Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 For
Intravenous Use Only: Fatal if Given by Other
Routes
(Additions and/or revisions underlined)
Fatal if given by other
routes. Death has occurred with intrathecal use.
Marqibo (vinCRIStine
sulfate LIPOSOME injection) has different dosage recommendations than
vinCRIStine sulfate injection. Verify drug name and dose prior to preparation
and administration to avoid overdosage.
5.2 Extravasation
Tissue Injury
(Additions and/or revisions underlined)
Extravasation can occur
with Marqibo and extravasation causes tissue injury. Only administer through a secure and
free-flowing venous access line. If extravasation is suspected, discontinue
infusion immediately and consider local treatment measures.
5.3 Neurologic Toxicity
(Additions and/or revisions underlined)
Sensory and motor
neuropathies are common and are cumulative. Monitor patients for symptoms of peripheral
motor and sensory, central and autonomic neuropathy, such as hypoesthesia,
hyperesthesia, paresthesia, hyporeflexia, areflexia, neuralgia, jaw pain, decreased
vibratory sense, cranial neuropathy, ileus, burning sensation, arthralgia,
myalgia, muscle spasm, or weakness, both before and during treatment.
Orthostatic hypotension may occur. The risk of neurologic toxicity is greater
if Marqibo is administered to patients with preexisting neuromuscular disorders
or when other drugs with risk of neurologic toxicity are being given. In the
studies of relapsed and/or refractory adult ALL patients, Grade greater than or
equal to 3 neuropathy events occurred in 32.5% of patients.
Patients with
preexisting severe neuropathy should be treated with Marqibo only after careful
risk-benefit assessment. Interrupt, reduce the dose, or discontinue Marqibo
based on severity.
5.4 Myelosuppression
(Additions and/or revisions underlined)
Neutropenia,
thrombocytopenia, or anemia may occur with Marqibo. Monitor complete blood counts prior to each dose of
Marqibo. For Grade 3 or 4 neutropenia, thrombocytopenia, or anemia,
consider Marqibo dose delay or reduction, as well as supportive care
measures.
5.5 Tumor Lysis Syndrome
(Additions and/or revisions underlined)
Tumor lysis syndrome (TLS)
may occur in patients with ALL receiving Marqibo. Anticipate, monitor for, and
manage
as appropriate.
5.6 Constipation
and Bowel Obstruction
(Additions and/or revisions underlined)
Ileus, bowel obstruction,
and colonic pseudo-obstruction have occurred. Marqibo can cause constipation.
Institute a prophylactic
bowel regimen to mitigate potential constipation, bowel obstruction, and
paralytic ileus. Consider adequate dietary fiber intake, hydration, and stool
softeners. Use additional laxative products as needed.
5.7 Fatigue
(Additions and/or revisions underlined)
Marqibo can cause severe
fatigue. Consider dose delay, reduction, or discontinuation of
Marqibo as appropriate.
5.8 Hepatic Toxicity
(Additions and/or revisions underlined)
Fatal hepatic
toxicity and increased aspartate aminotransferase (AST) occurred.
Grade greater than or equal to 3 increased AST occurred in 6% to 11%
of patients in clinical trials. Monitor hepatic function tests. Interrupt or reduce the dose of Marqibo
as appropriate.
5.9 Embryo-Fetal Toxicity
(Additions and/or revisions underlined)
Based on findings from
nonclinical studies and the mechanism of action, Marqibo can cause fetal harm when administered to a
pregnant woman. In toxicology studies in rats, vincristine sulfate
liposome injection was teratogenic and caused embryo-fetal mortality
at exposures less than those reported in patients at the recommended
dose.
Advise pregnant women of the potential risk to a fetus. Advise
females of reproductive potential to use effective contraception during treatment
with Marqibo and for 6 months after the last dose. Advise males with female
partners of reproductive potential to use effective contraception during
treatment with Marqibo and for 3 months after the last dose.
6
Adverse Reactions
(Additions and/or revisions underlined)
The following clinically
significant adverse reactions are described elsewhere in the labeling:
For Intravenous Use Only
Extravasation Tissue Injury
Neurologic Toxicity
Myelosuppression
Tumor Lysis Syndrome
Constipation and Bowel
Obstruction
Fatigue
Hepatic Toxicity
6.1 Clinical
Trials Experience
(Additions and/or revisions underlined)
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in clinical
practice.
Acute Lymphoblastic
Leukemia
Relapsed or Refractory Philadelphia Chromosome
Negative ALL
The safety of Marqibo was evaluated in a total of 83 adults
in two trials: study 1 and study 2. Patients received Marqibo 2.25 mg/m2 once every
seven days. Adverse reactions were observed in 100% of patients. The most
common adverse reactions (>30%) were constipation (57%), nausea (52%),
pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia
(38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia
(32%).
Adverse reactions of Grade
3 or greater were reported in 96% of patients. Adverse reactions of Grade 3 or
greater and occurring in greater than or equal to 5% of patients are summarized
in Table 2.
A
total of 76% of patients experienced serious adverse reactions during
the studies. The most frequent serious adverse reactions included
febrile neutropenia (20%), pyrexia (13%), hypotension (7%), respiratory
distress (6%), and cardiac arrest (6%).
Twenty-eight
percent of patients experienced adverse reactions leading to treatment
discontinuation. The most frequent adverse reactions that caused
treatment discontinuation were peripheral neuropathy (10%),
leukemia-related (7%), and
tumor lysis syndrome (2%).
Dose
reduction, delay, or omission occurred in 53% of patients.
Adverse
reactions related to neuropathy and leading to treatment discontinuation were
decreased vibratory sense, facial palsy, hyporeflexia, constipation, asthenia,
fatigue, and musculoskeletal pain, each reported in at least 1 patient.
