Proposal to change access to azithromycin and lamivudine and list roxithromycin dispersible tablets approved

Medicines

Decision

PHARMAC is pleased to announce the approval of a proposal relating to changing access to azithromycin and lamivudine and the listing of roxithromycin dispersible tablets to take effect from 1 July 2017.

This was the subject of a consultation letter dated 8 May 2017 and an updated consultation letter dated 12 May 2017.

In summary, the effect of the decision is that:

  • Azithromycin (Apo-Azithromycin, Zithromax) funding criteria will be widened to include the treatment of non-cystic fibrosis bronchiectasis in children.
  • Lamivudine (Zeffix) funding criteria will be widened to include prophylaxis of hepatitis B reinfection in immunocompromised patients receiving rituximab-based treatment for malignancy.
  • Roxithromycin dispersible tablets (Rulide D), through an agreement with Sanofi-Aventis New Zealand Ltd, will be funded for children under 12 years of age. Over 8000 children will benefit from a dispersible form of this antibiotic.

The decision is as consulted on, with the exception of the following:

  • Following consideration of feedback to consultation, ‘Mycobacterium infections’ has been amended to read ‘atypical mycobacterial infections’ to clarify the intent of the Special Authority to exclude tuberculosis and leprosy.
  • In addition, following consideration of feedback to consultation, the Original Pack ‘OP’ rule was added to lamivudine oral liquid 5 mg per ml.

Details of the decision

Azithromycin – for treatment of non-cystic fibrosis bronchiectasis in children

  • Funding criteria for azithromycin 250 mg and 500 mg tablets (Apo-Azithromycin) and granules for oral liquid 200 mg per 5 ml (40 mg per ml) (Zithromax) will be widened in Section B (Community) and in Part II of Section H (Hospital) of the Pharmaceutical Schedule from 1 July 2017 to allow funding of more than 5 days’ treatment in children with non-CF bronchiectasis and people with atypical mycobacterial infections.
  • To effect this change, the current restrictions for azithromycin in Section B of the Pharmaceutical Schedule will be replaced by the following:

AZITHROMYCIN – Maximum of 5 days treatment per prescription; can be waived by endorsement Special Authority

For Endorsement, patient has either:

1. Received a lung transplant and requires treatment or prophylaxis for bronchiolitis obliterans syndrome*; or
2. Cystic fibrosis and has chronic infection with Pseudomonas aeruginosa or Pseudomonas related gram negative organisms*.

Indications marked with * are Unapproved Indications

Special Authority for Waiver of Rule

Initial application – (bronchiolitis obliterans syndrome, cystic fibrosis and atypical Mycobacterialinfections) from any relevant specialist. Approvals valid without further renewal unless notified for applications meeting the following criteria:

Any of the following:

  1. Patient has received a lung transplant and requires treatment or prophylaxis for bronchiolitis obliterans syndrome*; or
  2. Patient has cystic fibrosis and has chronic infection with Pseudomonas aeruginosa or Pseudomonas-related gram negative organisms*; or
  3. Patient has an atypicalmycobacterialinfection.

Indications marked with * are Unapproved Indications

Initial application – (non-cystic fibrosis bronchiectasis*) only from a respiratory specialist or paediatrician. Approvals valid for 12 months for applications meeting the following criteria:

All of the following:

  1. For prophylaxis of exacerbations of non-cystic fibrosis bronchiectasis*; and
  2. Patient is aged 18 and under; and
  3. Either:

3.1 Patient has had 3 or more exacerbations of their bronchiectasis, within a 12 month period; or
3.2 Patient has had 3 acute admissions to hospital for treatment of infective respiratory exacerbations within a 12 month period.

Indications marked with * are Unapproved Indications

Renewal – (non-cystic fibrosis bronchiectasis*) only from a respiratory specialist or paediatrician. Approvals valid for 12 months for applications meeting the following criteria:

All of the following:

  1. The patient has completed 12 months of azithromycin treatment for non-cystic fibrosis bronchiectasis; and
  2. Following initial 12 months of treatment, the patient has not received any further azithromycin treatment for non-cystic fibrosis bronchiectasis for a further 12 months, unless considered clinically inappropriate to stop treatment; and
  3. The patient will not receive more than a total of 24 months’ azithromycin cumulative treatment (see note).

The patient must have had no more than 1 prior approval.

Note: no further renewals will be subsidised. A maximum of 24 months of azithromycin treatment for non-cystic fibrosis bronchiectasis will be subsidised.

