SUMMARY OF THE RISKMANAGEMENT PLAN FOR ECALTA® … · Risk Management Plan Summary 21April 2017 PFIZER CONFIDENTIAL Page 1 SUMMARY OF THE RISKMANAGEMENT PLAN FOR ECALTA® 100 MG

ECALTA (Anidulafungin) Pfizer PFE Switzerland GmbH, ZurichRisk Management Plan Summary 21 April 2017

PFIZER CONFIDENTIALPage 1

SUMMARY OF THE RISK MANAGEMENT PLAN

FOR

ECALTA® 100 MG (ANIDULAFUNGIN)

POWDER FOR SOLUTION FOR INFUSION

This RMP summary is based on Part VI of the EU RMP for ECALTA (anidulafungin), version 12.0, dated 21 April 2017

Date: 21 April 2017

Version number: 2.0

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SUMMARY OF THE RISK MANAGEMENT PLAN (RMP) FOR ECALTA

The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine.

The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimise them.

The RMP summary of Ecalta is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the “Arzneimittelinformation / Information sur le médicament” approved and published in Switzerland, e.g., by mentioning risks occurring in populations or indications not included in the Swiss authorization. Please note that the reference document which is valid and relevant for the effective and safe use of Ecalta in Switzerland is the “Arzneimittelinformation / Information sur le médicament” (see www.swissmedic.ch) approved and authorized by Swissmedic. Pfizer PFE Switzerland GmbH is fully responsible for the accuracy and correctness of the content of the published summary RMP of Ecalta.

OVERVIEW OF DISEASE EPIDEMIOLOGY

Fungal infections that are resistant to drugs commonly used to treat them are increasing in occurrence and this has lead to the need to develop new therapies (ie, antifungal drugs). More serious fungal infections, ie, those that have entered the bloodstream, have also become increasingly common in recent years. Once thought of as a relatively rare, the Candidaspecies (a type of fungus) are the fourth leading cause of bloodstream infections in hospitalized patients.1 Advances in transplantation technology and cancer treatment (eg, chemotherapy), and the extensive use of antibiotics have resulted in more patients being put at risk for such infections.2

The serious infections that enter the bloodstream, known as invasive candidiasis and candidemia, are usually found in people with severely depressed immune systems from diseases such as cancer or AIDS, or from bone marrow or organ transplants. Although less common than Candida, infections with Aspergillus (a type of fungus), has increased dramatically as well. The number of deaths related to these infections is high. Due to the serious nature of underlying disease in many of the patients with these infections, the overall death rates may be as high as 61% for Candida infections and up to 88% in patients with severe Aspergillus infections.

SUMMARY OF TREATMENT BENEFITS

There are multiple treatment options for the serious bloodstream infections, such as candidemia and invasive candidiasis in adult patients. Echinocandins are one class of drugs to treat fungal infections. The echinocandins that are approved for use in serious fungal infections include anidulafungin, caspofungin and micafungin.

A recent analysis of data from 7 clinical studies (1915 patients) confirmed that treatment with an echinocandin was associated with a decrease in death.3

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Anidulafungin is approved in the European Community for treatment of invasive candidiasis in adult patients. In the main clinical trials, anidulafungin was more effective than fluconazole (the gold standard at the time of evaluation) or at least as effective as fluconazole in the various measures of effectiveness and was well-tolerated in these patients.

UNKNOWNS RELATING TO TREATMENT BENEFITS

In clinical trials, a similar number of men and women were treated with anidulafungin or fluconazole, most patients were white, and well over 90% patients had candidaemia. About a third of patients were 65 years of age or older (elderly patients).

To date, experience with anidulafungin in the pediatric population is limited. Twenty-five (25) children with neutropenia at risk for invasive fungal infections in one study showed that anidulafungin was well-tolerated; however, the study was not designed to assess the effectiveness.

Pregnant women were not allowed in anidulafungin studies. There are insufficient safety data in pregnancy/lactation to recommend the use of anidulafungin during pregnancy without clear potential benefit.

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SUMMARY OF SAFETY CONCERNS

Important Identified Risks

Risk What is Known PreventabilityAnaphylaxis and Infusion-associated reactions

Adverse events related to infusion with anidulafungin have been reported, such as rash, pruritis (itching), hot flush, and hives. These side effects are common (may affect up to 1 in 10 people).Life-threatening allergic reactions that might include difficulty breathing with wheezing or worsening of an existing rash have been rarely reported with anidulafungin (may affect up to 1 in 100 people).

