qthis medicinal product is subject to additional monitoring. This will allow quick identification of new safety

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1 Parsabiv q (etelcalcetide) Frequently Asked Questions qthis medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Please refer to the product Summary of Product Characteristics on the electronic Medicines Compendium website for further information. Contents General...1 Pharmacokinetic/Pharmacodynamic (PK/PD)...1 Dosing and Administration...2 Efficacy...3 Safety profile and tolerability...4 Prescribing Information...5 General What is the appropriate patient for Parsabiv? Parsabiv is indicated for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) on haemodialysis therapy SmPC (4.1) Does a patient need to be on Vitamin D sterols or Phosphate binders prior to initiating Parsabiv? How long can I leave Parsabiv at room temperature before administering it to a dialysis patient? Parsabiv may be used as part of a therapeutic regimen including phosphate binders and/or vitamin D sterols, as appropriate SmPC (4.2, 5.1) Store Parsabiv in a refrigerator (2 C 8 C). Keep the vial in the outer carton in order to protect from light. Once removed from the refrigerator: Parsabiv is stable for a maximum of 7 cumulative days if stored in the original carton. No special temperature storage requirements are needed. If removed from the original carton Parsabiv is stable for a maximum of 4 hours if protected from direct sunlight. 1 The shelf life is three years SmPC (6.3, 6.4) How is the Parsabiv mechanism of action different from Mimpara? The calcium sensing receptor (CaSR) on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. 1 Mimpara (cinacalcet) directly lowers PTH levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium 1 Parsabiv is a synthetic peptide which reduces PTH levels by binding to and activating the calcium sensing receptor Mimpara SmPC (5.1) 2. Parasbiv SmPC (5.1) Pharmacokinetic/Pharmacodynamic (PK/PD) How is Parsabiv eliminated and what is the half life? IV administration three times per week at the end of a haemodialysis session resulted in an effective half-life of 3 to 5 days. Haemodialysis was the primary route of clearance and elimination (approximately 60% of the administered dose) SmPC (5.2) 1 UKIE-P (3) August 2017

2 Dosing and Administration How is Parsabiv administered? Parsabiv should not be diluted. 1 Parsabiv is administered by bolus injection into the venous line of the dialysis circuit at the end of the haemodialysis treatment during rinse-back (also known as wash back ) or intravenously after rinse-back. When given during rinseback at least 150 ml of rinse-back volume should be administered after injection. If rinse-back is completed and Parsabiv was not administered, then it may be administered intravenously followed by at least 10 ml saline flush volume. 1 Can you provide dosing guidance for initiating patients on Parsabiv? The recommended starting dose is 5 mg, 3 times per week for all appropriate patients. Corrected serum calcium should be at or above the lower limit of the normal range prior to administration of the first dose of Parsabiv. 1 Is there a recommended process and/or dose for patients switching from Mimpara? Parsabiv should not be initiated until 7-days after the last dose of Mimpara, and only provided that corrected serum calcium (Ca) is at or above the lower limit of the normal range. 1 After switching from Mimpara, the starting dose of Parsabiv should be 5 mg TIW. 1 How often should lab values be measured in patients on Parsabiv? PTH should be measured after 4 weeks from initiation or dose adjustment of Parsabiv, and approximately every 1-3 months during maintenance. Dose adjustment may be necessary at any time during treatment including the maintenance phase. 1 Serum calcium should be measured within 1 week of initiation or dose adjustment of Parsabiv. Once the maintenance phase has been established for a patient, corrected serum calcium should be measured approximately every 4 weeks. 1 Can you provide information on Parsabiv titration to achieve my desired PTH levels? Parsabiv should be titrated so that doses are individualised between 2.5 mg and 15 mg. The dose may be increased in 2.5 mg or 5 mg increments, no more frequently than every 4 weeks to a maximum dose of 15 mg 3 times per week to achieve the desired target PTH. 1 If PTH is below 100pg/mL, reduce the dose or temporarily stop administration. If the dose is stopped, then reinitiate at a lower dose once PTH returns to >150 pg/ml and pre-dialysis serum corrected calcium (cca) 8.3 mg/dl. 1 2