Indications marked with * are Unapproved Indications

  • A similar restriction will apply in Part II of Section H of the Pharmaceutical Schedule from 1 July 2017, as follows: 

Restricted

Initiation – bronchiolitis obliterans syndrome, cystic fibrosis and atypical Mycobacterialinfections

Any of the following:

  1. Patient has received a lung transplant and requires treatment or prophylaxis for bronchiolitis obliterans syndrome*; or
  2. Patient has cystic fibrosis and has chronic infection with Pseudomonas aeruginosa or Pseudomonas-related gram negative organisms*; or
  3. Patient has an atypical MycobacterialinfectionFor any other condition for five days' treatment, with review after five days.

Indications marked with * are Unapproved Indications

Initiation - non-cystic fibrosis bronchiectasis*

Respiratory specialist or paediatrician

Re-assessment required after 12 months

All of the following:

  1. For prophylaxis of exacerbations of non-cystic fibrosis bronchiectasis*; and
  2. Patient is aged 18 and under; and
  3. Either:

3.1 Patient has had 3 or more exacerbations of their bronchiectasis, within a 12 month period; or
3.2 Patient has had 3 acute admissions to hospital for treatment of infective respiratory exacerbations within a 12 month period.

Indications marked with * are Unapproved Indications

Continuation - non-cystic fibrosis bronchiectasis*

Respiratory specialist or paediatrician

Re-assessment required after 12 months

All of the following:

  1. The patient has completed 12 months of azithromycin treatment for non-cystic fibrosis bronchiectasis; and
  2. Following initial 12 months of treatment, the patient has not received any further azithromycin treatment for non-cystic fibrosis bronchiectasis for a further 12 months, unless considered clinically inappropriate to stop treatment; and
  3. The patient will not receive more than a total of 24 months’ azithromycin cumulative treatment (see note).

Note: A maximum of 24 months of azithromycin treatment for non-cystic fibrosis will be subsidised in the community.

Indications marked with * are Unapproved Indications 

Initiation – other indications

Re-assessment required after 5 days

For any other condition.

Continuation – other indications

Re-assessment required after 5 days

For any other condition.

For the avoidance of doubt, there is no change to the maximum of 5 days funded treatment per prescription for any indication which can be waived by Special Authority for certain indications. 

Lamivudine – for prophylaxis of hepatitis B reinfection in immunocompromised patients receiving treatment for malignancy

  • Funding criteria for lamivudine 100 mg tablets and oral liquid 5 mg per ml (Zeffix) will be widened in Section B of the Pharmaceutical Schedule from 1 July 2017 to include prophylaxis of hepatitis B reinfection in immunocompromised patients receiving rituximab in combination with immunosuppressive chemotherapy for malignancy as shown (additions in bold, deletions in strikethrough)

Special Authority for Subsidy

Initial application only from a gastroenterologist, infectious disease specialist, paediatrician, general physician or medical practitioner on the recommendation of a gastroenterologist, infectious disease specialist, paediatrician or general physician. Approvals valid for 1 year for applications meeting the following criteria:

Any of the following:

  1. Hepatitis B virus (HBV) DNA-positive cirrhosis prior to liver transplantation; or
  2. Hepatitis B surface antigen (HBsAg)-positive and has had a liver, kidney, heart, lung or bone marrow transplant; or
  3. Hepatitis B virus naïve patient HBV-naïve patient who has received a liver transplant from a an anti-HBc (H hepatitis B core antibody (anti-HBc)-positive donor; or
  4. Hepatitis B surface antigen HBsAg-positive patient who is receiving chemotherapy for a malignancy, or high dose steroids (at least 20 mg/day for at least 7 days), or who has received such treatment within the previous two months; or
  5. Hepatitis B surface antigen HBsAg-positive patient who is receiving anti-tumour necrosis factor treatment; or
  6. Hepatitis B core antibody (anti-HBc) Anti-HBc-positive patient who is receiving rituximab in combination with immunosuppressive chemotherapies for a malignancy. plus high dose steroids (e.g. R-CHOP)
  • Some minor changes have been made for consistency of language that do not change the intent of the existing criteria.
  • There are no changes the renewal criteria.
  • A similar restriction will apply in Part II of Section H of the Pharmaceutical Schedule from 1 July 2017.
  • The OP rule will be added to the Zeffix brand of lamivudine oral liq 5 mg per ml, 240 ml in Section B of the Pharmaceutical Schedule from 1 July 2017.

Roxithromycin dispersible tablet for children

Roxithromycin (Rulide D) 50 mg dispersible tablet will be listed in Section B and Part II of Section H of the Pharmaceutical Schedule from 1 July 2017 at the following price and subsidy (ex-manufacturer, excluding GST):

Chemical and presentation Brand Pack size Proposed price and subsidy
Roxithromycin tab dispersible 50 mg Rulide D 10 $7.19

Roxithromycin dispersible tablets will be restricted to children under 12 years of age.

