Rubraca
Generic
Name: rucaparib
Dosage Form: tablet, film coated
Medically reviewed by
Drugs.com. Last updated on Apr 1, 2018.
Indications
and Usage for Rubraca
1.1
Maintenance Treatment of Recurrent Ovarian Cancer
Rubraca is indicated for the maintenance treatment of adult
patients with recurrent epithelial ovarian, fallopian tube, or primary
peritoneal cancer who are in a complete or partial response to platinum-based
chemotherapy [see Dosage and Administration (2.1)].
1.2
Treatment of BRCA-mutated Ovarian Cancer After 2 or More Chemotherapies
Rubraca is indicated for the treatment of adult patients with
deleterious BRCA mutation (germline and/or
somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal
cancer who have been treated with two or more chemotherapies. Select patients
for therapy based on an FDA-approved companion diagnostic for Rubraca [see Dosage and Administration (2.1)].
Rubraca
Dosage and AdministrationRecommended Dose
The recommended dose of
Rubraca is 600 mg (two 300 mg tablets) taken orally twice daily with or without
food.
Continue treatment until
disease progression or unacceptable toxicity.
If a patient misses a dose
of Rubraca, instruct the patient to take the next dose at its scheduled time.
Vomited doses should not be replaced.
Dose Modifications for Adverse Reactions
To manage adverse reactions,
consider interruption of treatment or dose reduction. Recommended dose
reductions are indicated in Table
1.
Table 1. Recommended Dose Adjustments
|
|
Dose Reduction
|
Dose
|
|
Starting Dose
|
600 mg twice daily (two 300 mg tablets)
|
|
First Dose Reduction
|
500 mg twice daily (two 250 mg tablets)
|
|
Second Dose Reduction
|
400 mg twice daily (two 200 mg tablets)
|
|
Third Dose Reduction
|
300 mg twice daily (one 300 mg tablet)
|
2.3
Patient Selection for Treatment of BRCA-mutated Ovarian Cancer
Select patients for the treatment of epithelial ovarian,
fallopian tube, or primary peritoneal cancer with Rubraca based on the presence
of a deleterious BRCA mutation (germline
and/or somatic) [see Indications and Usage (1.2) and Clinical Studies (14.2)]. Information on the FDA-approved test
for the detection of a tumor BRCA mutation
in patients with ovarian cancer is available at:
http://www.fda.gov/CompanionDiagnostics.
Dosage
Forms and StrengthsTablets (200 mg): blue, round,
immediate-release, film-coated, debossed with “C2”.Tablets (250 mg): white,
diamond, immediate-release, film-coated, debossed with “C25”.Tablets (300 mg): yellow,
oval, immediate-release, film-coated, debossed with “C3”.Contraindications
None.
Warnings
and Precautions
5.1
Myelodysplastic Syndrome/Acute Myeloid Leukemia
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 (≤ Grade 1).
Monitor complete blood counts for cytopenia at baseline and monthly thereafter
for clinically significant changes during treatment. For prolonged
hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose
according to Table 1 [see
Dosage and Administration (2.2)] 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
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 [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
Adverse
Reactions
The following serious
adverse reactions are discussed elsewhere in the labeling:
Myelodysplastic Syndrome/Acute
Myeloid Leukemia
[see Warnings and Precautions (5.1)].Clinical Trials Experience
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: < 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%).
Table 2. Adverse Reactions in ARIEL3
Occurring in ≥ 20% of Patients
|
|
a National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE version 4.03)
|
|
b Consists of grouped related terms
that reflect the medical concept of the adverse reaction
|
|
Adverse reactions
|
Rubraca
N=372
|
Placebo
N=189
|
|
Gradesa 1-4
%
|
Grades 3-4
%
|
Gradesa 1-4
%
|
Grades 3-4
%
|
|
Gastrointestinal Disorders
|
|
Nausea
|
76
|
4
|
36
|
0.5
|
|
Abdominal
pain/distentionb
|
46
|
3
|
39
|
0.5
|
|
Constipation
|
37
|
2
|
24
|
1
|
|
Vomiting
|
37
|
4
|
15
|
1
|
|
Diarrhea
|
32
|
0.5
|
22
|
1
|
|
Stomatitisb
|
28
|
1
|
14
|
0.5
|
|
General Disorders and Administration Site Conditions
|
|
Fatigue/asthenia
|
73
|
7
|
46
|
3
|
|
Skin and Subcutaneous Tissue Disorders
|
|
Rashb
|
43
|
1
|
23
|
0
|
|
Nervous System Disorders
|
|
Dysgeusia
|
40
|
0
|
7
|
0
|
|
Investigations
|
|
AST/ALT
elevation
|
38
|
11
|
4
|
0
|
|
Blood and Lymphatic System Disorders
|
|
Anemia
|
39
|
21
|
5
|
0.5
|
|
Thrombocytopenia
|
29
|
5
|
3
|
0
|
|
Neutropenia
|
20
|
8
|
5
|
1
|
|
Respiratory, Thoracic, and Mediastinal Disorders
|
|
Nasopharyngitis/Upper
respiratory tract infectionb
|
29
|
0.3
|
18
|
1
|
|
Metabolism and Nutrition Disorders
|
|
Decreased
appetite
|
23
|
1
|
14
|
0
|
Adverse reactions occurring
< 20% of patients treated with Rubraca include headache (18%),
dizziness (19%), dyspepsia (19%), insomnia (15%), dyspnea (17%), pyrexia (13%),
peripheral edema (11%), and depression (11%).
