Published: 12 December 2005

Publications

Salamol Inhalers - New Zealand Brand Switching Complaints Investigation

Wellington
12 December 2005

Introduction

On 2 December 2004, Medsafe approved Salamol CFC-free inhaler for distribution in New Zealand. Salamol was approved on the basis that it met the international guidelines for registration of inhalers including clinical studies demonstrating interchangeability with Ventolin inhalers. The clinical data submitted showed no indication of device failure that was likely to be a particular problem.

The New Zealand sponsor, Airflow Products Ltd., commenced supply of Salamol CFC-free to the New Zealand Market in February 2005 under a supply contract with PHARMAC. Salamol is manufactured by IVAX Pharmaceuticals, Waterford, Ireland, a company with a number of years of experience in the manufacture and supply of asthma therapy products.

Following Medsafe approval, PHARMAC announced that there would be a brand switch for the supply of Salbutamol inhalers in New Zealand from Ventolin to Salamol CFC-free, effective from 1 July 2005. Patients receiving Ventolin were gradually switched to Salamol. This changeover corresponded with an increase in the number of complaints concerning Salamol received by health professionals, Medsafe, PHARMAC, and by the Centre for Adverse Reactions Monitoring (CARM).

In April 2005 PHARMAC delayed complete transfer to sole supply whilst investigations were undertaken, particularly testing co-ordinated by Medsafe. In June 2005 PHARMAC announced that Ventolin would be subsidised at the same level as Salamol for the next two years maintaining patient choice. Since June 2005 the number of reports to CARM has reduced significantly.

This report aims to summarise:

• The extent and nature of the complaints received, as reported by CARM;
• The investigative actions taken by Medsafe to establish root cause(s);
• The consideration given by the Medicines Adverse Reactions Committee (MARC), the sponsor and the manufacturer of Salamol, to the advice that should be given to patients and health professionals regarding the correct use of Salamol;
• The corrective actions taken by the sponsor and manufacturer of Salamol.

Background

Complaints reported to CARM began in late March 2005. By 31 July 2005 CARM had received 873 reports, exceeding the normal capacity of CARM's processing systems, and exceeding the usual reporting rate for brand switching complaints.

The complaints were categorised by CARM into the following groups:

Device Blocking,
Poor Spray,
Emptying Quickly,
Unpleasant taste,
Decreased Therapeutic Effect,
Other adverse event,
Requiring Treatment (steroids/emergency nebulisation).

In many reports more than one category of complaint was identified.

Where detailed, the most commonly reported problems were those of decreased therapeutic effect, blocking of the device and unpleasant taste.

Based on CARM analysis to 19 May 2005, eight reported events required treatment with or without a visit to an Emergency Department. Seven of these events were reported as due to decreased therapeutic effect and one was due to device blocking.

Inhaler Blocking

Several of the complaints made to CARM referred to the device being 'caked' with deposit resulting in malfunction. Many reports indicated that patients had not experienced this problem with Ventolin.

Both the Salamol and the Ventolin data sheets indicated that the inhaler needed to be actuated until a spray was produced prior to first use and needed to be cleaned weekly. Similarly, the package inserts for both Ventolin and Salamol indicated that the inhalers should be cleaned weekly and actuated before use.

CARM reports that when complainants were informed that Salamol required regular cleaning patients indicated that they were unaccustomed to having to clean the Ventolin inhaler, or found cleaning impractical or inconvenient, therefore did not clean the Salamol inhaler in order to keep it functioning.

Spray pattern

Some complainants reported that the spray pattern was different with Salamol, i.e. pressure was not felt in the mouth, leading to the impression that it was not working properly and hence leading to multiple actuations.

Salamol CFC-free does have a softer spray compared to that of Ventolin CFC-free. Clinical studies submitted to Medsafe by the manufacturer IVAX have shown that whilst both Salamol CFC-free and Ventolin CFC-free meet the international requirements for particle size distribution using a twin stage liquid impinger and multistage impactor, Ventolin CFC-free was found to have different dose distribution characteristics to that of Salamol CFC-free in that a higher proportion of the dose impacted on the "throat section" of the apparatus and less reached the 'lung section', thus generating a different 'mouth-feel' following administration.

Alcohol content

Complainants also reported an unpleasant alcohol taste, a particular problem for children with a subsequent reluctance or refusal to use the inhaler. There was also a well publicised but unconfirmed report of failure of roadside alcohol breath test following use of the Salamol inhaler.

