*
`
` Pharmorubicin is a registered trademark of Pharmacia & Upjohn S.P.A.
` PFS is a registered trademark of Pfizer Enterprises SARL
` Pfizer Canada Inc., Licensee
`
` ©
`
` Pfizer Canada Inc., 2014
`
`
`
`PRODUCT MONOGRAPH
`
`PrPHARMORUBICIN* PFS
`
`
`epirubicin hydrochloride injection
`
`
`
`2 mg/mL
`
`Professed Standard
`
`
`
`
`
`Antineoplastic agent
`
`
`Date of Revision:
`July 09, 2014
`
`
`
`Pfizer Canada Inc
`17,300 Trans-Canada Highway
`Kirkland, Quebec H9J 2M5
`
`Submission Control No.: 173657
`
`Ex. 1061-0001
`
`

`
`
`
`
`
`Table of Contents
`
`PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3
`SUMMARY PRODUCT INFORMATION ........................................................................3
`INDICATIONS AND CLINICAL USE ..............................................................................4
`CONTRAINDICATIONS ...................................................................................................4
`WARNINGS AND PRECAUTIONS ..................................................................................5
`ADVERSE REACTIONS ..................................................................................................11
`DRUG INTERACTIONS ..................................................................................................15
`DOSAGE AND ADMINISTRATION ..............................................................................15
`OVERDOSAGE ................................................................................................................19
`ACTION AND CLINICAL PHARMACOLOGY ............................................................19
`STORAGE AND STABILITY ..........................................................................................21
`SPECIAL HANDLING INSTRUCTIONS .......................................................................22
`DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................24
`
`PART II: SCIENTIFIC INFORMATION ...............................................................................26
`PHARMACEUTICAL INFORMATION ..........................................................................26
`CLINICAL TRIALS ..........................................................................................................27
`DETAILED PHARMACOLOGY .....................................................................................31
`TOXICOLOGY .................................................................................................................32
`REFERENCES ..................................................................................................................33
`
`PART III: CONSUMER INFORMATION ..............................................................................39
`
`
`
`
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`
`PHARMORUBICIN® PFS*
`
`
`
`epirubicin hydrochloride injection
`
`PART I: HEALTH PROFESSIONAL INFORMATION
`
`CAUTION
`
`
`
`
`
`
`
`
`PHARMORUBICIN PFS (EPIRUBICIN HYDROCHLORIDE INJECTION) IS A POTENT
`DRUG AND SHOULD BE USED ONLY BY PHYSICIANS EXPERIENCED WITH
`CANCER CHEMOTHERAPEUTIC DRUGS (SEE WARNINGS AND PRECAUTIONS).
`BLOOD COUNTS AND HEPATIC FUNCTION TESTS SHOULD BE PERFORMED
`REGULARLY.
`IRREVERSIBLE CARDIAC TOXICITY MAY OCCUR AS THE
`CUMULATIVE DOSE APPROACHES 1000 mg/m2. CARDIAC MONITORING IS ADVISED
`IN THOSE PATIENTS WHO HAVE RECEIVED MEDIASTINAL RADIOTHERAPY,
`OTHER ANTHRACYCLINE OR ANTHRACENE THERAPY, WITH PRE-EXISTING
`CARDIAC DISEASE, OR RECEIVED PRIOR EPIRUBICIN CUMULATIVE DOSES
`EXCEEDING 650 mg/m2.
`
`(AML) WITH OR WITHOUT A
`SECONDARY ACUTE MYELOID LEUKEMIA
`PRELEUKEMIC PHASE (MYELODYSPLASTIC SYNDROME OR MDS) HAS BEEN
`REPORTED IN PATIENTS TREATED WITH EPIRUBICIN-CONTAINING REGIMENS.
`THE CUMULATIVE RISK OF DEVELOPING TREATMENT-RELATED AML/MDS IN
`7110 PATIENTS WITH EARLY BREAST CANCER WHO RECEIVED ADJUVANT
`TREATMENT WITH EPIRUBICIN-CONTAINING REGIMENS WAS ESTIMATED AS
`0.27% AT 3 YEARS, 0.46% AT 5 YEARS, AND 0.55% AT 8 YEARS.
