Dorset Medicines Advisory Group

SHARED CARE GUIDELINE FOR THE USE OF PHOSPHATE BINDERS IN THE MANAGEMENT OF HYPERPHOSPHATAEMIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE.

INDICATION

This document provides guidance for the prescribing of phosphate binders for the management of hyperphosphatemia in patients receiving haemodialysis or peritoneal dialysis and patients with chronic kidney disease stage 4 or 5 who are not receiving dialysis. This shared care guideline covers adult patients under the care of the Dorset Renal Unit.

Patients with chronic renal failure have reduced ability to excrete phosphate. Phosphate accumulation enhances parathyroid activity and leads to the calcification of arteries, significantly contributing to the excess cardiovascular morbidity in these patients, especially in younger age groups. Adequate control of serum phosphate levels is thought to be beneficial for the prevention of vascular and cardiac calcification in patients with renal failure and control of parathyroid hormone.

A number of oral phosphate binders are available which may be used in the context of a multiple therapeutic approach. These include calcium acetate, calcium carbonate, calcium acetate/magnesium carbonate, lanthanum, sevelamer and sucroferric oxyhydroxide. These products may be used in combination with 1-hydroxycholecalciferol (alfacalcidol) or one of its analogues and/or cinacalcet to control the development of secondary hyperparathyroidism and renal bone disease.

A calcium-based phosphate binder is generally used as the initial phosphate binder therapy for the treatment for hyperphosphatemia. Calcium acetate is preferred over calcium carbonate due to its lower elemental calcium content for the equivalent phosphate binding capacity, however patient preference in formulation should be taken into consideration. A non-calcium-based phosphate binder should be used in patients who cannot tolerate a calcium-based phosphate binder, whose serum calcium exceeds 2.5mmol/L or whose parathyroid levels are less than 15pmol/L. Calcium-based and non-calcium-based phosphate binders may be used in combination if required to achieve target serum phosphate and calcium levels. Aluminium-based phosphate binders may be used if other phosphate binders are contraindicated, not tolerated or are ineffective.

The calcium-based phosphates binders are amber drugs with shared care guidance. The use of calcium-based phosphate binders in patients who are not on dialysis is off-label, however their use in this patient group is in accordance with national guidance (NICE, 2013).

Lanthanum and sevelamer are amber drugs with shared care guidance for patients with chronic kidney disease stage 4 or 5 who are not receiving dialysis.

Lanthanum and sevelamer are red drugs for patients receiving haemodialysis or peritoneal dialysis. For patients receiving dialysis who were initiated on lanthanum or sevelamer prior to April 2020, the GP may continue to prescribe in accordance with this shared care guideline. For patients receiving dialysis that have been initiated on lanthanum or sevelamer after April 2020, prescribing should be maintained by the specialist.

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AREAS OF RESPONSIBILITY FOR SHARED CARE

Patients should be at the centre of any shared care arrangements. Individual patient information and a record of their preferences should accompany shared care prescribing guidelines, where appropriate. Transfer of clinical responsibility to primary care should only be considered where the person’s clinical condition is considered stable. Referral to the GP should only take place once the GP has agreed to this in each individual case, and the hospital or specialist will continue to provide prescriptions until a successful transfer of responsibilities. The GP should confirm the agreement and acceptance of the shared care prescribing arrangement and that supply arrangements have been finalised. The secondary/tertiary provider must supply an adequate amount of the medication to cover the transition period. The patient should then be informed to obtain further prescriptions from the GP. When clinical responsibility for prescribing is transferred to general practice, it is important that the GP, or other primary care prescriber, is confident to prescribe the necessary medicines. Shared care agreements play a key role in enabling primary care prescribers to prescribe medicines with which they may not initially be familiar. Clinical responsibility for prescribing is held by the person signing the prescription, who must also ensure adequate monitoring has taken place.

The specialist may be consultant nephrologist, speciality registrar in renal medicine or specialist renal dietitian.

REFERRAL AND INITIATION Shared Care is only appropriate if it provides the optimum solution for the patient.

o Patients will only be referred to the GP once the GP has agreed in each individual case.

o Arrangements to transfer treatment from secondary to primary care may be made from 3 months after initiation of treatment, once the condition has been stabilised.

