-----------------------DOSAGE AND ADMINISTRATION-----------------------
`Administer DOXIL at an initial rate of 1 mg/min to minimize the risk of
`infusion reactions. If no infusion related reactions occur, increase rate of
`infusion to complete administration over 1 hour. Do not administer as bolus
`injection or undiluted solution (2.1).
`• Ovarian cancer: 50 mg/m2 IV every 4 weeks for 4 courses minimum (2.2)
`• AIDS-related Kaposi’s Sarcoma: 20 mg/m2 IV every 3 weeks (2.3)
`• Multiple Myeloma: 30 mg/m2 IV on day 4 following bortezomib which is
`administered at 1.3 mg/m2 bolus on days 1, 4, 8 and 11, every 3 weeks (2.4)
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`Single dose vial: 20 mg/10 mL and 50 mg/30 mL (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`• Hypersensitivity reactions to a conventional formulation of doxorubicin
`HCl or the components of DOXIL (4, 5.2)
`• Nursing mothers (4, 8.3)
`---------------------------WARNINGS AND PRECAUTIONS--------------------
`• Hand-Foot Syndrome may occur. Dose modification or discontinuation
`may be required (5.4)
`• Radiation recall reaction may occur (5.5)
`------------------------------ADVERSE REACTIONS------------------------------
`Most common adverse reactions (>20%) are asthenia, fatigue, fever, anorexia,
`nausea, vomiting, stomatitis, diarrhea, constipation, hand and foot syndrome,
`rash, neutropenia, thrombocytopenia and anemia (6).
`
`To report SUSPECTED ADVERSE REACTIONS contact Ortho Biotech
`Products, LP at (888) 227-5624 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`---------------------------------DRUG INTERACTIONS----------------------------
`• DOXIL may interact with drugs known to interact with conventional
`formulations of Doxorubicin HCl. (7)
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`• DOXIL can cause fetal harm when used during pregnancy. (5.6, 8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 05/2007
`
`6 AD ERSE REACTIONS
`V
`6.1 Overall Adverse Reactions Profile
`6.2 Adverse Reactions in Clinical Trials
`6.3 Post Marketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFI
` POPULATIONS
`C
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NON CLINICAL TOXICOLOGY
`-
`13.1 Carcinogenesis, Mutagenesis, and Impairment of
`Fertility
`14 CLINICAL STUDIES
`14.1 Ovarian Cancer
`14.2 AIDS-Related Ka osi’s Sarcoma
`p
`14.3 Multiple Myeloma
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use DOXIL
`safely and effectively. See full prescribing information for DOXIL.
`DOXIL® (doxorubicin HCl liposome injection) for intravenous infusion
`Initial U.S. Approval: 1995
`
`WARNING: INFUSION REACTIONS, MYELOSUPPRESSION,
`CARDIOTOXICITY, LIVER IMPAIRMENT, SUBSTITUTION
`See full prescribing information for complete boxed warning.
`• Myocardial damage may lead to congestive heart failure and may
`occur as the total cumulative dose of doxorubicin HCl approaches 550
`mg/m2. Cardiac toxicity may also occur at lower cumulative doses with
`mediastinal irradiation or concurrent cardiotoxic agents (5.1).
`• Acute infusion-related reactions, sometimes reversible upon
`terminating or slowing infusion, occurred in up to 10% of patients.
`Serious and sometimes fatal allergic/anaphylactoid-like infusion
`reactions have been reported. Medications/emergency equipment to
`treat such reactions should be available for immediate use (5.2).
`• Severe myelosuppression may occur (5.3)
`• Reduce dosage in patients with impaired hepatic function (2.6).
`• Accidental substitution of DOXIL resulted in severe side effects. Do
`not substitute on mg per mg basis with doxorubicin HCl (2.1).
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indications and Usage, Multiple Myeloma (1.3)
`
`5/2007
`Dosage and Administration, Multiple Myeloma (2.4)
`
`5/2007
`----------------------------INDICATIONS AND USAGE----------------------------
`DOXIL is an anthracycline topoisomerase inhibitor indicated for:
`• Ovarian cancer (1.1)
`After failure of platinum-based chemotherapy.
`• AIDS-related Kaposi’s Sarcoma (1.2)
`After failure of prior combination chemotherapy or intolerance to such
`therapy. Results are based on objective response rate; no results are available
`from controlled trials that demonstrate clinical benefit.
`• Multiple Myeloma (1.3)
`In combination with bortezomib in patients who have not previously received
`bortezomib and have received at least one prior therapy.
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING-- INFUSION REACTIONS, MYELOSUPPRESSION,
`CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL
`SUBSTITUTION
`
`INDICATIONS AND USAGE
`1.1 Ovarian Cancer
`1.2 AIDS-Related Ka osi’s Sarcoma
`p
`1.3 Multiple Myeloma
`2 DOSAGE AND ADMINISTRATION
`2.1 Usage and Administration Precautions
`2.2 Patients With Ovarian Cancer
`2.3 Patients With AIDS-Related Kaposi’s Sarcoma
`2.4 Patients With Multiple Myeloma
`2.5 Dose Modification Guidelines
`2.6 Patients With Impaired Hepatic Function
`2.7 Preparation for Intravenous Administration
`2.8 Procedure for Proper Handling and Disposal
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WA
`S AND PRECAUTIONS
`RNING
`5.1 Cardiac Toxicity
`5.2
`Infusion Reactions
`5.3 Myelosuppression
`5.4 Hand-Foot Syndrome (HFS)
`5.5 Radiation Recall Reaction
`5.6 Fetal Mortality
`5.7 Toxicity Potentiation
`5.8 Monitoring: Laboratory Tests
`
` 1
`
`
`
`1
`
`ARBUTUS - EXHIBIT 2034
`Moderna Therapeutics, Inc. v. Arbutus Biopharma Corporation
`IPR2019-00554
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY,
`LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION
`1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity.
`Myocardial damage may lead to congestive heart failure and may occur as the total
`cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in
`patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of
`50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2
`or between 500-550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL
`was 11%. Prior use of other anthracyclines or anthracenediones should be included in
`calculations of total cumulative dosage. Cardiac toxicity may also occur at lower
`cumulative doses in patients with prior mediastinal irradiation or who are receiving
`concurrent cyclophosphamide therapy [see Warnings and Precautions (5.1)].
`2. Acute infusion-related reactions including, but not limited to, flushing, shortness of
`breath, facial swelling, headache, chills, back pain, tightness in the chest or throat,
`and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In
`most patients, these reactions resolve over the course of several hours to a day once the
`infusion is terminated. In some patients, the reaction has resolved with slowing of the
`infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-
`like infusion reactions have been reported. Medications to treat such reactions, as well
`as emergency equipment, should be available for immediate use. DOXIL should be
`administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions
`[see Warnings and Precautions (5.2)].
`3. Severe myelosuppression may occur [see Warnings and Precautions (5.3)].
`4. Dosage should be reduced in patients with impaired hepatic function [see Dosage and
`Administration (2.6) and Use in Specific Populations (8.6)].
`5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side
`effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis
`[see Dosage and Administration (2.1)].
`
`INDICATIONS AND USAGE
`1
`1.1 Ovarian Cancer
`DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with
`ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.
`
`1.2 AIDS-Related Kaposi’s Sarcoma
`DOXIL is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients with
`disease that has progressed on prior combination chemotherapy or in patients who are intolerant
`to such therapy.
`
`
`
`2
`
`

