BOUDRY, Switzerland--(BUSINESS WIRE)--Celgene International Sàrl, a wholly owned subsidiary of Celgene Corporation (NASDAQ: CELG), today announced that Swissmedic, the regulatory authority for Switzerland, has granted approval of REVLIMID® (lenalidomide) for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) after prior therapy that included bortezomib and chemotherapy/rituximab. This is the third approval worldwide of REVLIMID® for this indication, and Celgene’s fourth oncology approval in Switzerland in 2014.
MCL is a form of non-Hodgkin’s lymphoma (NHL) and occurs when a specific type of white blood cells – B lymphocytes – become cancerous and grow out of control in an area of the lymph node known as the mantle zone. In Switzerland, over 1,500 cases of NHL are diagnosed every year, and over 460 people die.1 MCL accounts for around 3–6% of all NHL cases, and has a very poor prognosis, with a median survival time of just 3–5 years.2 By the time they are diagnosed, most patients are already in the advanced stages of the disease, with it having spread to multiple lymph nodes, blood, spleen, bone marrow and the gastrointestinal tract.3
“MCL is a rare B-cell lymphoma of the elderly that usually responds quite well to first-line treatment. However, even intensive treatment does not prevent relapse in the majority of patients and new therapeutic options are needed,” said Prof. Dr. med. Christoph Renner, Onkozentrum Hirslanden Zürich. “Therefore, having access to lenalidomide, an immunomodulatory drug with a well-known safety profile, will definitely enrich our therapeutic armamentarium.”
Tuomo Pätsi, President of Celgene Europe, the Middle East and Africa (EMEA), added, “Following the Swissmedic approvals earlier this year of IMNOVID® (pomalidomide) for relapsed/refractory multiple myeloma and ABRAXANE® (nab-paclitaxel) for metastatic pancreatic cancer and metastatic breast cancer, today’s announcement is another step forward in our continued commitment to making treatments available for patients in Switzerland. We are especially pleased that REVLIMID® is now approved for MCL in the home country of our EMEA headquarters.”
The Swissmedic decision for the MCL indication was based the results of MCL-001, a phase II, multi-centre, single arm, open-label study evaluating REVLIMID® (25 mg once per day on days 1–21 of each 28-day cycle) in 134 patients with MCL who had received prior treatment with rituximab, cyclophosphamide, an anthracycline (or mitoxantrone), and bortezomib alone or in combination.4
In the study, the overall response rate (the primary endpoint of the trial) was 28% (37/134) with a complete response rate of 7% (10/134). The median duration of response was 16.6 months (95% CI, 7.7–26.7).
The most common grade 3/4 adverse events reported in =5% of patients were neutropenia (43%), thrombocytopenia (28%), anaemia (11%), pneumonia (9%), fatigue (7%), leukopenia (7%), febrile neutropenia (6%), diarrhoea (6%) and dyspnoea (6%).
About REVLIMID®
REVLIMID is approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle-East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.
REVLIMID is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anaemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in Europe for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
In addition, REVLIMID is approved in the United States for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.
Swiss Regulatory Information for REVLIMID® based on Swissmedic Approval
Revlimid (lenalidomide) is indicated in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one previous drug treatment.
Revlimid (lenalidomide) is indicated for the treatment of patients with anaemia requiring transfusions resulting from myelodysplastic syndrome with low or intermediate risk 1 associated with a deletion 5q cytogenetic abnormality with or without other cytogenetic abnormalities.
Revlimid (lenalidomide) is indicated for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) after prior therapy that included bortezomib and chemotherapy/rituximab.
SPECIAL DOSAGE INSTRUCTIONS
The treatment must be initiated and monitored by an experienced haematologist or oncologist.
Paediatric patients:
Revlimid has not been investigated in paediatric patients. For that reason Revlimid should not be used in this age group.
Elderly patients:
Dose adjustments are not necessary. Since elderly patients are more likely to have reduced renal function, renal function should be monitored on a regular basis in these patients. Revlimid has been used in clinical studies in patients aged up to 95 years.
Patients with renal function disorders:
No dose adjustment is required in mild renal insufficiency (ClCr 80-50 ml/min). In MCL patients with renal impairment dose reduction should be considered accordingly. In MCL patients with creatinine clearance between 30 and 60 ml/min, the initial dose must not exceed 10 mg.
Patients with liver function disorders:
Revlimid has not been investigated in patients with disorders of liver function and there are no special dosage recommendations.
CONTRAINDICATIONS
Pregnancy
Women of childbearing potential except when all of the conditions of the Pregnancy Prevention Programme have been fulfilled (see “Warnings and Precautions”).
Hypersensitivity to lenalidomide or any of the excipients.
WARNINGS AND PRECAUTIONS
Pregnancy Prevention Programme
Programme in female patients
The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless it has been proven that the patient cannot become pregnant.
Programme for male patients
For male patients taking Revlimid, clinical data have demonstrated the presence of this active substance in the semen. Therefore, male patients with partners of childbearing potential should use condoms during sexual intercourse during treatment with Revlimid and for at least 7 days after the end of the treatment.