Specialist Responsibilities 1 To assess the patient and establish the need for a phosphate binder. 2 To initiate and titrate therapy to determine optimal dose level according to the agreed protocol for the use of phosphate binders in renal patients. The first three months of treatment will be prescribed through the Dorset Renal Unit. 3 To obtain consent from the patient’s GP to continue prescribing once treatment has been stabilised ensuring they are provided with appropriate prescribing information and any additional information requested. 4 To review patients regularly in clinic, monitor phosphate and calcium levels and undertake all necessary monitoring. 5 To notify the GP at regular intervals, up to every 6 months, to confirm that the patient has been reviewed and for supply to be continued for a 6-month period, results of necessary monitoring to be shared with the GP in this notification. 6 To be available for advice if the patient’s condition changes and to provide the GP with up-to-date information when changes are made to the patient’s prescription following consultant review. 7 To ensure that procedures are in place for the rapid re-referral of the patient by the GP. 8 To ensure the patient/ carer has given informed consent to their treatment. 9 To discontinue treatment if no longer thought to be beneficial.

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General Practitioner Responsibilities 1 Initially, to refer the patient for specialist advice. 2 Where appropriate, to continue to supply the phosphate binder as per doses agreed with the specialist after the initial three-month titration period and once relevant information has been received and agreed with the consultant. 3 To deal with general health issues of the patient. 4 To liaise with the consultant regarding any complications of treatment. 5 To refer the patient to the specialist if the patient’s condition changes.

Patient's role (or that of carer) 1 Report to the specialist or GP if he or she does not have a clear understanding of the treatment. 2 Attend appropriate consultant and GP appointments. 3 Share any concerns in relation to treatment with their phosphate binder. 4 Use written and other information on the medication, including taking their phosphate binder with meals and adhering to their prescribed diets. 5 Seek help urgently if suspect side effects, or otherwise unwell.

SUPPORTING INFORMATION

Patient Counselling Phosphate binders should be taken just before, during or directly after a meal or snack. Patients should adhere to prescribed diets.

Duration of treatment Lifelong.

Monitoring Requirements and Responsibilities All patients receiving phosphate binders will have their calcium, phosphate and parathyroid hormone levels routinely measured. Additionally, patients taking Osvaren® will have their magnesium levels monitored every 6 months. Results will be shared with the GP via Dorset Care Record

Pregnancy and Breastfeeding

Calcium carbonate is considered suitable for use in pregnant and breastfeeding women.

There is limited or no data for the use of calcium acetate, calcium acetate/magnesium carbonate, lanthanum and sevelamer in pregnant women. Their use may be considered in pregnant women and a careful risk benefit analysis should be conducted for both mother and foetus.

Calcium acetate may be used in pregnant and breastfeeding women if clearly indicated.

The manufacturers of lanthanum recommend that lanthanum is not used during pregnancy.

Sevelamer is less suitable for pregnant women as it may reduce the absorption of fat-soluble vitamins and folic acid.

Osvaren® is not recommended for women who are breastfeeding as calcium acetate and magnesium carbonate may be excreted in human milk to such an extent that effects on the breastfed infant are likely.

It is unknown whether sevelamer and lanthanum are excreted in human milk, however because of their low bioavailability, they are unlikely to be excreted in the breast milk in significant amounts. Sevelamer may cause vitamin deficiencies in the mother.

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Contact Information Renal Secretaries 01305 255269 Dietitian Office 01305 255377 Dietitian Mobile 07833484301

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BINDER LICENSED LICENSED CAUTIONS AND DRUG INTERACTIONS ADVERSE REACTIONS INDICATION DOSE CONTRAINDICATIONS