`

`
`
`The treatment of patients with AIDS-related Kaposi’s sarcoma is based on objective tumor
`response rates. No results are available from controlled trials that demonstrate a clinical benefit
`resulting from this treatment, such as improvement in disease-related symptoms or increased
`survival.
`
`1.3 Multiple Myeloma
`DOXIL in combination with bortezomib is indicated for the treatment of patients with
`multiple myeloma who have not previously received bortezomib and have received at least one
`prior therapy.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Usage and Administration Precautions
`Liposomal encapsulation can substantially affect a drug’s functional properties relative to
`those of the unencapsulated drug. Therefore DO NOT SUBSTITUTE one drug for the other.
`
`Do not administer as a bolus injection or an undiluted solution. Rapid infusion may
`increase the risk of infusion-related reactions [see Warnings and Precautions (5.2)]. DOXIL
`must not be given by the intramuscular or subcutaneous route.
`
`Until specific compatibility data are available, it is not recommended that DOXIL be mixed
`with other drugs.
`
`DOXIL should be considered an irritant and precautions should be taken to avoid
`extravasation. With intravenous administration of DOXIL, extravasation may occur with or
`without an accompanying stinging or burning sensation, even if blood returns well on aspiration
`of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion
`should be immediately terminated and restarted in another vein. The application of ice over the
`site of extravasation for approximately 30 minutes may be helpful in alleviating the local
`reaction.
`
`2.2 Patients With Ovarian Cancer
`DOXIL (doxorubicin HCl liposome injection) should be administered intravenously at a
`dose of 50 mg/m2 (doxorubicin HCl equivalent) at an initial rate of 1 mg/min to minimize the
`risk of infusion reactions. If no infusion-related adverse reactions are observed, the rate of
`infusion can be increased to complete administration of the drug over one hour. The patient
`should be dosed once every 4 weeks, for as long as the patient does not progress, shows no
`evidence of cardiotoxicity [see Warnings and Precautions (5.1)], and continues to tolerate
`treatment. A minimum of 4 courses is recommended because median time to response in clinical
`trials was 4 months. To manage adverse reactions such as hand-foot syndrome (HFS), stomatitis,
`
`
`
`3
`
`