`
`
`
`SUMMARY PRODUCT INFORMATION
`
`
`Route of
`Administration
`Intravenous
`
`Dosage Form /
`Strength
`Sterile solution for
`injection / 2 mg/mL
`
`Clinically Relevant Nonmedicinal
`Ingredients
`Not Applicable.
`For a complete listing see Dosage Forms,
`Composition and Packaging section.
`
`
`
`
`PHARMORUBICIN PFS (epirubicin hydrochloride injection) Product Monograph
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`INDICATIONS AND CLINICAL USE
`
`PHARMORUBICIN PFS (epirubicin hydrochloride injection) has been used successfully as a
`single agent and in combination with other chemotherapeutic agents to produce regression in a
`variety of tumour types such as lymphoma, lung, cancer of the breast, ovary and stomach.
`
`PHARMORUBICIN PFS is recommended for the treatment of metastatic breast cancer.
`
`PHARMORUBICIN PFS may also be used as a component in the adjuvant treatment of early
`stage breast cancer for pre- and peri- menopausal women.
`
`PHARMORUBICIN PFS is also recommended in small cell lung cancer (both limited and
`extensive disease) advanced non-small cell lung cancer, non-Hodgkin's lymphoma, Hodgkin's
`disease, Stage III and IV (FIGO) ovarian carcinoma and metastatic and locally unresectable
`gastric carcinoma.
`
`
`
`CONTRAINDICATIONS
`
` •
`
`
`
` Hypersensitivity to epirubicin or any other component of the product, or other anthracyclines
`or anthracenediones such as doxorubicin hydrochloride, daunorubicin hydrochloride,
`mitoxantrone or mitomycin C.
`• marked persistent myelosuppression induced by prior treatment with other antitumour agents
`or by radiotherapy
`•
`severe hepatic impairment
`•
`severe myocardial insufficiency
`•
`recent myocardial infarction
`•
`severe arrhythmias
`• history of severe cardiac disease
`• previous
`treatments with maximum cumulative doses of epirubicin and/or other
`anthracyclines and anthracenediones (see WARNINGS AND PRECAUTIONS).
`
`
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`

`
`
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`Serious Warnings and Precautions
`
`• PHARMORUBICIN PFS (EPIRUBICIN HYDROCHLORIDE INJECTION) IS A
`POTENT DRUG AND SHOULD BE USED ONLY BY PHYSICIANS EXPERIENCED
`WITH CANCER CHEMOTHERAPEUTIC DRUGS
`(SEE WARNINGS AND
`PRECAUTIONS). BLOOD COUNTS AND HEPATIC FUNCTION TESTS SHOULD BE
`PERFORMED REGULARLY. IRREVERSIBLE CARDIAC TOXICITY MAY OCCUR AS
`THE CUMULATIVE DOSE APPROACHES 1000 mg/m2. CARDIAC MONITORING IS
`ADVISED
`IN THOSE PATIENTS WHO HAVE RECEIVED MEDIASTINAL
`RADIOTHERAPY, OTHER ANTHRACYCLINE OR ANTHRACENE THERAPY, WITH
`PRE-EXISTING CARDIAC DISEASE, OR RECEIVED PRIOR EPIRUBICIN
`CUMULATIVE DOSES EXCEEDING 650 mg/m2.
`
` •
`
` SECONDARY ACUTE MYELOID LEUKEMIA (AML) WITH OR WITHOUT A
`PRELEUKEMIC PHASE (MYELODYSPLASTIC SYNDROME OR MDS) HAS BEEN
`REPORTED IN PATIENTS TREATED WITH EPIRUBICIN-CONTAINING REGIMENS.
`THE CUMULATIVE RISK OF DEVELOPING TREATMENT-RELATED AML/MDS IN
`7110 PATIENTS WITH EARLY BREAST CANCER WHO RECEIVED ADJUVANT
`TREATMENT WITH EPIRUBICIN-CONTAINING REGIMENS WAS ESTIMATED AS
`0.27% AT 3 YEARS, 0.46% AT 5 YEARS, AND 0.55% AT 8 YEARS.
