Zydelig - Dear Health Care Professional Letter

 
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This is duplicated text of a letter from Gilead Sciences Canada, Inc. (Gilead Canada)
 Contact the company for a copy of any references, attachments or enclosures.

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Authorization with conditions of ZYDELIG™ (idelalisib) for follicular lymphoma

March 27, 2015

Dear Health Care Professional,

Gilead Sciences Canada, Inc. (Gilead Canada) is pleased to announce that Health Canada has issued a Notice of Compliance with Conditions under the Notice of Compliance with Conditions (NOC/c) policy for ZYDELIG™ (idelalisib) tablets for the treatment of patients with follicular lymphoma who have received at least two prior systemic regimens and are refractory to both rituximab and an alkylating agent.

Health Canada has issued a marketing authorization with conditions under the NOC/c policy for ZYDELIG to reflect the promising nature of the clinical data with ZYDELIG in patients with follicular lymphoma and the need for further follow-up to verify the clinical benefit. ZYDELIG is of high quality and possesses an acceptable safety profile based on the benefit/risk assessment. As part of its condition, Gilead Canada has undertaken to provide Health Canada with the following information:

  • Interim topline analysis for the most recent analysis (data cut of 11 June 2014) of Study 101-09, a Phase 2 Study to Assess the Efficacy and Safety of Idelalisib in Subjects with Indolent B-Cell Non-Hodgkin Lymphomas Refractory to Rituximab and Alkylating Agents.
  • Final study report for Study 101-09, a Phase 2 Study to Assess the Efficacy and Safety of Idelalisib in Subjects with Indolent B-Cell Non-Hodgkin Lymphomas Refractory to Rituximab and Alkylating Agents. The trial is anticipated to complete in May 2015 and the clinical study report is expected in December 2015.

Indications and Clinical Use

ZYDELIG (idelalisib), indicated as monotherapy, has been issued marketing authorization with conditions for the treatment of patients with follicular lymphoma who have received at least two prior systemic regimens and are refractory to both rituximab and an alkylating agent. Patients should be advised about the conditional market authorization for this indication.

There are clinically significant adverse events associated with ZYDELIG. The most serious warnings and precautions associated with the use of ZYDELIG in patients with follicular lymphoma are:

  • Hepatotoxicity
  • Severe diarrhea/colitis, including fatal cases
  • Pneumonitis, including fatal cases

See the ZYDELIG Product Monograph for further details, including monitoring for adverse events and dose modifications.

Other Uses of ZYDELIG

ZYDELIG (idelalisib), indicated in combination with rituximab for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL), has been issued marketing authorization without conditions.

Action and Clinical Pharmacology

Idelalisib selectively inhibits phosphatidylinositol 3-kinase delta (PI3Kδ), which is hyperactive in B-cell malignancies and is central to multiple signaling pathways that drive proliferation, survival, homing, and retention of malignant cells in lymphoid tissues and bone marrow. Idelalisib is a selective inhibitor of adenosine-5'-triphosphate (ATP) binding to the catalytic domain of PI3Kδ, resulting in inhibition of the phosphorylation of the key lipid second messenger phosphatidylinositol (PIP) and prevention of Akt phosphorylation.

Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B cells and in primary tumor cells. Idelalisib inhibits homing and retention of malignant B cells in the tumor microenvironment, including lymphoid tissues and the bone marrow.

Authorization with conditions for ZYDELIG was based on the safety and efficacy of ZYDELIG in a single-arm, multicenter clinical trial that included 72 patients with follicular lymphoma who failed to respond or who had relapsed within 6 months of both rituximab therapy and an alkylating agent (separately or in combination). Subjects received ZYDELIG 150 milligrams (mg) taken orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee (IRC)-assessed overall response rate (ORR).

An ORR of 54.2% (95% CI: 42, 66) was observed with 8.3% (6 out of 72 patients) meeting the criteria for complete response (CR) and 45.8% (33 out of 72 patients) meeting the criteria for partial response (PR). The median duration of response (DOR), progression-free survival, or overall survival could not be estimated due to the immaturity of the data. Of the subjects who did not respond, 24 (33.3%) had stable disease, 8 (11.1%) had progressive disease, and 1 (1.4%) was not evaluable.

Serious Warnings and Precautions

ZYDELIG should only be prescribed by a qualified physician who is experienced in the use of anti-cancer agents.

