NHS Greater Glasgow & Clyde Area Drug and Therapeutics Committee
Greater Glasgow and Clyde Medicines
Medicines Update

PostScript 74 (March 2013)

 This edition contains articles on:

 

  • Abiraterone: new treatment for advanced prostate cancer
  • Safety: Use of LHRH analogues in prostate cancer
  • Kid’s corner: codeine based analgesia
  • ADTC decisions
  • New drugs: apixaban, dapagliflozin, ivacaftor, temocillin
  • New clinical guidelines
  • PostScript Extra: Oral NSAIDs

 

Abiraterone: new treatment for advanced prostate cancer

 

Abiraterone is a new type of treatment for prostate cancer. It is licensed for metastatic castration resistant prostate cancer (mCRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.

 

It received marketing authorisation in September 2011 and was approved for restricted use by the Scottish Medicines Consortium, following a resubmission, in August 2012.  It is included in the NHSGGC Adult Formulary for specialist use only in patients whose disease has progressed on or after docetaxel chemotherapy in accordance with the West of Scotland protocol.

 

Prostate cancer

There are approximately 32,000 new cases of prostate cancer in the UK each year, equating to 22% of new cancers in men. It accounts for more than 10,000 deaths per year in the UK and is the second most common cause of cancer death in men. The identification of cases has increased dramatically over the last 20 years, largely due to the increased availability of prostate specific antigen (PSA) blood tests. The lifetime risk of diagnosis for men in the UK is 1 in 14. It predominantly affects older men and it is uncommon in men under the age of 50 years.  In many cases the diagnosis is not life-threatening and treatment is not always necessary. However, when it metastasises, predominantly to the bones, it will almost invariably lead to a high burden of symptoms including pain and spinal cord compression and, ultimately, to death.

 

Current treatments

Treatment of the primary tumour depends on the stage, PSA level and pathological grade (Gleason score) at diagnosis as well as the likelihood of the cancer causing further problems during the patient’s remaining life.  In most cases prostate cancer is dependent on the male sex hormones (androgens), principally testosterone, for growth and survival. Thus, for patients with metastatic disease, androgen deprivation is the initial treatment. Although nearly all patients benefit initially from this treatment, benefits are usually short-lived (average 18 months). Surgical castration is now rarely performed. Pharmacological castration with luteinizing hormone releasing hormone (LHRH) agonists, eg triptorelin, is the usual first line treatment, often followed by the later addition of a non-steroidal anti-androgen, eg bicalutamide. If these treatments have failed, patients are considered to have castration resistant prostate cancer (CRPC).

 

The diagnosis of metastatic CRPC (mCRPC) is ominous, as treatment options are limited and prognosis is generally poor.  Chemotherapy, in the form of docetaxel with prednisolone, has been shown to improve overall survival and quality of life for some men, but many are not suitable for or do not wish to undergo this.

 

Abiraterone and how it works

Recently it has become clear that many CRPCs are still highly dependent for growth and survival on very low levels of circulating androgens. These are produced by the adrenal glands and even the cancer cells themselves. Abiraterone is a novel drug that works by inhibiting the chemical synthesis of these androgens in these tissues, thus denying the tumour of these very low levels of androgens.

 

What are the benefits?

Two large, randomised, placebo-controlled phase III trials have demonstrated clinically and statistically significant improvements in overall survival, pain control, time to bone complications and quality of life as well as tumour shrinkage and reductions in PSA. The first of these trials was conducted in patients who had exhausted all proven therapy and the median improvement in overall survival was 4.6 months.

 

How is it given?

Abiraterone is given orally at a dose of 1000 mg (4 x 250 mg tablets) once daily. It is given continuously until clear evidence of therapeutic failure. Tablets should be taken on an empty stomach and it is essential that patients receive corticosteroids for the duration of abiraterone therapy.

 

What are the side effects?

Abiraterone works by inhibiting the cytochrome p450 proteins CYP17. This results in an increase in mineralocorticoid production, which can cause hypertension, low blood potassium levels and fluid retention. Concomitant corticosteroid administration reduces these unwanted effects by a negative feedback loop.