CALCIUM CONTAINING BINDERS

Calcium Acetate Correction of Initially one tablet Cautions: Increased risk of hypercalcaemia with Constipation, flatulence, hyperphosphatemia three time a day with History of nephrolithiasis. vitamin D and thiazide diuretics. diarrhoea, hypercalcaemia, Available as: associated with each meal. Sarcoidosis. gastro-intestinal disturbance, chronic renal failure Cardiac effects of digoxin Reduced absorption of: nausea, vomiting. Phosex 1000mg in patients The dose should be and verapamil are enhanced Tablets undergoing dialysis. adjusted according to in the presence of • Oral Anti-Cancer Drugs Mild hypercalcaemia may be (£19.79 per 180 serum phosphate, as hypercalcaemia. Eltrombopag; take 2 hours prior to associated with muscle tablets) long as Administration of adrenaline or 4 hours after binder, weakness, constipation, hypercalcaemia does in patients with estramustine; avoid, neratinib; anorexia, nausea, vomiting. Renacet 475mg not occur, to a hypercalceamia may lead to separate administration by 4 hours. and 950mg maximum 12 tablets severe arrhythmia. More severe hypercalcaemia Tablets are Non- per day. • Anti-Malarial Drugs Chloroquine may be associated with Formulary. Contraindications: and hydroxychloroquine; arrhythmia, confusion, Tablets should be Hypersensitivity to the active separate administration by 4 delirium, stupor, coma. swallowed whole. substance or any of the hours, proguanil; separate Tablets may be excipients. administration by 2 hours. Hypercalciuria. broken but should not Hypercalcaemia or be chewed due to conditions associated with • Antiretrovirals Skin reactions. their bitter taste. hypercalcaemia. Ledipasvir; separate administration Conditions associated with by 4 hours, dolutegravir; take 2 Overdose with calcium Calcium Phosphate binding Dose as required by hypercalciuria. hours prior to or 6 hours after products can lead to soft Carbonate agent in the the individual patient binder, raltegravir; avoid, rilpivirine; tissue calcification and milk- management of depending on serum Contraindications take 4 hours before or 2 hours after alkali syndrome/metabolic Available as: renal failure in phosphate level. For Calcium Carbonate Only: binder, velpatasvir; separate alkalosis. patients on renal Primary hyperparathyroidism. administration by 4 hours. Adcal 1500mg dialysis. For Adcal, the usual Vitamin D overdose. Patients should seek medical Chewable Tablets dose is Severe renal failure • Bisphosphonates/Strontium. advice before taking antacids (£8.70 per 100 2 to 8 tablets per day. untreated by dialysis. containing calcium salts, to

5 Dorset Medicines Advisory Group tablets) Osteoporosis due to Not used in this patient group. avoid adding to calcium load. The tablets should be prolonged immobilisation. Calcichew chewed or sucked, Renal stones. (Relative • Oral Iron Preparations 1250mg Chewable not swallowed whole. contraindications.) Take 1 hour before or 2 hours after Tablets oral iron. are Non- Patients with fructose Formulary. intolerance, glucose- • Levothyroxine galactose malabsorption or Separate administration by 4 hours. sucrose-isomaltase insufficiency should not take • Quinolones (Ciprofloxacin, Adcal or Osvaren. levofloxacin, moxifloxacin, ofloxacin.) Take 2 hours before or 4 hours after binder.

• Tetracyclines (Doxycycline, demeclocycline, lymecycline, minocycline, oxytetracycline, tetracycline, tigacycline.) Separate administration by 3 hours.

• Zinc Separate administration.

Calcium Acetate Treatment of Initially one tablet As for calcium acetate. As for calcium acetate. As for calcium acetate. and hyperphosphatemia three time a day with Magnesium associated with food, adjusted Contraindications: Increased risk of metabolic acidosis Hypermagnesaemia. Carbonate chronic renal according to serum Hypophosphatemia, with polystyrene sulfonate (resonium). insufficiency in phosphate. Usual Hypermagnesemia, Mild hypermagnesaemia may Available as: patients undergoing dose: 3 to 10 tablets myasthenia gravis, third- Manufacturer advises that other drugs be associated with gastro- dialysis. per day. Maximum degree AV block. should be taken 2 hours before or 3 intestinal disturbance, Osvaren dose 12 tablets per hours after Osvaren to reduce possible cystospasm, muscle 435mg / 235mg day. interference with absorption of other weakness, lethargy, missing Tablets. drugs. deep-tendon reflexes and (£24.00 per 180 The tablets may be disturbed AV-conduction and tablets) broken along the Reduced absorption of: ventricular stimulus.