Salamol CFC-free contains ethanol as a pharmaceutical excipient, in common with other pharmaceuticals and CFC-free inhalers. The amount of ethanol present in Salamol is very small (less than 1 g per inhaler). In therapeutic doses the amount of ethanol would not have a pharmacological effect or affect driving.

In relation to patients' religious beliefs and other reasons for avoiding alcohol, the sponsor has confirmed that Salamol is registered and available in some predominantly Muslim countries. Should a patient not wish to use Salamol CFC-free, alternative bronchodilator inhalers without alcohol are available in New Zealand.

UK Situation

Since the clogging and malfunction of the inhaler, and subsequent loss of therapeutic effect formed the majority of complaints received, this aspect formed the main focus of Medsafe investigations, with a comparison of the New Zealand situation with what had occurred following release of Salamol in the UK.

Salamol CFC-free was approved for use in the UK in March 2000 and the manufacturer, IVAX Pharmaceuticals, reports that Salamol is now sold in Europe, the Middle East, Africa and the USA.

In the first ten months of marketing in the UK there were 204 consumer complaints (131 complaints per million units distributed). The majority of complaints related to dose delivery failure following excessive drug deposition around the actuator stem block (clogging or blocking). Cleaning of returned inhalers following the instructions given in the patient information leaflets produced a fully functional product in the majority of cases. Further study concluded that the instructions to clean the inhaler on a weekly basis were adequate if followed accurately by the user.

A number of steps were implemented by the UK sponsor to reduce the number of complaints, and to increase patient awareness of the cleaning required to ensure the continued correct functioning of the product.

• The patient leaflet was redesigned to highlight the proper cleaning instructions in both normal and emergency use.
• When the issues first came to light, the sales force was advised of the need to raise patient awareness of cleaning requirements. The company also used its asthma nurses to reinforce the importance of cleaning compliance with doctors, pharmacists and patients.
• The manufacturer's Quality Assurance department continued to monitor the level of complaints.

The issue was also addressed in the UK by a patient education campaign, in association with the National Asthma Campaign. The launch of Salamol CFC-free in the UK coincided with the introduction of other CFC-free inhaler formulations, therefore there was a general campaign of health professional and patient education at the time. The campaign included the different physical characteristics of CFC-free inhalers, such as taste and feel when inhaling, and emphasised the need for weekly cleaning.

Since 2001, IVAX reports a decreasing trend of reported complaints against increasing sales in the UK, whilst returned inhalers assessed as faulty were at a consistently low level.

Investigations

Summary of initial testing

Approximately 16 new inhalers from the two batches of Salamol being distributed in New Zealand, and 33 inhalers reported as being faulty and returned by patients were subjected to a modified regime of finished product testing based on the 'registered' Salamol inhaler test methods and specifications. These specifications and test methods are based on those established for metered dose inhalers by the BP / Ph Eur (British Pharmacopoeia / European Pharmacopoeia).

Testing was carried out on behalf of Medsafe by ESR (Institute of Environmental Science and Research) in Porirua and by the TGA (Australian Therapeutic Goods Administration) Laboratories in Canberra (TGAL).

The tests performed were selected to examine the issues being raised by patients. In particular the aim of the testing was to:

• Confirm whether new Salamol Inhalers from both the batches being distributed met the relevant finished product specifications
• Determine whether the reportedly faulty inhalers were operating correctly
• Determine the reason for any issues identified
• Propose and demonstrate a means of remedying any issues identified

Initial test details (BP / Ph Eur)

• Dose deposition - This test measures the dose emitted from the inhaler into a chamber system. Salbutamol deposited at a particular location in the system is indicative of the dose likely to be received within a patient's lower respiratory system.
• Multistage Impactor - This test is similar to the dose deposition test but provides a more precise measure of the size of the spray droplets and their likely distribution within the lung.
• Content Uniformity - This test measures the variability of dose delivered between actuations by measuring the variability between ten doses taken throughout the 'life' of an inhaler.
• Average dose per valve actuation - This test determines the average dose calculated from ten actuations and compares this with the stated dose.
• Number of doses per container - The number of doses an inhaler delivers is counted.
• Product appearance - The inhaler is examined for the absence of external damage, corrosion or leakage.
• Corrosion of can and valve - The inhaler is cut open and examined for corrosion or physical changes.