3 Dosing and Administration I am concerned about the potential of Parsabiv to lower cca levels. What are the recommendations for titration based on cca levels? If corrected serum calcium levels fall below the lower limit of the normal range (8.3 mg/dl) and/or symptoms of hypocalcaemia occur, the following management is recommended 1: Corrected serum calcium value or clinical symptoms of hypocalcaemia*: <8.3 mg/dl (2.08 mmol/l) and 7.5 mg/dl (1.88 mmol/l) <7.5 mg/dl (1.88 mmol/l) or symptoms of hypocalcaemia Recommendations If clinically indicated: Start or increase calcium supplements, calcium-containing phosphate binders, and/or vitamin D sterols. Increase dialysate calcium concentration. Consider reducing Parsabiv dose. Stop Parsabiv until corrected serum calcium levels are 8.3 mg/dl (2.08mmol/L) and symptoms of hypocalcaemia (if present) have resolved. If clinically indicated: Start or increase calcium supplements, calcium containing phosphate binders, and/or vitamin D sterols. Increase dialysate calcium concentration. Reinitiate Parasabiv at a dose 5 mg lower than the last administered dose. If patient s last administered dose was 2.5 mg or 5 mg, reinitiate at 2.5 mg once corrected serum calcium levels are 8.3 mg/dl (2.08 mmol/l) and symptoms of hypocalcaemia (if present) have resolved. * Total calcium was measured using Roche modular analyser. For albumin levels <4.0 g/dl cca (mg/dl) = Total Ca (mg/dl) + (4 - albumin[g/dl])* 0.8. What if a patient misses their dose of Parsabiv? If a regularly scheduled haemodialysis treatment is missed, do not administer any missed doses. Parsabiv should be administered at the next haemodialysis treatment at the same dose. If doses are missed for more than 2 weeks, then Parsabiv should be administered at 5 mg, (or 2.5 mg if that was the patient s last administered dose), and titrated to achieve the desired PTH. 1 Efficacy How long can I treat a patient with Parsabiv? What long term efficacy data is available? A 52-week, single arm extension study to the placebo-controlled and switch studies was conducted to characterise the long term safety and efficacy of Parsabiv in 891 SHPT patients with CKD on haemodialysis. At the end of 52 weeks, Parsabiv was not associated with any new safety findings and demonstrated maintenance of treatment effect as evidenced by a decrease in pre-dialysis PTH by >30% from baseline in 2/3rd of patients. In addition Parsabiv decreased pre-dialysis PTH to 300 pg/ml in more than 50% of patients SmPC (5.1) 3

4 Safety profile and tolerability Is there a risk of adynamic bone disease with Parsabiv? Adynamic bone may develop if PTH levels are chronically suppressed below 100 pg/ml. If PTH levels decrease below the recommended target range, the dose of vitamin D sterols and/or Parsabiv should be reduced or therapy discontinued. After discontinuation, therapy can be resumed at a lower dose to maintain PTH in the target range SmPC (4.4) Should I be concerned about hypocalcaemia with Parsabiv and what can I do to address the risk? Most events of asymptomatic blood calcium decreased and symptomatic hypocalcaemia were mild or moderate in severity. In the combined placebo-controlled studies, a higher proportion of patients in the Parsabiv group compared with patients in the placebo group developed at least one serum cca value < 7.0 mg/dl (1.75 mmol/l) (7.6% Parsabiv; 3.1% placebo). In these studies 1% of patients in the Parsabiv group and 0% of patients in the placebo group discontinued treatment due to the adverse event of low serum calcium. 1 Parsabiv treatment should not be initiated in patients if the corrected serum calcium is less than the lower limit of the normal range. 1 Patients should be advised to seek medical attention if they experience symptoms of hypocalcaemia and should be monitored for the occurrence of hypocalcaemia. Serum calcium levels should be measured prior to initiating treatment, within 1 week of initiation or dose adjustment, and every 4 weeks during treatment. If clinically meaningful decreases in corrected serum calcium levels occur, steps should be taken to increase serum calcium levels SmPC (4.4, 4.8) What is the difference between blood calcium decreased and hypocalcaemia? In the placebo-controlled and head-to-head studies, decrease in blood calcium and hypocalcaemia were defined as: Blood Calcium Decrease: asymptomatic reductions in calcium below 7.5 mg/dl or clinically significant (ie, required medical management) asymptomatic reductions in serum corrected calcium between 7.5 and < 8.3 mg/dl. Hypocalcaemia: symptomatic reductions in serum corrected calcium < 8.3 mg/dl SmPC (4.8) Does the Parsabiv SmPC have warning language regarding heart failure or QT prolongation? Decreased myocardial performance, hypotension, and congestive heart failure (CHF), may be associated with significant decreases in