Table 3. Laboratory Abnormalities in
ARIEL3 Occurring in ≥ 25% of Patients
|
|
a Patients were allowed to enter
clinical studies with laboratory values of CTCAE Grade 1.
|
|
Laboratory Parametera
|
Rubraca
N=372
|
Placebo
N=189
|
|
Grade 1-4
%
|
Grade 3-4
%
|
Grade 1-4
%
|
Grade 3-4
%
|
|
Chemistry
|
|
Increase in
creatinine
|
98
|
0.3
|
90
|
0
|
|
Increase in
cholesterol
|
84
|
4
|
78
|
0
|
|
Increase in ALT
|
73
|
7
|
4
|
0
|
|
Increase in AST
|
61
|
1
|
4
|
0
|
|
Increase in
Alkaline Phosphatase
|
37
|
0.3
|
10
|
0
|
|
Hematology
|
|
Decrease in
hemoglobin
|
88
|
13
|
56
|
1
|
|
Decrease in platelets
|
44
|
2
|
9
|
0
|
|
Decrease in
leukocytes
|
44
|
3
|
29
|
0
|
|
Decrease in
neutrophils
|
38
|
6
|
22
|
3
|
|
Decrease in
lymphocytes
|
29
|
5
|
20
|
3
|
Treatment of BRCA-mutated Recurrent Ovarian Cancer After 2 or
More Chemotherapies
Rubraca 600 mg twice daily
as monotherapy has also been studied in 377 patients with epithelial ovarian,
fallopian tube or primary peritoneal cancer who have progressed after 2 or more
prior chemotherapies in two open-label, single arm trials. In these patients,
the median age was 62 years (range: 31 to 86), 100% had an ECOG performance
status of 0 or 1, 38% had BRCA-mutated ovarian
cancer, 45% had received 3 or more prior lines of chemotherapy, and the median
time since ovarian cancer diagnosis was 43 months (range: 6 to 197).
Table 4. Adverse Reactions Reported in
≥ 20% of Patients with Ovarian Cancer After ≥ 2 Chemotherapies
Treated with Rubraca in Study 10 and ARIEL2
|
|
|
Adverse Reaction
|
All Ovarian Cancer Patients
(N = 377)
%
|
|
|
Gradesa 1-4
|
Grades 3-4
|
|
|
a National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE version 4.03)
|
|
|
Gastrointestinal Disorders
|
|
|
|
|
Nausea
|
77
|
5
|
|
|
Vomiting
|
46
|
4
|
|
|
Constipation
|
40
|
2
|
|
|
Diarrhea
|
34
|
2
|
|
|
Abdominal Pain
|
32
|
3
|
|
|
General Disorders
|
|
|
|
|
Asthenia/Fatigue
|
77
|
11
|
|
|
Blood and Lymphatic System Disorders
|
|
|
|
|
Anemia
|
44
|
25
|
|
|
Thrombocytopenia
|
21
|
5
|
|
|
Nervous System Disorders
|
|
|
|
|
Dysgeusia
|
39
|
0.3
|
|
|
Metabolism and Nutrition Disorders
|
|
|
|
|
Decreased
appetite
|
39
|
3
|
|
|
Respiratory, Thoracic, and Mediastinal Disorders
|
|
|
|
|
Dyspnea
|
21
|
0.5
|
|
The following adverse
reactions have been identified in < 20% of the 377 patients treated
with Rubraca 600 mg twice daily: dizziness (17%), neutropenia (15%), rash
(includes rash, rash erythematous, rash maculopapular and dermatitis) (13%),
pyrexia (11%), photosensitivity reaction (10%), pruritus (includes pruritus and
pruritus generalized) (9%), Palmar-plantar erythrodysaesthesia syndrome (2%),
and febrile neutropenia (1%).