6 Dorset Medicines Advisory Group score line but the tablets should not be • Oral Anti-Cancer Drugs Severe hypermagnesaemia crushed or chewed. Bosutinib; take 12 hours before may be associated with Osvaren, certinib; separate arterial hypotension, paralytic administration by 2 hours, dasatinib; ileus, flaccis paralysis, coma, separate administration by 2 hours, respiratory arrest and cardiac erlotinib; take 2 hours before or 4 arrest. hours after Osvaren, gefitinib; separate administration, lapatinib; Hyperkalaemia. avoid, nilotinib; separate administration by at least 2 hours, Magnesium induced osteal pazopanib; take 1 hour before or 2 mineralisation disturbance. hours after Osvaren, Patients should seek medical • Antifungals (Itraconazole and advice before taking antacids ketocontazole) containing magnesium salts, Separate administration by 2 hours. to avoid adding to magnesium load. • Antipsychotics (Chlorpromazine, levomepromazine, fluphenazine pericyazine, prochlorperazine, promazine, trifluoperazine) Separate administration.

• Antiretrovirals Atazanavir; take 2 hours before or 1 hour after Osvaren, bictegravir; separate administration by 2 hours, elvitegravir; separate administration by 4 hours, tipranavir; separate administration by 2 hours.

• Aspirin (high dose). Separate administration.

• Cefuroxime Separate administration.

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• Cholic Acid Separate administration.

• Digoxin Separate administration by 2 hours.

• Dipydridamole (immediate release) Separate administration.

• Fexofenadine Separate administration by 2 hours.

• Gabapentin Take 2 hours after Osvaren.

• Gemfibrozil Separate administration

• Glucocorticoids (Deflazacort and dexamethasone) Separate administration by 2 to 3 hours.

• Mycophenolate Separate administration.

• Nitrofurantoin Separate administration.

• Penicillamine Separate administration by 2 hours.

• Rifampicin Take 1 hour before Osvaren.

• Riociguat Take 1 hour before or 2 hours after Osvaren.

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• Rosuvastatin Separate administration by 2 hours.

• Sulpride Separate administration by 2 hours.

• Ursodeoxycholic acid Separate administration by 2 hours.

Cautions Lanthanum may increase gastric PH. Common Lanthanum Hyperphosphateami 1.5g to 3g daily in Gastrointestinal disorders. Constipation, diarrhoea, Carbonate a in chronic renal divided doses, dose Patients predisposed to Reduced absorption of: dyspepsia, electrolyte failure patients on to be adjusted gastrointestinal obstruction, imbalance, flatulence, Available as: haemodialysis or according to serum ileus, subileus and • Chloroquine and gastrointestinal discomfort, continuous phosphate perforation. hydroxychloroquine. gastrointestinal disorders, Fosrenol ambulatory concentration (PO). Separate administration by 2 headache, laryngitis, nausea, chewable tablets: peritoneal dialysis. Contraindications hours. vomiting. The tablets must be Hypersensitivity to lanthanum 500mg tablets Hyperphosphateami chewed completely carbonate or to any of the • Ciprofloxacin, Levofloxacin, Uncommon (£124.06 per 90) a in patients with and not swallowed excipients. Moxifloxacin, Ofloxacin. Allergic skin reactions, chronic kidney whole. Hypophosphataemia. Take 2 hours before or 4 hours alopecia, appetite changes, 750mg tablets disease not on after lanthanum. arthralgia, asthenia, burping, (£182.60 per 90) dialysis who have a The powder should Patients with glucose- chest pain, dizziness, dry serum phosphate be mixed with a small galactose malabsorption • Demeclocycline, Doxycycline, mouth, eosinophilia, 1000mg tablets level of 1.78mmol/L quantity of soft food should not take lanthanum. Lymecycline,Minocycline, hyperglycaemia, (£193.59 per 90) or more that cannot (applesauce or other Oxytetracycline, Tetracycline. hyperhidrosis, be controlled by a similar food product) hyperparathyroidism, ileus, Fosrenol Powder: low phosphate diet. and consumed within Separate administration by 2 hours. increased risk infection, 15 minutes. intestinal obstruction, 750mg sachet • Ketoconazole intestinal perforation, irritable (£182.60 per 90) The powder is Separate administration by 2 bowel syndrome, malaise, insoluble and must hours. oesophagitis, oral disorders, 1000mg sachet not be dissolved in osteoporosis, pain, (£193.59 per 90) liquid for • Levothyroxine, Liothyronine peripheral oedema, administration. Separate administration by 2 stomatitis, subileus, sweating hours. increased, altered taste, thirst, vertigo, weight loss.

