assessment report (d-75) es/h/113/psur-12...

Paricalcitol 1/34 FAR-D75

ES/H/PSUR/0016/002

ASSESSMENT REPORT (D-75)

ES/H/113/PSUR-12 ES/H/PSUR/0016/002

PRODUCT: ZEMPLAR

ACTIVE SUBSTANCE: (Paricalcitol) ASSESSOR:

Natividad Galiana/ Miguel Angel Maciá División de Farmacología y Farmacovigilancia Agencia Española de Medicamentos y Productos sanitarios Phone:918225315

CONTACT FOR THE DISCUSSION OF THE ASSESSMENT REPORT:

Dr. Miguel Angel Maciá División de Farmacología y Farmacovigilancia Agencia Española de Medicamentos y Productos sanitarios Phone:918225315

PERIOD COVERED BY THIS PSUR: 9th August 2009- 8th August 2010

DATE OF THE ASSESSMENT REPORT: 14th January 2011

SUBDIRECCIÓN GENERAL

DE MEDICAMENTOS DE USO HUMANO

División de Farmacoepidemiología y

Farmacovigilancia

agencia española dem e d i c a m e n t o s yproductos sanitarios


ES/H/PSUR/0016/002

Pharmaceutical form(s) Injection, capsules MAH(s) Abbott IBD/EBD 17 April 1998 PSUR 12th PSUR – (9th August 2009- 8th August 2010) Rapporteur / (P)RMS SPAIN Assessor Natividad Galiana/ Miguel Angel Maciá Contact point Dr. Miguel Angel Maciá

Phone:918225315

TIME TABLE

Procedure Start Date November 2010

Date of preliminary AR (AR-D40)

14-January-2011

Deadline for comments to P-RMS (D70)

17-february-2011

Clockstop/ RFI / LoQ

Procedure Restart Date

Date of Draft Final AR

Deadline for comments to P-RMS

Date of Final AR 22-September-2011

Discussion at PhVWP

DLP of the next PSUR submission and period of PSUR

August 2013

In addition to the innovator PSUR, the assessment report covers the following PSURs of

additional products authorised in the P-RMS:

MAHs MR procedure number

(if applicable)

Period covered by the PSUR

The following PSURs of products not authorised in the P-RMS* have been submitted as

part of the worksharing procedure.

MAHs MR procedure number

(if applicable)

Period covered by the PSUR


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1. Introduction ...................................................................................................................... 4

2. Data Review ..................................................................................................................... 4

3. Conclusions ................................................................................................................... 32


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1. Introduction Paricalcitol is a synthetic vitamin D (calcitriol) analogue. Paricalcitol injection is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal insufficiency (chronic kidney disease [CKD] Stage 5). Paricalcitol capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stages 3 and 4, or CKD Stage 5 patients on haemodialysis or peritoneal dialysis. This assessment report deals with the 12th PSUR, which covers the period from 9th August 2009 to 8th August 2010. 2. Data Review 2.1 Worldwide marketing authorisation status Paricalcitol injection was first approved in the United States, on 17th April 1998 (IBD and EU-HBD). It has been approved trough a MRP in the EU under the trade name Zemplar. The first European date of approval was 9th August 2002 (Spain). Paricalcitol injection is approved in 57 countries (including 20 MS and Norway). It is available in 2 g/ml and 5 g/ml formulations. Paricalcitol injection has been approved in over 60 countries. The first date of approval for paricalcitol capsules was 26th May 2005 in the United States. Oral paricalcitol was approved trough a MRP in the EU. The first European date of approval was 6th September 2006 (Spain). Paricalcitol capsules are available in soft gelatine capsule formulations containing 1, 2, and 4 g. They are approved in 50 countries (including 22 MS and Norway). 2.2 Actions taken for safety reasons During this period of time there have been no changes in the regulatory status for safety reasons. 2.3 Changes to the reference safety information

The Reference Safety Information documents for paricalcitol are the Company Core Data Sheets (CCDSs), which include the Company Core Safety Information (CCSI). The CCDS is an internal reference document that includes the safety information considered by the Company to be most relevant and helpful in describing the drug's benefits and risks. It should be noted that the country-specific prescribing information might differ from the CCDS due to local regulations or additional details resulting from the regulatory approval process. The CCDSs were updated in July 2010 as part of the labelling alignment project. The following changes have been made to the CCDS documents between December 2008 and July 2010:


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-Injection ● The headers were updated and sections rearranged throughout the document to align with the CCDS template and Council for International Organizations of Medical Sciences (CIOMS) guidelines. ● Updated the description of paricalcitol in the Description and Pharmacologic Properties sections. ● Reworded dose titration information and removed elevated calcium level in the Dosage and Administration section. ● Moved the Pediatric and Geriatric wording from the Pregnancy and Lactation section to the Dosage and Administration section. ● Added a warning regarding chronic hypercalcemia to the Warnings and Precautions section. ● Deleted information in the Laboratory Tests subsection as it was no longer relevant. ●In the Drug Interactions section, added several drug interactions regarding concomitant use of paricalcitol with prescription-based phosphate or vitamin D related products, calcium-containing products or thiazides, magnesium containing products and vitamin D preparations, and aluminium containing products and vitamin D preparations. ● Revised the Adverse Reactions section to update adverse events to adverse reactions, incorporate adverse reactions from additional Phase 2 to Phase 4 and other clinical studies or postmarketing observations and to change from COSTART to MedDRA terms. ● Updated the Overdosage section to state that paricalcitol is not significantly removed by dialysis and to include additional treatment information. -Capsule ● The headers were updated and sections rearranged throughout the document to align with the CCDS template and CIOMS guidelines. ● Updated the description of paricalcitol in the Description and Pharmacologic Properties sections. ● Reworded dose titration information to align with paricalcitol injection CCDS and removed elevated calcium level in the Dosage and Administration section. ● Moved the Pediatric and Geriatric wording from the Pregnancy and Lactation section to the Dosage and Administration section. ● Added a warning to the Warnings and Precautions section regarding digitalis toxicity to align with paricalcitol injection. ● In the Drug Interactions section, added a drug interaction regarding digitalis toxicity. Also added several drug interactions regarding concomitant use of paricalcitol with prescription-based phosphate or vitamin D related products, calcium-containing products or thiazides, magnesium containing products and vitamin D preparations, aluminum containing products and vitamin D preparations and cholestyramine. ● Updated the ADRs listed in the Adverse Reactions section from COSTART to MedDRA. ● Updated the Overdosage section to state that paricalcitol is not significantly removed by dialysis. Assessor’s comments At the time of the assessment of this PSUR, there are one type I variation (ES/H/113/02-04/IB) and two type II variation (ES1H/113/01l05/I1/47 and ESIH/113/02-04/II/48) under review. Var IB-049 was aimed to reformat the Zemplar Solution for injection ADRs in the Zemplar Capsules SmPC from CO-START to MedDRA.


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The objective of Var II-47 is aimed to amend the Zemplar Solution injection 2mcg/ml and 5 mcg/ml SmPCs Sections 4.4 “ Special warnings and precautions for use”. Section 4.8 “ Undesirable effects” and Section 4.9 “ Overdose”. The objective of Var II 48 is aimed to amend the Zemplar Capsules 1mcg, 2mcg, 4mcg SmPC sections 4.4 Special warnings and precautions for use and 4.5 Interacctions with other medicinal products and other forms of interaction. 2.4 Patient exposure The sales data is only available for the full month; thus, sales are given for the 12-month period, 01 August 2009 through 31 July 2010, whereas the safety data in this report covers the period 09 August 2009 through 08 August 2010.

From available sales volume data for the period, approximately 250,466 patient-years of exposure to paricalcitol injection and 38,823 patient-years of exposure to paricalcitol capsules have been estimated by the MAH (assuming DDDs of 1.8 g and 1.5 g, respectively). There were a total of 289,290 patient-years of exposure to paricalcitol. This figure represents an increase of 4% from the last PSUR reporting period; according to the MAH, this increase is partially attributed to an increase in distribution. The estimated cumulative patient exposure since IBD (17th April 1998) is 1,494,776 patient-years. Additionally, there were 605 patients enrolled in clinical studies during the period covered by this PSUR who were exposed to paricalcitol. Assessor’s comments According to sales volume data, during the current review period the patient exposure has increased by 4%. 2.5 Adverse reactions A total of 183 medically confirmed reports (109 serious reports, 74 non serious reports) describing 427 AERs have been collected during the period covered by this PSUR. These AERs are presented in the following table:

Unlisted

Listed

Serious

242

18

Non serious

112

55

According to the MAH, the sum of serious and nonserious reports from the tabulation report may exceed the overall number of unique reports tabulated due to handling of single reports that contain both serious and nonserious events within the Adverse Event Global Information System (AEGIS) database. Additionally, 72 unique consumer reports describing 177 Adverse Event (AEs) were completed in AEGIS during the current review period. These reports involved 55 unlisted and 6 listed serious adverse events (SAEs), and 91 unlisted and 25 listed nonserious AEs.