7
Drug Interactions
7.1 Effects of
Other Drugs on Marqibo
(Additions and/or revisions underlined)
Strong CYP3A Inhibitors
Concomitant use of
strong CYP3A4 inhibitors may increase the concentrations of vincristine, which
may increase the risk of adverse reactions. Avoid concomitant use of strong
CYP3A inhibitors.
Strong CYP3A Inducers
Concomitant use of
strong CYP3A4 inducers may decrease the concentrations of vincristine, which
may decrease antitumor activity. Avoid concomitant use of strong CYP3A
inducers.
P-glycoprotein
Inhibitors and Inducers
Concomitant use of
Marqibo with P-glycoprotein inhibitors or inducers may alter the
pharmacokinetics or pharmacodynamics of vincristine. Avoid the concomitant use
of P-gp inhibitors or inducers.
7.2 Effects of Marqibo on Other Drugs
(Additions and/or revisions underlined)
Phenytoin
Simultaneous oral or
intravenous administration of phenytoin and chemotherapy combinations that
included non-liposomal vincristine sulfate have been reported to reduce blood
levels of phenytoin and to increase seizure activity. Monitor phenytoin
blood levels and seizure activity as appropriate.
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR)
conversion; additions are/or revisions underlined)
Risk Summary
Based on findings from
nonclinical studies and its mechanism of action, Marqibo can cause fetal
harm when administered to a pregnant woman. There are insufficient data on
use of vincristine sulfate in pregnant women to evaluate for a drug-associated
risk. In animal reproduction studies, intravenous administration of vincristine
sulfate liposome injection to pregnant rats during organogenesis caused
adverse developmental outcomes including increased embryo-fetal mortality,
alterations to growth, and structural abnormalities. Advise pregnant women of the potential risk to a
fetus.
The estimated background
risk of major birth defects and miscarriage for the indicated population is
unknown.
All
pregnancies have a background risk of birth defect, loss, or other adverse
outcomes. In the U.S. general population, the estimated background risk of
major birth defects and miscarriage in clinically recognized pregnancies is 2%
to 4% and 15% to 20%, respectively.
Data
Animal Data
In
an embryo-fetal developmental study,
pregnant rats were administered vincristine sulfate liposome injection
intravenously during the period of organogenesis at vincristine sulfate doses
of 0.022 to 0.09 mg/kg/day...
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR)
conversion; additions are/or revisions underlined)
Risk Summary
There are no data on the presence of vincristine
sulfate or its metabolites in human milk
, the effects on the breastfed
child, or the effects on milk
production. Because of the potential
for serious adverse reactions in
a breastfed child, advise women not to
breastfeed
during treatment with Marqibo and for at least 1 week after the last dose.
8.3 Females and
Males of Reproductive Potential
(Newly added subsection)
Marqibo can cause fetal
harm when administered to a pregnant woman.
Pregnancy Testing
Verify the pregnancy status
in females of reproductive potential prior to initiating Marqibo.
Contraception
Females
Advise females of
reproductive potential to use effective contraception during treatment with
Marqibo and for 6 months after the last dose.
Males
Based on genotoxicity
findings with non-liposomal vincristine, advise males with female partners of
reproductive potential to use effective contraception during treatment with
Marqibo and for 3 months after the last dose.
Infertility
Based on findings in humans
with non-liposomal vincristine sulfate and in animals administered vincristine
sulfate liposome injection, Marqibo may impair fertility.
Gonadal dysfunction has
been reported in both male and female post-pubertal patients who received
multi-agent chemotherapy, including non-liposomal vincristine sulfate. The
degree to which testicular or ovarian functions are affected is age-, dose-,
and agent-dependent. Recovery may occur in some, but not all patients.
In animals, adverse effects
on male reproductive organs were not reversible after a recovery period.
8.5 Geriatric Use
(Additions and/or revisions underlined)
Of the total number of
patients in clinical studies of Marqibo, 11% were aged 65 years or older.
Clinical studies of Marqibo did not include sufficient numbers of patients aged
65 and older to determine whether they respond differently from younger
patients. In general,
dose selection for an elderly patient should be cautious, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
8.6 Hepatic Impairment
(Additions and/or revisions underlined)
Monitor patients closely
for adverse reactions, including hepatic toxicity. No dose adjustment is recommended
for patients with mild or moderate hepatic impairment. The influence of severe hepatic impairment on the exposure,
safety and efficacy of Marqibo has not been evaluated.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING
INFORMATION
(Additions and/or revisions underlined)
Healthcare providers are advised to discuss the following
with patients prior to treatment with Marqibo: Extravasation Tissue Injury
Neurologic
Toxicity and Fatigue
Advise
patients to contact their healthcare providers if they experience new or
worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness
in the feet or hands.
Marqibo
may cause fatigue and symptoms of peripheral neuropathy. Advise patients not to
drive or operate machinery if they experience any of these symptoms.
Constipation
and Bowel Obstruction
Myelosuppression
Instruct
patients to notify their healthcare providers if they experience fever,
productive cough, or decreased appetite.
Embryo-Fetal
Toxicity
Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive
potential to inform their healthcare provider of a known or suspected pregnancy.
Advise
females of reproductive potential to use effective contraception during
treatment with Marqibo and for 6 months after the last dose [see Use in Specific Populations (8.3)].
Advise males with female partners of reproductive
potential to use effective contraception during treatment with Marqibo and for
3 months after the last dose.
Lactation
Advise
women not to breastfeed during treatment with Marqibo and for 1 week after the
last dose.
Drug
Interactions
Advise
patients to inform their healthcare providers of all concomitant medications,
including prescription medicines, over-the-counter drugs, vitamins, and herbal
products.
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