothyroxine sodium reference material chromatogram.||Standard requirement for pharmaceutical products.|
|By UV||No specification||The spectrum of the sample is concordant with that of the levothyroxine sodium reference material.|
|Levothyroxine sodium content (% label claim)||90.0 - 110.0||90.0 - 105.0||Standard requirement for pharmaceutical products.
The upper limit for assay (levothyroxine) is tighter for the new formulation than the old formulation.
|Drug-related impurities content (%)||The specification for impurities is significantly improved for the new formulation compared to
that for the old formulation.
GSK developed an improved test method capable of detecting impurities that the old method was unable to detect. The new method is used to test the new formulation. The limit for liothyronine sodium is tighter for the new formulation and the content of tetrac, HDPhDB acid, unspecified impurities and total impurities is controlled. Testing of the old formulation using the new test method indicates that the old formulation also contained tetrac, HDPhDB acid and unspecified impurities.
The acceptance criteria for impurities were found to be acceptable based on: ICH Guideline, Impurities In New Drug Products, Q3B(R), (refer to www.ich.org/LOB/media/MEDIA421.pdf for the current version of this guideline), and the impurity content of the old formulation of Eltroxin tablets and Eltroxin tablets marketed in Europe.
|Liothyronine sodium||≤ 2.0||≤ 1.0|
|Tetrac*||No specification||≤ 1.0|
|HDPhDB acid**||No specification||≤ 2.5|
|Any unspecified impurity||No specification||≤ 1.0|
|Total||No specification||≤ 5.0|
|Loss on drying at 105°C (%w/w)||No specification||3.0 - 6.5||Surrogate test for water content (permitted by ICH guideline Q6A).|
|Hardness||2.5 to 5.0 Kp||No specification||Hardness is not included in the specification for the new formulation as hardness testing is performed as an in-process control during manufacture. This is acceptable and is supported by ICH guideline Q6A.|
|Friability (performed only when hardness fails)||≤ 1.0 %||No specification||Tablet friability is not included in the specification for the new formulation as friability testing is performed as an in-process control during manufacture. This is acceptable and is supported by ICH guideline Q6A.|
|Dissolution (% levothyroxine sodium released)||55 % dissolution at 80 minutes||70 % dissolution in 45 minutes||Standard pharmacopoeial requirement for tablets.|
|Microbial limits test:||Standard pharmacopoeial requirement for tablets.
The acceptance criteria applied for the new formulation are those specified in the European Pharmacopoeia.
|Total viable aerobic count (cfu/mL)|
|Bacteria||No specification||Not more than 103|
|Fungi||No specification||Not more than 102|
|E. coli||No specification||Absent from 1 g|
|Packaging components||To be inspected||No specification||It is not currently a standard requirement to include this type of specification in the shelf-life specifications as packaging materials are controlled during the manufacturing process.|
* tetraiodothyroacetic acid
How is the safety and efficacy of a New-Intermediate Risk Medicine established?
In relation to tablet formulations, the safety and efficacy of a New-Intermediate Risk Medicine is usually established by the demonstration of bioequivalence with a medicine that has already been approved as both safe and effective on the basis of clinical trial data. It is internationally accepted that demonstration of bioequivalence is an acceptable surrogate for performing full clinical trials. Conducting a bioequivalence trial is significantly cheaper and quicker than performing a full clinical assessment on the new product and is favoured amongst generic medicine manufacturers.
How is bioequivalence determined?
Bioequivalence is determined by comparing, as a ratio, the rate and extent of absorption, metabolism and excretion (plasma profile) of two medicines in the body. Medsafe evaluated the new formulation of Eltroxin against internationally accepted criteria for quality, safety, and bioequivalence.
Any brand or formulation change can affect the bioavailability of a medicine (how a medicine is absorbed, metabolised and excreted). As the assessment of bioequivalence is based on population statistics, even where bioequivalence is proven for two medicines, it is possible that a small proportion of patients may experience either an increased or decreased therapeutic effect when changed from one product to another. This occurs because of an individual's variability in how the medicine is absorbed, metabolised, and excreted.
For medicines that have a wide therapeutic index, i.e. the safety and efficacy of the product remains unchanged across a broad range of plasma levels of the medication, the effect of individual variability on bioavailability is likely to be unnoticeable and very few patients will report adverse effects.