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The first 5 SOCs, in descending order of report volume, from the prior PSUR included: 1. General disorders and administration site conditions, 2. Cardiac disorders, 3. Investigations, 4. Gastrointestinal disorders, and 5. Infections and infestations. During the current period the top 5 SOCs, by volume, included: 1. General disorders and administration site conditions, 2. Nervous system disorders, 3. Gastrointestinal disorders, 4. Cardiac disorders, and 5. Injury, poisoning and procedural complications. Assessor’s comments Following the assessment of previous PSURs, the MAH was urged to follow Volume 9A. In the last PSUR, the MAH declared to interpret Volume 9A and ICH guidelines for selection, evaluation and presentation of spontaneous reports conservatively. Despite of this, reports that were deemed not related by the reporter were included in the event analysis. The MAH was required to perform a causality assessment in the next PSURs. Cases evaluated as related to paricalcitol by the MAH should then be included in summary tabulations and line listings. Cases deemed as not related to paricalcitol should then be included in PSURs but separately and clearly identified, similarly to consumers reports. In the current PSUR, the cases deemed as not related and the consumer reports have been included separately and clearly identified for the analysis. Nevertheless, the cases evaluated as related have been poorly discussed and analysed. The MAH should include a discussion of medically confirmed reports evaluated as related (spontaneous, solicited) similarly to consumer and not-related reports. 2.5.1 Fatal cases There were 52 reports describing a fatal event or outcome. In 19 cases, the reporter deemed the fatal event or outcome as not related to paricalcitol. Among the remaining 33 reports, there were further analyzed 17 medically confirmed reports. Of these reports, 7 were spontaneous reports from healthcare professionals or authorities, 9 were from solicited reports and 1 was a report from a clinical trial. The following table summarizes the primary causes of death from the 17 reports as categorized by MedDRA SOC. Reports that did not describe a cause of death (COD), described the COD as "unknown," or described multiple causes of death were


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categorized in the General disorders and administration site conditions SOC. Of the 11 reports categorized in the General disorders and administration site conditions SOC, there were 6 reports in which the only reported PT for the COD was Death.

The time to onset (TTO) of the fatal event from initiation of paricalcitol therapy was reported in 4 of the 17 reports as the following: 43 days, 218 days, 268 days, and 288 days. An approximate TTO was reported in 4 additional reports as the following: 2 months, 7 months, 15 months, and 3 years. Among the medically confirmed reports, the distribution of indications for paricalcitol use was: hyperparathyroidism secondary (n=7), hyperparathyroidism (n=4), nephropathy (n=1), renal failure and hyperparathyroidism secondary (n=1), and unknown indication (n = 4). Assessor’s comments No more of the 50% of the reports have described the cause of death. Among these, the highest number was general disorders and administration site conditions follow by cardiac disorders. Limited information has been provided in order to evaluate the relationship between the ADRs and the cause of death. 2.5.2 Blood disorders A total of 6 reports (4 medically confirmed reports and 2 from consumers) meeting PSUR inclusion criteria were retrieved by the search. One medically confirmed report (0656951) and 1 consumer report (0625222) is referenced in the Fatal Outcomes Section 2.5.1. One medically confirmed report (0655551) fell within the cumulative review of pancreatitis and is described in Section 2.5.4. According to the MAH, of the remaining 2 medically confirmed reports, none contained events from the Blood and lymphatic system disorders SOC where the reporter deemed these event(s) 'not related' to paricalcitol. Of the 2 reports from consumers, one report described thrombotic thrombocytopenic purpura and is referenced in the Fatal Outcomes Section 2.5.1. And one report described anaemia and provided limited information for medical analysis of the event. According to the MAH, the consumer reports were reviewed and did not provide any new safety information. Assessor’s comments Two reports had a fatal outcome. One of the causes of death of one of them was thrombotic thrombocytopenic purpura and leukopenia in the other. The information submitted does not allow achieve definitive conclusion. If further reports of these ADRs are received and included in future PSURs, each case should be fully described and detailed information for each report should be presented separately.


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2.5.3 Cardiac disorders There were 31 reports describing adverse events from the Cardiac disorders SOC received during the current review period (26 were medically confirmed and 5 were from consumers). Of the 26 medically confirmed reports, 16 reports described fatal events or outcomes. Within the fatal outcomes, 1 described the cause of death as stroke, 2 described congestive cardiac failure as the cause of death, 1 described the causes of death as MI CAD, arteriolosclerosis, 1 had an unknown cause of death, 1 described cardiac arrest as a cause of death (confounded by sepsis, diabetes, heart disease), 1 described acute MI as the cause of death and 1 had an unknown cause of death. Of the remaining 10 medically confirmed reports, 3 reports described cardiac adverse events that according to the MAH were considered to be 'not related' by the reporter. The remaining 7 medically confirmed reports described the following 14 cardiac events: 2 reports each of Angina pectoris, Atrial fibrillation, and 1 report each of Aortic valve disease, Aortic valve disease mixed, Arrhythmia, Arteriosclerosis coronary artery, Bradycardia, Cardiac failure, Coronary artery disease, Coronary artery occlusion, Myocardial infarction, and Tachyarrhythmia. Two reports describing cardiac failure and arrhythmia had insufficient information for causality assessment. According to the MAH, the remaining reports were confounded by concurrent medical conditions, and/or concomitant drugs. Data mining scores are reviewed at regular intervals as part of our standardized surveillance process. Based on their data mining scores the events of acute myocardial infarction and anginal pectoris were noted as signals (15 June 2010). A White Paper covering these medical concepts is being prepared. If the conclusions of this white paper result in an impact to the safety profile of paricalcitol, this information will be communicated through the customary regulatory processes. This information will also be discussed in the next PSUR. Assessor’s comments More than 50% of the cardiac disorders events described fatal events. According to the MAH, data mining scores are reviewed at regular intervals. Based on the data mining scores the events of acute myocardial Infarction and anginal pectoris were noted as signal. The conclusions of this review should be submitted whatever the outcome. In addition, in the study GERM/AUT-05-01 it has been observed that at least 50% of the cardiac disorders reported were related to ischemic coronary disease (Please see section 2.6.1). Despite of coronary disease is common in the treated population and that the study does not have a control group, this number of events is a concern. These events are not listed as adverse reactions in the cardiac SOC of current SmPC. In light of this, a search of ischemic coronary events in all controlled studies in treated and control groups including and estimation of the incidence should be presented by the MAH. 2.5.4 Gastrointestinal disorders There were 35 reports describing adverse events from the Gastrointestinal disorders SOC received during the current review period (26 medically confirmed and 9 from consumers) Three medically confirmed reports and 1 consumer report described a fatal outcome and 6 were considered to be 'not related' by the reporter. The causes of death


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described in the fatal reports were gastrointestinal haemorrhage (labeled event), unknown, and thrombosis mesenteric vessel. One medically confirmed report fell within the cumulative review of pancreatitis. According to the MAH, the single report of pancreatitis had insufficient information for medical assessment of causality. Although 2 reports of Nausea, 2 reports of Diarrhoea and 1 report of Vomiting provided no apparent alternate etiology for the events, 4 out of 5 of those reports missed important information such as time to onset and concomitant medications. The remaining reports were confounded by concomitant medications or medical histories. In the most recent update to the CCDS, the terms Abdominal discomfort, Constipation, Diarrhea, Dysphagia, Gastritis, Intestinal ischemia, and Rectal hemorrhagewere added to the injection CCDS. No other CCDS changes are recommended at this time. Of the 26 medically confirmed reports, there were 7 reports where the reporter deemed the event as 'not related' to paricalcitol therapy. The distribution of events across these 7 reports included: 2 reports of Vomiting and 1 report each of Dysphagia, Gastritis erosive, Upper gastrointestinal haemorrhage, Haemorrhoids, Colitis ischaemic and Retroperitoneal haematoma. There were 9 reports from consumers received during the current review period; 1 report described a Fatal Outcome. In the remaining 8 reports the distribution of events across these reports included: Dry mouth (n = 2), Nausea (n = 3), Abdominal pain upper (n = 2), Abdominal hernia (n = 1), and 1 report each of Abdominal pain, Defaecation urgency, Diarrhoea, Flatulence and Gastric disorder. Cumulative review of Pancreatitis This cumulative review includes reports of pancreatitis coincident with paricalcitol that were completed in AEGIS from 17 April 1998 (IBD) through 08 August 2010. The MedDRA search terms used in selecting the reports were from the Acute pancreatitis (narrow) SMQ. A total of 4 reports meeting PSUR inclusion criteria were retrieved by the search. All 4 reports were medically confirmed Of the 4 medically confirmed reports, in 1 report (0494610) the reporter deemed this event of interest as 'not related' to paricalcitol and Abbott agreed with this assessment. Of the remaining 3 reports, 2 were spontaneous reports from healthcare professionals or authorities, and 1 was a solicited report from a post-marketing observational study. The outcome of the event of interest was reported as not resolved (n = 2), and death (n = 1). Cumulative incidences of abdominal pain/abdominal tenderness/abdominal discomfort In the PSUR 11 the MAH was requested to present the cumulative incidences of abdominal pain, abdominal tenderness and abdominal discomfort because these are unlisted ADRs and some cases had been included in the last PSUR. The MAH considered all completed Company sponsored pre-marketed or post-marketing clinical studies for paricalcitol injection and capsule formulations for this response. The ADRs of interest were classified by MedDRA Higher Level terms including specific PTs. Within each group of subjects, the total number and proportion of subjects experiencing this classification of ADRs were presented overall and by MedDRA Higher Level Terms and PTs for each treatment group. In all completed paricalcitol Phase 2 to 4 studies of 1,222 subjects, there were two adverse events for abdominal discomfort (0.2%) and one adverse event of abdominal pain (< 0.1%) using primary MedDRA system organ class (SOC) and PT. All events were considered mild and possibly related.