serum calcium. Decreases in serum calcium can prolong the QT interval, potentially resulting in ventricular arrhythmia. Serum calcium levels should be closely monitored in patients with a history of congestive heart failure, congenital long QT syndrome, previous history of QT prolongation, family history of long QT syndrome, sudden cardiac death, and other conditions that predispose to QT prolongation and ventricular arrhythmia while being treated with Parsabiv SmPC (4.4) cca = corrected calcium; Ca = calcium; CaSR = calcium-sensing receptor; CKD = chronic kidney disease; IV = intravenous; PD = pharmacodynamics; PK = pharmacokinetics; PTH = parathyroid hormone; SHPT = secondary hyperparathyroidism; TIW = three times a week. 4

5 Parsabiv q (etelcalcetide) Brief Prescribing Information Please refer to the Summary of Product Characteristics (SmPC) before prescribing Parsabiv. Pharmaceutical Form: Parsabiv contains etelacalcetide (as hydrochloride) 5 mg/ml solution for injection in vials of 2.5 mg, 5 mg and 10 mg. Indication: Parsabiv is indicated for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) on haemodialysis therapy. Dosage and Administration: The recommended initial dose of etelcalcetide is 5 mg administered 3 times per week. Corrected serum calcium should be at or above the lower limit of the normal range prior to administration of first dose of Parsabiv, a dose increase, or reinitiation after a dose stop. Parsabiv should not be administered more frequently than 3 times per week. Parsabiv should be titrated so that doses are individualised between 2.5 mg and 15 mg 3 times per week to achieve the desired parathyroid hormone (PTH) target, while maintaining serum calcium at or above the lower limit of normal. The dose may be increased in 2.5 mg or 5 mg increments no more frequently than every 4 weeks. PTH should be measured after 4 weeks from initiation or dose adjustment, and approximately every 1-3 months during maintenance. Serum calcium should be measured within 1 week of initiation or dose adjustment and approximately every 4 weeks during maintenance. If clinically meaningful decreases in corrected serum calcium levels occur, steps should be taken to increase serum calcium levels. Please refer to the Parsabiv SmPC for further details on dose adjustments based on PTH and calcium levels. Parsabiv may be used in combination with phosphate binders and/ or vitamin D sterols. If a regularly scheduled haemodialysis treatment is missed, do not administer any missed doses. Parsabiv should not be initiated in patients until 7 days after the last dose of cinacalcet. Method of administration: Parsabiv is administered by bolus injection into the venous line of the dialysis circuit at the end of the haemodialysis treatment during rinse-back, or intravenously after rinseback. When given during rinse-back, at least 150 ml of rinseback volume should be administered after injection. If rinseback is completed and Parsabiv was not administered, then it may be administered intravenously followed by at least 10 ml saline flush volume. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Parsabiv should not be initiated if corrected serum calcium is less than the lower limit of the normal range. Special Warnings and Precautions: Hypocalcaemia: Parsabiv treatment should not be initiated in patients if the corrected serum calcium is less than the lower limit of the normal range. Potential manifestations of hypocalcaemia include paraesthesias, myalgias, muscle spasm and seizures. Since etelcalcetide lowers serum calcium, patients should be advised to seek medical attention if they experience symptoms of hypocalcaemia and should be monitored for the occurrence of hypocalcaemia. Serum calcium levels should be closely monitored in patients with congenital long QT syndrome, previous history of QT prolongation, family history of long QT syndrome or sudden cardiac death and other conditions that predispose to QT prolongation and ventricular arrhythmia. Serum calcium levels should be closely monitored in patients with a history of a convulsion disorder. Worsening heart failure: Serum calcium levels should be monitored in patients with a history of congestive heart failure. Co-administration with other medicinal products: Administer Parsabiv with caution in patients receiving any other medicinal products known to lower serum calcium. Patients receiving Parsabiv should not be given cinacalcet. Concurrent administration may result in severe hypocalcaemia. Adynamic bone: Adynamic bone may develop if PTH levels are chronically suppressed below 100 pg/ml. If PTH levels decrease below the recommended target range, the dose of vitamin D sterols and/or Parsabiv should be reduced or therapy