`
`
`• SEVERE LOCAL TISSUE NECROSIS ASSOCIATED WITH EXTRAVASATION
`DURING ADMINISTRATION
`
` •
`
` MYOCARDIA TOXICITY, MANIFESTED IN ITS MOST SEVERE FORM BY
`POTENTIALLY FATAL CONGESTIVE HEART FAILURE (CHF)
`
` SEVERE MYELOSUPRESSION
`
` •
`
`
`
`Cardiac Function:
`
`Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e., acute) or
`late (i.e., delayed) events.
`
`Early (i.e., Acute) Events. Early cardiotoxicity of epirubicin consists mainly of sinus
`tachycardia and/or ECG abnormalities such as non-specific ST-T wave changes.
`Tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, and
`bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These
`effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of
`
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`Ex. 1061-0005
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`
`
`clinical importance, and are generally not a consideration for the discontinuation of epirubicin
`treatment.
`
`Late (i.e., Delayed) Events. Delayed cardiotoxicity usually develops late in the course of
`therapy with epirubicin or within 2 to 3 months after treatment termination, but later events
`several months to years after completion of treatment have also been reported. Delayed
`cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs
`and symptoms of congestive heart failure (CHF) such as dyspnea, pulmonary edema, dependent
`edema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm.
`Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and
`represents the cumulative dose-limiting toxicity of the drug.
`
`Cardiac function should be assessed before patients undergo treatment with epirubicin and must
`be monitored throughout therapy to minimize the risk of incurring severe cardiac impairment.
`The risk may be decreased through regular monitoring of LVEF during the course of treatment
`with prompt discontinuation of epirubicin at the first sign of impaired function. The appropriate
`quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes
`multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline
`cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended,
`especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO
`determinations of LVEF should be performed, particularly with higher, cumulative anthracycline
`doses. The technique used for assessment should be consistent throughout follow-up.
`
`Congestive heart failure and/or cardiomyopathy may be encountered several weeks after
`discontinuation of PHARMORUBICIN PFS therapy.
`
`Given the risk of cardiomyopathy, a cumulative dose of 900 to 1000 mg/m2 epirubicin should
`generally not be exceeded. Risk factors for cardiac toxicity include active or dormant
`cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area,
`previous therapy with other anthracyclines or anthracenediones, and concomitant use of other
`drugs with the ability to suppress cardiac contractility or cardiotoxic drugs. Anthracyclines
`including epirubicin should not be administered in combination with other cardiotoxic agents
`unless the patient’s cardiac function is closely monitored.
`
`Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents,
`especially those with long half-lives such as trastuzumab, may also be at an increased risk of
`developing cardiotoxicity. The reported half-life of trastuzumab is approximately 28-38 days
`and may persist in the circulation for up to 27 weeks. Therefore, physicians should avoid
`anthracycline-based therapy for up to 27 weeks after stopping trastuzumab when possible. If
`anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
`
`Cardiac function monitoring must be particularly strict in patients receiving high cumulative
`doses and in those with risk factors. While cardiotoxicity with epirubicin may occur at lower
`cumulative doses whether or not cardiac risk factors are present, it may be more likely to occur at
`lower cumulative doses in patients with these risk factors.
`
`
`PHARMORUBICIN PFS (epirubicin hydrochloride injection) Product Monograph
`
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`
`Ex. 1061-0006
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`

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`
`
`Available evidence appears to indicate that cardiotoxicity is cumulative across members of the
`anthracycline and anthracene class of drugs. Patients who have previously received other
`anthracyclines and anthracenes are at particular risk for possible cardiotoxic effects of
`PHARMORUBICIN PFS at a lower total dose than previously untreated patients and, therefore,
`should be carefully monitored. The total dose of PHARMORUBICIN administered to a patient
`should take into account: prior or concomitant therapy with related compounds such as
`doxorubicin and daunorubicin or anthracene derivatives; and/or radiotherapy to the mediastinal
`area.