The following list is a summary of the most serious warnings and precautions:

  • Hepatotoxicity:
    Elevations of hepatic enzymes in the blood (ALT and AST) greater than 5 times the upper limit of normal [Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4] have been observed in clinical trials of ZYDELIG. These laboratory findings were generally observed within the first 12 weeks of treatment, were asymptomatic, and were reversible within 3-4 weeks with dose interruption. While most patients resumed treatment at a lower dose, the recurrence of ALT and AST elevations was common.

  • Severe Diarrhea/Colitis:
    Cases of severe diarrhea/colitis were reported commonly and occurred relatively late (months) after the start of a therapy with ZYDELIG. Severe diarrhea due to ZYDELIG responds poorly to antimotility agents. Most cases resolved within a few weeks with drug interruption and additional symptomatic treatment (e.g., anti-inflammatory corticosteroid agents such as enteric budesonide) but some had a fatal outcome.

  • Pneumonitis:
    Cases of pneumonitis, some with fatal outcome, have occurred with ZYDELIG. Time to occurrence of pneumonitis after the start of therapy with ZYDELIG was highly variable, ranging from a few weeks to over one year.

For further details, see the ZYDELIG Product Monograph.

Adverse Reactions

Safety was assessed in 146 patients with previously treated indolent non-Hodgkin lymphoma (iNHL) who were treated with ZYDELIG monotherapy at a dose of 150 mg BID. Serious adverse reactions were reported in 73 (50%) patients treated with ZYDELIG. The most frequent serious adverse reactions were pneumonia (15%), diarrhea (11%), and pyrexia (9%). Among the 146 patients who received ZYDELIG, 62 (43%) had dose interruptions, 34 (23%) had dose reductions, and 36 (25%) had drug discontinuation due to adverse reactions. Patients may have had more than 1 type of dose modification. The most common reasons for dose modifications were diarrhea, elevated transaminases, and neutropenia.

Drug Interactions

Idelalisib is metabolized primarily via aldehyde oxidase, and to a lesser extent via CYP3A and glucuronidation (UGT1A4).

A clinical drug interaction study found that coadministration of ZYDELIG with rifampin (a strong CYP3A inducer) resulted in a ~75% reduction in idelalisib plasma AUCinf Coadministration of ZYDELIG with strong CYP3A inducers such as rifampin, phenytoin, St. John's Wort, or carbamazepine should be avoided.

A clinical drug interaction study found that coadministration of ZYDELIG with midazolam (a sensitive CYP3A substrate) resulted in a ~140% increase in Cmax and a ~440% increase in AUCinf of midazolam. Accordingly, ZYDELIG is considered to be a strong CYP3A inhibitor. Coadministration of ZYDELIG with CYP3A substrates may increase their systemic exposures.

Caution is recommended if ZYDELIG is coadministered with narrow therapeutic index CYP3A substrates (e.g., alfentanil, cyclosporine, sirolimus, tacrolimus, pimozide, fentanyl, quinidine, ergotamine, dihydroergotamine).

For further information on drug interactions, see the ZYDELIG Product Monograph.

Dosage and Administration

The recommended dose of ZYDELIG is 150 mg administered orally twice daily.

For information on dose modifications, see the ZYDELIG Product Monograph.

For the complete prescribing information and information available for the patients/caregivers, please consult the  ZYDELIG Product Monograph or by request by contacting Gilead Canada at 1-866-207-4267.

Should you have medical enquiries regarding ZYDELIG, please contact the Gilead Canada Medical Information Department at 1-866-207-4267.

Sincerely,

Original signed by

Josée Brisebois, PhD
Director, Medical Affairs

Gilead Sciences Canada, Inc.
6711 Mississauga Road
Suite 600
Mississauga, Ontario
L5N 2W3

Reporting Suspected Side Effects
Canada Vigilance Program
Marketed Health Products Directorate
Health Products and Food Branch
Health Canada
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Address Locator: 0701C
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Telephone: 613-957-0337 or Fax: 613-957-0335

To report an Adverse Reaction, consumers and health professionals may call toll free:
Telephone: 1-866-234-2345
Fax: 1-866-678-6789
Email: CanadaVigilance@hc-sc.gc.ca

The Adverse Reaction Reporting Form and the Adverse Reaction Guidelines can be found on the Health Canada website or in  The Canadian Compendium of Pharmaceuticals and Specialties.

For other inquiries related to this communication, please contact Health Canada at:

Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS)
Email: bmors_enquiries@hc-sc.gc.ca
Telephone: 613-941-3171
Facsimile: 613-941-1365

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