Other Warnings and Precautions
Neutropenia and thrombocytopenia are among the most important dose-limiting toxicities of lenalidomide. Patients taking Revlimid for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. A dose reduction may become necessary (see Dosage/Administration).
Lenalidomide has a strong immunosuppressant effect. Therefore, concomitant treatment with other immunomodulating agents should be undertaken only with caution. The effect of vaccinations may be impaired. Vaccinations with live organisms should not be given during treatment with lenalidomide due to the risk of infection.
Since hypothyroidism has been observed, thyroid hormone levels should be checked before starting treatment and during treatment.
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors. Patients with known risk factors – including previous thrombosis – should be closely monitored, and measures should be taken to minimise all modifiable risk factors (eg. smoking, hypertension, and hyperlipidaemia).
The risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) is increased. Therefore there is a need to be especially alert to the symptoms of thrombosis or thromboembolism. Patients must be instructed to seek medical help if symptoms such as shortness of breath, cough, chest pain or pain and/or swelling of the arms and legs occur. Treatment with erythropoietic agents and hormone replacement therapy can increase the risk of thromboembolism and thus should not be given.
Venous and arterial thromboembolic events
In patients with multiple myeloma using the combination of lenalidomide and dexamethasone, and in patients with MCL using monotherapy lenalidomide, there is an association with an increased risk of venous thromboembolic events (primarily deep vein thrombosis and pulmonary embolism) and arterial thromboembolic events (primarily myocardial infarction and cerebrovascular events).
Consequently, patients with known risk factors for thromboembolism – including previous thrombosis – must be closely monitored. Measures should be taken to minimise all modifiable risk factors (e.g. smoking cessation, control of hypertension and hyperlipidaemia).
The decision whether to take antithrombotic prophylactic measures should be made after careful assessment for each patient individually.
If a thromboembolic event occurs, treatment with lenalidomide must be discontinued. Once the patient’s condition has stabilised, treatment with lenalidomide may be resumed if required, with continuation of the anticoagulation.
Prolongation of the QTc interval has been observed on the ECG during treatment with lenalidomide. Concurrent treatment with drugs prolonging QT interval and treatment of patients with long QT syndrome should take place only with great caution and regular ECG monitoring (see “Properties/Effects”).
Angioedema and severe dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. These events are potentially life-threatening. Discontinuation of Revlimid should be considered if there is the occurrence of a skin rash = grade 2 with an exfoliative or bullous appearance or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected. Revlimid should not be resumed following discontinuation of the drug because of these reactions. Patients with severe grade 4 rash associated with thalidomide treatment should not receive Revlimid.
Tumour lysis syndrome (TLS) may occur including in patients with lymphoma. The patients at risk of tumour lysis syndrome are those with a high tumour burden prior to the start of treatment. These patients should be closely monitored, especially during the first cycle or dose-escalation, and appropriate precautions taken.
Tumor Flare Reaction
Careful monitoring and evaluation for tumor flare reaction (TFR) is recommended. Tumor flare may mimic progression of disease (PD). In the pivotal MCL-001 study, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity and all were assessed as treatment-related. The majority of the events occurred in cycle 1. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients in study MCL-001 that experienced Grade 1 and 2 TFR were treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. The decision to take therapeutic measures for TFR should be made after careful clinical assessment of the individual patient. In patients with Grade 3 or 4 TFR, withhold treatment with lenalidomide until TFR resolves to = Grade 1 and patients may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.
Revlimid capsules contain lactose. Patients with a rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.
Hepatic Disorders
Hepatic failure, including fatal cases, has been reported in patients treated with lenalidomide in combination with dexamethasone: acute hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis have been reported. The mechanisms of severe drug-induced hepatotoxicity remain unknown although, in some cases, pre-existing viral liver disease, elevated baseline liver enzymes, and possibly treatment with antibiotics might be risk factors.
Abnormal liver function tests were commonly reported and were generally asymptomatic and reversible upon dosing interruption. Once parameters have returned to baseline, treatment at a lower dose may be considered. Cases of transiently abnormal liver function tests (mainly transaminases) have been reported in patients treated with Revlimid. Treatment with Revlimid should be suspended. Treatment with Revlimid can be continued once the levels have returned to baseline. Successful re-challenge without recurrence of elevated liver enzymes has been reported in some patients.
Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal impairment in order to avoid plasma levels which may increase the risk for higher haematological side effects or hepatotoxicity. Monitoring of liver function is recommended, particularly when there is a history of or concurrent viral liver infection or when lenalidomide is combined with medications known to be associated with liver dysfunction.
Cases of transiently abnormal liver function tests (mainly transaminases) have been reported in patients treated with Revlimid. Treatment with Revlimid should be suspended. Treatment with Revlimid can be continued once the levels have returned to baseline. Successful re-challenge without recurrence of elevated liver enzymes has been reported in some patients.