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In paricalcitol injection placebo controlled studies, there were no reports either abdominal pain or abdominal discomfort. Including Study M02-516 paricalcitol injection studies active controlled studies there were only 3 (0.7%) subjects with abdominal discomfort in calcitriol group and 1 (0.3%) subject in paricalcitol group using primary MedDRA SOC and PT. In this review of comparator pre- and post-marketing clinical studies with paricalcitol capsules in placebo controlled studies, there were two reported cases of abdominal discomfort and one case of abdominal pain in patients receiving paricalcitol. In paricalcitol injection placebo controlled studies, there were no reports either abdominal pain or abdominal discomfort. Assessor’s comments Reporter causality for events in this SOC was probably related in nearly 50% of the 15 cases described. Gastrointestinal disorders, particularly Gastrointestinal haemorrhage, should continue to be closely monitored. Cases of pancreatitis have been cumulative reviewed in this PSUR. During the period covered by the actual PSUR one new case of pancreatitis have been reported. Relevant information has not been provided. Cases of pancreatitis should continue to be closely monitored and detailed information should be presented. In the last PSUR the following unlisted ADRs were reported: abdominal pain/ abdominal tenderness and one case of abdominal discomfort. The MAH was requested to present the cumulative incidences of these ADRs considered all completed company sponsored pre-marketed or post-marketing clinical studies. From this review, there were no reports either abdominal pain or abdominal discomfort in paricalcitol injection placebo controlled studies. On the other hand, two reported cases of abdominal discomfort and one case of abdominal pain were detected in patients receiving paricalcitol capsules. The cumulative incidence was 0.2 % and 0.1% respectively. Detailed information about percentage of these ADRs in the control group should be presented in order to evaluate and compare the incidences of these ADRs. 2.5.5. General disorders and administration site conditions A total of 59 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 38 reports were medically confirmed reports and 21 reports were from consumers. Of the 59 reports, 16 medically confirmed reports and 9 consumer reports also fell within the current review of fatal outcomes. These reports are referenced in the Fatal Outcomes section 2.5.1. Of the remaining 22 medically confirmed reports, 3 reports contained events from the General disorders and administration site conditions SOC where the reporter deemed the event(s) 'not related' to paricalcitol and Abbott agreed with the assessment. The remaining 18 medically confirmed reports described principally asthenia, chills, malaise, and one each cases Ill-defined disorder (“tunnelitis), abasia and calcinosis. 2.5.6 Hepatobiliary disorders

There were no reports received during the current period which described events from the Hepatobiliary disorders SOC.

Assessor’s comments


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Hepatobiliary disorders should continue to be monitored. 2.5.7 Immune system disorders

No new safety concerns were identified for the Immune system disorders SOC during the current review period.

Assessor’s comments Immune system should continue to be monitored.

2.5.8 Infections A total of 29 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 20 reports were medically confirmed reports and 9 reports were from consumers. Of the 29 reports, 5 medically confirmed reports, and 1 consumer report also fell within the current review of fatal outcomes. Of the remaining 15 medically confirmed reports, 10 reports contained events from the Infections and infestations SOC where the reporter deemed the event(s) 'not related' to paricalcitol and Abbott agreed with the assessment. In the most recent update to the CCDS, the terms Nasopharyngitis, Upper respiratory tract infection, and Vaginal infection were added to the injection CCDS.

Assessor’s comments Infectious should continue to be closely monitored. 2.5.9 Metabolism and nutrition disorders

A total of 17 reports meeting PSUR inclusion criteria were retrieved by the search, of which 15 reports were medically confirmed and 2 reports were received from consumers. Of the medically confirmed reports, 1 report is described in the cumulative review of pancreatitis, presented in Section 2.5.1. Of the remaining 14 medically confirmed reports, 3 reports (0595712, 0597397, 0633788) contained events from the Metabolism and nutritional disorders SOC where the reporter deemed the event(s) 'not related' to paricalcitol and Abbott agreed with the assessment. Of the remaining 11 medically confirmed reports in the Metabolism and nutritional disorders SOC, 7 present hypercalcemia, 2 calciphylaxis, 1 diabetic foot and 1 hypervitaminosis.

Assessor’s comments More than 41% of the metabolism and nutrition disorders described have been cases of hypercalcaemia. Section 4.5 of the SPC states that vitamin D-related medicinal products should not be taken concomitantly with paricalcitol, due to an increase risk of hypercalcaemia. The EU Guideline on SmPCs regarding section 4.5, recommends that where the concomitant use is not recommended this information needs be cross-


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referred to section 4.4. In the light of the clinically relevant concern, the MAH should consider to include this precaution for use in section 4.4. of the SmPC. Two cases of calciphylaxis have been included in this PSUR. Calciphylaxis is a serious and unlisted ADRs, therefore it should be closely monitored in the next PSURs. 2.5.10. Musculoskeletal and Connective Tissue Disorders A total of 18 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 8 reports were medically confirmed reports and 10 reports were from consumers. No medically confirmed reports or consumer reports fell within the current review of fatal outcomes. Of the 8 medically confirmed reports, 2 reports contained events from the Musculoskeletal and connective tissue disorders SOC where the reporter deemed the event(s) 'not related' to paricalcitol and Abbott agreed with the assessment. The remaining reports in which causality was probably related or not reported described the non-serious events of Muscle spasms, Arthralgia, Back pain, Pain in extremity and Bone pain and the serious events of Arthralgia and Soft tissue necrosis. In the most recent update to the CCDS, the terms Arthralgia, Joint stiffness, Muscle twitching and Myalgia were added to the injection CCDS.

Assessor’s comments Musculoskeletal and connective tissue disorders should continue to be closely monitored.

2.5.11. Neoplasms A total of 6 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 5 reports were medically confirmed reports and 1 report was from a consumer. Of the 6 reports, 2 medically confirmed reports and the 1 consumer report also fell within the current review of fatal outcomes. (colon cancer, metastasic bronchial carcinoma, troat cancer) Of the remaining 3 medically confirmed reports, 2 reports contained events from the Neoplasms benign, malignant and unspecified (including cysts and polyps) SOC where the reporter deemed the event(s) 'not related' to paricalcitol and Abbott agreed with the assessment. And one metastases to lung.

Assessor’s comments In the past, the MAH has been strongly exhorted to follow Volume 9A Guideline and to include a summary of the main characteristics of serious and fatal reports

2.5.12. Nervous system disorders A total of 42 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 31 reports were medically confirmed reports and 11 reports were from consumers. Of the 42 reports, 6 medically confirmed reports and 2 consumer reports also fell within the current review of fatal outcomes. The remaining 34 reports, in which casuality was probably related, possibly related or not reported, described 19 non serious events of described the nonserious events of


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headache (n = 5), dizziness (n = 3), dysgeusia (n = 3), tremor (n = 2) and 1 report each of neuropathy peripheral, syncope, lethargy, somnolence, burning sensation and loss of consciousness. The reports describing serious events were 1 report each of Cerebral infarction, Unresponsive to stimuli, Carotid artery stenosis, Concussion, Subarachnoid haemorrhage, Traumatic brain injury, Abasia, Confusional state, Sensory disturbance, Disorientation, Hypoaesthesia, Dysarthria, Somnolence, Convulsion, and Loss of consciousness. Of the 31 medically confirmed reports, there were 6 reports where the reporter deemed the event as “not related” to paricalcitol therapy and Abbott agreed with the assessment.

