Usage
Rucaparib is prescribed for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. It is also used to treat BRCA-mutated advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have been treated with two or more chemotherapies. Additionally, it is indicated for the treatment of metastatic castration-resistant prostate cancer in patients with a deleterious BRCA gene mutation (germline and/or somatic).
It’s pharmacological classification is as a PARP (poly (ADP-ribose) polymerase) inhibitor, a targeted therapy for cancers with specific genetic mutations. PARP enzymes play a role in DNA repair, and inhibiting them prevents cancer cells with BRCA mutations from repairing damaged DNA, leading to cell death.
Alternate Names
Rucaparib is also known by the brand name Rubraca. There are no widely used alternate names or regional variations.
How It Works
Pharmacodynamics: Rucaparib exerts its anti-cancer effects through PARP inhibition, leading to synthetic lethality in cancer cells with BRCA1/2 mutations, disrupting DNA repair mechanisms and causing apoptosis.
Pharmacokinetics:
- Absorption: Rucaparib is administered orally and is absorbed systemically, but its bioavailability is unknown.
- Metabolism: Rucaparib is primarily metabolized by CYP3A4 with minor contribution from CYP1A2.
- Elimination: Renal and fecal elimination pathways contribute. Unchanged rucaparib accounts for approximately 45% of radioactivity in urine and 95% in feces after a single oral dose of radiolabeled rucaparib.
Mode of Action: Rucaparib binds to and inhibits PARP enzymes, blocking their ability to repair single-strand DNA breaks in cancer cells. In the absence of functioning BRCA proteins (due to BRCA mutation), these single-strand breaks are converted to double-strand breaks during DNA replication, preventing cells from dividing and ultimately leading to cell death.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Rucaparib’s primary mechanism is PARP enzyme inhibition. It is also a weak inhibitor of CYP2C8, CYP2D6, and UGT1A1, a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of OCT1, and a weak inhibitor of OCT2. It inhibits BCRP (breast cancer resistance protein).
Dosage
Standard Dosage
Adults:
The standard dose is 600 mg (two 300 mg tablets) orally twice daily, approximately 12 hours apart, with or without food. Treatment continues until disease progression or unacceptable toxicity.
Children:
The safety and efficacy of rucaparib in children have not been established.
Special Cases:
- Elderly Patients: No dose adjustments are required unless there is evidence of renal or hepatic dysfunction. Some older individuals may have increased sensitivity to side effects.
- Patients with Renal Impairment: No dose adjustment is necessary for mild or moderate renal impairment (CrCl ≥30 mL/minute). For severe renal impairment (CrCl <30 mL/minute), rucaparib is not recommended unless the potential benefit outweighs the risk.
- Patients with Hepatic Dysfunction: No dose adjustment is necessary for mild or moderate hepatic impairment. Rucaparib is not recommended in patients with severe hepatic impairment.
- Patients with Comorbid Conditions: Close monitoring is essential for patients with comorbid conditions, especially those affecting renal or hepatic function. Careful evaluation of risks and benefits is needed.
Clinical Use Cases
Rucaparib is not indicated for use in the settings of intubation, surgical procedures, mechanical ventilation, intensive care unit (ICU) use, or emergency situations. It is specifically intended as an anticancer therapy in the maintenance setting or after multiple lines of chemotherapy.
Dosage Adjustments
Dose reductions may be required if a patient experiences adverse reactions. Recommended reductions follow a stepwise approach (600 mg BID -> 500 mg BID -> 400 mg BID -> 300 mg BID).
Side Effects
Common Side Effects
Nausea, vomiting, fatigue, rash, low blood counts (thrombocytopenia, anemia, leukopenia, neutropenia), constipation, decreased appetite, taste changes, abdominal pain, elevated liver enzymes, elevated cholesterol levels, headache, dizziness, diarrhea.
Rare but Serious Side Effects
Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), severe thrombocytopenia, severe anemia, severe neutropenia, severe hepatic dysfunction, and embryo-fetal toxicity.
Long-Term Effects
Secondary malignancies such as MDS/AML are potential long-term complications. Chronic fatigue and other persistent side effects may also occur.
