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Rucaparib

Generic name: rucaparib systemic

Brand names: Rubraca

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Rubraca: 200 mg [contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake]

Rubraca: 250 mg, 300 mg

Pharmacology

Mechanism of Action

Rucaparib is a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor, including PARP1, PARP2, and PARP3. PARP enzymes are involved in DNA transcription, cell cycle regulation, and DNA repair. By inhibiting PARP, rucaparib may cause increased formation of PARP-DNA complexes, resulting in DNA damage, apoptosis, and cancer cell death. Increased cytotoxicity and anti-tumor activity due to rucaparib was observed in tumor cell lines deficient in BRCA1/2 and other DNA repair genes.

Pharmacokinetics/Pharmacodynamics

Absorption

Cmax is increased by 20%, AUC is increased by 38%, and Tmax is delayed by 2.5 hours following a high-fat meal (as compared to the fasting state)

Distribution

113 to 262 L (following a single IV dose of 12 to 40 mg)

Metabolism

Primarily hepatic via CYP2D6; minor pathways include CYP1A2 and CYP3A4

Time to Peak

1.9 hours

Half-Life Elimination

Terminal: 17 to 19 hours (following a single oral 600 mg dose)

Protein Binding

70%

Use in Specific Populations

Special Populations: Renal Function Impairment

Patients receiving rucaparib 600 mg twice daily with baseline CrCl 60 to 89 mL/minute and those with CrCl between 30 to 59 mL/minute had approximately 15% and 32% higher steady-state AUC, respectively, compared to patients with normal renal function (CrCl 90 mL/minute or above).

Use: Labeled Indications

Ovarian cancer, advanced: Treatment of deleterious germline and/or somatic BRCA mutation associated (as detected by an approved test) ovarian cancer (epithelial, fallopian tube, or primary peritoneal) in patients who have been treated with 2 or more prior lines of chemotherapy.

Ovarian cancer, recurrent (maintenance): Maintenance treatment of recurrent ovarian cancer (epithelial, fallopian tube, or primary peritoneal) in patients who are in complete or partial response to platinum-based chemotherapy.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Note: Administer only to patients with deleterious germline and/or somatic BRCA mutation, as detected by an approved test. Rucaparib is associated with a moderate emetic potential; antiemetics may be necessary to prevent nausea and vomiting.

Ovarian cancer, advanced: Oral: 600 mg twice daily until disease progression or unacceptable toxicity (Oza 2017; Swisher 2017).

Ovarian cancer, recurrent (maintenance): Oral: 600 mg twice daily until disease progression or unacceptable toxicity (Coleman 2017).

Missed doses: If a dose is missed, administer the next dose at its scheduled time. Do not repeat or replace a vomited dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Consider therapy interruption or dose reduction if adverse events occur.

Recommended rucaparib dose reductions:

Starting dose: 600 mg twice daily

1st dose reduction: 500 mg twice daily

2nd dose reduction: 400 mg twice daily

3rd dose reduction: 300 mg twice daily

Secondary myelodysplastic syndrome/acute myeloid leukemia (MDS/AML): Discontinue

Administration

Rucaparib is associated with a moderate emetic potential; antiemetics may be necessary to prevent nausea and vomiting.

Administer orally twice daily (~12 hours apart) with or without food. Do not repeat a vomited dose.

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).

Drug Interactions

Agomelatine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Agomelatine. Monitor therapy

Alosetron: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Alosetron. Management: Avoid concomitant use of alosetron and moderate CYP1A2 inhibitors whenever possible. If combined use is necessary, monitor for increased alosetron effects/toxicities. Consider therapy modification

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bendamustine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Bendamustine. Management: Consider alternatives to moderate CYP1A2 inhibitors during therapy with bendamustine due to the potential for increased bendamustine plasma concentrations and increased bendamustine toxicity. Consider therapy modification

Bromazepam: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Bromazepam. Monitor therapy

Caffeine and Caffeine Containing Products: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

ClomiPRAMINE: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of ClomiPRAMINE. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

DULoxetine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of DULoxetine. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Melatonin: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Melatonin. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

OLANZapine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of OLANZapine. Monitor therapy

Pentoxifylline: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pentoxifylline. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Pirfenidone: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: Avoid concomitant use of pirfenidone and moderate CYP1A2 inhibitors whenever possible. If combined, decrease the pirfenidone dose to 1,602 mg per day (534 mg three times daily) and monitor for increased pirfenidone toxicities. Consider therapy modification

Pomalidomide: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pomalidomide. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Propranolol: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Propranolol. Monitor therapy

Ramelteon: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ramelteon. Monitor therapy

Ramosetron: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ramosetron. Monitor therapy

Rasagiline: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Rasagiline. Management: Limit rasagiline dose to 0.5 mg once daily in patients taking moderate CYP1A2 inhibitors. Consider therapy modification