Assessor’s comments During the current PSUR, 15 reports describing serious events have been described. Nevertheless, limited information is provided in relation the aetiology of nervous system disorders. Moreover, although no cases of epilepsy have been described, one of these cases was a convulsion case. In the last PSUR the MAH presented a cumulative review of cases of epilepsy/convulsion received, the information provided by these cases did not suggest a casual role of paricalcitol. Therefore, nervous system disorders should be closely monitored specially epilepsy/convulsion and some efforts should be made in order to provide more information. 2.5.13. Respiratory, Thoracic and Mediastinal disorders A total of 23 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 16 reports were medically confirmed reports and 7 reports were from consumers. Four medically confirmed reports and 1 consumer report also fell within the current review of fatal outcomes and are referenced in the Fatal Outcomes Section 2.5.1. The most frequent adverse event was dyspnoea. There were three confirmed reports where the reporter deemed the events not related to paricalcitol (Abbott agreed). In the most recent update to the CCDS, the terms Cough, Dyspnea, Orthopnea, Pulmonary edema, and Wheezing were added to the injection CCDS.

Assessor’s comments Respiratory, thoracic and mediastinal disorders should continue to be closely monitored. 2.5.14. Skin disorders There were 23 reports describing adverse events from the Skin and subcutaneous tissue disorders SOC received during the current review period. None of the reports described a fatal event/outcome. Of the 23 reports, 1 was considered to be 'not related' by the reporter (Abbott agreed with the assessment) and 4 were from consumers. Of the remaining 18 medically confirmed reportss, the most frequent cutaneous ADRs were Pruritus (9), Erythema (2) and rash (2). Additionally, one case each of panniculitis, eczema nummular, skin lesion, rash maculo-papular and pemphigoid were reported. Panniculitis required hospitalization.


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In the most recent update to the CCDS, the terms Alopecia, Blister, Hirsutism, Night sweats, Pruritus, Rash pruritic, and Skin burning sensation were added to the injection CCDS. Assessor’s comments Although no cases of bullous, exfoliative skin disorders or hypersensitivity reactions have been received during the period covered by this PSUR, these ADRs should continue to be closely monitored.

2.5.15. Vascular disorders There were 19 reports describing adverse events from the Vascular disorders SOC received during the current review period. Of the 19 reports, 14 were medically confirmed and 5 were from consumers. Of the 14 medically confirmed reports, 5 reports described fatal events or outcomes. In 3 of the 5 fatal reports, the vascular disorders were considered 'not related' by the reporter (Abbott agreed with the assessment). These reports did not reveal any new safety information. In report 0627359 the cause of death was Coronary artery disease, Arteriosclerosis and Myocardial infarction confounded by a history of coronary artery disease and hypertension; and in report 0654436 the cause of death was Cardiac failure congestive, Hypertension, Renal failure confounded by a history of congestive heart failure, Hypertension, and Renal failure. The reports describing fatal events or outcomes are referenced in the Fatal Outcomes Section. Of the remaining 9 medically confirmed reports, 2 reports were considered to be 'not related' by the reporter (Abbott agreed with the assessment). The event distribution across the remaining 7 medically confirmed reports included: 1 report each of Hypovolaemic shock, Angiopathy, Arteriosclerosis obliterans, Hemorrhage, Hypertension, Peripheral arterial occlusive disease, and Thrombosis. Assessor’s comments Nine reports of vascular disorders have been received during the period covered by this PSUR. Despite of a lot of cases had medical histories that include multiple confounders, two of them described fatal events or outcomes and a highly percentage were serious cases so these ADRs should continue to be monitored. 2.5.16. Other ADRs

Other serious unlisted ADRs identified during the period covered by this PSUR include the following:

Psychiatric disorders

There were 11 reports describing adverse events from the Psychiatric disorders SOC received during the current review period. Of the 11 reports, 4 were from consumers. The events described in the 7 medically confirmed reports were nonserious adverse events of: Insomnia, Anxiety, Sleep disorder, Disorientation, Confusional state. One consumer report fell within the fatal outcomes review and is referenced in the Fatal Outcomes Section 2.5.1. In the most recent update to the CCDS, the terms Aspartate aminotransferase increased, Bleeding time prolonged, Heart rate irregular, Laboratory test abnormal, and Weight decreased were added to the injection CCDS.

Renal and Urinary disorders


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There were 15 reports describing adverse events from the Renal and Urinary SOC received during the current review period. Of the 15 reports, 2 were considered to be 'not related' by the reporter (Abbott agreed with the assessment), and 8 were from consumers.

Two medically confirmed reports and 6 consumer reports fell within the current review of fatal outcomes and are referenced in the Fatal Outcomes Section 2.5.1. The cause of death was the underlying condition of Renal failure.

The remaining 3 reports in which causality was unknown described Incontinence, Pollakiuria, Urinary incontinence and Renal failure acute.

Surgical and Medical Procedure

A total of 11 reports meeting PSUR inclusion criteria were retrieved by the search. All of he reports were medically confirmed. Two reports also fell within the current review of fatal outcomes and are referenced in the Fatal Outcomes Section 2.5.1. Three are not related to paricalcitol (Abbott agreed). The remaining described: parathyroidectomy, cardiac pacemaker insertion, hospitalization, catheter placement, leg amputation.

Injury, Poisoning and procedural complications A total of 36 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 24 reports were medically confirmed reports and 12 reports were from consumers. Of the 36 reports, 1 medically confirmed report and 3 consumer reports also fell within the current review of fatal outcomes. These are referenced in the Fatal Outcomes Section 2.5.1. Of the remaining 23 medically confirmed reports, 13 reports contained events from the Injury, poisoning and procedural complications SOC where the reporter deemed the event(s) 'not related' to paricalcitol and Abbott agreed with the assessment. The remaining 10 medically confirmed reports are described in a table in which: 2 reports each of Drug exposure during pregnancy, Fall, and Skin laceration; and 1 report each of Arteriovenous fistula thrombosis, Concussion, Contusion, Incorrect dose administered, Incorrect route of drug administration, Paternal drugs affecting foetus, Shunt occlusion, Skull fracture, and Traumatic brain injury.

Investigations A total of 31 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 18 reports were medically confirmed reports and 13 reports were from consumers. 3 medically confirmed reports contained events from the Investigations SOC where the reporter deemed the event(s) 'not related' to paricalcitol and Abbott agreed with this assessment. The remaining reports, in which causality was probably related or not reported, described the events of Blood calcium increased (n = 3), Blood pressure


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increased (n = 4), Hypercalcaemia (n = 2) Weight decreased n = 2, and 1 report each of Weight increased, Blood magnesium abnormal, Blood glucose decreased, Hepatic enzyme increased and Blood parathyroid hormone increased, Blood pressure increased (n = 2) and 1 report each of blood creatinine increased, Hyperkalaemia, Blood pressure decreased, Calcium phosphate product increased, and Blood parathyroid hormone abnormal. One medically confirmed report (0608472) and 1 consumer report (0606977) also fell within the current review of fatal outcomes and are referenced in the Fatal Outcomes Section2.5.1. One medically confirmed report (0655551) is described in the cumulative review of pancreatitis. There were 2 events of blood pressure increased with no apparent alternate etiology. However, hypertension is a known cause and complication of CKD. There was also no apparent alternate etiology for 2 reports each of the labeled events of hypercalcemia and blood calcium increased. In the remaining 11 reports the 16 events were confounded by Medical history (n = 9), Concomitant medications (n = 1), Intercurrent illness (n = 2) or provided limited information for evaluation (n = 4).

Assessor’s comments 2.1% of the events were renal and urinary disorders. More than 50% were referenced in the section fatal cases. Paricalcitol capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure, so the MAH should continue monitoring this ADR and if new cases are received, they should be properly described in the next PSURs. 2.5.17. Drug interactions A total of 32 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 23 were medically confirmed reports and 9 were from consumers. Of the 32 reports, 10 medically confirmed reports and 2 consumer reports also fell within the current review of fatal outcomes. These reports are referenced in the Fatal Outcomes Section. Of the remaining 13 medically confirmed reports, none of the reports described a "drug interaction" nor did they describe a situation where the adverse events reported were the result of a potential drug interaction between paricalcitol and another suspect medication. None of the reports described concomitant use of another vitamin D analogue product. These 13 reports described 70 adverse events and are listed by SOC in the following table:


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Assessor’s comments Limited information is provided about concomitant use of other medicinal products, particularly vitamin D-related medicinal products. Vitamin D-related medicinal products should not be taken concomitantly with paricalcitol due to an increased risk of hypercalcaemia. The MAH should make all the efforts to obtain this information in next PSURs. 2.5.18. Overdose A total of 3 reports meeting PSUR inclusion criteria were retrieved by the search, of which, 1 was a medically confirmed report and 2 were from consumers. The medically confirmed report was determined to be outside the scope of this review.