Table 5. Laboratory Abnormalities
Reported in ≥ 35% of Patients with Ovarian Cancer After ≥ 2
Chemotherapies Treated with Rubraca in Study 10 and ARIEL2
|
|
a At least one worsening shift in
CTCAE grade and by maximum shift from baseline.
|
|
b Increase in ALT/AST led to
treatment discontinuation in 0.3% of patients (1/377).
|
|
Laboratory Parameter
|
All Patients with Ovarian Cancer
(N = 377)
%
|
|
Grade 1-4 a
|
Grade 3-4
|
|
Clinical Chemistry
|
|
Increase in
creatinine
|
92
|
1
|
|
Increase in ALTb
|
74
|
13
|
|
Increase in ASTb
|
73
|
5
|
|
Increase in
cholesterol
|
40
|
2
|
|
Hematologic
|
|
Decrease in
hemoglobin
|
67
|
23
|
|
Decrease in
lymphocytes
|
45
|
7
|
|
Decrease in
platelets
|
39
|
6
|
|
Decrease in
absolute neutrophil count
|
35
|
10
|
Drug
InteractionsEffect of Rucaparib on Cytochrome p450 (CYP) Substrates
Co-administration of
rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or
CYP2C19 substrates [see Clinical Pharmacology (12.3)], 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.
USE IN
SPECIFIC POPULATIONSPregnancy
Risk Summary
Based on findings from
animal studies and its mechanism of action, Rubraca can cause fetal harm when
administered to pregnant women. There are no available data in pregnant women
to inform the drug-associated risk. In an animal reproduction study,
administration of rucaparib to pregnant rats during organogenesis resulted in
embryo-fetal death at maternal exposures that were 0.04 times the AUC0-24h in patients receiving
the recommended dose of 600 mg twice daily [see Data]. Apprise pregnant women of the potential
risk to a fetus.
The background risk of major
birth defects and miscarriage for the indicated population is unknown. In theU.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 a dose range-finding
embryo-fetal development study, pregnant rats received oral doses of 50, 150,
500, or 1000 mg/kg/day of rucaparib during the period of organogenesis.
Post-implantation loss (100% early resorptions) was observed in all animals at
doses greater than or equal to 50 mg/kg/day (with maternal systemic exposures
approximately 0.04 times the human exposure at the recommended dose based on
AUC0-24h).
Lactation
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.
Females and Males of Reproductive Potential
Pregnancy Testing
Pregnancy testing is
recommended for females of reproductive potential prior to initiating Rubraca.
Contraception
Females
Rubraca can cause fetal harm
when administered to a pregnant woman [see Use in
Specific Populations (8.1)]. Advise females
of reproductive potential to use effective contraception during treatment and
for 6 months following the last dose of Rubraca.
Pediatric Use
The safety and effectiveness
of Rubraca in pediatric patients have not been established.
Geriatric Use
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.
Hepatic Impairment
No starting dose adjustment
is recommended for patients with mild hepatic impairment (total bilirubin less
than or equal to upper limit of normal [ULN] and AST greater than ULN, or total
bilirubin between 1.0 to 1.5 times ULN and any AST). No recommendation for
starting dose adjustment is available for patients with moderate to severe
hepatic impairment (total bilirubin greater than 1.5 times ULN) due to a lack
of data [See Clinical Pharmacology (12.3)].
Renal Impairment
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 [See Clinical Pharmacology (12.3)].
Overdosage
There is no specific
treatment in the event of Rubraca overdose, and symptoms of overdose are not
established. In the event of suspected overdose, physicians should follow
general supportive measures and should treat symptomatically.
Rubraca
Description
Rucaparib is an inhibitor of
the mammalian polyadenosine 5'-diphosphoribose polymerase (PARP) enzyme. The
chemical name is
8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one
((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt.
The chemical formula of rucaparib camsylate is C19H18FN3O•C10H16O4S and the relative molecular
mass is 555.67Daltons.
The chemical structure of
rucaparib camsylate is shown below:
Rucaparib camsylate is a
white to pale yellow powder; formulated into a tablet for oral use. Rucaparib
shows pH-independent low solubility of approximately 1 mg/mL across the
physiological pH range.
Rubraca (rucaparib) tablets
contain rucaparib camsylate as the active ingredient. Each 200 mg tablet
contains 344 mg rucaparib camsylate equivalent to 200 mg rucaparib free
base. Each 250 mg tablet contains 430 mg rucaparib camsylate equivalent to
250 mg rucaparib free base. Each 300 mg tablet contains 516 mg rucaparib camsylate
equivalent to 300 mg rucaparib free base.
The inactive ingredients in
Rubraca tablets include: microcrystalline cellulose, sodium starch glycolate,
colloidal silicon dioxide, and magnesium stearate. The cosmetic blue film
coating for 200 mg tablets, cosmetic white film coating for 250 mg
tablets, and cosmetic yellow film coating for 300 mg tablets is Opadry II
containing polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol,
and talc. The coating is colorized as blue using brilliant blue aluminum lake
and indigo carmine aluminum lake, or yellow using yellow iron oxide.