 

Due to the small risk of severe hepatotoxicity, patients on abiraterone need to have their liver function monitored. Serum transaminases should be checked every two weeks for the first three months of treatment and monthly thereafter. Patients should also have their blood pressure monitored throughout treatment. Compliance with prednisolone should always be assessed in patients who experience hypertension or hypokalemia.

 

Costs

The list price for abiraterone is £2,900 + VAT for 30 days treatment, although it is available to the NHS in Scotland at a lower price due to a Patient Access Scheme. The average duration of therapy is around 8 months, although some patients may be on it for as long as 3 years.

 

The West of Scotland protocol for abiraterone is available to view on the West of Scotland intranet site.

 

Future issues

Abiraterone has recently received a marketing authorisation for first line use and this will be reviewed by SMC in due course. Early indications suggest this could mean another 160 patients per year in NHSGGC. The horizon scanning process has already identified this potential cost pressure and made some contingency plans for an SMC accepted status.

 

Safety: Use of LHRH analogues in prostate cancer

The oncology teams have become aware of several cases where patients have received GnRH analogues at the wrong intervals.

 

One patient had been transferred to the care of another consultant who reviewed the variability of PSA levels over recent years. It was established that the patient had been prescribed goserelin 3.6mg every three months for many years. This product should be administered monthly. Fortunately, there had not been any progression of the patient’s clinical condition. There are lessons for both the prescribing GP and dispensing pharmacist here. The wrong product was prescribed, but the disparity in collection time had not been picked up by the pharmacist.

 

A second case was a patient enrolled in a clinical trial who was prescribed three monthly triptorelin plus other treatments. After a rise in PSA levels, review of the patient’s case uncovered that he had been supplied with the monthly product in error on a three monthly basis. As well as having clinical implications, this could have led to the patient being withdrawn from the trial.

 

Triptorelin is the preferred GnRH analogue for prostate cancer in NHSGGC. There is no conclusive evidence to suggest one GnRH analogue is more effective or has fewer adverse events than others for metastatic prostate cancer. Triptorelin is administered using a smaller needle size compared to goserelin LA which may be easier for the patient.

 

Triptorelin (Decapeptyl SR)

  • 3mg                (administer every 28 days)
  • 11.25mg          (administer every 3 months)
  • 22.5mg            (administer every 6 months)

 

Goserelin (Zoladex, Zoladex LA) and leuprorelin (Prostap SR DCS, Prostap 3 DCS) both have formulations for monthly and 3 monthly injection.

 

Learning Points

Review of prescribing data in primary care suggests that there may be a wider issue with confusion between preparations. All healthcare professionals involved should review what is prescribed and dispensed.

 

  • GPs: a message is being added to ScriptSwitch to encourage a check of preparation and dosing schedule at each prescribing encounter.
  • Practice nurses: check at the point of administration how long it is since the last product was supplied or when the next injection is due. Is the interval appropriate?
  • Community pharmacists: if possible, check at the point of dispensing how long it is since the last product was supplied or when the next injection is expected. Is the interval appropriate? The patient or carer should be able to confirm how often they receive the injection.

 

Kid’s Corner: Codeine based analgesia in children

 

This is the first in an occasional series of articles which are relevant to paediatrics. Look out for “kid’s corner” pieces in other PostScript bulletins too.

 

Codeine is a widely used analgesic and is sometimes used post-operatively in children. A European review of the safety of medicines containing codeine licensed for pain relief in children (aged 0-18 years) was started in October 2012. This was triggered by concerns of an increased risk of morphine toxicity when certain susceptible children are given codeine for post-operative pain after surgery. These concerns follow the reporting of three fatalities, and one life-threatening case of respiratory depression in children given codeine after tonsillectomy or adenoidectomy in the treatment of obstructive sleep apnoea.

 

The BNFC cautions about the variable metabolism for codeine and the marked increase in side-effects that can occur with rapid metabolism. A faster metabolism results in higher-than-normal blood levels of morphine which can lead to toxic effects.

