Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia
Additions and/or
revisions underlined:
Myelodysplastic
Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with
RUBRACA, and are potentially fatal adverse reactions. In 2141 treated
patients with ovarian and prostate cancer [see Adverse Reactions (6.1)], MDS/AML occurred in 34
patients (1.6%), including those in long term follow-up. Of these, 14
occurred during treatment or during the 28-day safety follow-up (0.7%).
The duration of RUBRACA treatment prior to the diagnosis of MDS/AML ranged from
< 2 months to approximately 72 months. The cases were typical of secondary
MDS/cancer therapy-related AML; in all cases, patients had received previous
platinum-containing chemotherapy regimens and/or other DNA damaging agents.
In
ARIEL3, of patients with a germline and/or somatic BRCA mutation treated with RUBRACA, MDS/AML occurred in 9 out of
129 (7%) patients treated with RUBRACA and 4 out of 66 (6%) patients treated
with placebo. The duration of therapy with RUBRACA in patients who developed
secondary MDS/cancer therapy-related AML varied from 1.2 to 4.7 years.
In
TRITON3, MDS/AML occurred in 2 out of 201 patients (1%)
with a BRCA mutation treated with
RUBRACA. The duration of therapy with RUBRACA in patients who developed
secondary MDS/cancer therapy-related AML varied from 1.4 to 2.3 years.
…
6
Adverse Reactions
6.1 Clinical
Trials Experience
Extensive
changes; please refer to label for complete information
8
Use in Specific Populations
8.5 Geriatric Use
Additions and/or revisions underlined:
…
Of the 547 patients with mCRPC who received
RUBRACA in TRITON2 and TRITON3, 73% were age 65 or older and 31%
were 75 years or older. No major differences in safety were observed between younger
and older patients with mCRPC.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT
INFORMATION
Additions and/or revisions underlined:
…
Before you take
RUBRACA, tell your healthcare provider about all of your medical conditions,
including if you:
…
Females who are able to become
pregnant:
…
- Tell your healthcare provider right away if you
become pregnant or think you might be pregnant during treatment with
RUBRACA.
…
Tell your
healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and
herbal supplements. RUBRACA may affect the way other medicines work.
…
RUBRACA may cause
serious side effects.
See "What is
the most important information I should know about RUBRACA?"
…
The most common side effects of RUBRACA in people with
prostate cancer include:
tiredness or weakness
dizziness
muscle and joint pain
decreased weight
nausea
stomach area (abdominal)
pain
decrease in hemoglobin (anemia)
changes in how food tastes
decreased appetite
rash
changes in liver and kidney function tests
tingling sensation and
numbness
constipation
urinary tract infection
diarrhea
cough
vomiting
headache
low blood cell counts
bleeding
shortness of breath
reaction to sunlight
- swelling in your legs and
feet
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia
(AML) occur in patients treated with Rubraca, and are potentially fatal
adverse reactions. In 1594 treated
patients with ovarian
cancer [see Adverse Reactions
(6.1)], MDS/AML occurred in 32 patients
(2%), including those in long term follow-up. Of these, 14 occurred during treatment or during the 28-day safety follow-up (0.9%). The
duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from <
2 months to approximately 72
months. The cases were typical
of secondary MDS/cancer therapy-related AML; in all cases, patients had
received previous platinum-containing chemotherapy regimens and/or other DNA
damaging agents.
In ARIEL3, of patients with a germline and/or
somatic BRCA mutation treated with
Rubraca, MDS/AML occurred in 9 out of 129 (7%) patients
treated with Rubraca
and 4 out of 66 (6%) patients
treated with placebo.
The duration of therapy
with Rubraca in patients who developed secondary MDS/cancer therapy-related AML
varied from 1.2 to 4.7 years.
6
Adverse Reactions
6.1 Clinical Trials Experience
Extensive changes; please refer to label
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions and revisions underlined:
Rubraca is a prescription medicine used in adults for:
the maintenance treatment of ovarian cancer,
fallopian tube cancer,
or primary peritoneal cancer with a certain
type of inherited (germline) or acquired (somatic) abnormal BRCA gene when
your cancer has come back and you are in response (complete or
partial response) to a platinum-based chemotherapy.
The most common
side effects of Rubraca in people with ovarian cancer
include:
nausea · low blood cell
counts
tiredness or weakness · changes in how food tastes
decrease in hemoglobin (anemia) · shortness of breath
changes in liver and
kidney function tests · dizziness
vomiting · indigestion
diarrhea · reaction to sunlight
Approved Drug Label (PDF)
6
Adverse Reactions
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 practice.