`
`Anthracycline-induced cardiac failure is often resistant to currently available therapeutic and
`physical measures used for the treatment of cardiac failure. Early clinical diagnosis of drug-
`induced heart failure is essential. Treatment measures include digitalis, diuretics, peripheral
`vasodilators, low salt diet, and bed rest. Severe cardiac toxicity may occur precipitously without
`antecedent EKG changes. An EKG, echocardiogram or radionuclide angiography (MUGA)
`performed at baseline and prior to each dose or course after a cumulative dose of 650 mg/m2 is
`suggested. Transient EKG changes consisting of T-wave flattening, S-T depression and
`arrhythmias occurring up to two weeks after a dose or course of PHARMORUBICIN PFS are
`presently not considered indications for suspension of PHARMORUBICIN PFS therapy.
`
`PHARMORUBICIN PFS cardiomyopathy has been reported to be associated with a reduction of
`the ejection fraction as determined by radionuclide scan or echocardiography. None of these tests
`have yet consistently identified those individual patients that are approaching their maximally
`tolerated cumulative dose of PHARMORUBICIN PFS. If test results indicate a change in
`cardiac status associated with PHARMORUBICIN PFS therapy, the benefit of continued therapy
`must be carefully weighed against the risk of producing irreversible cardiac damage.
`
`Hematologic Toxicity:
`
`Careful hematologic monitoring is required since bone marrow depression, primarily of
`leukocytes may occur. Hematologic profiles should be assessed before and during each cycle of
`therapy with epirubicin, including differential white blood cell counts (WBC).
`
`With the recommended dosage schedule (see DOSAGE AND ADMINISTRATION) leukopenia
`is transient, reaching its nadir 10-14 days after treatment, with recovery usually occurring by the
`21st day. White blood cell counts as low as 1000/mm3 are to be expected during treatment with
`PHARMORUBICIN PFS.
`
`Red blood cell and platelet levels should be monitored since they may also be depressed.
`Haematologic
`toxicity may
`require dose
`reduction or delay or
`suspension of
`PHARMORUBICIN PFS therapy. Persistent myelosuppression may result in infection or
`haemorrhage.
`
`PHARMORUBICIN PFS may potentiate the toxicity of other anticancer therapies as well as
`radiation induced toxicity to the myocardium, mucosa and skin. Patients should recover from
`
`
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`
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`Ex. 1061-0007
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`

`
`
`
`acute toxicities (such as stomatitis, neutropenia, thrombocytopenia and generalized infections) of
`prior cytotoxic treatment before beginning treatment with PHARMORUBICIN PFS.
`
`While treatment with high doses of epirubicin (e.g., > 90 mg/m2 every 3 to 4 weeks) causes
`adverse events generally similar to those seen at standard doses (< 90 mg/m2 every 3 to 4 weeks),
`the severity of the neutropenia and stomatitis/mucositis may be increased. Treatment with high
`doses of the drug does require special attention for possible clinical complications due to
`profound myelosuppression.
`
`Immunosuppressant Effects/Increased Susceptibility to Infections
`
`Administration of live or live-attenuated vaccines in patients immunocompromised by
`chemotherapeutic agents including epirubicin, may result in serious or fatal infections.
`Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or
`inactivated vaccines may be administered; however, the response to such vaccines may be
`diminished
`
`Liver Function:
`
`Epirubicin is extensively metabolized by the liver and its major route of elimination is the
`hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and
`during treatment with epirubicin. Patients with elevated bilirubin or AST may experience slower
`clearance of drug with an increase in overall toxicity. Lower doses are recommended in these
`patients (see DOSAGE AND ADMINISTRATION). Patients with severe hepatic impairment
`should not receive epirubicin (see CONTRAINDICATIONS).
`
`Renal Function:
`
`Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary
`in patients with serum creatinine > 5 mg/dL (see DOSAGE AND ADMINISTRATION).
`
`
`
`PHARMORUBICIN PFS (epirubicin hydrochloride injection) Product Monograph
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`Page 8 of 42
`
`Ex. 1061-0008
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`

`
`
`
`Secondary Leukemia:
`
`The occurrence of secondary acute myeloid leukemia (AML) with or without a preleukemic
`phase (myelodysplastic syndrome or MDS) has been reported in patients treated with epirubicin-
`containing regimens. Such cases could have a short (1-3 years) latency period (see below and in
`Table 2 under ADVERSE REACTIONS).