Rubraca -
Clinical PharmacologyMechanism of Action
Rucaparib is an inhibitor of
poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and
PARP-3, which play a role in DNA repair. In vitro studies
have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP
enzymatic activity and increased formation of PARP-DNA complexes resulting in
DNA damage, apoptosis, and cancer cell death. Increased rucaparib-induced
cytotoxicity and anti-tumor activity was observed in tumor cell lines with
deficiencies in BRCA1/2 and other DNA
repair genes. Rucaparib has been shown to decrease tumor growth in mouse
xenograft models of human cancer with or without deficiencies in BRCA.
Pharmacodynamics
The pharmacodynamic response
of rucaparib has not been characterized.
Cardiac Electrophysiology
The effect of multiple doses
of Rubraca on QTc interval was evaluated in an open-label single-arm study in
56 patients with solid tumors who were administered continuous doses of Rubraca
ranging from 40 mg once daily (0.03 times the approved recommended dose) to 840
mg twice daily (1.4 times the approved recommended dose). The mean QTcF
increase from baseline (90% confidence interval [CI]) in population
pharmacokinetics estimated 95th percentile Cmax (3019 ng/mL) at steady state of 600 mg rucaparib
twice daily was 14.9 msec (11.1-18.7 msec).
Pharmacokinetics
The pharmacokinetic profile
of rucaparib was characterized in patients with cancer. Rucaparib demonstrated
linear pharmacokinetics over a dose range from 240 to 840 mg twice daily with
time-independence and dose-proportionality. The mean steady-state rucaparib Cmax was 1940 ng/mL (54%
coefficient of variation [CV]) and AUC0-12h was 16900 h·ng/mL (54% CV) at the approved
recommended dose. Accumulation was 3.5 to 6.2 fold.
Absorption
The median Tmax was 1.9 hours at the
approved recommended dose. The mean absolute bioavailability of rucaparib
immediate-release tablet was 36% with a range from 30% to 45%.
Following a high-fat meal,
the Cmax was
increased by 20% and AUC0-24h was increased by 38%, and Tmax was delayed by
2.5 hours, as compared to dosing under fasted conditions [see Dosage and Administration (2.2)].
Distribution
Rucaparib had a steady-state
volume of distribution of 113 L to 262 L following a single intravenous dose of
12 mg to 40 mg rucaparib.
In
vitro, the protein binding of rucaparib was 70% in human plasma at
therapeutic concentrations. Rucaparib preferentially distributed to red blood
cells with a blood-to-plasma concentration ratio of 1.83.
Elimination
The mean terminal T1/2 of rucaparib was 17 to
19 hours, following a single oral dose of 600 mg rucaparib. The apparent
clearance ranged from 15.3 to 79.2 L/hour, following rucaparib 600 mg twice
daily. The clearance ranged from 13.9 to 18.4 L/hour, following a single
intravenous dose of rucaparib 12 mg to 40 mg.
Metabolism
In
vitro, rucaparib had a low metabolic turnover rate and was
metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4.
Specific Populations
Age,
Race, and Body Weight
Based on population
pharmacokinetic analyses, age, race, and body weight did not have a clinically
meaningful effect on rucaparib exposure.
Renal
Impairment
In patients who received
Rubraca 600 mg twice daily, those with mild renal impairment (N=148; baseline
CLcr between 60 and 89 mL/min, as estimated by the Cockcroft-Gault method)
and those with moderate renal impairment (N=72; CLcr between 30 and 59 mL/min)
showed approximately 15% and 32% higher steady-state AUC, respectively,
compared to patients with normal renal function (N=143; CLcr greater than or
equal to 90 mL/min). The pharmacokinetic characteristics of rucaparib in
patients with CLcr less than 30 mL/min or patients on dialysis are unknown.
Hepatic
Impairment
Based on population
pharmacokinetic analyses, no apparent pharmacokinetic difference was observed
in 34 patients with mild hepatic impairment (total bilirubin less than or equal
to ULN and AST greater than ULN, or total bilirubin between 1.0 to 1.5 times
ULN and any AST) who received Rubraca 600 mg twice daily as compared to
patients with normal hepatic function (N=337). The pharmacokinetic characteristics
of rucaparib in patients with moderate to severe hepatic impairment (total
bilirubin greater than 1.5 times ULN) are unknown.
CYP
Enzyme Polymorphism
Based on population
pharmacokinetic analyses, steady-state concentrations following rucaparib 600
mg twice daily did not differ significantly across CYP2D6 or CYP1A2 genotype
subgroups.
Drug Interaction Studies
Effect
of Rucaparib on Other Drugs
Clinical Studies
A single dose of the
following drugs was administered before and following rucaparib 600 mg twice
daily for 7 days. The Cmax of each co-administered drug was ≤ 1.13-fold, and the AUC
changed as follows:
Caffeine (CYP1A2): caffeine
AUC increased by 2.55-foldMidazolam (CYP3A4): midazolam
AUC increased by 1.38-foldWarfarin (CYP2C9): warfarin
AUC increased by 1.49-foldOmeprazole (CYP2C19):
omeprazole AUC increased by 1.55-foldDigoxin (P-glycoprotein):
digoxin AUC increased by 1.20-fold
In Vitro Studies
Rucaparib inhibited CYP2C8,
CYP2D6, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Rucaparib
induced CYP1A2, and down regulated CYP3A4 and CYP2B6.