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Report 0608445 described a PT of Incorrect dose administered and described a patient who took a lower than prescribed dose of paricalcitol due to financial concerns. The report did not describe an overdose of paricalcitol. 2.5.19. Misuse No reports of overdose were received during the period covered by this PSUR. 2.5.20. Pregnancy and lactation A total of 2 reports of in utero exposure were received for the current review period. There was 1 report describing paricalcitol exposure in utero via paternal use of paricalcitol: Report 0591454, a solicited report, described a nonserious drug exposure in utero and transmission of drug via semen coincident with paternal use of paricalcitol therapy at an unknown time during pregnancy. Paternal age was 36 to 37 years during the pregnancy. There were no reported fetal adverse events. The outcome of the pregnancy was unknown at the time of this report. Missing information included concomitant medications, paricalcitol formulation, dose, and therapy status. The remaining report described an IUE based on maternal exposure to paricalcitol therapy: Report 0601469, a spontaneous report, described a nonserious drug exposure during pregnancy coincident with maternal use of oral paricalcitol therapy at an unknown time during pregnancy. There were no reported fetal adverse events. The outcome of the pregnancy was unknown at the time of the report. Missing information included concomitant medications, maternal age, and paricalcitol dose and therapy status. Assessor’s comments The outcome of the pregnancy is unknown. The MAH should submit the outcome of the pregnancies in order to evaluate the in-utero exposure. 2.5.21. Special populations A total of 103 reports meeting PSUR inclusion criteria were retrieved by the search, of which 68 were medically confirmed and 35 reports were from consumers. Of the 68 medically confirmed reports, 31 were spontaneous reports from healthcare professionals or authorities, 36 were from solicited reports (e.g., registries, observational studies), and 1 report was from a clinical trial. Of these 68 reports, the gender distribution was 33 females and 35 males. The median age was 72.5 years, with a range of 65 to 92 years (n = 68). Among the medically confirmed reports, the distribution of indications for paricalcitol use was: Hyperparathyroidism secondary (n = 33), Hyperparathyroidism (n = 12), Renal failure chronic (n = 8), Renal failure (n = 8), Nephropathy (n = 2), Blood parathyroid hormone increased (n = 2), Parathyroid disorder (n = 1), Renal disorder (n = 1), Renal impairment (n = 1), Renal osteodystrophy (n = 1), and unknown indication (n = 8) (Note: A single report may have more than 1 indication). There were 21 reports describing a fatal event/outcome. These reports are referenced in the Fatal Outcomes Section.


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The 68 reports described 210 adverse events. The PT distribution for these events by the most frequent SOC was:

General disorders and administration site conditions: 35.1% Cardiac disorders: 31.15% Gastrointestinal disorder: 23.11% Injury, poisoning and procedural complications: 18.9% Infections and infestations: 18.9% Respiratory, thoracic and mediastinal disorders: 15.7% Nervous system disorders: 12.6% Vascular disorders: 11.5%

Within the current analysis, the AEs occurring in patients≥ 65 years of age were reflective of the medical conditions generally observed in this patient population and are reflective of the known safety profile of paricalcitol. The CCDS contains the following wording: "Of the 40 patients receiving paricalcitol in the three Phase 3 placebo-controlled Chronic Renal Failure studies, 10 patients were 65 years or over. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients." Assessor’s comments General disorders, cardiac disorders and gastrointestinal disorders are the most frequent events in the elderly population. In the section 4.2 of the SPC is included that no overall differences in safety and effectiveness were observed between elderly patients, but greater sensitivity of some older individuals cannot be ruled out. Therefore, these ADRs should be closely monitored specially in this population. 2.5.22. Long-term treatment No reports have been received concerning new relevant safety information on this situation. 2.6. Studies There were 2 newly analyzed, 2 completed, and 2 ongoing Abbott-sponsored studies during the current PSUR review period (09 August 2009 through 08 August 2010). Study W10-127 and Study M10-312 were completed during the current review period; however the study reports are pending completion.

2.6.1 MAH’s response to the Assessment Report of the 11th PSUR

The following clinical study information was identified in the Asessement Report for PSUR 11 for further discussion in this PSUR: Study GERM/AUT-05-01 (Germany/Austria) was a Postmarketing Observational Study (PMOS) to evaluate the safety and efficacy of Zemplar® IV for the treatment of 2° HPT in ESRD patients on HD. The MAH was requested to provide the nature of the ADRs identified in this study. Safety was evaluated based on the assessment of adverse events. The number of patients enrolled was 1313 of which 1308 were included into the statistical analysis. A total of 507 adverse events have been observed in 21.1% (n=276) of patients. 211 adverse events were serious and were observed in 11.9% (n=155)


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of patients. 276 adverse events were related to the study medication, i.e. were adverse reactions, and were observed in 12.8% (n=167) of patients. 75 adverse reactions were serious and were observed in 4.3% (n=56) of patients. The safety profile observed in this study was consistent with the German/Austria Summary of Product Characteristics (SPC) ‘Fachinformation’ for Zemplar® (paricalcitol) i.v., with the most frequently reported adverse events (regardless of causality) being hyperphosphatemia (2.6%), hypercalcemia (2.4%), calcium phosphate product increased (0.8%), sepsis (0.7%), blood phosphorus increased (0.5%), pneumonia (0.5%), diarrhoea (0.5%), vomiting (0.5%), myocardial infarction (0.5%), shunt occlusion (0.5%), pruritus (0.5%) and arthralgia (0.5%). The most frequently reported outcomes were death (1.5%), renal transplant (0.8%) and hospitalization (0.7%). The MAH presented a listed of serious adverse drug reactions (analyzed population). According to this table, cardiac disorders, metabolism an nutrition disorders are the most frequent events. Assessor’s comments According to the listed of serious adverse drug reactions of the study GERM/AUT-05-01 presented by the MAH, 75 serious adverse reactions were described. Of these, nearly 15% were cardiac disorders and among these more than 50% were ischemic coronary events (myocardial infarction, angor, acute coronary syndrome, among others). This ADR is not reflected in the section 4.8 of the SPC. In light of this and given the recognised seriousness of this safety issue, an estimation of the incidence of ischemic coronary events in control studies in treated and control groups should be submitted in the next PSUR. Study P06-113 (Czech Republic) was a multicenter PMOS to evaluate safety and efficacy of Zemplar® Injection routine clinical use. The MAH was requested to provide a complete study report. 100 patients entered in this study and finally 83 patients finished this study. As this study was a PMOS, a brief study synopsis was prepared by the study site: The number of Serious adverse Event (SAEs) did not increase with the visit number. There was a random distribution of SAEs unrelated to the visit number. The type of adverse events are in the following table:


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Of the 100 subjects in this study, 4 % showed sign of significant hypercalcemia serious. Assessor’s comments In study P06-113 hypercalcaemia was serious in 4 % of the cases. Study P06-118 (Korea) was a PMOS of Zemplar IV in Korean patients under the new drug reexamination guidelines. This study was a regulatory commitment to the Korean license for paricalcitol. The MAH was requested to review 3 adverse event reports of parosmia. Below is a summary of the reports of events of parosmia reported on paricalcitol treated subjects from Study P06-118. All case reports were assessed by the site investigator and considered to be possibly related to study drug. 1. Subject 037-007 A 49 year old female reported an event of parosmia on 11 September 2007. No end date for the symptoms was reported. The principle investigator reported the comment that the subject smelled injected drug on her mouth. The principal investigator considered the event to be non-serious and possibly related to the study drug. No outcome or follow-up action was reported. 2. Subject 053-004 A 34 year old male reported an event of parosmia on 01 October 2007 with an end date of 05 December 2007 without any intervention. The principle investigator reported the comment that the subject smelled injected drug on his mouth. The principal investigator considered the event to be non-serious and possibly related to the study drug. Follow-up action was reported as none. 3. Subject 053-005 A 54 year old male reported an event of parosmia on 14 May 2007. End date was reported as ongoing. The principle investigator reported the comment that the subject smelled injected drug on his mouth. The principal investigator considered the event to be non-serious and possibly related to the study drug. Follow-up action was reported as none.


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Assessor’s comments A comprehensive description of the parosmia cases identified in study P06-118 has been presented. This is an unexpected ADR, therefore, parosmia should be monitored in the next PSURs.