`

`
`or hematologic toxicity the doses may be delayed or reduced [see Dosage and Administration
`(2.5)]. Pretreatment with or concomitant use of antiemetics should be considered.
`
`2.3 Patients With AIDS-Related Kaposi’s Sarcoma
`DOXIL (doxorubicin HCl liposome injection) should be administered intravenously at a
`dose of 20 mg/m2 (doxorubicin HCl equivalent). An initial rate of 1 mg/min should be used to
`minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are
`observed, the infusion rate should be increased to complete the administration of the drug over
`one hour. The dose should be repeated once every three weeks, for as long as patients respond
`satisfactorily and tolerate treatment.
`
`2.4 Patients With Multiple Myeloma
`Bortezomib is administered at a dose of 1.3 mg/m2 as intravenous bolus on days 1, 4 , 8 and
`11, every three weeks. DOXIL 30 mg/m2 should be administered as a 1-hr intravenous infusion
`on day 4 following bortezomib. With the first DOXIL dose, an initial rate of 1 mg/min should be
`used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions
`are observed, the infusion rate should be increased to complete the administration of the drug
`over one hour. Patients may be treated for up to 8 cycles until disease progression or the
`occurrence of unacceptable toxicity.
`
`2.5 Dose Modification Guidelines
`DOXIL exhibits nonlinear pharmacokinetics at 50 mg/m2; therefore, dose adjustments may
`result in a non-proportional greater change in plasma concentration and exposure to the drug
`[see Clinical Pharmacology (12.3)].
`
`Patients should be carefully monitored for toxicity. Adverse reactions, such as HFS,
`hematologic toxicities, and stomatitis may be managed by dose delays and adjustments.
`Following the first appearance of a Grade 2 or higher adverse reactions, the dosing should be
`adjusted or delayed as described in the following tables. Once the dose has been reduced, it
`should not be increased at a later time.
`
`
`
`4
`
`

`

`
`
`Recommended Dose Modification Guidelines
`Table 1: Hand-Foot Syndrome (HFS)
`Toxicity Grade
`Dose Adjustment
`Redose unless patient has experienced previous Grade 3 or 4 HFS. If
`1
`(mild erythema, swelling,
`so, delay up to 2 weeks and decrease dose by 25%. Return to original
`or desquamation not
`dose interval.
`interfering with daily
`activities)
`
`2
`(erythema, desquamation,
`or swelling interfering
`with, but not precluding
`normal physical
`activities; small blisters
`or ulcerations less than
`2 cm in diameter)
`
`3
`(blistering, ulceration, or
`swelling interfering with
`walking or normal daily
`activities; cannot wear
`regular clothing)
`
`4
`(diffuse or local process
`causing infectious
`complications, or a bed
`ridden state or
`hospitalization)
`
`Delay dosing up to 2 weeks or until resolved to Grade 0-1. If after
`2 weeks there is no resolution, DOXIL should be discontinued. If
`resolved to Grade 0-1 within 2 weeks, and there are no prior Grade 3-4
`HFS, continue treatment at previous dose and return to original dose
`interval. If patient experienced previous Grade 3-4 toxicity, continue
`treatment with a 25% dose reduction and return to original dose interval.
`
`Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease
`dose by 25% and return to original dose interval. If after 2 weeks there is
`no resolution, DOXIL should be discontinued.
`
`Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease
`dose by 25% and return to original dose interval. If after 2 weeks there is
`no resolution, DOXIL should be discontinued.
`
`
`Table 2: Hematological Toxicity
`Grade
`ANC
`1
`1,500 – 1,900
`
`Platelets
`75,000 - 150,000
`
`2
`
`3
`
`4
`
`1,000 - <1,500
`
`50,000 - <75,000
`
`500 – 999
`
`25,000 - <50,000
`
`<500
`
`<25,000
`
`
`
`
`
`Modification
`Resume treatment with no dose
`reduction
`Wait until ANC > 1,500 and platelets
`> 75,000; redose with no dose reduction
`Wait until ANC > 1,500 and platelets
`> 75,000; redose with no dose reduction
`Wait until ANC > 1,500 and platelets
`> 75,000; redose at 25% dose reduction
`or continue full dose with cytokine
`support
`
`5
`
`