`
`The quantified risk of developing acute myeloid leukemia (AML), including myelodysplastic
`syndrome (MDS), following epirubicin or epirubicin-containing therapy, has been estimated by
`analyzing data collected prospectively from 19 randomized trials for the adjuvant treatment of
`early breast cancer, that were either company-sponsored or conducted by independent
`institutions (including the National Institute of Canada's MA.5 trial, see CLINICAL TRIALS,
`Early Stage Breast Cancer Studies). As of 31 December 2001, 28 (0.39%) of the 7,110 evaluable
`patients treated with epirubicin, had presented with either AML or MDS. An additional 4
`patients were diagnosed with other types of leukemia: 3 with acute lymphoblastic leukemia
`(ALL), and 1 with chronic lymphocytic leukemia (CLL). The time elapsed from the start of
`adjuvant treatment to the diagnosis of AML/MDS ranged from 8 to 126 months, with a median
`of 33 months. Of the 23 cases of AML/MDS for whom cytogenetic information was available,
`in 12 there was evidence of balanced chromosome translocations, and in 7 these translocations
`involved chromosome 11 or 21. Therapy-induced leukemia secondary to topoisomerase
`inhibitors generally has a short induction period (6 months to 5 years) and is known to be
`associated with translocations involving chromosome 11 or 21.
`
`In this most recent analysis, the cumulative risk of developing AML/MDS in the 7,110 patients
`treated with epirubicin was 0.27% (95% confidence interval 0.14%, 0.40%) at 3 years, 0.46%
`(95% confidence interval 0.28%, 0.65%) at 5 years, and 0.55% (95% confidence interval, 0.33%,
`0.78%) at 8 years. AML/MDS rates increased with epirubicin dose per cycle, and cumulative
`dose. For instance, in the MA.5 trial, in patients that received intensive doses of epirubicin (120
`mg/m2), the incidence of AML/MDS was 1.1% at 5 years with no additional cases observed
`during the second 5 years (years 6-10) of follow-up.
`
`Since the completion of these analyses, in the period up to and including September 2003,
`further spontaneous, literature and study reports of AML/MDS have been received.
`
`In addition, in 10 trials for the treatment of advanced breast cancer (3061 patients, follow-up
`until March 1999), two cases of AML occurred. However, due to the small number of cases and
`the limited follow-up as a result of the natural history of advanced breast cancer in these patients,
`risk estimates could not be made for this patient population.
`
`General:
`
`PHARMORUBICIN PFS must not be administered by intramuscular or subcutaneous injection.
`
`Severe local tissue necrosis can occur if PHARMORUBICIN PFS is extravasated during
`intravenous administration. Extravasation may occur with or without an accompanying stinging
`
`
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`

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`
`
`
`or burning sensation even if blood returns well on aspiration of the infusion needle (see
`DOSAGE AND ADMINISTRATION). If signs or symptoms of extravasation occur the injection
`or infusion should be terminated immediately and restarted in another vein.
`
`As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including
`pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of
`epirubicin.
`
`PHARMORUBICIN PFS is mutagenic, clastogenic, and carcinogenic in animals and has been
`associated with an increased risk of secondary leukemia (AML) in clinical trials of adjuvant
`treatment of breast cancer (see ADVERSE REACTIONS). In addition, epirubicin could induce
`chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin should
`use effective contraceptive methods.
`
`Epirubicin may cause amenorrhea or premature menopause in premenopausal women.
`
`PHARMORUBICIN PFS imparts a red colouration to the urine for 1 or 2 days after
`administration. Patients should be advised to expect this during active therapy.
`
`Usage in Pregnancy:
`
`There is no conclusive information about epirubicin adversely affecting human fertility, or
`causing teratogenesis; however, at high doses PHARMORUBICIN PFS is embryotoxic and
`teratogenic in rats and embryotoxic and abortifacient in rabbits. There are no studies in pregnant
`women. Therefore, women of childbearing potential should be advised to avoid becoming
`pregnant during treatment and should use effective contraceptive methods.
