New Medicines Committee Briefing September 2018 Drug: N-acetylcisteine effervescent tablets (NACSYS®) is to be reviewed for use within: Primary care X Secondary care X

Summary N-acetylcisteine effervescent tablets (NACSYS®) is proposed as a 1st line mucolytic for adults, in respiratory disorders such as COPD and bronchitis. N-acetylcisteine effervescent tablets is proposed to replace carbocisteine as a first line mucolytic for adults. N-acetylcisteine is well established as a mucolytic, and is widely used worldwide, but a licensed oral product was only released in the UK in 2017. Initially, in February 2017, this was a powder packaged in sachets for administration as an oral solution. Since May 2017 a 600mg effervescent oral tablet has been available. The effervescent tablet is a once daily oral formulation, therefore offering a reduction in pill burden for patients in comparison to carbocisteine. The effervescent oral tablet is also a cost effective option compared to carbocisteine. It is estimated that ~ 80% of adult patients currently prescribed carbocisteine would be prescribed N- effervescent tablets instead.

Formulary application Consultants submitting application: Drs Shahul Khan and Ashwin Rahjan, consultant respiratory physicians.

Clinical Director supporting application: - Drs Khan and Rahjan have requested N-acetylcisteine’s addition to the joint formulary due to its lower oral dose burden compared to the current first line mucolytic carbocisteine. N-acetylcisteine effervescent tablets is also more cost effective compared to carbocisteine for primary and secondary care. Background Mucolytics such as acetylcysteine are recommended as part of anti-inflammatory therapy in stable COPD if patients have chronic productive cough. Treatment should continue if there is reduction in cough frequency or sputum production Mucolytic therapy may also be of benefit to other groups of patients with excessive mucus production (e.g. ).

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Acetylcisteine is well established as a mucolytic but has only more recently been available as a UK licensed product.

Current formulary status North Staffordshire formulary Currently non-formulary South Staffordshire formulary Currently non-formulary

Therapeutic class and mode of action Acetylcysteine is a mucolytic. The mucolytic action is mediated by a reduction in the viscosity of bronchial mucus. This is explained by the depolymerisation with the disulfide bridges between the macromolecules in the mucus being opened. In addition, acetylcisteine is a precursor of glutathione, an antioxidant. Acetylcysteine is a derivative of the natural amino acid , which serves as a substrate for the synthesis of glutathione in the body. Apart from the fact that acetylcisteine is able to normalise a state of glutathione depletion, it is able to conjugate with various toxic compounds. Licensed indications Acetylcisteine is indicated for use as a mucolytic in respiratory disorders such as in bronchitis, emphysema, mucoviscidoses and bronchiectasis. NACSYS® 600 mg effervescent tablets is indicated in adults only.

Dosage and administration The licensed dosage is 600mg once daily.

Safety and adverse effects

Warnings and precautions NACSYS contains 115mg of sodium per tablet in the form of sodium hydrogen carbonate and caution is advised in patients on a sodium restricted diet

Contraindications Hypersensitivity to n-acetylcisteine or any of the excipients.

Drug Interactions Simultaneous solution of NACSYS 600 mg effervescent tablets with other medicinal products is not recommended. To date, the inactivation of antibiotics by acetylcysteine has been reported only in in-vitro tests, whereby the relevant substances were mixed directly with each other. However, if oral antibiotics are required, it is advised that these should be taken two hours before or after Acetylcysteine. NACSYS® is not compatible with rubber or metals (e.g. iron, copper, nickel) therefore if administration is required via enteral feeding tubes only glass or plastic delivery systems are recommended Acetylcysteine should not be administered concomitantly with antitussive medicinal products because reducing the cough reflex may lead to a build-up of bronchial secretions. Acetylcysteine may enhance the vasodilatory effects of nitroglycerin. Caution is advised. Activated charcoal can decrease the effect of acetylcysteine due to reduced absorption. Acetylcysteine may have an effect on the values of salicylates by colorimetric analysis.

Presentation NACSYS® is available as a 600mg effervescent tablet.

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The tablet container(s) are packaged in cardboard boxes. The box contains 6, 2x6, 10, 2x10, 20 or 3x10 effervescent tablets.

The effervescent tablets are packaged in a propylene tube with a polyethylene cap and a desiccant

List of excipients : Sodium hydrogen carbonate (E500) , citric acid (E330), sucralose (E955), orange flavour (contains Orange Essential Oil, Orange Essential Oil Terpenless, Gum Arabic (E414), butylhydroxyanisole (E320), Citric acid monohydrate (E330) and Maltodextrin (DE19)) Patent Status Date of first authorisation/renewal of the authorisation: 11th May 2017 (MHRA marketing approval) Date of revision of the text: 11th May 2017

Guidance and Evidence Summary Mucolytics are recommended for select patient populations by the GOLD guidelines and by NICE guidance to reduce mucous production and viscosity and to reduce cough frequency.

NICE Guidance Y The latest NICE guidance published in 2010 is in the process of being updated and the existing recommendations regarding mucolytics is presented below. NICE CG 101 (June 2010) 1.2.3.7 Mucolytic drug therapy should be considered in patients with a chronic cough productive of sputum. 1.2.3.8 Mucolytic therapy should be continued if there is symptomatic improvement (for example, reduction in frequency of cough and sputum production). 1.2.3.9 Do not routinely use mucolytic drugs to prevent exacerbations in people with stable COPD.

