Suffolk PCT Drug & Therapeutics Committee New Medicine Report

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1 Suffolk PCT Drug & Therapeutics Committee New Medicine Report This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine Cinacalcet (Mimpara, Amgen) Document status Reviewed at March 2012 Suffolk D&TC meeting Date of last revision 22nd March 2012 Traffic light decision Red Hospital only Prescribers rating Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Mechanism of action Medicine class BNF Indication Cinacalcet is a calcimimetic agent which directly lowers parathyroid hormone (PTH) levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. Reductions in PTH levels correlate with cinacalcet concentration. [1] Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on maintenance dialysis therapy. Cinacalcet may be used as part of a therapeutic regimen including phosphate binders and/or vitamin D sterols, as appropriate. [1] Reduction of hypercalcaemia in patients with: parathyroid carcinoma. primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated. [1]

2 Dosage Treatment alternatives Place in therapy Secondary hyperparathyroidism in patients with end-stage renal disease on dialysis: Adult over 18 years, initially 30 mg once daily, adjusted every 2 4 weeks to max. 180 mg daily. [1] Hypercalcaemia of primary hyperparathyroidism or parathyroid carcinoma: Adult over 18 years, initially 30 mg twice daily, adjusted every 2 4 weeks according to response up to max. 90 mg 4 times daily. [1] Dietary modification to reduce phosphate intake, calcium salts, aluminium hydroxide, sevelamer, lanthanum, calcitriol, alfacalcidol or paricalcitol, modification of the dialysis regimen, total or partial surgical parathyroidectomy [2, 3] NICE guidance issued in January 2007 on the use of cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy stated: Cinacalcet is not recommended for the routine treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. Cinacalcet is recommended for the treatment of refractory secondary hyperparathyroidism in patients with end-stage renal disease (including those with calciphylaxis) only in those: who have very uncontrolled plasma concentration of intact parathyroid hormone (defined as greater than 85 picomol/litre) refractory to standard therapy, and a normal or high adjusted serum calcium concentration, and in whom surgical parathyroidectomy is contraindicated, in that the risks of surgery outweigh the benefits. Response to treatment should be monitored regularly and treatment should be continued only if a reduction in the plasma concentration of intact parathyroid hormone of 30% or greater is seen within 4 months of treatment. [2]

3 The NICE guidance was due to be considered for a review in December In May 2010, NICE took the decision to defer the review of the original guidance until results of the on-going EVOLVE trial are available. At this point the evidence base will again be assessed to ascertain the need for a review of the current guidance. This was still current in January There is no NICE guidance on primary hyperparathyroidism or parathyroid carcinoma. In March 2010, a Drug & Therapeutics Bulletin review of managing primary hyperparathyroidism in primary care concluded that [3] Asymptomatic primary hyperparathyroidism is a common disorder characterised by hypercalcaemia with raised or inappropriately normal parathyroid hormone concentrations. Co-existent vitamin D insufficiency or deficiency should be routinely screened for and managed. Investigations for a patient without symptoms of hypercalcaemia can be arranged in primary care, with a referral to secondary care for further management if appropriate. Parathyroidectomy is the only cure for the condition and the available evidence indicates that such surgery improves biochemical parameters and increases bone mineral density in those with asymptomatic primary hyperparathyroidism. However, there is no published randomised controlled trial evidence that surgery improves fracture risk, neuropsychiatric symptoms, cardiovascular outcomes or survival. It is therefore important that patients making a decision regarding surgery understand the limitations of the available evidence. Conservative follow-up is a reasonable option in appropriately selected patients (e.g. those declining or not meeting the criteria for surgery). However, it is important to be aware that after a decade or more, such patients will lose bone mass and may be at increased fracture risk. Regular follow-up is crucial in those managed conservatively to detect disease manifestations early and to refer the patient for further management, including assessment for surgery. Pharmacological options (e.g. cinacalcet and alendronate) are not recommended