UNDESIRABLE EFFECTS
Multiple myeloma
In placebo-controlled phase III studies 353 patients received the lenalidomide/dexamethasone combination and 350 patients the placebo/dexamethasone combination. At least one side effect was observed in 325 patients (92%) in the lenalidomide/dexamethasone group, compared with 288 patients (82%) in the placebo/dexamethasone group.
The most serious undesirable effects observed were venous thromboembolism (deep vein thrombosis, pulmonary embolism) and grade 4 neutropenia.
The most frequently observed undesirable effects in the lenalidomide/dexamethasone group were neutropenia (39.4%; grade 4: 5.1%), thrombocytopenia (18.4%, grades 3-4: 9.9%), fatigue (27.2%), constipation (23.5%), muscle cramps (20.1%), asthenia (17.6%), anaemia (17.0%), diarrhoea (14.2%) and rash (10.2%), insomnia (26.7%) and muscle weakness (10.1%). The occurrence of neutropenia and thrombocytopenia was mainly dose-dependent, and these conditions were successfully treated with dose reduction.
Myelodysplastic syndrome
In a placebo-controlled Phase III study 69 patients received 10 mg lenalidomide once daily and 67 patients received placebo.
The most serious undesirable effects observed were venous thromboembolisms (deep vein thrombosis, pulmonary embolism), grades 3-4 neutropenia, febrile neutropenia and grades 3-4 thrombocytopenia.
The most frequently observed undesirable effects in the lenalidomide group were neutropenia (76.8%; grades 3-4: 75.4%), thrombocytopenia (49.3%; grades 3-4: 40.6%), diarrhoea (37.7%), pruritus (27.5%), nausea (20.3%), fatigue (18.8%), constipation (17.4%), muscle spasm (17.4%), fever (15.9%), nasopharyngitis (14.5%), bronchitis (14.5%) and headache (14.5%). The occurrence of neutropenia and thrombocytopenia was mainly dose-dependent and these conditions were successfully treated with dose reduction.
Relapsed or refractory mantle cell lymphoma
In the pivotal MCL study, a total of 134 patients received at least 1 dose of Revlimid.
The most common type of serious adverse events was infection. Of the serious infections, pneumonia was the most frequently reported.
The most frequently observed undesirable effects were Pneumonia (14.2%; Grade 3-4: 9%), Upper respiratory tract infection (12.7%), neutropenia (48.5%; Grade 3-4: 43.3%), thrombocytopenia (35.8%; Grade 3-4: 27.6%), anaemia (30.6%; Grade 3-4: 11.2%), leucopenia (14.9%; Grade 3-4: 6.7%), decreased appetite (14.2%), hypokalaemia (12.7%; Grade 3-4: 2.2%), weight decreased (12.7%), cough (28.4%), dyspnoea (17.9%; Grade 3-4: 6%), diarrhoea (31.3%; Grade 3-4: 6%), nausea (29.9%), constipation (15.7%), vomiting (11.9%), rash (22.4%; Grade 3-4: 1.5%), pruritus (17.2%), back pain (13.4%; Grade 3-4: 1.5%), muscle spasms (12.7%), fatigue (33.6%; Grade 3-4: 6.7%), fever (23.1%; Grade 3-4: 2.2%), peripheral oedema (15.7%), and asthenia (14.2%; Grade 3-4: 3%).
Please see full Summary of Product Characteristics, available at www.swissmedicinfo.ch
About Celgene
Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. Celgene International Sàrl, located in Boudry, Switzerland, is a wholly owned subsidiary and international headquarters of Celgene Corporation. Celgene GmbH, located in Zurich, is the Swiss affiliate of Celgene Corporation. For more information, please visit www.celgene.com.
Forward-Looking Statements
This press release contains forward-looking statements, which are generally statements that are not historical facts. Forward-looking statements can be identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates,” “plans,” “will,” “outlook” and similar expressions. Forward-looking statements are based on management’s current plans, estimates, assumptions and projections, and speak only as of the date they are made. Celgene Corporation undertakes no obligation to update any forward-looking statement in light of new information or future events, except as otherwise required by law. Forward-looking statements involve inherent risks and uncertainties, most of which are difficult to predict and are generally beyond our control. Actual results or outcomes may differ materially from those implied by the forward-looking statements as a result of the impact of a number of factors, many of which are discussed in more detail in Celgene Corporation’s Annual Report on Form 10-K and its other reports filed with the Securities and Exchange Commission.
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References
1. http://eco.iarc.fr/EUCAN/Cancer.aspx?Cancer=38
2. Li Z-M, Zucca E, Ghielmini M. Open questions in the management of mantle cell lymphoma. Cancer Treatment Reviews 2013;39:602–609
3. Hitz F, Bargetzi M, Cogliatti S, et al. Diagnosis and treatment of mantle cell lymphoma. Swiss Med Wkly. 2013;143:w13868. http://www.smw.ch/content/smw-2013-13868/
4. Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study.J Clin Oncol 2013;31(29):3688-95. http://jco.ascopubs.org/content/early/2013/09/03/JCO.2013.49.2835
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