discontinued. Immunogenicity: No evidence of altered pharmacokinetic profile, clinical response or safety profile was associated with pre-existing or developing anti-etelcalcetide antibodies. Interactions: No interaction studies have been performed. There is no known risk of pharmacokinetic interaction with etelcalcetide. Fertility, pregnancy and lactation: There are no or limited data from the use of etelcalcetide in pregnant women. It is preferable to avoid the use of Parsabiv during pregnancy. It is unknown whether etelcalcetide is present in human milk. A risk to breastfed newborns/ infants cannot be excluded. No data are available on the effect of etelcalcetide on human fertility. Undesirable Effects: The incidence of adverse reactions from controlled clinical studies are: very common ( 1/10) blood calcium decreased, nausea, vomiting, diarrhoea and muscle spasms; common ( 1/100 to < 1/10) hypocalcaemia, hyperkalaemia, hypophosphataemia, headache, paraesthesia, worsening heart failure, QT prolongation, hypotension and myalgia. Please refer to the Parsabiv SmPC for further information on undesirable effects. Pharmaceutical Precautions: Store in a refrigerator (2 C 8 C). Keep the vial in the outer carton to protect from light. Clear colourless solution. For single use only. Legal Category: POM. Presentation, Basic Costs and Marketing Authorisation Number: Parsabiv 2.5 mg solution for injection Pack of 6 vials: ; EU/1/16/1142/002. Parsabiv 5 mg solution for injection Pack of 6 vials: ; EU/1/16/1142/006. Parsabiv 10 mg solution for injection Pack of 6 vials: ; EU/1/16/1142/010. Marketing Authorisation Holder: Amgen Europe B.V. Minervum 7061, 4817 ZK Breda, The Netherlands. Further information is available from Amgen Limited, 240 Cambridge Science Park, Milton Road, Cambridge, CB4 0WD. Parsabiv is a registered trademark of Amgen Inc. Date of PI preparation: December 2016 (Ref:UKIE-P ). This medicinal product is subject to additional monitoring. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Amgen Limited on +44 (0)

6 Mimpara (cinacalcet) Brief Prescribing Information Please refer to the Summary of Product Characteristics (SPC) before prescribing Mimpara. Pharmaceutical Form: Film-coated tablets containing 30, 60 and 90 mg cinacalcet (as hydrochloride). Indication: Treatment of secondary hyperparathyroidism (HPT) in adult patients with end-stage renal disease (ESRD) on maintenance dialysis therapy. Mimpara may be used as part of a therapeutic regimen including phosphate binders and/or vitamin D sterols, as appropriate. Reduction of hypercalcaemia in adult patients with parathyroid carcinoma or in patients with primary HPT for whom parathyroidectomy would be indicated based on serum calcium levels but in whom parathyroidectomy is not clinically appropriate or is contraindicated. This brief Prescribing Information does not address use of Mimpara in the paediatric population; refer to the SPC for details. Dosage and Administration: For oral use. Take with food or shortly after a meal. Tablets should be taken whole and not chewed, crushed or divided. Secondary hyperparathyroidism Adults and elderly (> 65 years): Starting dose for adults is 30 mg once per day. Dose should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH) in dialysis patients of between pg/ml ( pmol/l) in the intact PTH assay. PTH levels should be assessed at least 12 hours after dosing with Mimpara. PTH should be measured 1 to 4 weeks after initiation or dose adjustment and approximately every 1-3 months during maintenance. Corrected serum calcium should be measured and monitored and should be at or above the lower limit of the normal range prior to administration of first dose of Mimpara. During dose titration, serum calcium levels should be monitored frequently, and within 1 week of initiation or dose adjustment. Once the maintenance dose has been established, serum calcium should be measured approximately monthly. In the event that corrected serum calcium levels fall below 8.4 mg/dl (2.1mmol/L) and/or symptoms of hypocalcaemia occur, action should be taken. For recommended management of hypocalcaemia see SPC. Parathyroid carcinoma and Primary HPT Adults and elderly (>65 years): Starting dose for adults is 30 mg twice per day. Dose should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium concentration to or below the upper limit of normal. Serum calcium should be measured within 1 week after initiation or dose adjustment of Mimpara. Once maintenance dose levels have been established, serum calcium should be measured every 2 to 3 months. After titration to the maximum dose of Mimpara, serum calcium should be periodically monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of Mimpara therapy should