4 as an alternative to surgery but have a potential use in patients being managed conservatively because they refuse surgery or are considered poor operative risks Future alternatives Evidence for use None known The reviews of cinacalcet in 2005 and 2006 were based on the key clinical trials used to obtain the licensed indications for the product. Since the NICE guidance in 2007, there has been very little new information published on use of cinacalcet in patients with secondary hyperparathyroidism and end-stage renal disease on maintenance dialysis therapy. [4] NICE are waiting for the EVOLVE trial to conclude before reviewing the TA for cinacalcet. In 2010, the ADVANCE trial was published. ADVANCE evaluated the effects of cinacalcet and low dose vitamin D versus vitamin D alone on vascular calcification in subjects with CKD on haemodialysis. The study showed that the addition of cinacalcet resulted in significantly lower (p=0.009) coronary artery calcium volume scores compared to use of vitamin D alone. This supports the hypothesis that cinacalcet may favourably affect the progression of cardiovascular calcification compared with vitamin D monotherapy. [5] The EVOLVE (EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events) trial is assessing the effects of cinacalcet on mortality and cardiovascular morbidity in chronic kidney disease patients with secondary hyperparathyroidism who are receiving dialysis. The trial is ongoing but not recruiting participants now. A literature search identified a number of articles reviewing the treatment of primary hyperparathyroidism (PHPT) which included cinacalcet [6-8]. A review in the American Journal of Therapeutics in 2011 focussed specifically on cinacalcet. [9] Parathyroidectomy is curative for patients with PHPT; however, there are few options for patients who are not surgical candidates, who refuse surgery, or those with refractory PHPT after parathyroidectomy. Possible treatment options include

5 estrogens, raloxifene, bisphosphonates, calcitonin, and cinacalcet. Cinacalcet has been shown to decrease serum calcium and parathyroid hormone serum levels in patients with PHPT. These trials, however, have not studied the effect of cinacalcet on patient-oriented outcomes such as bone mineral density, nephrolithiasis, or other complications of PHPT. Cinacalcet may be considered to reduce serum calcium and parathyroid hormone serum levels in patients with PHPT who cannot or will not undergo surgery and those with refractory PHPT after parathyroidectomy. Because the effects of cinacalcet on bone mineral density are uncertain, more frequent monitoring of bone mineral density may be required along with a medication proven to improve bone mineral density. Future studies should evaluate the effect of cinacalcet on complications of PHPT. A review of parathyroid carcinoma published in the journal Head & Neck in March 2011, has the following information on cinacalcet - Cinacalcet was investigated in a single-arm dose titration trial with 29 participants diagnosed with parathyroid carcinoma, who received up to 360 mg/dl of drug. Calcium reduction of at least 0.25mmol/L (1 mg/dl) was seen in 62% of participants, with a decline in mean serum calcium of 0.42mmol/L. The greatest reduction was seen in patients with the highest calcium levels. Five withdrew as a result of adverse effects, and 7 patients died while on study or within 30 days of withdrawal. (Silverberg SJ, Rubin MR, et al. Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. J Clin Endocrinol Metab 2007; 92: ). Given that most patients who succumb to parathyroid cancer die of hypercalcemia, cinacalcet may represent a significant adjunct in treatment. [10] NNT 2 3 to reduce one patient s parathyroid hormone level below 250 g/l over 6 months. [11] Cautions (info from ref 1) Cinacalcet is not indicated for CKD patients not on dialysis. Seizures - threshold for seizures is lowered by significant reductions in serum calcium levels. Hypotension and/or worsening heart failure - isolated, idiosyncratic cases have been reported in patients with impaired cardiac function, in which a causal relationship to cinacalcet could not be completely excluded and may