Rucaparib inhibited the
P-glycoprotein (P-gp) efflux transporter, breast cancer resistance protein
(BCRP), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and
OATP1B3), organic anion transporters 1 and 3 (OAT1 and OAT3), multidrug and
toxin extrusion 1 and 2-k (MATE1 and MATE2-K), organic cation transporters 1
and 2 (OCT1 and OCT2), and multidrug resistance-associated protein 4 (MRP4). No
apparent inhibition was observed for MRP2, MRP3, or BSEP.
Effects
of Other Drugs on Rucaparib
Clinical Studies
In a population
pharmacokinetic (PPK) analysis, co-administration with proton pump inhibitors
had no clinically significant effect on steady-state concentrations of
rucaparib.
In Vitro Studies
Rucaparib was a substrate of
P-gp and BCRP; however, rucaparib was not a substrate of OATP1B1, OATP1B3,
OAT1, OAT3, and OCT2.
Nonclinical
ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have
not been conducted with rucaparib.
Rucaparib was clastogenic in
an in vitro chromosomal aberration assay
in cultured human lymphocytes. The clastogenic response in
mitotically-stimulated cells was anticipated based on the mechanism of action
of rucaparib and indicates potential genotoxicity in humans. Rucaparib was
not mutagenic in a bacterial reverse mutation (Ames) test.
Fertility studies with
rucaparib have not been conducted. In 3-month repeat-dose general toxicology
studies, rucaparib had no effects on male and female reproductive organs at
doses up to 100 mg/kg/day and 20 mg/kg/day in rats and dogs, respectively.
These dose levels resulted in systemic exposures of approximately 0.3 and 0.09
times the human exposure (AUC0-24h), respectively, at the recommended dose.
Clinical StudiesMaintenance Treatment of Recurrent Ovarian Cancer
The efficacy of Rubraca was
investigated in ARIEL3 (NCT01968213), a double-blind, multicenter clinical
trial in which 564 patients with recurrent epithelial ovarian, fallopian tube,
or primary peritoneal cancer who were in response to platinum-based
chemotherapy were randomized (2:1) to receive Rubraca tablets 600 mg orally
twice daily (n=375) or placebo (n=189). Treatment was continued until disease
progression or unacceptable toxicity. All patients had achieved a response
(complete or partial) to their most recent platinum-based chemotherapy.
Randomization was stratified by best response to last platinum (complete or
partial), time to progression following the penultimate platinum therapy (6 to
≤ 12 months and > 12 months), and tumor biomarker status. The
major efficacy outcome was investigator-assessed progression-free survival
(PFS) evaluated according to Response Evaluation Criteria in Solid Tumors
(RECIST), version 1.1 (v1.1).
The median age was 61 years
(range: 39 to 84) for patients receiving Rubraca and 62 years (range: 36 to 85)
for those on placebo; the majority were White (80%); and 100% had an ECOG
performance status of 0 or 1. All patients had received at least two prior
platinum-based chemotherapies (range: 2 to 7). A total of 34% of patients were
in complete response (CR) to their most recent therapy. The progression-free
interval to penultimate platinum was 6-12 months in 40% of patients and
> 12 months in 60%. Prior bevacizumab therapy was reported for 22% of
patients who received Rubraca and 23% of patients who received placebo.
Measurable disease was present at baseline in 37% of patients.
Tumor tissue samples were
tested using a clinical trial assay (CTA) (N=564), and the FoundationFocus™ CDx BRCA LOH test (n=518).
Of the samples evaluated with both tests, homologous recombination deficiency
(HRD) positive status (as defined by the presence of a deleterious BRCA
mutation or high genomic loss of heterozygosity) was confirmed by the FoundationFocus™ CDx BRCA LOH test for 94%
(313/332) of HRD-positive patients determined by the CTA; and of these, tumor
BRCA (tBRCA) mutant status was confirmed by the FoundationFocus™ CDx BRCA LOH test for 99%
(177/178) of tBRCA-positive patients determined by the CTA. Blood samples for
94% (186/196) of the tBRCA patients were evaluated using a central blood
germline BRCA test. Based on these results, 70% (130/186) of the tBRCA patients
had a germline BRCA mutation and 30% (56/186) had a somatic BRCA mutation.
ARIEL3 demonstrated a
statistically significant improvement in PFS for patients randomized to Rubraca
as compared with placebo in all patients, and in the HRD and tBRCA subgroups.