`
`Epirubicin should be used during pregnancy only if the potential benefit justifies the potential
`risk to the fetus. If PHARMORUBICIN PFS is to be used during pregnancy, or if the patient
`becomes pregnant during therapy, the patient should be informed of the potential hazard to the
`fetus. Mothers should be advised not to breast-feed while undergoing chemotherapy with
`PHARMORUBICIN PFS.
`
`
`
`Monitoring and Laboratory Tests:
`
`Initial treatment with PHARMORUBICIN PFS requires close observation of the patient and
`extensive laboratory monitoring. Like other cytotoxic drugs, PHARMORUBICIN PFS may
`induce hyperuricemia secondary to rapid lysis of neoplastic cells. The physician should monitor
`the patient's serum chemistry and blood uric acid level and be prepared to institute appropriate
`measures that might be necessary to control this problem. Hydration, urine alkalinization, and
`prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of
`tumor-lysis syndrome.
`
`PHARMORUBICIN PFS is not an anti-microbial agent.
`
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`
`
`Information to be given to the patient:
`
`Patients should be counseled about the known adverse effects that they could experience during
`chemotherapy with PHARMORUBICIN PFS, including cardiotoxicity, myelosuppression and
`risk of infection, thrombocytopenia, anemia, nausea, vomiting, and stomatitis.
`
`Physicians should also clearly lay out early on the risks and benefits of the various
`chemotherapeutic options available, thus enabling the patient to make an informed treatment
`choice. Patients should be aware that higher dose regimens may have a greater toxicity that
`includes secondary leukemia. Wherever possible, the physician should discuss the information
`presented in the ‘CONSUMER INFORMATION’ section.
`
`ADVERSE REACTIONS
`
`Dose limiting toxicities are myelosuppression and cardiotoxicity (see WARNINGS AND
`PRECAUTIONS). Other reactions reported are:
`
`Cutaneous - Reversible partial or complete alopecia occurs in most patients. Alopecia and lack
`of beard growth in males are usually reversible. Recall of skin reaction associated with prior
`radiotherapy may occur with PHARMORUBICIN PFS (epirubicin hydrochloride injection)
`administration. Local toxicity, rash/itch and skin changes may also occur.
`
`Gastrointestinal - Acute nausea and vomiting occurs frequently in most patients. This may be
`alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) has been reported to
`occur 5-10 days after administration. This may lead to ulceration and represents a site of origin
`for severe infections. Diarrhea has been reported. Most patients recover from this adverse event
`by the third week of therapy.
`
`Local - Severe cellulitis, vesication,
`if
`tissue necrosis can occur
`local pain and
`PHARMORUBICIN PFS
`is extravasated during administration (see DOSAGE AND
`ADMINISTRATION). Erythematous streaking and/or transient urticaria along the vein proximal
`to the site of administration may occur. Venous sclerosis may result from injection into small
`veins or repeated injection into the same vein. Following the recommended administration
`procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see
`SPECIAL HANDLING INSTRUCTIONS).
`
`Haematological
`leukopenia and/or granulocytopenia
`reversible
`- A dose-dependent,
`(neutropenia) are the predominant manifestations of epirubicin bone marrow/haematologic
`toxicity and represents the acute dose-limiting toxicity of this drug. Leukopenia and neutropenia
`are usually more severe after administration of high-dose regimens; under these conditions
`appropriate bone marrow support (eg. peripheral blood progenitor cells and/or colony-
`stimulating factors) may be required. Thrombocytopenia, anemia, pancytopenia, neutropenia and
`febrile neutropenia may also occur. Clinical consequences of severe myelosuppression include
`fever, infection, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.
`
`
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`
`
`Secondary Leukemia: see WARNINGS AND PRECAUTIONS.
`
`
`
`Body as a Whole - Phlebitis, thromboembolism, sepsis/septicemia, septic shock, fever and
`malaise/asthenia have been reported following administration of PHARMORUBICIN PFS.