6 Drug Interactions (info from ref 1) Adverse effects (info from ref 1) Cost within PbR be mediated by reductions in serum calcium levels. Clinical trial data showed hypotension occurred in 7% of cinacalcet-treated patients, 12% of placebotreated patients, and heart failure occurred in 2% of patients receiving cinacalcet or placebo. Cinacalcet treatment should not be initiated in patients with serum calcium (corrected for albumin) below the lower limit of the normal range. Due to the potential for 2 to 4 fold higher plasma levels of cinacalcet in patients with moderate to severe hepatic impairment (Child-Pugh classification), cinacalcet should be used with caution in these patients and treatment should be closely monitored. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Mimpara. Cinacalcet should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. It is not known whether cinacalcet is excreted in human milk. Following careful benefit/risk assessment, a decision should be made to discontinue either breast-feeding or treatment with cinacalcet. Cinacalcet has the potential to interact with other drugs as it is metabolised by multiple enzymes, predominantly CYP3A4 and CYP1A2 and is a potent inhibitor of CYP2D6. Data presented from controlled studies include 656 patients who received cinacalcet and 470 patients who received placebo for up to 6 months. The most commonly reported adverse reactions were nausea and vomiting, occurring in 31% cinacalcet and 19% placebo treated patients, and 27% cinacalcet and 15% placebo treated patients, respectively. Nausea and vomiting were mild to moderate in severity and transient in nature in the majority of patients. Discontinuation of therapy as a result of undesirable effects was mainly due to nausea (1% placebo; 5% cinacalcet) and vomiting (< 1% placebo; 4% cinacalcet). Other common side effects include anorexia, dizziness, paraesthesia, rash, myalgia, asthenia, hypocalcaemia, reduced testosterone levels. Excluded for renal dialysis, included for other uses.

7 tariff? The Payment by Results Draft Guidance for states - Drug exclusions 254. Due to the variation in funding and prescription practices across the country, the tariff for renal dialysis is not intended to fund the following drugs in : (a) ESAs: Darbopoetin alfa; Epoetin alfa, beta (including methoxy polyethylene glycol-epoetin beta), theta and zeta (b) drugs for mineral bone disorders: Cinacalcet; Sevelamer; Lanthanum Cost (prices from MIMS Feb 2012) 255. Organisations should continue with current funding arrangements for these drugs when used in renal dialysis or outpatient attendances in nephrology (TFC 361). For all other uses, the relevant tariff prices are intended to reimburse the associated costs of the drugs. 28 x 30mg = x 60mg = x 90mg = The minimum and maximum costs per 28 days for secondary hyperparathyroidism = to The minimum and maximum costs per 28 days for primary hyperparathyroidism or parathyroid cancer = to Comparative costs of other medicines (prices from MIMS NICE stated that the annual cost of cinacalcet treatment for one patient with secondary hyperparathyroidism and end-stage renal disease on maintenance dialysis therapy is estimated to be 1,300. Cinacalcet is given with standard therapy therefore its cost is additional to current drug expenditure. Drug Dose Cost for 28 days Aluminimum hydroxide 4-20 capsules daily in divided capsules doses with meals

8 Feb 2012) Lanthanum tablets 1.5-3g daily in divided doses Sevelamer tablets g daily in divided doses Alfacalcidol capsules mcg daily Paricalcitol injection Calculated on baseline PTH 694 (based on Potential number of patients & usage in Suffolk PCT 5mcg/ml level, given every other day using 20mcg) Clinical trials indicate that 56% of patients receiving cinacalcet will respond adequately to treatment and hence will remain on cinacalcet after the 12 week titration phase. [11] When NICE reviewed use of cinacalcet for patients with secondary hyperparathyroidism and end-stage renal disease on maintenance dialysis therapy in 2007 they concluded that the guidance was unlikely to result in a significant change in resource utilisation in the NHS. [2] It is estimated that there are 16,939 patients in England with end-stage renal disease currently receiving maintenance dialysis therapy. Of these, 1728 have very uncontrolled plasma levels of intact PTH, and in 28.5% of these patients this condition is refractory to standard therapy. Surgical parathyroidectomy is contraindicated in a number of patients, and the proportion of patients for whom this applies increases with age. It is estimated that there are 492 patients with end-stage renal disease in England who have very uncontrolled plasma levels of intact PTH. It is further estimated that in 55 of these patients surgical parathyroidectomy is contraindicated. Extrapolating the above figures for NHS Suffolk, indicates there are potentially 6 patients with uncontrolled PTH and 1 patient eligible for cinacalcet. The NICE estimates for use of cinacalcet were very conservative. Since Sept patients have received cinacalcet via Ipswich Hospital as outpatients and 1 patient has received cinacalcet via West Suffolk Hospital.