Test results from batch samples

All the tests described were performed on samples from the two batches of new Salamol inhalers available in New Zealand. All the inhalers tested gave satisfactory results that met the registered specifications.

Summary of extended testing

In addition to the above standard testing and in order to gain more information about the performance of new inhalers, the following tests were extended beyond the requirements usually employed for the standard pharmacopoeial tests:

• Dose deposition - This test was performed in a way that examined an inhaler's performance throughout its 'life'. Two inhalers from each batch were used and the test was performed on each inhaler in an 'as new' initial state then puffs were fired from each to simulate its use. One inhaler was cleaned as per instructions and tested on two further occasions throughout its life and the other was not cleaned and was tested once more. All the inhalers tested passed the test.
• Appearance - For each batch, one inhaler was fired two puffs then any solution on the actuator was allowed to dry, a further two puffs were fired and so on for a total of 56 puffs (the usual maximum number of doses used in one week, one week being the recommended interval between cleaning). The inhalers were assessed visually for appearance and though extensive white deposits were noted, the inhalers did not appear to block.
• Content Uniformity - The Eur. Ph. test for uniformity of delivered dose measures the amount of drug delivered to the patient (ex-actuator). One inhaler is tested for 10 doses throughout it's anticipated life-time, i.e. three doses at the beginning (actuations 1, 2, 3), four from the middle (actuations 99, 100, 101, 102) and three doses at the end (actuations 198, 199, 200). The EP limits for this test state that 9 of the 10 doses must be between ±25% of the average dose and all doses between ±35% of the average dose. This test was performed throughout the simulated 'life' of an inhaler and was modified to include one inhaler from each batch that was not cleaned and one inhaler from each batch that was cleaned prior to each test. A total of four Salamol inhalers, from two separate batches, were tested for uniformity of delivered dose. Three of four inhalers passed this test, the exception being one inhaler undergoing the 'cleaned' arm of the test where a high result was recorded. The results for this one inhaler failed the EP test because the doses 100 and 101 were greater than 135% of the average value. The significance of this deviation was further investigated and is reported under the 'Repeat testing' section of this report. It should be noted that this test was also performed on one inhaler of each batch using ten consecutive actuations. These inhalers passed the test.

Tests performed on inhalers returned as 'faulty'

Fifty inhalers returned to Air Flow products Ltd from patients, principally via pharmacies, were submitted to ESR for testing. Fourteen of these inhalers were not selected for testing because there was no physical evidence and / or no documented evidence received with them indicating a problem. A further three inhalers on initial testing proved to be empty so were excluded from further testing. (Note: in some cases, unused inhalers had been returned with faulty inhalers to pharmacies for replacement and these had been included with the samples submitted to ESR).

Of the 33 remaining inhalers, 13 failed one or other or both of the initial 'as received' tests which comprised a test actuation to check if a dose could be fired (27 inhalers tested) or dose deposition (33 inhalers tested).

The 27 inhalers which underwent both the initial test firing and dose deposition test went on for further testing, which included cleaning the inhalers as outlined in the patient instructions and the dose deposition test carried out. All of these inhalers passed.

Of the 27 that had passed the second dose deposition test after cleaning, six were selected to undergo further simulated use testing. These six comprised three, which had initially failed the dose deposition test, and three that had passed. Each of these six inhalers was subjected to a process designed to mimic patient use of an inhaler for one week at a rate of two puffs four times a day. One week's use equates to the recommended interval between cleaning of the inhaler by the patient. Each inhaler was fired twice then the actuator was allowed to air dry and the process was repeated until 56 puffs had been emitted. All six inhalers passed this simulated use test.

As part of the initial examination of the faulty inhalers the extent of salbutamol deposits on the inhaler actuator and valve stem was assessed. Inhalers were examined visually for deposits in both the actuator (the plastic part of the inhaler which is required to be cleaned by the patient according to the cleaning instructions) and in the valve stem (which is attached to the aerosol can and should not be cleaned). The content uniformity tests were performed in such a way that both the fired dose and any dose previously deposited inside the valve stem were measured. The results obtained showed that deposits could form inside the valve stem (which is significant because the patient instructions do not require this to be cleaned), however, the extent of the deposit was small compared with the internal diameter of the valve stem and, when assessed in conjunction with other test information obtained, appeared unlikely to contribute to blocking of the inhaler.

Interpretation of Initial Results

Tests performed on new inhalers concentrated on the inhaler's ability to produce an effective dose that, with correct inhaler technique, would be deposited in the lungs where the medicine would take effect. The tests employed were, in some cases, modified to test 'worst case' conditions and to simulate patient use of the inhaler.