`
`Drug-related adverse events also occurred in the following systems:
`
`Endocrine – amenorrhea and hot flashes
`
`Cardiovascular – asymptomatic drops in left ventricular ejection fraction and congestive heart
`failure, ventricular tachycardia, bradycardia, atrioventricular (AV) block, bundle branch block
`
`Ocular – conjunctivitis, keratitis
`
`Other - infection, pneumonia, acute lymphocytic leukemia, acute myelogenous leukemia,
`hyperuricemia
`
`Adverse Reactions in Early Breast Cancer Adjuvant Treatment:
`
`On-Study Events
`Integrated safety data are available from two studies (Studies MA.5 and GFEA-05 (FASG-05),
`see CLINICAL TRIALS, Early Stage Breast Cancer Studies) evaluating epirubicin-containing
`combination regimens in patients with early breast cancer. Of the 1260 patients treated in these
`studies, 620 patients received the higher-dose epirubicin regimen (FEC-100/CEF-120), 280
`patients received the lower-dose epirubicin regimen (FEC-50), and 360 patients received CMF.
`Serotonin-specific anti-emetic therapy and colony-stimulating factors were not used in these
`trials. Clinically relevant acute adverse events are summarized in Table 1.
`
`
`
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`
`Table 1. Clinically Relevant Acute Adverse Events in Patients with Early Breast Cancer
`
`
`
`
`
`Event
`
`
`
`FEC-100/CEF-120
`(N = 620)
`Grades
`Grades
`1-4
`3/4
`
`
`
`58.6
`67.2
`5.8
`5.4
`
`0
`4.0
`
`1.9
`0
`
`25.0
`8.9
`0.8
`0
`
`1.6
`6.1
`
`0
`
`% of Patients
`FEC-50
`(N = 280)
`Grades
`Grades
`1-4
`3/4
`
`
`
`49.6
`53.9
`12.9
`4.6
`
`69.3
`5.4
`
`1.1
`1.4
`
`83.2
`9.3
`7.1
`1.8
`
`15.0
`0
`
`1.1
`
`1.5
`10.5
`0
`0
`
`0
`0
`
`0
`0
`
`22.1
`0
`0
`0
`
`0
`0
`
`0
`
`19.3
`0.4
`0
`0
`
`CMF
`(N = 360)
`Grades
`Grades
`1-4
`3/4
`
`
`
`98.1
`95.8
`70.9
`51.4
`
`67.7
`69.1
`
`72.7
`4.5
`
`85.0
`52.9
`50.7
`5.8
`
`25.9
`NA
`
`38.4
`
`84.4
`8.1
`14.2
`7.2
`
`60.3
`78.1
`0.9
`3.6
`
`0
`6.4
`
`0.3
`0
`
`6.4
`1.9
`2.8
`0.3
`
`0.6
`1.1
`
`0
`
`6.7
`0
`0
`0
`
`Haematologic
`80.3
`Leukopenia
`80.3
`Neutropenia
`72.2
`Anemia
`48.8
`Thrombocytopenia
`Endocrine
`
`71.8
`Amenorrhea
`38.9
`Hot flashes
`Body as a Whole
`
`45.8
`Lethargy
`5.2
`Fever
`Gastrointestinal
`
`92.4
`Nausea/vomiting
`58.5
`Mucositis
`24.8
`Diarrhea
`2.9
`Anorexia
`Infection
`
`21.5
`Infection
`NA
`Febrile neutropenia
`Ocular
`
`14.8
`Conjunctivitis/keratitis
`Skin
`
`69.6
`56.6
`95.5
`Alopecia
`2.5
`0.3
`19.5
`Local toxicity
`1.4
`0.3
`8.9
`Rash/itch
`0.7
`0
`4.7
`Skin changes
`cyclophosphamide + epirubicin + fluorouracil
`FEC & CEF =
`CMF = cyclophosphamide + methotrexate + flurouracil
`NA = not available
`Grade 1 or 2 changes in transaminase levels were observed but were more frequently seen with CMF than with CEF.