`

`
`Stomatitis
`Table 3:
`Toxicity Grade
`1
`(painless ulcers,
`erythema, or mild
`soreness)
`
`2
`(painful erythema,
`edema, or ulcers, but can
`eat)
`
`3
`(painful erythema,
`edema, or ulcers, and
`cannot eat)
`
`4
`(requires parenteral or
`enteral support)
`
`
`
`
`Dose Adjustment
`Redose unless patient has experienced previous Grade 3 or 4
`toxicity. If so, delay up to 2 weeks and decrease dose by 25%. Return to
`original dose interval.
`
`Delay dosing up to 2 weeks or until resolved to Grade 0-1. If after
`2 weeks there is no resolution, DOXIL should be discontinued. If
`resolved to Grade 0-1 within 2 weeks and there was no prior Grade 3-4
`stomatitis, continue treatment at previous dose and return to original
`dose interval. If patient experienced previous Grade 3-4 toxicity,
`continue treatment with a 25% dose reduction and return to original dose
`interval.
`
`Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease
`dose by 25% and return to original dose interval. If after 2 weeks there is
`no resolution, DOXIL should be discontinued.
`
`Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease
`dose by 25% and return to DOXIL original dose interval. If after
`2 weeks there is no resolution, DOXIL should be discontinued.
`
`Multiple Myeloma
`For patients treated with DOXIL in combination with bortezomib who experience hand-
`foot syndrome or stomatitis, the DOXIL dose should be modified as described in Tables 1 and 3
`above. Table 4 describes dosage adjustments for DOXIL and bortezomib combination therapy.
`For bortezomib dosing and dosage adjustments, see manufacturer’s prescribing information.
`
`
`
`6
`
`

`

`Dosage adjustments for DOXIL + bortezomib combination therapy
`Patient status
`DOXIL
`Do not dose this cycle if before
`Fever ≥38°C and
`Day 4; if after Day 4, reduce
`ANC <1,000/mm3
`next dose by 25%.
`
`Do not dose this cycle if before
`Day 4; if after Day 4 reduce next
`dose by 25% in the following
`cycles if bortezomib is reduced
`for hematologic toxicity.
`
`
`Table 4:
`
`On any day of drug
`administration after Day 1 of
`each cycle:
`Platelet count <25,000/mm3
`Hemoglobin <8g/dL
`ANC <500/mm3
`
`Grade 3 or 4 non-hematologic
`drug related toxicity
`
`Neuropathic pain or peripheral
`neuropathy
`
`
`
`bortezomib
`Reduce next dose by 25%
`
`Do not dose; if 2 or more doses are not
`given in a cycle, reduce dose by 25% in
`following cycles.
`
`Do not dose until recovered to
`Grade <2 and reduce dose by
`25% for all subsequent doses.
`
`No dosage adjustments.
`
`Do not dose until recovered to Grade <2
`and reduce dose by 25% for all
`subsequent doses.
`
`See bortezomib manufacturer’s
`prescribing information for dosage
`adjustments in patients with neuropathic
`pain.
`
`2.6 Patients With Impaired Hepatic Function
`Limited clinical experience exists in treating patients with hepatic impairment with
`DOXIL. Based on experience with doxorubicin HCl, it is recommended that the DOXIL dosage
`be reduced if the bilirubin is elevated as follows: serum bilirubin 1.2 to 3.0 mg/dL - give ½
`normal dose; serum bilirubin > 3 mg/dL - give ¼ normal dose.
`
`No information, including dosage adjustments, is available for patients with multiple
`myeloma with hepatic impairment.
`
`2.7 Preparation for Intravenous Administration
`Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL.
`
`Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.
`
`DOXIL doses up to 90 mg must be diluted in 250 mL of 5% Dextrose Injection, USP prior
`to administration. Doses exceeding 90 mg should be diluted in 500 mL of 5% Dextrose Injection,
`USP prior to administration. Aseptic technique must be strictly observed since no preservative or
`bacteriostatic agent is present in DOXIL. Diluted DOXIL should be refrigerated at 2°C to
`8°C (36°F to 46°F) and administered within 24 hours.
`
`Do not use with in-line filters.
`
`Do not mix with other drugs.
`
`
`
`7
`
`