Tell your doctor or another healthcare professional immediately should any of the following occur: flushing, rash, pruritis (itching), hot flush, hives, sudden contraction of the muscles around the airways resulting in wheezing or coughing, difficulty of breathing. You should not be treated with anidulafungin if you are allergic to anidulafungin, other echinocandins (eg, CANCIDAS), or any of the other ingredients of this medicine.

Hepatobiliary events Liver problems, such as changes in blood tests of liver function, are common in patients treated with anidulafungin (may affect up to 1 in 10 people). In some patients with other serious medical conditions who were receiving additional medicines along with anidulafungin, significant liver problems have occurred, ie, abnormal flow of bile from the gallbladder into the intestine (cholestasis), which is uncommon (may affect up to 1 in 100 people).

Your doctor may decide to monitor your liver function more closely if you develop liver problems during your treatment.

Convulsions Although there is no clear evidence that the risk of seizures is caused by anidulafungin, seizures have been observed in patients treated with other drugs in this class (ie, echinocandins). The frequency of this event is common (may affect up to 1 in 10 people).

Tell your doctor or another healthcare professional immediately if you have a seizure

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Important Potential Risks

Risk What is KnownExacerbation of infusion-associated reactions by anaesthetics

Rats given high doses of anidulafungin experienced a worsening of allergic reactions related to infusion with anidulafungin and anesthesia. The cause of the worsening of these reactions in rats is unknown. Although the relevance of this finding to humans is unknown, any patient experiencing allergic reaction related to infusion and receiving concurrent anesthesia might be at risk. Your doctor may decide to monitor if you are given anaesthetics during your treatment with anidulafungin.

No instances of anesthesia-exacerbated infusion-associated reactions have been observed in humans.

QT Prolongation/Torsade de Pointes

Patients treated with anidulafungin often are seriously ill with other risk factors, such as heart disease or abnormalities in heart function. QT prolongation (an abnormal pattern seen on an electrocardiogram) or torsade de pointes (a rare heart condition) have not been reported in patients with candidemia or other forms of Candida infection, regardless of treatment with anidulafungin or another drug in the same class (echinocandin).

Missing Information

Risk What is KnownChildren / Adolescents The safety and the benefits of anidulafungin in children have not yet been

established. To date, experience with anidulafungin in the pediatric population is limited. Twenty-five (25) children with a low count of one type of white blood cell (neutrophils) at risk for invasive fungal infections in one study showed that anidulafungin was well-tolerated; however, the study was not designed to assess effectiveness.

Elderly A limited number of elderly patients were studied in clinical trials. Proportionally more severe adverse events were reported among elderly patients, but their frequency was similar to that of younger patients, except that respiratory distress was reported by more patients aged 65 and older.

Pregnant women Pregnant women were not allowed in anidulafungin studies. There are insufficient safety data in pregnancy/lactation to recommend the use of anidulafungin during pregnancy without clear potential benefit.

Resistance Anidulafungin is fungicidal for Candida species. Resistance to anidulafungin was not observed in laboratory experiments designed to detect it, including in vitro passage experiments and animal infection experiments. The MAH continue to monitor trends in resistance and will inform in the case of unexpected trends or findings.

SUMMARY OF ADDITIONAL RISK MINIMISATION MEASURES BY SAFETY CONCERN

There is no additional risk minimization activity for the identified or potential risks for anidulafungin.

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PLANNED POST AUTHORISATION DEVELOPMENT PLAN

List of Studies in Post Authorisation Development Plan

Study Objectives Efficacy/Safety IssueAddressed

Status Date forSubmission of Interim orFinal Reports

A8851008a

(Prospective, open-label, non-comparative, descriptive, multicenter, multinational study)

To evaluate the safety and efficacy of anidulafungin for the treatment of paediatric patients with invasive candidiasis

Paediatric patients

Ongoing May 2020b

Abbreviations: PASS=Post-authorisation safety studya. FUM 018 relates to the MAH’s commitment to incorporating a PK/PD component in the following three studies A8851019, A8851011 and A8851008, with submission of the results when available. Study A8851008 is a paediatric study investigating the treatment of invasive candidaemia in patients aged 0-18 years of age is the only study ongoing the final CSRs for A8851019 and A8851011 have been submitted to the EMA.b. Following approval of a modification to the Peadiatric Investigation Plan (PIP) (M06 04 July 2016), the completion time for the study has been extended to November 2019. In a further modification (M07 approved 27 January 2017) the indication in the youngest age cohort has been extended to include patients at high risk for candidiasis to help with recruitment

Studies Which are a Condition of the Marketing Authorisation

None of the studies listed above are a condition of the marketing authorization.