The pooled safety
population in the WARNINGS AND PRECAUTIONS section
reflect exposure to Rubraca at 600 mg BID in 1146 patients treated on
clinical trials including ARIEL3 and TRITON2.
…
8
Use in Specific Populations
8.5 Geriatric Use
Additions and/or
revisions underlined:
Of the 937 patients with ovarian cancer
who received Rubraca in clinical trials including ARIEL3, 41% were age
65 or older and 10% were 75 years or older. No major differences in safety were observed between
younger and older patients
with ovarian cancer.
...
Approved Drug Label (PDF)
7
Drug Interactions
Additions and/or
revisions underlined:
7.1
Effect of Rubraca on Other Drugs
Certain CYP1A2, CYP3A, CYP2C9, or CYP2C19 Substrates
Concomitant administration of Rubraca with CYP1A2,
CYP3A, CYP2C9, or CYP2C19 substrates can increase the systemic exposure of
these substrates [see Clinical
Pharmacology (12.3)], which may increase the frequency or severity
of adverse reactions of these substrates. If concomitant administration
is unavoidable between Rubraca and substrates of these enzymes where minimal
concentration changes may lead to serious adverse reactions, decrease the
substrate dosage in accordance with the approved prescribing
information.
If concomitant administration
with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing the
frequency of international normalized ratio (INR) monitoring.
8
Use in Specific Populations
8.6 Renal Impairment
Additions
and/or revisions underlined:
No dosage modification is recommended for
patients with mild to moderate renal impairment (creatinine clearance [CLcr]
between 30 and 89 mL/min, as estimated by the Cockcroft-Gault method) [see Clinical Pharmacology (12.3)].
Rubraca has not been studied in patients with CLcr less than 30
mL/min or patients on dialysis.
8.7 Hepatic Impairment
No dosage modification is recommended for patients
with mild to moderate hepatic impairment (total bilirubin less than or equal to
3 x upper limit of normal [ULN] or AST > ULN) [see Clinical Pharmacology (12.3)]. Rubraca has not been studied in
patients with severe hepatic impairment (total bilirubin > 3 x ULN and any
AST).
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia
(Additions and/or revisions are
underlined)
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur
uncommonly in patients treated with Rubraca, and are potentially fatal
adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in
12 patients (1.1%), including those in long term follow-up. Of these, 5
occurred during treatment or during the 28 day safety follow- up (0.5%).
The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged
from 1 month to approximately 28 months. The cases were typical of secondary
MDS/cancer therapy-related AML; in all cases, patients had received previous
platinum-containing chemotherapy regimens and/or other DNA damaging
agents.
Do not start Rubraca until patients have recovered from hematological
toxicity caused by previous chemotherapy (less than or equal to Grade 1).
Monitor complete blood counts for cytopenia at baseline and monthly
thereafter for clinically significant changes during treatment. For prolonged
hematological toxicities (greater than 4 weeks), interrupt Rubraca or
reduce dose according to Table 1 and
monitor blood counts weekly until recovery. If the levels have not recovered to
Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the
patient to a hematologist for further investigations, including bone marrow
analysis and blood
sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.
5.2 Embryo-Fetal Toxicity
(Additions and/or revisions are underlined)
Rubraca can cause fetal harm when administered to a pregnant woman
based on its mechanism of action and findings from animal studies. In an animal
reproduction study, administration of rucaparib to pregnant rats during the
period of organogenesis resulted in embryo-fetal death at exposures
that were 0.04 times the AUC0-24h in patients receiving the recommended human
dose of 600 mg twice daily. Apprise pregnant women of the potential risk to
a fetus. Advise females of reproductive potential to use effective
contraception during treatment and for 6 months following the last dose of
Rubraca.
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions are
underlined; tables have been added; please refer to label)
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 practice.
Maintenance Treatment of
Recurrent Ovarian Cancer
The safety of Rubraca for the maintenance treatment of patients with
epithelial ovarian, fallopian tube, or primary peritoneal cancer was
investigated in ARIEL3, a randomized (2:1), double-blind, placebo-controlled
study in which 561 patients received either Rubraca 600 mg BID (n=372) or
placebo (n=189) until disease progression or unacceptable toxicity. The median
duration of study treatment was 8.3 months (range: less than 1 month to 35
months) for patients who received Rubraca and 5.5 months for patients who
received placebo.