`

`
`
`Do not use with any diluent other than 5% Dextrose Injection.
`
`Do not use any bacteriostatic agent, such as benzyl alcohol.
`
`DOXIL is not a clear solution but a translucent, red liposomal dispersion.
`
`Parenteral drug products should be inspected visually for particulate matter and
`discoloration prior to administration, whenever solution and container permit. Do not use if a
`precipitate or foreign matter is present.
`
`Rapid flushing of the infusion line should be avoided.
`
`2.8 Procedure for Proper Handling and Disposal
`Caution should be exercised in the handling and preparation of DOXIL.
`
`The use of gloves is required.
`
`If DOXIL comes into contact with skin or mucosa, immediately wash thoroughly with soap
`and water.
`
`DOXIL should be considered an irritant and precautions should be taken to avoid
`extravasation. With intravenous administration of DOXIL, extravasation may occur with or
`without an accompanying stinging or burning sensation, even if blood returns well on aspiration
`of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion
`should be immediately terminated and restarted in another vein. DOXIL must not be given by
`the intramuscular or subcutaneous route.
`
`DOXIL should be handled and disposed of in a manner consistent with other anticancer drugs.
`Several guidelines on this subject exist [see References (15)].
`
`3 DOSAGE FORMS AND STRENGTHS
`• 20 mg/10 mL single use vial
`• 50 mg/30 mL single use vial
`4 CONTRAINDICATIONS
`DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a
`history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the
`components of DOXIL [see Warnings and Precautions (5.2)].
`
`DOXIL is contraindicated in nursing mothers [see Use in Specific Populations (8.3)].
`
`
`
`8
`
`

`

`
`5 WARNINGS AND PRECAUTIONS
`5.1 Cardiac Toxicity
`Special attention must be given to the risk of myocardial damage from cumulative doses of
`doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in
`patients who have received a total cumulative dosage of doxorubicin exceeding the currently
`recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in
`patients who have received radiotherapy to the mediastinal area or concomitant therapy with
`other potentially cardiotoxic agents such as cyclophosphamide.
`
`Prior use of other anthracyclines or anthracenodiones should be included in calculations of
`total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after
`discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should
`be administered DOXIL only when the potential benefit of treatment outweighs the risk.
`
`Cardiac function should be carefully monitored in patients treated with DOXIL. The most
`definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods,
`such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac
`function during anthracycline therapy. Any of these methods should be employed to monitor
`potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible
`cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully
`weighed against the risk of myocardial injury.
`
`In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at
`starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between
`450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with
`DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline
`if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a
`decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of
`normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and
`congestive heart failure (CHF) are in the table below.
`
`Number of Patients With Advanced Breast Cancer
`
`Table 5:
`
`Patients who Developed Cardiotoxicity (LVEF Defined)
`
`Cardiotoxicity (With Signs & Symptoms of CHF)
`
`Cardiotoxicity (no Signs & Symptoms of CHF)
`Patients With Signs and Symptoms of CHF Only
`
`
`
`DOXIL (n=250)
`10
`0
`10
`2
`
`In the randomized multiple myeloma study, the incidence of heart failure events (ventricular
`dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac
`
`
`
`9
`
`

`

`
`failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib
`group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as
`an absolute decrease of ≥15% over baseline or a ≥5% decrease below the institutional lower limit
`of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in
`the DOXIL + bortezomib arm (13%) experienced a reduction in LVEF.
`
`5.2
`
`Infusion Reactions
`Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in
`the randomized ovarian cancer study. These reactions were characterized by one or more of the
`following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain,
`back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope,
`bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the
`course of several hours to a day once the infusion is terminated. In some patients, the reaction
`resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL
`(0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with
`AIDS-related Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL
`therapy because of infusion-related reactions.
`
`Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion
`reactions have been reported. Medications to treat such reactions, as well as emergency
`equipment, should be available for immediate use.
`
`The majority of infusion-related events occurred during the first infusion. Similar reactions
`have not been reported with conventional doxorubicin and they presumably represent a reaction
`to the DOXIL liposomes or one of its surface components.
`
`The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion
`reactions [see Dosage and Administration (2)].
`
`5.3 Myelosuppression
`Because of the potential for bone marrow suppression, careful hematologic monitoring is
`required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and
`Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic
`toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe
`myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development
`of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare
`cases, death.
`
`
`
`10
`
`