2.6.2. Newly analysed company-sponsored studies Study M05-741(capsules) (The VITAL Study) was a phase 2, prospective, randomized, double-blind, placebo-controlled multicenter study to evaluate the safety and efficacy of paricalcitol capsules on reducing albuminuria in type 2 diabetic nephropathy subjects who are were treated with renin-angiotensin system inhibitors. This study was an investigational study conducted under the EU CTD and the US IND for paricalcitol. A total of 281 subjects were enrolled and randomized. Safety endpoints included: the number and percentage of subjects who reported treatment-emergent adverse events (TEAEs) through 30 days posttreatment, serious adverse events (SAEs), and fatal TEAEs; TEAEs leading to premature discontinuation; and events of interest (the number and percentage of subjects with hypercalcemia and who experienced a doubling of serum creatinine, required dialysis, or died); analysis of changes in hematology parameters, clinical chemistry variables, urinalysis parameters, and 24 hour urinalysis variables (electrolytes - calcium [Ca], phosphate [P], sodium; urea nitrogen); changes from last on-treatment observation to 30-day and 60-day posttreatment measurements in: serum Ca, phosphate, and creatinine, eGFR, UACR; and changes in vital signs (baseline to last on-treatment observation; last on-treatment observation to 30-day and 60-day posttreatment measurements). Serious cardiovascular events and decreased renal function are being added to the risk management plan as potential risks based on the results of the VITAL study (Study M05-741) and the increased risk of these events in the patient population with chronic renal failure. Serious cardiovascular adverse events are considered potential risks as opposed to identified risks because review of prior studies did not reveal a similar finding. In addition, the number of serious cardiovascular events in the VITAL study was low, the differences were not statistically significant, and subjects had multiple confounding cardiovascular risk factors, making assessment of causality difficult. Regarding the potential risk of decreased renal function, the change in the creatinine based estimation of eGFR during paricalcitol therapy in the VITAL study will need to be verified by a more direct measurement of GFR (e.g., iothalamate clearance), since other vitamin D receptor activators (i.e., calcitriol) are known to alter renal creatinine metabolism in a way that increases serum creatinine without altering true GFR. Because the 2 mcg group also experienced a significant reduction in systolic, but not diastolic, blood pressure, post-hoc analyses were performed to examine a potential association between declines in systolic blood pressure and serious cardiovascular events and the declines in eGFR. No association was found between cardiovascular events, eGFR declines and decreased blood pressure in the 2 mcg group. Post-hoc analyses identified the following risks factors for declines in eGFR: F gender, age < 65, no history of cardiovascular disease, and Stage 3 CKD. It is important to note that Study M05-741 was an off-label study that allowed for the use of 2 mcg


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paricalcitol daily without regard to a subject's PTH level, in contrast to its approved indication in which the 2 mcg daily dose is reserved only for patients with a PTH level > 500 pg/mL. Assessor’s comments The objective of the Study M05-741 was to evaluate the safety and efficacy of Paricalcitol capsules, but the criteria of inclusion was subjects with CKD and Type 2 diabetic nephropathy who were currently receiving treatment with stable RAAS therapy. This is a off- label use indication; paricalcitol capsules are indicated for the treatment of secondary hyperparathyroidism associated with CKD Stages 3 and 4, or CKD Stage 5 patients on haemodialysis or peritoneal dialysis. Despite of these, the increased risk of serious cardiovascular events and decreased renal function described on this study have been included as a potential risk in the RMP and should be monitored in the next PSURs. In addition, according to the MAH, vitamin D receptor activators are known to alter renal creatinine metabolism in a way that increases serum creatinine without altering true GFR. This information could be relevant not only for the investigation of possible renal adverse effects of paricalcitol, but also for clinical practice since creatinine based test for the measurement of renal function are widely used. Therefore The MAH should present in two months evidences supporting this statement, including: - Discussion of the relevance of this alleged interference in clinical practice and in study protocols. - As appropriate, proposal to include this information in the SmPC in order to give clear recommendations to clinicians. - As appropriate, a proposal to add an alternative measurement for evaluation of GFR in ongoing or new studies in addition to the creatinine based estimation. Study M10-221 was terminated in May 2009 due to low patient enrollment. This study evaluated the effects of paricalcitol injection on progression or regression of LeftVentricular Hypertrophy (LVH) in subjects with CKD stage 5 receiving HD compared to placebo. This interventional study was conducted under the US IND and the EU CTD. Assessor’s comments Due to low enrolment, the Study M10-2211 was prematurely terminated. So, efficacy and safety can not be evaluated.

2.6.3. Company-sponsored targeted safety studies Ongoing studies Study M10-030: (The PRIMO Study): Evaluates the effects of paricalcitol capsules on progression or regression of left ventricular hipertrofy (LVH) in subjects with CKD stage 3B/4 compared to placebo. This is an interventional study that is being conducted under the US IND and the EU CTD. Study W10-129 (Mexico) evaluates the efficacy and safety of 6 months treatment with paricalcitol injection or oral formulation in patients on dialysis with 2° HPT. The objective is to evaluate the efficacy of paricalcitol (IV and oral) through the assessment of the proportion of subjects who achieve at least a 50% reduction


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in iPTH at the final visit compared to the baseline level in patients on HD or peritoneal dialysis with 2° HPT treated with paricalcitol injection or oral. Secondary Objective: To study the safety of paricalcitol injection and oral based on the analysis of episodes of hypercalcemia (> 11.5 mg/dL), hyperphosphatemia (> 7.0 mg/dL) and elevations of calcium × phosphorus product (> 75). Terminated studies Study W10-127(Uruguay) ZAPHYRO was a Phase 4 study to evaluate the effectiveness and safety of 6 months of treatment with Zemplar® Injection in patients on dialysis with 2° HPT. The study report is pending completion. Study M10-312(Japan) evaluated the long-term safety and efficacy of paricalcitol injection in CKD subjects receiving HD with 2° HPT. This study was an open-label roll-over study from the Phase 2b (Study M10-309) study. The study report is pending completion. Assessor’s comments The report of studies W10-127 and M10-312 should be presented within the next PSUR. In addition, according to the previous comment, it should be use an alternative method of measurement of GFR as well as the creatinine serum level method to estimate the eGFR during paricalcitol therapy ( see section 2.6.2)

2.6.4. Published safety studies There were 2 published study noted in the scientific/medical literature regarding paricalcitol that contained important safety findings during the PSUR review period. Ross EA, Tian J, Abboud H, Hippensteel R, Melnick JZ, Pradhan RS, et al. Oral paricalcitol for the treatment of secondary hyperparathyroidism in patients on hemodialysis or peritoneal dialysis. Am J Nephrol. 2007;28(1):97-106. Background/Aims: Secondary hyperparathyroidism is a common complication of chronic kidney disease, resulting from inactivation of vitamin D receptor signalling and phosphate retention. Selective activation of vitamin D receptors with intravenous paricalcitol significantly reduced parathyroid hormone (PTH) levels with no significant hypercalcemia or hyperphosphatemia in predialysis and hemodialysis (HD) patients. This study investigates the effects of oral paricalcitol to reduce PTH in patients receiving chronic HD and peritoneal dialysis (PD). Methods: Eighty-eight patients were randomized in double-blind fashion to receive paricalcitol or placebo for 12 weeks. The dose of the study drug was adjusted weekly using the previous week's intact PTH (iPTH) level as well as calcium and Ca × P product levels. The primary end points were efficacy (two consecutive iPTH decreases of 30%) and safety (two consecutive calcium measurements > 11.0 mg/dl). Markers of biochemical bone activity were followed. Results: Demographic characteristics were similar between treatment groups. The mean paricalcitol doses (three times a week) over the entire treatment period for subjects with baseline iPTH 500 pg/ml and iPTH > 500 pg/ml were 3.9 and 7.6 mug, respectively. A statistically significant decrease in iPTH was seen after Week 1, with a mean 30% reduction occurring by Week 3. A significantly greater proportion of both HD and PD paricalcitol subjects (83%


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(33/40) and 100% (18/18), respectively) achieved two consecutive 30% decreases in iPTH. The treatment groups were not statistically different in regard to the hypercalcemia safety end point. Phosphate binder use and mean serum phosphorus levels were not different between the treatment groups. The markers of bone activity improved in the treated subjects and worsened in those on placebo. Conclusion: Paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients with minimal effect on serum calcium and phosphorus and no significant difference in adverse events as compared with placebo. Matias PJ, Jorge C, Ferreira C, Borges M, Aires I, Amaral T, et al. Cholecalciferol supplementation in hemodialysis patients: Effects on mineral metabolism, inflammation, and cardiac dimension parameters. Clin J Am Soc Nephrol. 2010;5(5):905-11. Background and objectives: Vitamin D deficiency is highly prevalent in chronic kidney disease. The aim of this study was to evaluate the effects of oral cholecalciferol supplementation on mineral metabolism, inflammation, and cardiac dimension parameters in long-term hemodialysis (HD) patients. Design, setting, participants, & measurements: This 1-year prospective study included 158 HD patients. Serum levels of 25- hydroxyvitamin D (25(OH)D), 1,25 dihydroxyvitamin D (1,25(OH) /sub 2/ D), intact parathyroid hormone, and plasma brain natriuretic peptide as well as circulating bone metabolism and inflammation parameters were measured before and after supplementation. Baseline 25(OH) D and 1,25 (OH) /sub 2/ D levels were measured twice (end of winter and of summer, respectively). Therapy with paricalcitol, sevelamer, and darbepoietin was evaluated. Results: There was an increase in serum 25(OH)D and 1,25(OH) /sub 2/ D levels after supplementation. Conversely, serum calcium, phosphorus, and intact parathyroid hormone were decreased. There was a reduction in the dosage and in the number of patients who were treated with paricalcitol and sevelamer. Darbepoietin use was also reduced, with no modification of hemoglobin values. Serum albumin increased and C-reactive protein decreased during the study. Brain natriuretic peptide levels and left ventricular mass index were significantly reduced at the end of the supplementation. Conclusions: Oral cholecalciferol supplementation in HD patients seems to be an easy and cost-effective therapeutic measure. It allows reduction of vitamin D deficiency, better control of mineral metabolism with less use of active vitamin D, attenuation of inflammation, reduced dosing of erythropoiesis-stimulating agents, and possibly improvement of cardiac dysfunction. Other articles (including reviews) -Cannata-Andía JB, Rodriguez-García M, Román-García P, Tuñón-le-Poultel D, López-Hernádez F, Rodríeguez-Puyol D. New therapies: calcimimetics, phosphate binders and vitamin D receptor activators. Pediatr Nephrol. 2010;25(4):609-16. -Mathew S, Lund RJ, Chaudhary LR, Geurs T, Hruska KA. Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol. 2008;19(8):1509-19.