9 Is the drug on the WSH or IHT formularies? Decisions from other bodies West Suffolk Hospital yes, only for primary hyperparathyroidism indication. Ipswich Hospital yes, for patients with secondary hyperparathyroidism meeting the criteria specified by NICE. SMC not recommended for any indication. Cambridgeshire JPG Green (with shared care), funded on a per patient basis following PCT approval for secondary hyperparathyroidism. Agreed Sept Norfolk TAG - Red (Hospital use only) for patients with secondary hyperparathyroidism meeting the criteria specified by NICE. Double Red for routine use in secondary hyperparathyroidism and parathyroid cancer. An internet search identified decisions from other PCTs for cinacalcet for secondary hyperparathyroidism. PCTS who have approved shared care Northern Ireland Cinacalcet Shared Care Guideline for management of secondary hyperparathyroidism (HPT) in renal disease Jan NHS Lincolnshire in association with United Lincolnshire Hospital Trust. Cinacalcet in the management of secondary hyperparathyroidism in adult patients with end-stage renal disease on dialysis Date of Issue: June %20rev%20June% pdf

10 Brighton & Sussex Univeristy Hospitals/Brighton & Hove City PCT Shared Care Protocol - Cinacalcet For Severe Hyperparathyroidism (secondary) May NHS Plymouth Shared care information for the prescribing of cinacalcet (secondary hyperparathyroidism) Last updated 14/10/10 Leicestershire Medicines Strategy Group shared care agreement for cinacalcet in the treatment of Secondary Hyperparathyroidism. Version- 1.1 Last reviewed - April %20Cinacalcet-sca%20v1.pdf North East Essex Medicines Management Committee Guidelines for Clinical And Prescribing Responsibility & Traffic Light Document July 2009 Cinacalcet = amber 1, Specialist initiation, GP to take over prescribing when patient is stabilised Policies/Guidelines4Clinic%20PrescResponsibilityTrafficLightDoc%20- %20%20reviewupdate%20Dec09.pdf Leeds Health Pathways - Cinacalcet hydrochloride for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy shared care guidelines. Date prepared: October PCTs who have decided to keep cinacalcet as red are Derbyshire Review Joint prepared Area Prescribing by Katie Smith, Committee East - Anglia Minutes Medicines of the meeting Information held on Service for Suffolk PCT Tuesday May be 13th freely December copied by 2011 NHS agencies Cinacalcet - RED for all indications, lengthy discussion around use for primary hyperparathyroidism atified%20minutes%2013%2012%2011%20a%20(2).pdf

11 I have found 1 shared care guideline for primary hyperparathyroidism Points for consideration Comments sought from Bournemouth D & T Committee Shared care guidelines for prescribing cinacalcet for primary hyperparathyroidism, Written Feb Dorset%20Formulary/Shared%20Care%20Guidelines/RBH%20Shared%20Care %20Cinacalcet.pdf In January 2007, NICE did not recommend cinacalcet for the routine treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy but did recommend it for the treatment of refractory secondary hyperparathyroidism. NICE guidance will be considered for review once the results of the on-going EVOLVE trial are available. Cinacalcet may be considered to reduce serum calcium and parathyroid hormone serum levels in patients with PHPT who cannot or will not undergo surgery and those with refractory PHPT after parathyroidectomy. Because the effects of cinacalcet on bone mineral density are uncertain, more frequent monitoring of bone mineral density may be required along with a medication proven to improve bone mineral density. Most patients who succumb to parathyroid cancer die of hypercalcemia, so cinacalcet may represent a significant adjunct in treatment. The cost of cinacalcet in the PBR tariff is excluded for renal dialysis, and included for other uses. An internet search identified a number of shared care agreements from other hospitals and PCTs across the country for the use of cinacalcet for the routine treatment of secondary hyperparathyroidism in patients with end-stage renal disease on dialysis therapy. Other PCTs have kept cinacalcet as a red drug. Drs Camilleri, Glancey & Williams, Consultant Nephrologists, Ipswich Hospital Drs Brahma, Clark, Gurnell, Majeed, Marath & Wijenaike, Endocrine Consultants, West Suffolk Hospital Decision review date March 2014