For medicines that have a narrow therapeutic index (as with levothyroxine), small changes in its bioavailability may alter the plasma levels leading to either decreased or increased therapeutic effect. This means that it is expected that a small number of patients treated with levothyroxine will invariably notice an increased or decreased therapeutic effect.
The purpose of most bioequivalence trials is to compare a formulation of a medicine (i.e. a generic medicine) with an unknown efficacy profile, against a medicine which has already been approved as both safe and effective on the basis of clinical trial data.
Bioequivalence data are generated from small clinical trials using a statistically significant sample of participants. In these trials participants receive samples of each medicine in a random sequence. After receiving each medicine, blood samples are taken from participants for a sufficient period to allow a profile of the drug's absorption and elimination to be obtained. Statistical profiles of the two medicines are then compared for each trial participant.
Three metrics are compared: Cmax ratio (the maximum level of drug in the body); AUC ratio (Area Under Curve - this is a measure of the total dose absorbed and eliminated by the participant), and Tmax (the time to maximum drug concentration).
Bioequivalence is required to be determined and expressed statistically. This is due to the inherent variability of drug absorption between individuals. This variability is handled statistically by summing the blood results obtained for each of the two medicines from each individual and comparing the means and distribution of Cmax, AUC, and Tmax. When the data are assessed in this way they can be deemed to be representative of the entire population.
By international definition two medicines are considered bioequivalent if: the ratio of the geometric means of the Cmax and AUC lies within the range of 80% and 125% at a 90% confidence level, and the difference in Tmax is not of concern clinically. This is a statistical calculation.
A common misconception is that the bioequivalence acceptance range correlates to 20% - 25% variability between the two medicines. The design of bioequivalence studies, as conducted for Eltroxin, correlates with a potential Type 1 error of up to 5%. This means that there is a 5% chance of two medicines being incorrectly judged bioequivalent when the bioequivalence acceptance criteria is met. To further reduce this risk additional parameters are evaluated, such as the comparability of dissolution profiles, and a full evaluation of the product as described above.
It is also important to note that even when a medicine meets the statistical requirements for bioequivalence there will still be a portion of the population whose individual variability falls outside the normal distribution. This is because bioequivalence studies are performed in a statistically significant sample of the population.
What information did GlaxoSmithKline provide to support the safety and efficacy of the new formulation of Eltroxin?
GlaxoSmithKline provided a bioequivalence study to support the clinical safety and effectiveness of the new formulation of Eltroxin. This study compared the new formulation of Eltroxin against a formulation of Eltroxin previously registered in New Zealand and currently marketed in Europe. This formulation was approved in New Zealand on 8 April 1981. This approach of building a bridge to a formulation that Medsafe has previously approved as safe and effective is permitted under New Zealand Medicine Guidelines.
An overview of the bioequivalence study provided for the new formulation of Eltroxin is presented in table 4.
Table 4: Overview of the bioequivalence study comparing the new formulation of Eltroxin against a formulation of Eltroxin previously registered in New Zealand and currently marketed in Europe.
|Study name||An open-label, single-centre, single dose, randomised, two-treatment, two-sequence crossover design study in healthy male and female volunteers to assess the bioequivalence of two ELTROXIN formulations.|
|Date of trial||17 December 2002 - 26 February 2003|
|Clinical site||PAREXEL GmbH, Institute of Clinical Pharmacology, Klinikum Westend, Haus 18, Spandauer Damm 130, D-14050 Berlin, Germany|
|Analytical site||W & T Laboratory, Turmstrabe 21, 10559 Berlin, Germany|
|Adverse events||No serious adverse event was observed during the study and no subject was withdrawn from the study due to an
adverse event. Adverse reactions were documented.
It is important to note the following in relation to adverse reactions in bioequivalence studies:
|Reference product||A formulation of Eltroxin tablets previously marketed in New Zealand and currently marketed in Europe.|
|Test product||The new formulation of Eltroxin that was approved by the Ministry of Health on 16 November 2006.|
|Study design||Open-label, single-centre, single dose, randomised, two-treatment, two-sequence crossover study in fasted healthy male and female volunteers.|
|Fasting period||10 hours pre-dose until 4 hours post-dose.
|Dose administered||A single 600 mcg dose (6 x 100 mcg tablets).
|Time of day of dose administration||8:30 am to 10 am|
|Times and nature of meals and snacks consumed on study days||Standardised low fibre meals at 4 and 10 hours following the dose, and a snack 14 hours following the dose.|
|Limitations applied to subjects' diet and medication during trial period||No alcohol or xanthine-containing products were permitted for 24 hours prior to dosing until collection of the
final blood sample during each period.