Scottish Medicines Consortium (SMC) N

All Wales Medicines Strategy Group (AWMSG) N

Regional Drug and Therapeutic Centre (RDTC) N

Midlands Therapeutics Review and Advisory Committee (MTRAC) N

Efficacy Mucolytics have been available for over fifty years with many studies originating during the 1970’s through to the mid 2000’s. Acetylcysteine has been available since the 1960s There is an absence of head to head studies of mucolytics in any respiratory condition. A 2015 Cochrane review conducted by Poole et al. considered the place of mucolytics and includes nineteen clinical studies of acetylcysteine over a forty-year period. The review considered thirty-four studies involving mucolytics with 9,367 participants, of these; • Nineteen (19) studies were with acetylcysteine • Four (4) studies were with carbocisteine • The remaining studies included (1) and other mucolytics not available in the UK 3

The review concluded that the likelihood that a patient could be exacerbation-free during the study period was greater among mucolytic groups (Peto odds ratio (OR) 1.75, 95% confidence interval (CI) 1.57 to 1.94). However, it was also noted that more recent studies demonstrated less benefit of treatment than was reported in earlier studies in the review. The overall number needed to treat with mucolytics for an additional beneficial outcome for an average of 10 months - to keep an additional participant free from exacerbations - was eight (NNTB 8, 95% CI 7 to 10). Use of mucolytics was associated with a reduction of 0.03 exacerbations per participant per month (mean difference (MD) -0.03, 95%CI -0.04 to -0.03; participants = 7164; studies = 28; I2 = 85%) compared with placebo, that is, about 0.36 per year, or one exacerbation every three years. The authors reported that very high heterogeneity was noted for this outcome, so results need to be interpreted with caution. Most importantly the type or dose of mucolytic did not seem to alter the effect size, nor did the severity of COPD, including exacerbation history. Cost Analysis

Current UHNM prices for NMC review

Medication Dose Price excl VAT Price incl. VAT (30 day supply) (30 day supply) NACSYS® 600mg od Commercially confidential Commercially confidential Carbocisteine 375mg 750mg tds Commercially confidential Commercially confidential capsules Carbocisteine sachets for 750mg tds Commercially confidential Commercially confidential oral solution

Current primary care prices for NMC review

Medication Dose Price excl VAT – list price (30 day supply) NACSYS® 600mg od £5.50 Carbocisteine 375mg 750mg tds £14.04 capsules Carbocisteine sachets for 750mg tds £23.10 oral solution Carbocisteine syrup 750mg tds £37.76

Predicted expenditure for NMC review

It is predicted that ~ 80% of adult patients currently prescribed carbocisteine would be prescribed acetylcisteine instead. 4

Predicted cost saving for UHNM UHNM Carbocisteine usage April 2017- March 2018 Carbocisteine capsule 1879 patients Carbocisteine solution 284 patients Carbocisteine sachets 71 patients Expenditure - commercially confidential

Predicted annual carbocisteine expenditure if 80% switch to acetylcysteine = commercially confidential Predicted annual acetylcisteine expenditure if 80% current adult carbocisteine patients Rx 30 days NACSYS instead = commercially confidential

Predicted annual cost saving for UHNM = commercially confidential

Predicted cost saving for CCG CCG Carbocisteine usage July 2017- June 2018 Carbocisteine capsules/tablets 4901 patients Carbocisteine solution 606 patients Carbocisteine sachets 55 patients Total expenditure = £292,602.97 Patients received an average of 157 days treatment (assume on 750mg tds, and based on items dispensed for carbocisteine capsules/tablets).

Predicted annual CCG carbocisteine expenditure if 80% switch to NACSYS = £58520.60 Predicted annual CCG NACSYS® expenditure (estimate 4450 patients) - If patient receives average of 157 days of treatment, estimated annual NACSYS expenditure for CCGs = £128085.33

Predicted cost saving for CCG per annum = 292602.97-58520.60-128085.33 = £105997.04 per annum

Predicted annual cost saving for health economy = £117304.03 per annum

Addendum 26/9/2018 Due to great variability in price between different N-acetylcisteine oral formulations, the NMC advised that N-acetylcisteine should be considered as an addition to the joint formulary if NACSYS® is the only brand prescribed, and that prescribing is brand specific.

Cost savings were initially calculated on the presumption that patients are prescribed carbocisteine 750mg tds. Primary care advised that stable patients should be reducing to 750mg bd, thus predicted annual saving for the health economy may be ~ 33% less than first predicted. However it was mentioned anecdotally that many patients in primary care are maintained on 750mg tds, thus it is difficult to determine the recalculated annual saving relating to a switching from carbocisteine to NACSYS®. It was agreed that the annual cost saving for primary and secondary care would still be significant, regardless of the percentage of patients on carbocisteine 750mg tds vs 750mg bd.

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Produced by Xin Wei Tan Advanced Specialist Pharmacist –Secondary/Primary Care Interface University Hospital of North Midlands Telephone: 01782 674541 e-mail: [email protected] Produced for use within the NHS. Not to be reproduced for commercial purposes.

References

1. Summary of Product Characteristics. NACSYS 600mg effervescent tablets. Atlantic Pharma. Last updated 12th October 2017. 2. Summary of Product Characteristics. Acetylcysteine 200mg Powder for Oral Solution. Colonis Pharma Limited. Last updated 14th March 2017. 3. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. NICE Clinical guideline [CG101] Published date: June 2010 4. GOLD 2018 Global Strategy for the Diagnosis, Management and Prevention of COPD 5. Poole et. al. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database of Systemic Reviews 2015. Issue 7

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