`

`
`
`DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic
`toxicity may be more severe when DOXIL is administered in combination with other agents that
`cause bone marrow suppression.
`
`In patients with relapsed ovarian cancer, myelosuppression was generally moderate and
`reversible. In the three single-arm studies, anemia was the most common hematologic adverse
`reaction (52.6%), followed by leukopenia (WBC< 4,000 mm3; 42.2%), thrombocytopenia
`(24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most
`common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3;
`36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse
`Reactions (6.2)].
`
`In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support
`their blood counts [see Dosage and Administrations (2.5)].
`
`For patients with AIDS-related Kaposi’s sarcoma who often present with baseline
`myelosuppression due to such factors as their HIV disease or concomitant medications,
`myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of
`20 mg/m2 [see Adverse Reactions (6.2)]. Leukopenia is the most common adverse reaction
`experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis
`occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably
`related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow
`suppression or neutropenia.
`
`Table 10 presents data on myelosuppression in patients with multiple myeloma receiving
`DOXIL and bortezomib in combination [see Adverse Reactions (6.2)].
`
`5.4 Hand-Foot Syndrome (HFS)
`In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50
`mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized
`by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and
`the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%)
`discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described
`above [see definitions of HFS grades in Dosage and Administration (2.5)].
`
`Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at
`20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing.
`
`In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30
`mg/m2 every three weeks experienced HFS.
`
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`HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most
`patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy
`need not occur. However, dose modification may be required to manage HFS [see Dosage and
`Administration (2.5)]. The reaction can be severe and debilitating in some patients and may
`require discontinuation of treatment.
`
`5.5 Radiation Recall Reaction
`Recall reaction has occurred with DOXIL administration after radiotherapy.
`
`5.6 Fetal Mortality
`Pregnancy Category D
`
`DOXIL can cause fetal harm when administered to a pregnant woman. There are no
`adequate and well-controlled studies in pregnant women. If DOXIL is to be used during
`pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of
`the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment
`with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing
`potential should be advised to avoid pregnancy during treatment with Doxil. [see Use in Specific
`Populations (8.1)].
`
`5.7 Toxicity Potentiation
`The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies.
`Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the
`hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of
`doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have
`been reported to be increased by the administration of doxorubicin HCl.
`
`5.8 Monitoring: Laboratory Tests
`Complete blood counts, including platelet counts, should be obtained frequently and at a
`minimum prior to each dose of DOXIL [see Warnings and Precautions (5.3)].
`
`6 ADVERSE REACTIONS
`6.1 Overall Adverse Reactions Profile
`The following adverse reactions are discussed in more detail in other sections of the
`labeling.
`
`• Cardiac Toxicity [see Warnings and Precautions (5.1)]
`•
`Infusion reactions [see Warnings and Precautions (5.2)]
`• Myelosuppression [see Warnings and Precautions (5.3)]
`
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`• Hand-Foot syndrome [see Warnings and Precautions (5.4)]
`The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever,
`nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and
`neutropenia, thrombocytopenia and anemia.
`
`The most common serious adverse reactions observed with DOXIL are described in
`Section 6.2.
`
`The safety data described below reflect exposure to DOXIL in 1310 patients including:
`239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and
`318 patients with multiple myeloma [see Adverse Reactions in Clinical Trials (6.2)].
`
`6.2 Adverse Reactions in Clinical Trials
`Because clinical trials are conducted under widely varying conditions, the adverse reaction
`rates observed cannot be directly compared to rates on other clinical trials and may not reflect the
`rates observed in clinical practice.
`
`The following tables present adverse reactions from clinical trials of DOXIL in ovarian
`cancer and AIDS-Related Kaposi’s sarcoma.
`
`Patients With Ovarian Cancer
`The safety data described below are from 239 patients with ovarian cancer treated with
`DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum
`of 4 courses in a randomized, multicenter, open-label study. In this study, patients received
`DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87
`years of age, 91% Caucasian, 6% Black and 3% Hispanic and othe