Results from a blinded independent radiology review were consistent. At the time
of the analysis of PFS, overall survival (OS) data were not mature (with 22% of
events).
Efficacy results are
summarized in Table 6 and Figures
1, 2, and 3.
Table 6. Efficacy Results - ARIEL3
(Investigator Assessment)
|
|
a. All randomized patients.
|
|
b. HRD includes all patients with a
deleterious germline or somatic BRCA mutation or high genomic loss of
heterozygosity, as determined by the CTA.
|
|
c. tBRCA includes all patients with a
deleterious germline or somatic BRCA mutation, as determined by the CTA.
|
|
|
Rubraca
|
Placebo
|
|
All Patientsa
|
|
Patients, N
|
375
|
189
|
|
PFS events, n
(%)
|
234 (62%)
|
167 (88%)
|
|
PFS, median in
months
|
10.8
|
5.4
|
|
HR (95% CI)
|
0.36 (0.30, 0.45)
|
|
p-value
|
< 0.0001
|
|
HRD Groupb
|
|
Patients, N
|
236
|
118
|
|
PFS events, n
(%)
|
134 (57%)
|
101 (86%)
|
|
PFS, median in
months
|
13.6
|
5.4
|
|
HR (95% CI)
|
0.32 (0.24, 0.42)
|
|
p-value
|
< 0.0001
|
|
tBRCA Groupc
|
|
Patients, N
|
130
|
66
|
|
PFS events, n
(%)
|
67 (52%)
|
56 (85%)
|
|
PFS, median in
months
|
16.6
|
5.4
|
|
HR (95% CI)
|
0.23 (0.16, 0.34)
|
|
p-value
|
< 0.0001
|
Figure
1. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by Investigator: All
Patients
Figure
2. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by
Investigator: HRD Group
Figure
3. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by
Investigator: tBRCA Group
Treatment of BRCA-mutated Ovarian Cancer After 2 or More
Chemotherapies
The efficacy of Rubraca was
investigated in 106 patients in two multicenter, single-arm, open-label
clinical trials, Study 10 (NCT01482715) and ARIEL2 (NCT01891344), in
patients with advanced BRCA-mutant ovarian
cancer who had progressed after 2 or more prior chemotherapies. All 106
patients received Rubraca 600 mg orally twice daily as monotherapy until
disease progression or unacceptable toxicity. Objective response rate (ORR) and
duration of response (DOR) were assessed by the investigator and IRR according to
RECIST v1.1.
The median age of the
patients was 59 years (range: 33 to 84), the majority were White (78%), and
100% had an ECOG performance status of 0 or 1. All patients had received at
least two prior platinum-based chemotherapies and 43% had received 3 or more
prior lines of platinum-based chemotherapy. There were 18/106 patients (17%)
who had deleterious BRCA mutations
detected in tumor tissue and not in whole blood specimens. Tumor BRCA mutation status was verified retrospectively in
96% (64/67) of the patients for whom a tumor tissue sample was available by the
companion diagnostic FoundationFocus™ CDxBRCA test, which is FDA
approved for selection of patients for Rubraca treatment.
Efficacy results are
summarized in Table 7.
Table 7. Overall Response and Duration of
Response in Patients with BRCA-mutant Ovarian Cancer Who Received 2 or More
Chemotherapies in Study 10 and ARIEL2
|
|
|
Investigator-assessed
N=106
|
|
Objective
Response Rate (95% CI)
|
54% (44, 64)
|
|
Complete
Response
|
9%
|
|
Partial Response
|
45%
|
|
Median DOR in
months (95% CI)
|
9.2 (6.6, 11.6)
|
Response assessment by
independent radiology review was 42% (95% CI [32, 52]), with a median DOR of
6.7 months (95% CI [5.5, 11.1]). Investigator-assessed ORR was 66% (52/79; 95%
CI [54, 76]) in platinum-sensitive patients, 25% (5/20; 95% CI [9, 49]) in
platinum-resistant patients, and 0% (0/7; 95% CI [0, 41]) in
platinum-refractory patients. ORR was similar for patients with a BRCA1 gene mutation or BRCA2 gene
mutation.
How
Supplied/Storage and HandlingHow Supplied
Rubraca is available as 200
mg, 250 mg, and 300 mg tablets.
200 mg Tablets:
Blue, round, and debossed with
“C2” on one sideSupplied in bottles of 60
tablets (NDC: 69660-201-91)
250 mg Tablets:
White, diamond, and debossed
with “C25” on one sideSupplied in bottles of 60
tablets (NDC: 69660-202-91)
300 mg Tablets:
Yellow, oval, and debossed
with “C3” on one sideSupplied in bottles of 60
tablets (NDC: 69660-203-91)Storage
Store at 20°C to 25°C (68°F
to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Patient
Counseling Information
Advise the patient to read
the FDA-approved patient labeling (Patient Information).