`
`Delayed Events
`Table 2 describes the incidence of delayed adverse events in patients participating in the MA.5
`and GFEA-05 (FASG-05) trials.
`
`
`
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`
`Page 13 of 42
`
`Ex. 1061-0013
`
`

`
`Table 2. Long-term Adverse Events in Patients with Early Breast Cancer (5-year follow-up
`data)*
`
`
`
`
`
`Event
`
`Cardiac events
`Asymptomatic drops in
`LVEF
`CHF
`AML/MDS
`AML
`MDS
`
`FEC-100/CEF-120
`(N=620)
`
`1.8
`
`
`
`1.5
`
`0.8
`0
`
`% of Patients
`FEC-50
`(N=280)
`
`1.4
`
`0.4
`
`0
`0
`
`CMF
`(N=360)
`
`0.8
`
`
`
`0.3
`
`0.3
`0
`
`Page 14 of 42
`
`
`*In study MA.5 cardiac function was not monitored after 5 years. In study GFEA-05 (FASG-05) monitoring of
`cardiac function was optional.
`
`Within the first 5 year follow-up period, two cases of acute lymphoid leukemia (ALL) were also
`observed in patients receiving epirubicin. However, an association between anthracyclines such
`as epirubicin and ALL has not been clearly established.
`
`Over the 10 year follow-up period for study GFEA-05 (FASG-05), the overall incidence of
`cardiac events in patients treated with FEC-100 remained similar to that reported in patients
`receiving FEC-50. There were, however, two new cases of decreased left ventricular ejection
`fraction reported in FEC-100 treated patients. Therefore, the incidence of decreased left
`ventricular ejection fraction was 1.1 % (3/280) in the FEC-50 group and 3% (8/266) in the FEC-
`100 group. No new cases of delayed CHF were reported. Thus the frequency of CHF remains at
`0.4% (1/280) in the FEC-50 and at 1.1% (3/266) in the FEC-100 group. In a subset of patients
`from this study who were without disease at median follow up time of 102 months, a subsequent
`analysis of long term cardiac function identified 2 patients with CHF amongst the 85 FEC-100
`patients evaluated (see reference 72). Cardiac function was not monitored after 5 years in MA.5
`study.
`
`No new cases of secondary leukemia were reported in the 10 year follow up for both MA.5 and
`GFEA-05 (FASG-05) trials.
`
`Postmarketing Surveillance:
`
`The following adverse reactions have been derived from spontaneous case reports, literature
`cases and clinical studies. The criteria for including these adverse reactions is based on the
`seriousness. Because these reactions are reported voluntarily from a population of uncertain size,
`it is not always possible to reliably estimate their frequency or establish a causal relationship to
`drug exposure.
`
`Cardiac disorders: Myocardial infarction
`
`Infections and infestations: sepsis/septic shock, pneumonia
`
`PHARMORUBICIN PFS (epirubicin hydrochloride injection) Product Monograph
`
`Ex. 1061-0014
`
`

`
`
`
`Metabolism and nutrition disorders: hyperuricemia
`
`Vascular disorders: haemorrhage, embolism arterial
`
`Respiratory, thoracic and mediastinal disorders: interstitial lung disease, pulmonary embolism
`
`Gastrointestinal: pain or burning sensation, erythema, erosions, ulcerations, bleeding,
`dehydration, hyperpigmentation of the oral mucosa
`
`Cutaneous: flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to
`irradiated skin (radiation-recall reaction)
`
`Hypersensitivity Reactions: urticaria, anaphylaxis, fever, chills, shock
`
`Vascular: phlebitis, thrombophlebitis
`
`Urological: red colouration of urine for 1 to 2 days after administration
`
`DRUG INTERACTIONS
`
`Epirubicin is mainly used in combination with other cytotoxic drugs. Additive toxicity may
`occur especially with regard to bone marrow/haematologic and gastro-intestinal effects (see
`WARNINGS AND PRECAUTIONS). The use of epirubicin in combination chemotherapy with
`other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive
`compounds (e.g., calcium channel blockers), requires monitoring of cardiac function throughout
`treatment.
`
`Cimetidine