 

Review of NHSGGC prescribing shows use of codeine-based analgesia for children in post-operative care as well as other acute and primary care prescribing. The MHRA make the suggestions below and further information may follow when the review is concluded:

 

Safety points:

  • Patients may respond differently to codeine. Carers should be advised to seek professional help if symptoms of codeine toxicity occur.
  • Symptoms include reduced consciousness, lack of appetite, somnolence, respiratory depression, ‘pin-point’ pupils, nausea and vomiting.
  • Prescribers should start treatment at the lowest dose and review regularly.

 

New drugs

 

Apixaban in atrial fibrillation and stroke prevention

This drug has been accepted by SMC for the prevention of stroke in patients with atrial fibrillation with ≥1 risk factor. The evidence indicates apixaban, a selective direct factor Xa inhibitor, is superior to warfarin in terms of safety and efficacy. There is no direct comparative evidence with the other new agents, but indirect comparison suggests that apixiban may have a slightly improved safety profile.

 

It has been added to the Adult Total Formulary in line with the NHS HIS consensus statement for dabigatran and rivaroxaban. It is restricted to:

  • patients currently on warfarin who have poor INR control despite evidence that they are complying,
  • patients with allergy or intolerable side effects from coumarin anticoagulants,
  • patients for whom warfarin has been clinically excluded as a therapeutic option but anticoagulation is deemed safe and appropriate.

 

Preference over warfarin for practical rather than clinical reasons remains non-Formulary. Further consideration at both local and national level may result in changes to this advice. Any such alteration will be published in PostScript.

 

Dapagliflozin (Forxiga®)

This is the first in a new class of antidiabetic agent which increases the urinary excretion of glucose by inhibiting reabsorption in the kidney. It is licensed for type 2 diabetes mellitus and has been added to the Adult Total Formulary in line with the positioning accepted by SMC; ie in combination with metformin (as part of dual therapy), where a sulphonylurea is not suitable. This gives the medicine a similar positioning as DPP-4 inhibitors and GLP-1 agonists and it will be incorporated in the next revision of the diabetes guideline. It has not been accepted for use as monotherapy, or as part of triple therapy, or in combination with insulin.

 

Some safety signals highlighted are an increase in urinary tract and genital infections. Efficacy is dependent on renal function and dapagliflozin is not recommended in patients with moderate to severe renal impairment (eGFR <60ml/min).

 

Ivacaftor (Kalydeco®)

This medicine was not recommended for use in NHS Scotland by SMC as the treatment’s cost in relation to its health benefits on the evidence submitted to date was judged to be not sufficient to gain acceptance. It is licensed for the treatment of cystic fibrosis in patients age 6 years and older who have a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. 

 

In response to advice from the Scottish Government, access to this medicine for suitable patients is available via the Group Patient Request process (website requires NHS Network access). It is estimated that there are 22 patients in NHSGGC for whom this treatment may be suitable.

 

Temocillin

Following appeal, this drug is included in the Adult Total Formulary restricted to specialist use only on the advice of a microbiologist or an infectious disease physician as second line therapy in severely-ill patients with confirmed ESBL- or AmpC related infections. It is intended that this drug would replace some use of meropenem, a drug whose prescribing has increased by 170% since 2007. Although more expensive than meropenem, the change is to prevent or reduce the risk of development of carbopenem resistance. Temocillin prescriptions should be reviewed on a daily basis and patients transferred to oral antibiotics when appropriate. National guidance is awaited which will confirm this place in therapy.

 

New guidelines

The clinical guidelines below were posted onto the electronic resource directory on Staffnet in January 2013.

 

Management of Dry Eye in Primary Care

NHSGGC Primary Care COPD Guideline

Immunisation Guideline and Best Practice Document January 2013

GGC Heart MCN Guidelines for the Management of Atrial Fibrillation

 

PostScript Extra: Oral NSAIDs

The most recent edition of PostScript Extra considers the latest evidence for use of oral NSAIDs taking into account gastrointestinal and cardiovascular side effects. It considers specific patient scenarios and offers advice on appropriate treatments in different circumstances.