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-Schulz W. From native vitamin D3 through calcitriol to vitamin D receptor activators. Internist Prax. 2010;50(1):121-34. -Zittermann A, Tenderich G, Koerfer R. Vitamin D and the adaptive immune system with special emphasis to allergic reactions and allograft rejection. Inflamm Allergy Drug Targets. 2009;8(2):161-8. -Cozzolino M, Brandenburg V. Paricalcitol and outcome: A manual on how a vitamin D receptor activator (VDRA) can help us to get down the "U." Clin Nephrol. 2009; 71(6):593-601. Assessor’s comments We noted that the Ross E.A. et al study was published in 2007. This period was covered by the PSUR 7-8 (9th August 2006- 8th August 2007) and the PSUR 9 (9th August 2007- 8th February 2008). 2.7. Other information

2.7.1. Efficacy-related information A total of 5 reports meeting PSUR inclusion criteria were retrieved by the search, all of which were medically confirmed reports. Of the 5 reports, in 1 report (0602351) the reporter deemed the lack of effect as 'not related' to treatment with paricalcitol and Abbott agreed with the assessment. Of the remaining 4 medically confirmed reports, 3 were spontaneous reports from healthcare professionals or authorities and 1 was a solicited report (e.g., registries, observational studies). The gender distribution was 2 females and 2 males. Patient age was reported in 2 of the 4 reports as 42 years and 87 years. The TTO of the event from initiation of paricalcitol therapy was reported as approximately 1 month in 1 report and was unknown in the remaining reports. The distribution of indications for paricalcitol use was: hyperparathyroidism (n = 2), hyperparathyroidism secondary, renal failure chronic, blood parathyroid hormone (n = 1), and unknown indication (n = 1) (Note: a single report may contain multiple indications). The outcome for this event of interest was reported as resolved (n = 1), resolving (n = 1), not resolved (n = 1), and unknown/not reported (n = 1). The 4 medically confirmed reports of lack of effect described the following nonserious events: Blood parathyroid hormone increased (n = 2) and Blood parathyroid hormone abnormal (n = 2). Two reports provided limited information to make a medical assessment of the relationship of the event to treatment with paricalcitol. Assessor’s comments Lack effect and blood parathyroid hormone increased should continue to be closely monitored.

2.7.2. Risk management plan


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A Risk Management Plan (RMP), Version 1.0 according to the European Medicines Agency (EMA) template, was submitted in September 2007 to support the submission of paricalcitol capsules in the EU. Version 2.0 was created and submitted in parallel with PSUR 12 in September 2010. Serious cardiovascular events and decreased renal function (eGFR) were added as important potential risks revealed by clinical trial data. Based on the review of the postmarketing and clinical data received during this review period, focused analysis of serious cardiovascular events and decreased renal function events from clinical studies is recommended. Additional clinical studies to evaluate renal function are currently being developed. Updates on these events will be included in future PSUR(s). The important identified risks and the planned actions are described in the following table:


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Assessor’s comments The RMP proposed is endorsed.


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3. Conclusions

In the light of the information provided in the reviewed PSUR no new concern about the benefit to risk balance of this drug has been raised.

-Topics related to the quality of the PSUR:

Following the assessment of previous PSURs, the MAH was urged to follow Volume 9A. In the last PSUR, the MAH declared to interpret Volume 9A and ICH guidelines for selection, evaluation and presentation of spontaneous reports conservatively. Despite of this, reports that were deemed not related by the reporter were included in the event analysis. The MAH was required to perform a causality assessment in the next PSURs. Cases evaluated as related to paricalcitol by the MAH should then be included in summary tabulations and line listings. Cases deemed as not related to paricalcitol should then be included in PSURs but separately and clearly identified, similarly to consumers reports. In the current PSUR, the cases deemed as not related and the consumer reports have been included separately and clearly identified for the analysis. Nevertheless, the cases evaluated as related have been poorly discussed and analysed. The MAH should include a discussion of medically confirmed reports evaluated as related (spontaneous, solicited) similarly to consumer and not-related reports. -Safety concerns on the PSUR: Fatalities and the following ADRs should continue to be closely monitored: thrombocytopenia ; haemorrhages; heart failure/pulmonary oedema; myocardial ischemia; hypertension/blood pressure increased; gastrointestinal haemorrhage; hepatic reactions; hypersensitivity reactions; infections; hypercalcaemia; bullous or exfoliative skin disorders; venous and arterial thrombosis, embolism, and thromboembolism; and lack of effect and blood parathyroid hormone increased. If further reports of these ADRs are received and included in future PSURs, each case should be fully described and detailed information for each report should be presented separately. In addition, renal and urinary disorders should be closely monitored. If new cases are received these should be fully described. On the other hand, one case of parosmia was identified in study P06-118. This is an unexpected ADR, so it should be monitored in the next PSURs. Finally, two cases of calciphylaxis have been included in this PSUR. Calciphylaxis is a serious and unlisted ADRs, therefore it should be closely monitored in the next PSURs. According to the MAH, based on the data mining scores the events of acute myocardial infacrtion and anginal pectoris were noted as signal. The conclusions of this review should be submitted whatever the outcome.

With regards to the CSP:

In section 4.5 of the SPC is stated that vitamin D-related medicinal products should not be taken concomitantly with paricalcitol, due to an increase risk of hypercalcaemia. The EU Guideline on SmPCs regarding section 4.5, recommends that where the concomitant use is not recommended this information needs be cross-referred to section 4.4. In the light of the clinically relevant concern, the MAH should consider to include this precaution for use in section 4.4. of the SmPC.


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In two months, the MAH is requested to present:

Evidences supporting that vitamin D receptor activators are known to

alter renal creatinine metabolism, in a way that increases serum creatinine without altering true GFR, including:

- Discussion of the relevance of this alleged interference in clinical practice and in study protocols. - As appropriate, proposal to include this information in the SmPC in order to give clear recommendations to clinicians. - As appropriate, a proposal to add an alternative measurement for evaluation of GFR in ongoing or new studies in addition to the creatinine based estimation.

In the next PSUR, the MAH is requested to provide with:

Detailed information about percentage in the control group of the relevant studies by the oral formulation of abdominal pain, abdominal tenderness and abdominal discomfort should be presented in order to evaluate and compare the incidences of these ADRs.

A total of 2 reports of in utero exposure were received during this PSUR. The MAH should submit the outcome of the pregnancy in order to evaluate the utero exposure.

Report of studies W10-127 and M10-312 is pending in the current PSUR and should be presented in the next PSUR.

Summary of the main characteristics of serious and fatal reports of neoplasma cases.

The MAH should be submitted detailed information about concomitant use of the other medicinal products, particularly vitamin D- related medicinal products.

A search of ischemic coronary events in all controlled studies in treated and control groups including and estimation of the incidence should be presented by the MAH. In the study GERM/AUT-05-01has been observed that at least 50% of the cardiac disorders reported were related to ischemic coronary disease. Despite of coronary disease is common in the treated population and that the study does not have a control group, this number of events is a concern.

The next PSUR have to follow a 3-yearly cycle.