No grapefruit or grapefruit juice was permitted within seven days prior to the first dose of study medication until collection of the final blood sample during each period.
Medicines known to interfere with levothyroxine pharmacokinetics were not permitted for at least seven days prior to dosing and throughout the study unless approved by the Investigator and GSK. Subjects taking regular medicines (or a course of medication including herbal remedies or vitamin supplements), whether prescribed or not were excluded from the study. Over the counter preparations were not permitted for 48 hours before each study day until the end of the study period.
No subject was taking any regular medication prior to or during the study.
8 subjects received concomitant medications during the study. 3 subjects took 5 concomitant medications during the reference product treatment period and 5 subjects received 5 concomitant medications during the reformulated product treatment period. Drugs administered during treatment periods of the study were: paracetamol (po), lincomycin (po), ibuprofen (po), acetylsalicylic acid (po) and dexpanthenol ointment (topical). Acetylsalicylic acid (aspirin) and paracetamol were most commonly administered. Salicylates interfere with the protein binding of levothyroxine, therefore, the timing of salicylate use was examined to assess any effect on pharmacokinetic parameters. Only subject no. 7 had salicylate use within the 48-hour period of intensive pharmacokinetic sampling, which resulted in no apparent effect on this subject's pharmacokinetic parameters.
|Limitations on subjects' posture and physical activity on study days||Subjects remained upright or semi-recumbent for 4 hours after dosing and refrained from serious exercise for 24 hours prior to dosing and during the sample collection period.|
|Time between dosing of the reference and test products||37-39 days|
|Number of subjects who completed the study||36|
|Age range||20-40 years|
|Weight range||BMI of 19.3-26.2 kg/m²; body weight 50-75 kg (females), 55-80 kg (males).|
|Ethnicity||35 Caucasian and one of 'other' origin (not further specified).|
|Subject withdrawals and reasons||No subjects withdrew from the study.|
|Serum sampling times||Pre-dose at 0.5, 0.25 and 0 hours and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24 and 48 hours post-dose|
|Significant deviations from the study protocol||There were no significant deviations from the study protocol.|
|Entities measured||Levothyroxine (T4) and its physiologically active metabolite tri-iodothyronine (T3) were measured. In a blood sample, a proportion of T4 and T3 is bound to proteins and the remainder is free (not bound to proteins). Both total (bound + unbound) and free (unbound) T4 and T3 were measured.|
|Analytical test method||Serum samples were tested using an Abbott AXSYM microparticle enzyme immunoassay.
|Results||Cmax (the maximum level of drug in the body); AUC (Area Under Curve - this is a measure of the total dose
absorbed and eliminated by the participant), and Tmax (the time to maximum drug concentration) values for total
T4, total T3 and corrected total T4 (results adjusted to account for levothyroxine produced by the body) were
compared for the two products.
In all but one instance the calculated bioequivalence values fell within the internationally accepted range of 0.8 to 1.25. The Cmax value for baseline corrected total levothyroxine (TT4) fell outside the accepted limits of 0.8 to 1.25. This result was considered acceptable given that: Cmax is not clinically important for this medicine because of its long half life (greater than 5 days), AUC is the better predictor of efficacy and safety; and the observed compliance of the remaining measurements. In addition, there is a lack of international consensus over the scientific validity of comparing baseline corrected values.
Did Medsafe require any further information from GlaxoSmithKline prior to the distribution of the new formulation in New Zealand?
Yes. Medsafe directed the manufacturer to:
- Notify healthcare professionals of the formulation change, including dose recommendations, and the importance of thyroid monitoring.
- Label the packs containing the new formulation with the words 'New Formulation' for an appropriate period of time.
- Provide a patient resource to enable the comparison of the new formulation tablets with the previous Eltroxin tablets.
See the attachments in the timeline above for copies of these documents.
- Patterson S, Jones B. 2006. Bioequivalence and Statistics in Clinical Pharmacology. Florida:Chapman and Hall CRC. Pg 30