ROPINIRole: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of ROPINIRole. Monitor therapy

Ropivacaine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ropivacaine. Monitor therapy

Tasimelteon: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Tasimelteon. Monitor therapy

Theophylline Derivatives: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Theophylline Derivatives. Management: Consider avoidance of this combination. If coadministration is necessary, monitor for increased theophylline serum concentrations and toxicities when combined. Theophylline dose reductions will likely be required. Exceptions: Dyphylline. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of TiZANidine. Management: If combined use cannot be avoided, initiate tizanidine in adults at 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors. Consider therapy modification

Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (if needed) of ubrogepant should be limited to 50 mg. Consider therapy modification

Warfarin: Rucaparib may increase the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (11%)

Central nervous system: Fatigue (≤73%), dizziness (19%) headache (18%), insomnia (15%), depression (11%)

Dermatologic: Skin rash (43%)

Endocrine & metabolic: Increased serum cholesterol (84%)

Gastrointestinal: Nausea (76%), abdominal distention (≤46%), abdominal pain (≤46%), dysgeusia (40%), constipation (37%), vomiting (37%), diarrhea (32%), stomatitis (28%), decreased appetite (23%), dyspepsia (19%)

Hematologic & oncologic: Decreased white blood cell count (44%; grades 3/4: 3%), anemia (39%, grades 3/4: 21%), decreased absolute lymphocyte count (29%, grades 3/4: 5%), thrombocytopenia (29%, grades 3/4: 5%), neutropenia (20%; grades 3/4: 8%)

Hepatic: Increased serum ALT (≤73%), increased serum AST (≤61%), increased serum alkaline phosphatase (37%)

Neuromuscular & skeletal: Weakness (≤73%)

Renal: Increased serum creatinine (98%)

Respiratory: Nasopharyngitis (≤29%), upper respiratory tract infection (≤29%), dyspnea (17%)

Miscellaneous: Fever (13%)

<1%, postmarketing, and/or case reports: Acute myelocytic leukemia, myelodysplastic syndrome

Warnings/Precautions

Concerns related to adverse effects:

  • Bone marrow suppression: Anemia, neutropenia, lymphocytopenia, and thrombocytopenia were commonly observed in clinical trials. Monitor blood counts as clinically necessary. Do not initiate treatment until after hematologic recovery (to grade 1 or lower) from prior chemotherapy. Interrupt treatment or reduce the dose for prolonged hematologic toxicity (>4 weeks); monitor blood counts weekly until recovery.
  • GI toxicity: Rucaparib is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.
  • Secondary malignancy: Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) has been reported (rarely) in patients receiving rucaparib; may be potentially fatal. Some cases have occurred during or within 28 days following treatment. The duration of therapy prior to diagnosis of MDS/AML ranged from 1 month to ~28 months. The cases were typical of secondary MDS or cancer-therapy related AML and all patients had received prior chemotherapy with platinum agents and/or other DNA-damaging medications. Monitor blood counts (for cytopenia and for clinically significant changes) at baseline and then monthly thereafter. Interrupt treatment and/or reduce the dose for prolonged (>4 weeks) hematological toxicities; monitor blood counts weekly until recovery. If prolonged hematologic toxicity occurs and blood counts do not recover to ≤grade 1 after 4 weeks or if MDS/AML is suspected, further hematology evaluation (including bone marrow and cytogenetic analyses) is necessary. If MDS/AML is confirmed, discontinue therapy.

Concurrent drug therapy issues:

  • Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

  • BRCA-mutation status: Select patients for the treatment of advanced ovarian cancer (not maintenance therapy) based on the presence of deleterious or suspected deleterious BRCA mutations. Information on approved tests for the detection of BRCA mutations may be found at http://www.fda.gov/companiondiagnostics.

Monitoring Parameters

BRCA mutation testing (for treatment of advanced ovarian cancer [not maintenance therapy]); complete blood count at baseline and monthly thereafter, or as clinically indicated (weekly until recovery for prolonged hematologic toxicity); pregnancy test (prior to treatment initiation in females of reproductive potential); monitor for signs/symptoms of MDS/AML. Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to rucaparib may cause fetal harm.

Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use effective contraception during therapy and for 6 months after the last rucaparib dose.

Patient Education

What is this drug used for?

  • It is used to treat ovarian, fallopian tube, or peritoneal cancer.

Frequently reported side effects of this drug

  • Nausea
  • Vomiting
  • Constipation
  • Diarrhea
  • Abdominal pain
  • Abdominal swelling
  • Mouth irritation
  • Mouth sores
  • Change in taste
  • Lack of appetite
  • Headache
  • Stuffy nose
  • Sore throat
  • Common cold symptoms
  • Trouble sleeping
  • Dizziness

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

  • Infection
  • Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
  • Swelling of arms or legs
  • Depression
  • Severe loss of strength and energy
  • Weight loss
  • Shortness of breath
  • Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated February 5, 2020.