Feedback received

We appreciate all of the feedback that we received and acknowledge the time people took to respond. All consultation responses received by Friday 26 May 2017 were considered in their entirety in making a decision on the proposed changes. Most responses were supportive of the proposal, and the following issues were raised in relation to specific aspects of the proposal:

Theme

Comment

Azithromycin – for treatment of non-cystic fibrosis bronchiectasis in children

Supportive of the proposal for azithromycin.

Noted

In regards to the non-CF bronchiectasis criteria, considered that criteria 3.1 and 3.2 were duplicates and therefore 3.2 was redundant (particularly the criteria requiring three exacerbations prior to being eligible for funding).

 

 

The criteria:

“3.1 Patient has had 3 or more exacerbations of their bronchiectasis, within a 12 month period; or

3.2 Patient has had 3 acute admissions to hospital for treatment of infective respiratory exacerbations within a 12 month period.”

are similar, however we note that 3.1 includes both hospitalised and non-hospitalised exacerbations while 3.2 includes hospitalised exacerbations only.

The criteria are in line with advice from the Anti-infective Subcommittee [PDF, 148 KB], which was developed following review of the 2014 Thoracic Society of Australia and New Zealand (TSANZ) clinical practice guideline for Chronic Suppurative Lung Disease and Bronchiectasis (https://www.thoracic.org.au/journal-publishing/command/download_file/id/36/filename/TSANZ-ChronicSuppurativeLungDisease-Guidelines-2016-web.pdf(external link))

Considered there was no scientific or clinical justification to limit azithromycin to 24 month cumulative dosing and considered the 12 month stand down is not appropriate or justified.

A maximum 24-month cumulative treatment is based on the advice received from PTAC at its August 2015 meeting [PDF, 378 KB], based on TSANZ guideline (see above) which recommend a finite duration of treatment of 12-24 months. The Special Authority criteria are clear that a 12 month stand-down period is not required if it is considered clinically inappropriate to stop treatment.

Considered that unrestricted community use (5 days for any indication) is potentially driving resistance. Wider access to azithromycin is not warranted with the availability of other macrolides, especially the new dispersible formulation of roxithromycin, and individual variations could be managed through rapid NPPA applications. Considered that, under PHARMAC Factors for Consideration and azithromycin’s potential for resistance, PHARMAC should consider restricting azithromycin for named indications (provided) under endorsement and other indications under Special Authority.

We are aware that there is variation between different DHB’s guidelines on azithromycin usage and we are also aware of the need for antimicrobial stewardship and maintaining clinically appropriate access.

This issue will be considered further at the next Anti-infective Subcommittee meeting.

Noted concerns regarding resistance, but considered that, randomised controlled trial evidence of the effectiveness of azithromycin at preventing exacerbations and the costs of a 2 week hospital admission for exacerbation, outweigh risks of resistance.

Noted.

Support widening access of azithromycin for mycobacterial infections.

Noted.

 

Surprised to see the restrictions for azithromycin were altered in the updated proposal before all consultations had been reviewed.

Noted. An amended proposal was released on 12 May due to early consultation feedback identifying a genuine mistake by PHARMAC in the proposed Special Authority criteria in the original consultation. PHARMAC considers urgent amendment to the proposal was therefore appropriate.

 

Considered mycobacterial infections should read non-tuberculous mycobacterial infections as azithromycin should not be used as TB therapy.

Noted. In line with the criteria for clarithromycin the wording has been amended to ‘atypical mycobacterial infections’.

The Special Authority and HML restrictions have been amended as follows (amendments in bold and strikethrough):

Special Authority for Waiver of Rule

Initial application – (bronchiolitis obliterans syndrome, cystic fibrosis and atypical mycobacterial infections) from any relevant specialist. Approvals valid without further renewal unless notified for applications meeting the following criteria:

Any of the following:

  1. Patient has received a lung transplant and requires treatment or prophylaxis for bronchiolitis obliterans syndrome*; or
  2. Patient has cystic fibrosis and has chronic infection with Pseudomonas aeruginosa or Pseudomonas-related gram negative organisms*; or
  3. Patient has an atypical mycobacterial infection.

Indications marked with * are Unapproved Indications

Requests for listing azithromycin for prophylaxis against Mycobacterium avium intracellulare complex in immunocompromised patients and HIV patients with a CD4 count <50 in line with international guidelines, again where clarithromycin cannot be used due to contraindications or drug-drug interactions with antiretroviral treatment.

Noted. This will be considered by the Anti-infective Subcommittee at its next meeting.