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SUMMARY OF CHANGES TO THE RISK MANAGEMENT PLAN OVER TIME

Version Date Safety Concerns Comment1.0, 1.1, 1.2 11 July 2007 Identified Risks

Infusion-related reactions Hepatobiliary eventsPotential Risks Convulsions Anesthetic exacerbation of

infusion-associated reactions QT prolongation/Torsade de

pointesMissing information Children/adolescents Neutropenic patients Pregnant women Elderly

Updated based oninteractions with EMA. Version 1.2 represents agreed initial RMP.

2.0 19 September 2008 No change to safety concerns. Provide updated information up to 31 July 2008 as part of routine review in line with the PSUR submission

2.1 9 March 2009 No change to safety concerns. Updated to include drug format without solvent for dilution with water for injections (WFI) and included risk management activities during transition to use of WFI for preparation of concentrate

2.2 20 May 2009 No change to safety concerns. Revised per Day 150 Assessment Report Updated Letter to Healthcare Professionals in Annex 7, and SPC in Annex 2

3.0 31 January 2009 No change to safety concerns. Provide updated information to 31 January 2009 as part of routine review in line with the PSUR submission. Also updated in response to Assessment report for PSUR 2.

4.0 21 September 2009 No change to safety concerns. Merge RMP v 2.2 and 3.0 to cover both anidulafungin presentations

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Version Date Safety Concerns Comment5.0 21 March 2011 No change to safety concerns. Provided updated

information to 31 January 2011 as part of routine review in line with PSUR submission. Also updated in response to Assessment Report for PSUR 6

6.0 27 January 2012 No change to safety concerns. Included the ongoing FUMs to the body of the RMP.

7.0 26 March 2012 No change to safety concerns. Provided updated information to 31 January 2012 as part of routine review in line with PSUR submission.

8.0 01 June 2012 No change to safety concerns. Provided updated information in response to CHMP LoOI, dated 24 May 2012

9.0 31 Aug 2012 Added patients with deep tissue infections to table containing Important limited/missing information.

Provided updated information in response to EMA/439075/2012, dated 29 June 2012

10.0 05 Apr 2013 No change to safety concerns. Updated to new EMA template and provided updated information to 31 January 2013 as part of routine review in line with PSUR submission.

11.0 11 Nov 2013 Removed neutropenic patients and patients with deep tissue infection from Missing Information.

Updated with data from studies in subjects with neutropenia and deep tissue infection.

12.0 21 April 2017 Convulsion moved from important potential risk to important identified risk.

Planned post-authorization development plan updated forongoing study A8851008.

PASS A8851030 and Global Antifungal Surveillance Program were completed.

Final study report for PASS A8851030 was submitted to EMA (variation approved and PAM fulfilled in February 2016).

The 2013 results of the Global Antifungal Surveillance Program were submitted to EMA in February 2015. In April 2015, the CHMP concluded that all issues were resolved and that no further action is required.

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REFERENCES

1 Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US

hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39:309-317.

2 Voss A, dePau B. High-dose fluconazole therapy in patients with severe fungal infections. Eur J Clin Microbiol Infect Dis 1999; 18:165-74.

3 Andes DR, Safdar N, Baddley JW, et al. Impact of Treatment Strategy on Outcomes in Patients with Candidemia and Other Forms of Invasive Candidiasis: A Patient-LevelQuantitative Review of Randomized Trials. Clin Infect Dis. 2012;54(8):1110–22.

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Documents

SUMMARY OF THE RISKMANAGEMENT PLAN FOR ECALTA® … · Risk Management Plan Summary 21April 2017 PFIZER CONFIDENTIAL Page 1 SUMMARY OF THE RISKMANAGEMENT PLAN FOR ECALTA® 100 MG