12 References 1. Summary of Product Characteristics. Mimpara. Amgen Ltd. Last revised 21/02/12. Accessed via on 28/02/12 2. NICE technology appraisal. Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. January Managing primary hyperparathyroidism in primary care. Drug & Therapeutics Bulletin 2010; 48 (3): Cunningham J, Locatelli F et al. Secondary hyperparathyroidism: Pathogenesis, disease progression, and therapeutic options. Clinical Journal of the American Society of Nephrology 2011; 6 (4): Raggi P, Chertow GM et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant 2011; 26 (4): McKenzie-Feder J, Sirrs S et al. Primary hyperparathyroidism: An overview. International Journal of Endocrinology 2011, Padmanabhan H. Outpatient management of primary hyperparathyroidism. Am L Med 2011; 124 (10): Al-Azem A; Khan A. Primary hyperparathyroidism. Can Med Assoc J 2011; 183 (e10): e685-e Dillon ML, Frazee LA. Cinacalcet for the treatment of primary hyperparathyroidism. American Journal of Therapeutics 2011; 18 (4): Owen RP, Silver CE, et al. Parathyroid carcinoma: A review. Head and Neck 2011; 33 (3): Smith K. Suffolk PCT Drug & Therapeutics Committee New Medicine Report Cinacalcet. November 2009

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14 Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this- Rank: Methodology Description Meta-analysis: A statistical analysis that combines or integra independent clinical trials considered by the analyst to be "co analysing the original data, also sometimes called: pooling, q 1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explici and explicit criteria to assess their quality. Both are sometimes called "overviews." 2 Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals) Individuals are randomly allocated to a control group and a g intervention. Otherwise the two groups are identical for any s followed up for specific end points. 3 Cohort studies Groups of people are selected on the basis of their exposure for specific outcomes. 4 Case-control studies "Cases" with the condition are matched with "controls" witho to look for differences between the two groups. 5 Cross sectional surveys Survey or interview of a sample of the population of interest 6 Case reports. A report based on a single patient or subject; sometimes col 7 Expert opinion A consensus of experience from the good and the great. 8 Anecdotal Something a bloke told you after a meeting or in the bar. Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008 To Decide if a Medication Is To Be Used In Suffolk Criterion to be measured Tends to poor Medium Quality of evidence in the papers reviewed Low Medium Magnitude of effect inferred from trials reviewed Low Medium Are trial end-points surrogate markers or clinical outcomes? Surrogate marker Clinical usefulness of trial end-points Low Medium Known Side Effect Profile High Medium Known Interactions High Medium Concern re Possible Side Effects Not Yet Uncovered High Medium Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium

15 NNT 2 to 3 for reduction on parathyroid hormone level below 250g/l High Medium over 6 months Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Same Condition (not applicable) Severity of Condition to be Treated Severe x Medium Novel drug or member of existing class novel Uptake (estimated proportion of people with this condition likely to be Both Primary & Secondary prev prescribed the medication under consideration maximum and minimum uptake) Is the drug to be used in Suffolk? Prescriber s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are metoo products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire) To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green Experience Of The Condition Specific Specific Specific Diagnosis Specific Specific Specific Monitoring Progress Of Treatment Difficult Specific General Therapy Patient Selection Difficult Specific Specific Initiation Of Treatment Difficult Difficult Easy Dose Titration Difficult Specific Easy Monitoring Of Side Effects Complex Easy Easy Method Of Administration Complex Normal Normal Discontinuation Of Treatment Complex Complex Easy References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14: Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2

16 QIPP Rating Red Traffic Light