The initial tests on returned inhalers were designed to determine whether the inhalers operated on receipt even though there was evidence either visually or as information received that the inhaler did not operate as expected. (Note that there is a theoretical possibility that a blocked inhaler could become unblocked in transit.)

Further testing on returned inhalers examined whether, after cleaning, the inhalers performed correctly. This testing was extended to ensure that 'worst case' conditions were examined by taking a range of inhalers submitted as faulty and subjecting them to simulated patient use for one week (the interval between recommended cleaning of the inhaler).

Overall Initial Testing Results

• New Salamol inhalers met their product specifications.
• Of the inhalers reported to be faulty about 40% (13 of 33) were not operating effectively when tested. Sixty percent, although perceived to be faulty, operated correctly.
• All the reportedly faulty inhalers that were subsequently cleaned, operated correctly and provided a dose that met the requirements for metered dose inhalers.
• All reportedly faulty inhalers that were cleaned, subjected to simulated patient use, then retested at the recommended cleaning time met the requirements.

These initial results were published in a media statement, by Airflow Products, dated 8 June 2005.

Preliminary conclusions based on initial testing

• Patients experienced problems with respect to poor performance because the inhalers had been blocked.
• Testing suggested that a cause of patient perception of lack of effect was that in some cases the inhalers had been blocked.
• In some cases, patients perceived a problem that was not, on testing, proven to have affected the performance of the inhaler.
• Cleaning of Salamol inhalers is very important. All inhalers tested after cleaning operated correctly.
• Testing performed suggests that cleaning according to the instructions provided with the inhaler should result in correct operation and performance.

The following area of further investigation was identified:

More information was required to explain the cause of the BP / Ph Eur dose uniformity failure reported for one new inhaler following cleaning.

Repeat testing

In July 2005 Medsafe requested repeat dose uniformity testing of one inhaler from the batch of Salamol CFC-free that failed the initial dose uniformity testing (i.e. gave a high result). Testing was conducted by TGAL, Canberra, with one inhaler cleaned every 56 shots (based on eight doses a day for seven days) as described in the patient information leaflet.

TGAL reported its results in October 2005. A second inhaler of the same batch was also tested for BP aerodynamic assessment of fine particles.

TGAL Results

The repeat testing met the requirements of the BP / Ph Eur for Uniformity of delivered dose and the manufacturer's requirements for aerodynamic assessment of fine particles.

When the separate dose uniformity results for the two samples of the same batch were combined, the BP / Ph Eur requirements were not met in that three of the twenty individual results were outside of 75.0-125% of the combined mean. The justification for combining the results was, in the opinion of Medsafe, tenuous in that a different cleaning regime was followed for each inhaler.

Information from New Zealand Sponsor and Irish Manufacturer

Throughout the complaints and investigation process communication with Airflow Products and IVAX Pharmaceuticals remained open and the information provided has been of acceptable quality. IVAX has clinical and market experience with Salamol worldwide and continues to monitor the inhaler via clinical studies and safety monitoring.

On request from Medsafe IVAX provided comments on the dose uniformity testing results performed on behalf of Medsafe. IVAX considered that the introduction of inhaler cleaning into the pharmacopoeial dose uniformity test on samples taken over the course of a few hours in a laboratory was not valid because it was not in accordance with the Patient information leaflet (PIL) or the pharmacopoeial method. IVAX considered the dose uniformity data from the uncleaned Salamol containers to be valid in the context of a laboratory based pharmacopoeial test and that failure to dry the mouthpiece after cleaning may have influenced the data from the cleaned inhalers.

IVAX considered that the test results and the Medsafe summary of initial testing supported the effectiveness of the PIL cleaning regime with exception of the dose uniformity data for the reasons given and that a more appropriate test for the effectiveness of the cleaning process would be to evaluate performance over the lifetime of the inhaler by a patient rather than the laboratory.

Based on the latter comment, IVAX presented two reports, the first investigating the in-use performance of Salamol when cleaned according to the PIL and when an 'emergency' dose is required and the second investigating the performance of Salamol if misused with regards to cleaning i.e. the inhaler used for extended periods without cleaning. Both studies showed that Salamol functioned correctly whether cleaned or uncleaned. Also, in the event that the inhaler did not function due to lack of cleaning, once cleaned according to the PIL the inhaler would continue to function correctly. However, IVAX recommends that all patients follow the cleaning instructions to obtain optimum product performance.