Dose interruptions due to an adverse reaction of any grade occurred
in 65% of patients receiving Rubraca and 10% of those receiving placebo; dose
reductions due to an adverse reaction occurred in 55% of Rubraca patients and
4% of placebo patients. The most frequent adverse reactions leading to dose
interruption or dose reduction of
Rubraca were thrombocytopenia (18%), anemia (17%), nausea (15%), and
fatigue/asthenia (13%).
Discontinuation due to adverse reactions occurred in 15% of Rubraca
patients and 2% of placebo patients. Specific adverse reactions that most
frequently led to discontinuation in patients treated with Rubraca were anemia
(3%), thrombocytopenia (3%) and nausea (3%).
7
Drug Interactions
7.1 Effect of Rucaparib on Cytochrome p450 (CYP) Substrates
(Newly added section)
Co-administration of rucaparib can increase the systemic exposure of
CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of
toxicities of these drugs.
Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if
clinically indicated. If co-administration with warfarin (a CYP2C9 substrate)
cannot be avoided, consider increasing the frequency of international
normalized ratio (INR) monitoring.
8
Use in Specific Populations
8.2 Lactation
(Additions and/or revisions are
underlined)
Risk Summary
There is no information regarding the presence of rucaparib in human
milk, or on its effects on milk production or the breast-fed child.
Because of the potential for serious adverse reactions in breast-fed children
from Rubraca, advise lactating women not to breastfeed during treatment with
Rubraca and for 2 weeks following the last dose.
8.5 Geriatric Use
(Additions and/or revisions are
underlined)
In clinical studies 40% (297/749) of
patients with ovarian cancer treated with Rubraca were 65 years
of age or older and 9% (65/749) were 75 years or older. Grade 3-4 adverse
reactions occurred in 65% of patients 65 years or older and in 63% of patients
75 years or older. For patients 65 years or older, the most common Grade 3-4 adverse reactions were anemia, fatigue/asthenia,
and ALT/AST increase. No major differences in safety were observed
between these patients and younger
patients for the maintenance treatment of recurrent ovarian cancer or
for the treatment of BRCA-mutated ovarian cancer after two or more chemotherapies.
8.7 Renal Impairment
(Additions and/or revisions are
underlined)
No starting dose adjustment is recommended for patients with mild to
moderate renal impairment (baseline creatinine clearance [CLcr] between
30 and 89 mL/min, as estimated by the Cockcroft-Gault method). There is no
recommended starting dose for patients with CLcr less than 30 mL/min or
patients on dialysis due to a lack of data.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
(Additions and/or revisions are
underlined)
…
What is Rubraca?
Rubraca is a prescription medicine used for:
the maintenance treatment of adults with
ovarian cancer, fallopian tube cancer, or primary peritoneal cancer whose
cancer has come back and who are in response (complete or partial
response) to a platinum-based chemotherapy.
treatment
of adults with ovarian cancer, fallopian tube cancer, or primary peritoneal
cancer who have certain “BRCA” gene mutations, either inherited
(germline) or acquired (somatic), and who have been treated with
2 or more chemotherapy medicines for their cancer.
Your healthcare provider will perform a test to make sure Rubraca is
right for you.
It is not known if Rubraca is safe and effective in children.
Before you take Rubraca, tell your healthcare provider
about all of your medical
conditions, including if you:
are pregnant or plan to become pregnant. Rubraca
can harm your unborn baby and may cause loss of pregnancy (miscarriage). You
should not become pregnant during treatment with Rubraca.
If you are able to become pregnant, your
healthcare provider may do a pregnancy test before you start treatment with
Rubraca.
Females who are able to become pregnant should
use effective birth control during treatment and for 6 months after the last
dose of Rubraca. Talk to your healthcare provider about birth control methods
that may be right for you.
Tell your healthcare provider right away if you
become pregnant.
are breastfeeding or plan to breastfeed. It is
not known if Rubraca passes into breast milk. Do not breastfeed during
treatment and for 2 weeks after the last dose of Rubraca. Talk to your
healthcare provider about the best way to feed your baby during this time.
…
What are the possible side effects of Rubraca? Rubraca may cause serious
side effects.
The most common side effects of Rubraca include:
nausea
low blood cell counts
tiredness or weakness
mouth sores
vomiting
upper respiratory tract infection
decrease in hemoglobin (anemia)
shortness of breath
changes in how food tastes
rash
constipation
changes in liver or kidney function blood tests
decreased appetite
stomach (abdomen) pain
diarrhea
increased cholesterol levels
…
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