Adverse Drug Reactions (ADR)
Severe hematologic toxicities, including MDS/AML, require immediate discontinuation of rucaparib. Severe liver injury is also a serious ADR requiring intervention.
Contraindications
Hypersensitivity to rucaparib. Breastfeeding.
Drug Interactions
Rucaparib interacts with many drugs, including strong and moderate CYP3A4 inhibitors and inducers, some opioids, benzodiazepines, NSAIDs, antidepressants, and others. Refer to a comprehensive drug interaction database for a complete list. Alcohol and food interactions are not considered clinically significant.
Pregnancy and Breastfeeding
Pregnancy: Rucaparib is contraindicated during pregnancy due to the risk of embryo-fetal toxicity. Effective contraception should be used during treatment and for 6 months following the last dose for female patients, and for 3 months following the last dose for male patients.
Breastfeeding: Rucaparib is contraindicated during breastfeeding. Women should not breastfeed during treatment and for 2 weeks after the final dose.
Drug Profile Summary
- Mechanism of Action: PARP inhibitor, induces synthetic lethality in BRCA-mutated cancer cells.
- Side Effects: Nausea, vomiting, fatigue, myelosuppression, hepatotoxicity.
- Contraindications: Pregnancy, breastfeeding, hypersensitivity.
- Drug Interactions: Numerous drug interactions, particularly with CYP3A4 modulators. Consult a drug interaction database.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 600 mg BID orally. Adjustments may be needed based on adverse effects.
- Monitoring Parameters: Complete blood counts (CBC) monthly, liver function tests (LFTs), renal function, and BRCA mutation status before treatment initiation.
Popular Combinations
Rucaparib is generally used as monotherapy. Combined use with other anticancer therapies needs careful consideration due to potential overlapping toxicities.
Precautions
- General Precautions: Monitor for hematological toxicity, hepatic function, and renal function. Ensure patients are tested for BRCA mutation status before treatment. Advise patients on effective contraception.
- Specific Populations: See above sections for pregnancy, breastfeeding, children, elderly, renal/hepatic dysfunction.
- Lifestyle Considerations: Patients should avoid prolonged sun exposure and use sun protection.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Rucaparib?
A: The standard recommended dose is 600 mg orally twice daily for adults. Dosage adjustments are made for toxicity but not specifically for age, renal or hepatic impairment.
Q2: What is the mechanism of action of Rucaparib?
A: Rucaparib is a PARP inhibitor that selectively targets cancer cells with BRCA mutations. It inhibits PARP enzymes, which are involved in DNA repair, leading to DNA damage accumulation and ultimately cell death.
Q3: What are the most common side effects of Rucaparib?
A: Common side effects include nausea, vomiting, fatigue, low blood cell counts (anemia, thrombocytopenia, neutropenia), constipation, decreased appetite, changes in taste, and abdominal pain.
Q4: What are the serious side effects of Rucaparib?
A: Serious side effects include myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), severe low blood counts, and embryo-fetal toxicity.
Q5: Can Rucaparib be used during pregnancy or breastfeeding?
A: No, Rucaparib is contraindicated in pregnancy and breastfeeding due to potential harm to the fetus or neonate.
Q6: What are the key drug interactions with Rucaparib?
A: Rucaparib interacts with many drugs, notably CYP3A4 inhibitors and inducers. Refer to a comprehensive drug interaction database for a complete list before initiating therapy.
Q7: What monitoring parameters are essential for patients on Rucaparib?
A: Complete blood count (CBC) monitoring is necessary monthly due to the risk of myelosuppression. Liver and renal function should also be monitored.
Q8: How should Rucaparib be administered?
A: Rucaparib is administered orally twice daily with or without food. The tablets should be swallowed whole and not crushed, chewed, or dissolved.
Q9: Are there any dietary restrictions while taking Rucaparib?
A: There are no specific dietary restrictions, but patients should maintain a healthy diet and discuss any concerns with their healthcare provider.
Q10: How long is Rucaparib treatment usually continued?
A: Treatment is typically continued until disease progression or unacceptable toxicity occurs.