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Annex I : CSP

In FAR: Agreed CSP (see Annex-I attached)

1

CORE SAFETY PROFILE

ZEMPLAR SOLUTION FOR INJECTION 4. CLINICAL PARTICULARS 4.2 Posology and method of administration Zemplar solution for injection is administered via haemodialysis access. Adults 1) Initial Dose should be calculated based on baseline parathryroid hormone (PTH) levels: The initial dose of paricalcitol is based on the following formula: Initial dose (micrograms) = baseline intact PTH level in pmol/l 8 OR

= baseline intact PTH level in pg/mL 80 and administered as an intravenous (IV) bolus dose no more frequently then every other day at any time during dialysis. The maximum dose safely administered in clinical studies was as high as 40 micrograms. 2) Titration Dose: The currently accepted target range for PTH levels in end-stage renal failure subjects undergoing dialysis is no more than 1.5 to 3 times the non-uremic upper limit of normal, 15.9 to 31.8 pmol/l (150-300 pg/ml), for intact PTH. Close monitoring and individual dose titration are necessary to reach appropriate physiological endpoints. If hypercalcaemia or a persistently elevated corrected Ca x P product greater than 5.2 mmol2/l2 (65 mg2/dl2) is noted, the dosage should be reduced or interrupted until these parameters are normalised. Then, paricalcitol administration should be reinitiated at a lower dose. Doses may need to be decreased as the PTH levels decrease in response to therapy. The following table is a suggested approach for dose titration:

Suggested Dosing Guidelines (Dose adjustments at 2 to 4 week intervals)

iPTH Level Relative to Baseline

Paricalcitol Dose Adjustment

Same or increased Decreased by < 30%

Increase by 2 to 4 micrograms

Decreased by ≥30%, ≤60% Maintain Decreased > 60% IPTH < 15.9 pmol/l (150 pg/mL)

Decrease by 2 to 4 micrograms

Once dosage has been established, serum calcium and phosphate should be measured at least monthly. Serum intact PTH measurements are recommended every three months. During dose adjustment with paricalcitol, laboratory tests may be required more frequently.

2 Hepatic impairment

Unbound concentrations of paricalcitol in patients with mild to moderate hepatic impairment are similar to healthy subjects and dose adjustment is not necessary in this patient population. There is no experience in patients with severe hepatic impairment.

Paediatric population (0-18 years) The safety and efficacy of Zemplar in children have not been established. There is no data available on children under 5 years. The currently available data on paediatric patients are described in Section 5.1.

Geriatric population (>65years) There is a limited amount of experience with patients 65 years of age or over receiving paricalcitol in the phase III studies. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients. 4.3 Contraindications Hypersensitivity to active substance or to any of the excipients. Vitamin D toxicity Hypercalcemia 4.4 Special warnings and precautions for use Over suppression of parathyroid hormone may result in elevations of serum calcium levels and may lead to metabolic bone disease. Patient monitoring and individualized dose titration is required to reach appropriate physiological endpoints. If clinically significant hypercalcemia develops, and the patient is receiving a calcium-based phosphate binder, the dose of the calcium-based phosphate binder should be reduced or interrupted. Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis is prescribed concomitantly with paricalcitol (see section 4.5). Caution should be exercised if co-administering paricalcitol with ketoconazole (see section 4.5). This medicinal product contains 20% v/v of ethanol (alcohol). Each dose may contain up to 1.3g ethanol. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high risk groups such as patients with liver disease or epilepsy. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed with paricalcitol injection. However, an interaction study between Ketoconzole and paricalcitol has been performed with the capsule formulation. Phosphate or vitamin D-related medicinal products should not be taken concomitantly with paricalcitol, due to an increased risk of hypercalcaemia and Ca x P product elevation. High doses of calcium-containing preparations or thiazide diuretics may increase the risk of hypercalcaemia. Aluminium-containing preparations (e.g., antacids, phosphate-binders) should not be administered chronically with Vitamin D medicinal products, as increased blood levels of aluminum and aluminum bone toxicity may occur. Magnesium-containing preparations (e.g. antacids) should not be taken concomitantly with vitamin D preparations, because hypermagnesemia may occur. Ketoconazole is known to be a non-specific inhibitor of several cytochrome P450 enzymes. The available in vivo and in vitro data suggest that ketoconazole may interact with enzymes that are

3 responsible for the metabolism of paricalcitol and other vitamin D analogs. Caution should be taken while dosing paricalcitol with ketoconazole (see Section 4.4). The effect of multiple doses of ketaconazole administered as 200 mg, twice daily (BID) for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-∞ approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone. The results of this study indicate that following oral administration of paricalcitol the maximum amplification of the paricalcitol AUC ∞ from a drug interaction with ketoconazole is not likely to be greater than about two-fold. Digitalis toxicity is potentiated by hypercalcaemia of any cause, so caution should be applied when digitalis is prescribed concomitantly with paricalcitol (see Section 4.4). 4.6 Pregnancy and lactation Pregnancy: There are no adequate data from the use of paricalcitol in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Zemplar should not be used in pregnancy unless clearly necessary. Lactation: Animal studies have shown excretion of paricalcitol or its metabolites in breast milk, in small amounts. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with paricalcitol should be made taking into account the benefit of breast-feeding to the child and the benefit of paricalcitol therapy to the woman. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects Approximately 600 patients were treated with Zemplar in Phase II/III/IV clinical trials. Overall, 6% of the Zemplar treated patients reported adverse reactions. The most common adverse reaction associated with Zemplar therapy was hypercalcaemia, occurring in 4.7% of patients. Hypercalcaemia is dependent on the level of PTH oversuppression and can be minimised by proper dose titration. Adverse events at least possibly related to paricalcitol, both clinical and laboratory are displayed by MedDRA System Organ Class, Preferred Term and frequency. The following frequency groupings are used: Very common ( ≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10,000, <1/1000); very rare (<1/10000), not known (can not be estimated from the available data). System Organ Class Preferred Term Frequency Investigations Bleeding time prolonged,

aspartate aminotransferase increased, laboratory test abnormal, weight decreased

Uncommon

Cardiac disorders Cardiac arrest, arrhythmia, atrial flutter

Uncommon

Blood and lymphatic system disorders

Anaemia, leukopenia, lymphadenopathy

Uncommon

Nervous system disorders Headache, dysgeusia Common

4

Coma, cerebrovascular accident, transient ischemic attach, syncope, myoclonus, hypoaesthesia, paraesthesia, dizziness

Uncommon

Eye disorders Glaucoma, conjunctivitis Uncommon Ear and labyrinth disorders Ear disorder Uncommon Respiratory, thoracic and mediastinal disorders

Pulmonary oedema, asthma, dyspnoea, epistaxis, cough

Uncommon

Rectal haemhorrhage, colitis, diarrhoea, gastritis, dyspepsia, dysphagia, abdominal pain, constipation, nausea, vomiting, dry mouth, gastrointestinal disorder

Uncommon Gastrointestinal disorders

Gastrointestinal haemorrhage unknown Pruritus Common Skin and subcutaneous tissue

disorders Bullous dermatitis, alopecia, hirsutism, rash, hyperhidrosis

Uncommon

Musculoskeletal and connective tissue disorders

Arthralgia, joint stiffness, back pain, muscle twitching, myalgia

Uncommon

Hypoparathyrodism Common Endocrine Disorders Hyperparathyrodism Uncommon Hypercalcaemia, Hyperphosphataemia

Common

Metabolism and nutrition disorders

Hyperkalaemia, hypocalcemia, anorexia,

Uncommon

Infections and infestations Sepsis, pneumonia, infection , pharyngitis, vaginal infection, influenza

Uncommon

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Breast cancer Uncommon

Vascular disorders Hypertension, hypotension Uncommon General disorders and administration site conditions

Gait disturbance, oedema peripheral, pain, injection site pain, pyrexia, chest pain, condition aggravated, asthenia, malaise, thirst

Uncommon

Hypersensitivity Uncommon Immune system disorders Laryngeal oedema, angioedema, uritcaria

Not Known

Reproductive system and breast disorders

Breast pain, erectile dysfunction

Uncommon

Psychiatric disorders Confusional state, delirium, depersonalization, agitation, insomnia, nervousness

Uncommon

4.9 Overdose No case of overdose has been reported. Overdosage of paricalcitol may lead to hypercalcemia.

5 In the event of an overdose, signs and symptoms of hypercalcemia (serum calcium levels) should be monitored and reported to a physician. Treatment should be initiated as appropriate. Paricalcitol is not significantly removed by dialysis. Treatment of patients with clinically significant hypercalcaemia consists of immediate dose reduction or interruption of paricalcitol therapy and includes a low calcium diet, withdrawal of calcium supplements, patient mobilisation, attention to fluid and electrolyte imbalances, assessment of electrocardiographic abnormalities (critical in patients receiving digitalis), and haemodialysis or peritoneal dialysis against a calcium-free dialysate, as warranted. Zemplar solution for injection contains 30% v/v of propylene glycol as an excipient. Isolated cases of Central Nervous System depression, haemolysis and lactic acidosis have been reported as toxic effect associated with propyleneglycol administration at high doses. Although they are not expected to be found with Zemplar administration as propyleneglycol is eliminated during the dialysis process, the risk of toxic effect in overdosing situations has to be taken into account.

assessment report (d-75) es/h/113/psur-12...

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