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Sevelamer For Sevelamer Initially 2.4g to 4.8g in Cautions Sevelamer is not absorbed and may Constipation, diarrhoea, Carbonate and 3 divided doses (PO), Gastrointestinal disorders reduce the bioavailability of other gastrointestinal discomfort, Available as: Sevelamer adjusted according to medicinal products, when administering gastrointestinal disorders, Hydrochloride: serum phosphate Contraindications any medicinal product where a nausea, vomiting. Sevelamer concentration. Hypersensitivity to active reduction in bioavailability could have a Carbonate Hyperphosphatemia ingredients or any of the significant clinical effect on safety or Skin reactions. in patients receiving For Sevelamer excipients. efficacy, the medicinal product should Generic haemodialysis or Carbonate: Usual Bowel obstruction be administered at least one hour 800mg Tablets peritoneal dialysis. dose 6g daily in 3 Hypophosphatemia before or three hours after sevelamer (£55.70 per 180) For Sevelamer divided doses. carbonate. Carbonate Only: Sevelamer carbonate 800 Renvela 800mg Hyperphosphatemia For Sevelamer mg film-coated tablets Reduced absorption of: Tablets in patients with Hydrochloride: contain lactose. Patients with chronic kidney Usual dose 2.4g to rare hereditary problems of • Ciprofloxacin Renvela 2.4g disease not on 12g daily in 3 divided galactose intolerance, total • Take one hour before or three powder dialysis who have a doses. lactase deficiency or hours after sevelamer.) (£167.04 per 60 serum phosphate glucose-galactose sachets) level of 1.78mmol/L The tablets must be malabsorption should not Levothyroxine or more. swallowed whole. Do take this medicine. (Take one hour before or three hours not crush, chew or after sevelamer.) Sevelamer Sevelamer break into pieces. Hydrochloride Hydrochloride is not licensed for patients The sachets should Renagel not receiving be dispersed in 60mL 800mg Tablets dialysis. on water or mixed with a small amount of beverage or food and consumed within 30 minutes.

Aluminium hydroxide AluCaps have been discontinued Unlicensed products are available. Red formulary status.

Sucroferric Oxyhydroxide Available as: Velphoro 500mg Chewable Tablets are Non-Formulary.

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References

Drugs in pregnancy and lactation. Available at: https://about.medicinescomplete.com/publication/drugs-in-pregnancy-lactation/

Joint Formulary Committee (2020), British National Formulary. Available at: https://bnf.nice.org.uk/

KDIGO, 2017. Clinical Practice Guideline Update for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-related mineral and bone disorder (CKD-MBD). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340919/

NHS Business Services Authority (2020), Drug Tariff (online). Available at: https://www.nhsbsa.nhs.uk/pharmacies-gp-practices-and-appliance-contractors/drug-tariff/drug-tariff- part-viii

NICE, 2013. Clinical Guideline (CG157): Chronic Kidney Disease (stage 4 or 5): Management on hyperphosphatemia. Available at: https://www.nice.org.uk/guidance/cg157

Product SPC’s available at: https://www.medicines.org.uk/emc

The manufacturer’s summary of product characteristics (SPC) and the most current edition of the British National Formulary should be consulted for full information on contra-indications, warnings, side-effects and drug interactions.

Written By Dorset Renal Team August 2020 Approved Dorset Medicines Advisory Group September 2020 By

Review August 2022, or before in the light of new evidence and/or Date recommendations

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