IVAX also submitted a third report, a clogging study on Salamol CFC-free and Ventolin CFC-free (New Zealand source), designed to mimic typical patient use whilst accommodating laboratory testing. Two shots were actuated four times daily for each product over the course of 25 days (non-consecutive). Each inhaler was washed weekly as described in the PIL. Both products displayed a consistent plume shape and sound. No clogging was observed for either product.

Medsafe Comment

Medsafe was reassured that the product testing of new and returned inhalers had met specification and continued to do so following cleaning, and considered that the additional information submitted by IVAX further supported the inhaler cleaning regime stated in the PIL.

Patient information (MARC recommendations)

The MARC reviewed the preliminary testing results for Salamol. One of the recommendations of the 122^nd Medicines Adverse Reactions Committee (MARC) meeting, 9 June 2005, was for Medsafe to request the sponsor of Salamol to update the information on the New Zealand package insert to provide clear instructions regarding cleaning the inhaler once weekly.

In April and May 2005 Air Flow Products had distributed Dear Health Professional letters to doctors, pharmacists and asthma educators via the asthma societies. These letters addressed the efficacy, cleaning, ethanol content and taste of Salamol inhalers. In addition a patient information leaflet on inhaler cleaning was distributed to doctors, pharmacists and asthma educators via the asthma societies. The consumer information leaflet was revised and distributed to all pharmacists in August 2005.

The June MARC meeting also recommended that Medsafe convey updated information to prescribers through a 'red Dear Health Professional' letter. At the 123^rd MARC meeting in September 2005 Medsafe requested that the Ministers' Delegate reject this recommendation because:

• PHARMAC had decided to continue funding Ventolin at the same level as Salamol, maintaining patient choice.
• The sponsor of Salamol had already communicated inhaler cleaning advice to prescribers, pharmacists and asthma educators.
• The outcome of additional testing was still awaited.

At their 123^rd meeting MARC supported the decision of the Ministers' Delegate to reject the recommendation considering the prescriber and patient information already disseminated by Airflow Products in April / May 2005 to be satisfactory.

Medsafe also included notices on the cleaning of Salamol inhalers and the complaints investigation in the June and December 2005 issue of Prescriber Update.

At the September MARC meeting the committee recommended that Medsafe should explore options with relevant stakeholders in order to improve the management of future brand-switching issues arising from brand changes to sole subsidised supply medicines.

The committee reiterated its previous opinion that the issue was predominantly one of insufficient patient education, considering it vital to provide adequate information to patients prior to a change of sole subsidised supply by PHARMAC and subsequently at the point of dispensing. They considered that, in the case of Salamol the flow of information from the sponsor to prescribers, pharmacists and on to patients had not been timely and may have contributed to heightened patient concern.

Summary / Conclusions

Salamol inhalers are sensitive to cleaning and require cleaning in the manner described in the Patient information leaflet.

• The launch of Salamol CFC-free inhalers onto the New Zealand market generated a significant number of patient complaints.
• The complaints centred on decreased therapeutic effect generally associated with the blocking of the inhaler device, and unpleasant taste / mouth-feel.
• The blocking of the inhaler appeared due to inadequate cleaning of the device. This was confirmed by testing of new and returned inhalers by ESR and TGAL, supported by data available from the manufacturer, IVAX.
• All the new inhalers tested were found to meet their release specifications and international pharmacopoeial requirements for CFC-free inhalers.
• During initial testing of new inhalers, one inhaler from a batch of new Salamol inhalers gave a high result for a modified pharmacopoeial dose uniformity test. The deviant result was not duplicated and taking other investigational findings into account, was discounted as a spurious result, the real issue being the importance of inhaler cleaning.
• There appeared to be a lack of patient awareness regarding the cleaning requirements of Salamol inhalers, although, both Salamol and Ventolin inhalers carry statements to clean weekly.
• Although brand switching information and cleaning information was available on the launch of Salamol in New Zealand, the amount and level of distribution of information appears to have been insufficient at launch in order to adequately inform patients and health professionals about the importance of cleaning.
• The amount and distribution of patient information, particularly on cleaning of the device, has been improved.

In conclusion, following investigation and testing Medsafe was satisified that Salamol met the international requirements and guidelines for quality, safety and efficacy required for a medicine registered and distributed in New Zealand.