be considered. Contra-indications: Hypocalcaemia. Hypersensitivity to the active substance or to any of the excipients. Special Warnings and Precautions: Cinacalcet is not indicated for Chronic Kidney Disease (CKD) patients not on dialysis. Serum Calcium: Life threatening events and fatal outcomes associated with hypocalcaemia have been reported in adult patients treated with Mimpara, including QT prolongation and ventricular arrhythmia. Caution is advised in patients with other risk factors for QT prolongation. Mimpara treatment should not be initiated in patients with a serum calcium (corrected for albumin) below the lower limit of the normal range. Seizures: Cases of seizures have been reported. Threshold for seizures is lowered by significant reductions in serum calcium levels. Serum calcium levels should be closely monitored, particularly in patients with a history of a seizure disorder. Hypotension and/or worsening heart failure: Cases have been reported in patients with impaired cardiac function, in which a causal relationship to Mimpara could not be excluded. Coadministration with other medicinal products: Administer Mimpara with caution in patients receiving any other medicinal products known to lower serum calcium. Closely monitor serum calcium. Patients receiving Mimpara should not be given etelcalcetide. Concurrent administration may result in severe hypocalcaemia. General: Adynamic bone disease may develop if PTH levels are chronically suppressed below approximately 1.5 times the upper limit of normal. If PTH levels decrease below the recommended target range, the dose of Mimpara and/or vitamin D sterols should be reduced or therapy discontinued. Testosterone levels: In adult ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment. The clinical significance of these reductions is unknown. Hepatic impairment: Mimpara should be used with caution in patients with moderate to severe hepatic impairment and treatment should be closely monitored. Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take Mimpara. Interactions: Cinacalcet is metabolised in part by the enzyme CYP3A4 and in vitro data indicate that cinacalcet is in part metabolised by CYP1A2. Dose adjustment of Mimpara may be required for specific medications, and if a patient starts/stops smoking. Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments of concomitant medication may be required when Mimpara is administered with individually titrated, narrow therapeutic index substances that are predominantly metabolised by CYP2D6. Please consult the SPC for information on interactions with other medicinal products. Fertility, pregnancy and Lactation: There are no clinical data relating to the effect of Mimpara on fertility. Mimpara should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. It is unknown whether Mimpara is excreted in human milk. A decision should be made whether to discontinue breastfeeding or to discontinue treatment with Mimpara. Undesirable Effects: Secondary hyperparathyroidism, parathyroid carcinoma and primary hyperparathyroidism: In controlled studies and singlearm studies, the most commonly reported adverse reactions were nausea and vomiting. Nausea and vomiting were mild to moderate in severity and transient in nature in the majority of patients. Other adverse reactions seen in clinical trials and post-marketing experience were: (very common: 1/10) nausea, vomiting and (common: 1/100 to < 1/10) hypersensitivity reactions, anorexia, decreased appetite, seizures, dizziness, paraesthesia, headache, hypotension, upper respiratory infection, dyspnoea, cough, dyspepsia, diarrhoea, abdominal pain, abdominal pain upper, constipation, rash, myalgia, muscle spasms, back pain, asthenia, hypocalcaemia, hyperkalaemia, reduced testosterone levels. Hypersensitivity reactions including angioedema and urticaria have been reported in post-marketing use of Mimpara. Dizziness and seizures may have a major influence on the ability to drive and use machines. Please consult the SPC for a full description of adverse reactions. Pharmaceutical Precautions: No special storage precautions. Legal Category: POM. Presentation, Basic NHS Costs and Marketing Authorisation Numbers: Mimpara 30 mg: Pack of 28: EU/1/04/292/002 Mimpara 60 mg: Pack of 28: EU/1/04/292/006 Mimpara 90 mg: Pack of 28: EU/1/04/292/010 Marketing Authorisation Holder: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands. Further information is available from Amgen Limited, 240 Cambridge Science Park, Milton Road, Cambridge, CB4 0WD. Mimpara is a registered trademark of Amgen Inc. Date of PI preparation: August 2017 (ref: UKIE-P ) Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Amgen Limited on +44 (0) UKIE-P (2) August 2017