MDS/AML: Advise patients
to contact their healthcare provider if they experience weakness, feeling
tired, fever, weight loss, frequent infections, bruising, bleeding easily,
breathlessness, blood in urine or stool, and/or laboratory findings of low
blood cell counts, or a need for blood transfusions. These may be signs of
hematological toxicity or a more serious uncommon bone marrow problem called
‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have
been reported in patients treated with Rubraca [see
Warnings and Precautions (5.1)].
Embryo-Fetal Toxicity: Advise
females to inform their healthcare provider if they are pregnant or become
pregnant. Inform female patients of the risk to a fetus and potential loss of
the pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive
potential to use effective contraception during treatment and for 6 months
after receiving the last dose of Rubraca [see Warnings
and Precautions (5.2) and Use in Specific
Populations (8.1, 8.3)].
Photosensitivity: Advise
patients to use appropriate sun protection due to the increased susceptibility
to sunburn while taking Rubraca [see Adverse Drug
Reactions (6.1)].
Lactation: Advise females
not to breastfeed during treatment and for 2 weeks after the last dose of
Rubraca [see Use in Specific Populations (8.2)].
Dosing Instructions: Instruct
patients to take Rubraca orally twice daily with or without food. Doses should
be taken approximately 12 hours apart. Advise patients that if a dose of
Rubraca is missed or if the patient vomits after taking a dose of Rubraca,
patients should not take an extra dose, but take the next dose at the regular
time [see Dosage and Administration (2.1)].
Distributed by:
Clovis Oncology, Inc.
Boulder, CO 80301
1-844-258-7662
Rubraca is a registered
trademark of Clovis Oncology, Inc.
|
This Patient Information has been
approved by the U.S. Food and Drug Administration.
|
Revised: April
2018
|
|
PATIENT INFORMATION
Rubraca® (roo-brah'-kah)
(rucaparib)
Tablets
|
|
What is the most important information I
should know about Rubraca?
Rubraca may cause serious side effects including:
Bone marrow problems called Myelodysplastic Syndrome
(MDS) or a type of cancer of the blood called Acute Myeloid Leukemia (AML). Some
people who have cancer and who have received previous treatment with
chemotherapy or certain other medicines for their cancer have developed MDS
or AML during or after treatment with Rubraca. MDS or AML may lead to death.
If you develop MDS or AML, your healthcare provider will stop treatment with
Rubraca.
Symptoms of low blood cell counts are common during treatment with Rubraca,
but can be a sign of serious problems, including MDS or AML. Tell your
healthcare provider if you have any of the following symptoms during
treatment with Rubraca:
|
|
· weakness
· weight
loss
· fever
|
· frequent
infections
· blood
in urine or stool
· shortness
of breath
|
· feeling
very tired
· bruising
or bleeding more easily
|
|
Your healthcare
provider will do blood tests to check your blood cell counts:
before
treatment with Rubraca.every
month during treatment with Rubraca.weekly if you have low blood cell counts for a
long time. Your healthcare provider may stop treatment with Rubraca
until your blood cell counts improve.
|
|
See "What are possible side effects of Rubraca?" for more
information about side effects.
|
|
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.the 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.
|
|
Tell your healthcare provider about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
|
|
How should I take Rubraca?
Take
Rubraca exactly as your healthcare provider tells you.Your
healthcare provider may temporarily stop treatment with Rubraca or
change your dose of Rubraca if you have side effects. Do not change your
dose or stop taking Rubraca unless your healthcare provider tells you
to.Take
Rubraca 2 times a day. Each dose should be taken about 12 hours apart.Take
Rubraca with or without food.If you
miss a dose of Rubraca, take your next dose at your usual scheduled
time. Do not take an extra dose to make up for a missed dose.If you
vomit after taking a dose of Rubraca, do not take an extra dose. Take
your next dose at your usual time.If you take too much Rubraca, call your
healthcare provider or go to the nearest emergency room right away.
|
|
What should I avoid while taking Rubraca?
Avoid spending time in sunlight. Rubraca can make your skin sensitive to the
sun (photosensitivity). You may sunburn more easily during treatment with
Rubraca. You should wear a hat and clothes that cover your skin and use
sunscreen to help protect against sunburn if you have to be in the sunlight.
|
|
What are the possible side effects of Rubraca?
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 include:
|
|
· nausea
· tiredness
or weakness
· vomiting
· decrease
in hemoglobin (anemia)
· changes
in how food tastes
· constipation
· decreased
appetite
· diarrhea
|
· low
blood cell counts
· mouth
sores
· upper
respiratory tract infection
· shortness
of breath
· rash
· changes
in liver or kidney function blood tests
· stomach
(abdomen) pain
· increased
cholesterol levels
|
|
These are not
all of the possible side effects of Rubraca. For more information, ask your
healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.
|
|
How should I store Rubraca?