Requests for funding of azithromycin for post-haematopoietic cell transplant bronchiolitis obliterans and for pulmonary graft-versus-host disease (GVHD).

PHARMAC has received an application for azithromycin – post transplant (bone marrow/SCT) for BOS. This application was assessed by PTAC at its August 2016 meeting and given a High priority, it is currently under assessment by PHARMAC. Further information on this proposal is available on the Application tracker(external link).

PHARMAC has not received a funding application for pulmonary GVHD disease. We would welcome an application for this indication.

Lamivudine – for prophylaxis of hepatitis B reinfection in immunocompromised patients receiving treatment for malignancy

Request the Original Pack or Wastage rule is applied to lamivudine liquid.

The OP rule has been added.

Support the widening of access for lamivudine for prophylaxis of hepatitis B reactivation in immunocompromised patients receiving treatment for malignancy.

Noted.

Supports the provision to increase access to all patients treated with rituximab when HBsAg positive, regardless of underlying condition.

 

The restriction for treatment of malignancy should be removed as many patients now receive rituximab with other immunosuppressive regimens for HML-approved, non-malignant, indications e.g. auto-immune disease.

Funded access to lamivudine for patients who are hepatitis B surface antigen positive or hepatitis B surface antigen negative/core antibody positive has been considered by the Anti-infective Subcommittee on a number of occasions. The criteria are in line with the clinical advice we have received that lamivudine prophylaxis should be restricted to hepatitis B surface antigen positive patients receiving chemotherapy for malignancy or high dose steroids or an anti-tumour necrosis factor agent, and for surface antigen negative hepatitis B surface antigen negative/core antibody positive patients with malignancy receiving rituximab in combination with immunosuppressant chemotherapy.

The Subcommittee considered lamivudine prophylaxis for all patients receiving rituximab for any indication, however it did not include this group of patients in its recommendation.

Requests for clarifications and wider funded access including:

  • the words ‘HBV seronegative’ should be used instead of ‘HBV-naïve’
  • patients who are receiving treatment with other biologics, not limited to tumour necrosis factor alpha inhibitors but including cytokine or integrin inhibitors, and tyrosine kinase inhibitors;
  • patients undergoing chemotherapy for lymphomas, bone marrow or stem cell transplantation. In line with the Asian-Pacific Guidelines
  • broader groups of clinicians that could apply for Special Authority

Widening of access to lamivudine prophylaxis with other biologics, additional indications or via additional clinician groups is out of scope of this proposal.

PHARMAC intend to seek further advice from the Anti-infective Subcommittee to clarify use in patients on other immunosuppressants and biologics.

100mg lamivudine tablets should also be made available for people with HIV with need for dose modifications e.g. paediatric patients or patients with reduced renal function.

 

 

Lamivudine 150mg tablets and the 10 mg per ml liquid are currently funded for people with HIV. Paediatric patients who require a lower dose can currently access the funded liquid preparation. Adults that require access to a lower strength tablet for clinical reasons could apply for funding via Named Patient Pharmaceutical Assessment. PHARMAC intends to provide the consultation feedback to the Anti-infective Subcommittee for consideration.

Suggest the replacement of lamivudine with entecavir or tenofovir in the setting of rituximab based chemotherapy regimens for patients who are HBsAg positive.

 

PHARMAC notes the feedback, the use of entecavir in preference to lamivudine has been discussed at the October 2016 meeting of the Anti-infective Subcommittee [PDF, 143 KB]. The Subcommittee recommended PHARMAC should consider widening access to entecavir or tenofovir, for the prevention of HBV reactivation in surface antigen negative/core antibody positive patients receiving rituximab for malignancy, should it obtain significant price discounts.

Roxithromycin - dispersible tablets for children

Welcomed the additional formulation being funded for use in children and feel it would enable more prescribers to use a well-tolerated macrolide with a favourable pharmacokinetic profile. This is less likely to promote development of antimicrobial resistance, in keeping with antimicrobial stewardship objectives.

Noted.

Considered funding should be extended to include adults and children over 12 years of age who are unable to swallow tablets by endorsement.

The advice we have received is that roxithromycin dispersible tables should be funded for paediatric patients. The minutes are available here [PDF, 77 KB]. We note, as per the Anti-infective Subcommittee’s advice, that erythromycin or penicillin liquid may be a funded alternative for other patients. However, we would welcome a funding application for roxithromycin dispersible tablets for use in other patients, particularly if there is an unmet clinical need. We would then seek clinical advice accordingly.

More information

If you have any questions about this decision, you can email us at enquiry@pharmac.govt.nz or call our toll free number (9 am to 5 pm, Monday to Friday) on 0800 66 00 50.