Store Rubraca at room temperature between 68°F
to 77°F (20°C to 25°C).
|
|
Keep Rubraca and all medicines out of the reach of children.
|
|
General information about the safe and effective use of Rubraca
Medicines are sometimes prescribed for purposes other than those listed in a
Patient Information leaflet. Do not use Rubraca for a condition for which it
was not prescribed. Do not give it to other people, even if they have the
same symptoms you have. It may harm them. You can ask your healthcare
provider or pharmacist for more information about Rubraca.
|
|
What are the ingredients in Rubraca?
Active ingredient: rucaparib
Inactive ingredients: microcrystalline
cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium
stearate. The film coating contains polyvinyl alcohol, titanium dioxide,
polyethylene glycol/macrogol, and talc. The blue film coating contains
brilliant blue aluminum lake and indigo carmine aluminum lake. The yellow
film coating contains yellow iron oxide.
Distributed by: Clovis Oncology, Inc.Boulder,Colorado80301
For more information, go to www.Rubraca.com or call 1-844-258-7662.
|
|
|
|
|
|
Principal
Display Panel - Rubraca tablets 200 mg Bottle Label
NDC 69660-201-91
Rubraca®
(rucaparib) tablets
200 mg*
60 tablets
Each tablet contains 344 mg
rucaparib camsylate equivalent to 200 mg rucaparib
Rx only
Keep out of reach of
children
Principal
Display Panel - Rubraca tablets 250 mg Bottle Label
NDC 69660-202-91
Rubraca®
(rucaparib) tablets
250 mg*
60 tablets
Each tablet contains 430 mg
rucaparib camsylate equivalent to 250 mg rucaparib
Rx only
Keep out of reach of
children
Principal
Display Panel - Rubraca tablets 300 mg Bottle Label
NDC 69660-203-91
Rubraca®
(rucaparib) tablets
300 mg*
60 tablets
Each tablet contains 516 mg
rucaparib camsylate equivalent to 300 mg rucaparib
Rx only
Keep out of reach of
children
|
Rubraca
rucaparib tablet, film coated
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:69660-201
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
rucaparib
camsylate (rucaparib)
|
rucaparib
|
200 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
cellulose,
microcrystalline
|
|
|
sodium
starch glycolate type a potato
|
|
|
silicon
dioxide
|
|
|
magnesium
stearate
|
|
|
Polyvinyl
Alcohol, Unspecified
|
|
|
titanium
dioxide
|
|
|
polyethylene
glycol, unspecified
|
|
|
talc
|
|
|
FD&C
Blue No. 1
|
|
|
FD&C
Blue No. 2
|
|
|
|
Product
Characteristics
|
|
Color
|
blue (BLUE)
|
Score
|
no score
|
|
Shape
|
ROUND (ROUND)
|
Size
|
11mm
|
|
Flavor
|
|
Imprint
Code
|
C2
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:69660-201-91
|
60 TABLET,
FILM COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA209115
|
12/19/2016
|
|
|
|
Rubraca
rucaparib tablet, film coated
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:69660-203
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
rucaparib
camsylate (rucaparib)
|
rucaparib
|
300 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
cellulose,
microcrystalline
|
|
|
sodium
starch glycolate type a potato
|
|
|
silicon
dioxide
|
|
|
magnesium
stearate
|
|
|
Polyvinyl
Alcohol, Unspecified
|
|
|
titanium
dioxide
|
|
|
polyethylene
glycol, unspecified
|
|
|
talc
|
|
|
Ferric
Oxide Yellow
|
|
|
|
Product
Characteristics
|
|
Color
|
yellow
(YELLOW)
|
Score
|
no score
|
|
Shape
|
OVAL (OVAL)
|
Size
|
16mm
|
|
Flavor
|
|
Imprint
Code
|
C3
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:69660-203-91
|
60 TABLET,
FILM COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA209115
|
12/19/2016
|
|
|
|
Rubraca
rucaparib tablet, film coated
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:69660-202
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
rucaparib
camsylate (rucaparib)
|
rucaparib
|
250 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
cellulose,
microcrystalline
|
|
|
sodium
starch glycolate type a potato
|
|
|
silicon
dioxide
|
|
|
magnesium
stearate
|
|
|
Polyvinyl
Alcohol, Unspecified
|
|
|
titanium
dioxide
|
|
|
polyethylene
glycol, unspecified
|
|
|
talc
|
|
|
|
Product
Characteristics
|
|
Color
|
white (WHITE)
|
Score
|
no score
|
|
Shape
|
DIAMOND
(DIAMOND)
|
Size
|
15mm
|
|
Flavor
|
|
Imprint
Code
|
C25
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:69660-202-91
|
60 TABLET,
FILM COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA209115
|
05/01/2017
|
|
|
|
Labeler - Clovis Oncology, Inc. (830871518)
|
Clovis Oncology, Inc.
