Olatab

Approved Indications (Adults):

• Advanced Ovarian Cancer:
• Maintenance treatment of adults with BRCA-mutated (germline or somatic) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy.
• Maintenance treatment for platinum-sensitive relapsed ovarian cancer, regardless of BRCA status.
• Monotherapy in BRCA-mutated advanced ovarian cancer after ≥3 lines of chemotherapy.
• Breast Cancer:
• Treatment of germline BRCA-mutated (gBRCA), HER2-negative, metastatic breast cancer in adults who have been previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.
• Pancreatic Cancer:
• Maintenance treatment of adults with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed following ≥16 weeks of first-line platinum-based chemotherapy.
• Prostate Cancer:
• Treatment of adults with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone.

Important Off-Label/Clinically Accepted Uses:

• Endometrial and gastric cancers with DDR gene mutations (under investigation).
• Small cell lung cancer, biliary tract cancers, and melanoma in combination with other agents in clinical trials.
• Combination therapy with immune checkpoint inhibitors (e.g., durvalumab) in HR-deficient tumors.

Route of Administration: Oral (film-coated tablets).

Recommended Dose (Adults):

• 300 mg orally twice daily (total 600 mg/day) until disease progression or unacceptable toxicity.

Special Populations:

• Pediatrics:
  Not indicated. Safety and efficacy not established.
• Elderly:
  No dose adjustment required based on age alone. Monitor renal function.
• Renal Impairment:
• Mild (CrCl 51–80 mL/min): No adjustment.
• Moderate (CrCl 31–50 mL/min): Reduce to 200 mg twice daily.
• Severe (CrCl <30 mL/min): Not recommended.
• Hepatic Impairment:
• Mild (Child-Pugh A): No adjustment.
• Moderate/Severe: Insufficient data; use with caution.

Administration Guidelines:

• Swallow tablets whole with water.
• May be taken with or without food.
• If a dose is missed, take as soon as remembered unless next dose is due within 2 hours.

Olaparib is a PARP inhibitor (poly [ADP-ribose] polymerase), specifically inhibiting PARP-1 and PARP-2 enzymes. These enzymes are essential for repairing single-strand DNA breaks via the base excision repair (BER) pathway. In cancer cells with deficient homologous recombination repair (HRR), such as BRCA1/2-mutated cells, inhibition of PARP leads to accumulation of DNA damage, resulting in double-strand breaks and cell death—a process known as synthetic lethality. Additionally, Olaparib traps PARP enzymes on damaged DNA, further enhancing cytotoxicity in HR-deficient tumors.

• Absorption: Rapid; peak plasma concentration reached in 1.5–3 hours after oral administration.
• Bioavailability: Moderate (exact figure not defined due to formulation differences).
• Distribution: Volume of distribution ~158 L; plasma protein binding ~82%.
• Metabolism: Extensively metabolized in the liver, primarily via CYP3A4.
• Active Metabolites: None; metabolites are inactive.
• Elimination Half-life: ~14 to 15 hours.
• Excretion:
• ~44% in urine
• ~42% in feces (mostly as metabolites)
• Steady-State: Achieved in approximately 3–4 days with twice-daily dosing.

• Pregnancy:
• Contraindicated in pregnancy due to teratogenicity and embryofetal toxicity observed in animal studies.
• Women of reproductive potential must use effective contraception during treatment and for at least 6 months after the final dose.
• Lactation:
• Contraindicated during breastfeeding.
• Unknown if excreted into human milk.
• Discontinue breastfeeding during treatment and for at least 1 month after the last dose due to potential for serious adverse effects in infants.

• Primary Class: Antineoplastic Agent
• Subclass: PARP Inhibitor (Poly [ADP-ribose] Polymerase Inhibitor)
• Mechanism-based Class: Targeted DNA Damage Repair Inhibitor

• Known hypersensitivity to Olaparib or any component of the formulation.
• Pregnancy and breastfeeding.
• Severe renal impairment (CrCl <30 mL/min).
• Concomitant use with strong CYP3A inducers (e.g., rifampin, phenytoin).

• Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML):
  Rare but serious risk. Monitor complete blood count (CBC) at baseline and monthly thereafter.
• Pneumonitis:
  Reported in clinical trials. Discontinue immediately if suspected.
• Bone Marrow Suppression:
  Anemia, neutropenia, and thrombocytopenia may occur. Monitor CBCs regularly.
• Renal Impairment:
  Dose adjustment required in moderate impairment. Avoid in severe renal dysfunction.
• Drug Interactions:
  Avoid concomitant use with strong CYP3A4 inducers/inhibitors.
• Fertility:
  Olaparib may impair fertility in both males and females based on animal data.

Common (≥10%):

• Hematologic: Anemia, neutropenia, thrombocytopenia
• Gastrointestinal: Nausea, vomiting, diarrhea, dyspepsia, decreased appetite
• General: Fatigue, headache, dizziness
• Respiratory: Cough, dyspnea

Serious and Rare:

• Myelodysplastic syndrome (MDS)
• Acute myeloid leukemia (AML)
• Pneumonitis
• Severe infections
• Hypersensitivity reactions
• Secondary malignancies (rare)

Onset Timing:

• Hematologic toxicities typically develop within 8 weeks of therapy initiation.
• GI and fatigue may begin within the first few days and often improve over time.

• Strong CYP3A Inhibitors (e.g., Itraconazole, Clarithromycin):
  ↑ Olaparib plasma levels → ↑ toxicity. Consider dose reduction or avoid.
• Strong CYP3A Inducers (e.g., Rifampin, Carbamazepine, St. John’s Wort):
  ↓ Olaparib exposure → ↓ efficacy. Avoid use.
• Moderate CYP3A inhibitors/inducers:
  Use with caution; monitor closely.
• Food Interactions:
  Food does not significantly affect absorption. Can be taken with or without meals.
• Alcohol:
  No direct interaction, but caution due to potential CNS effects (fatigue, dizziness).

• FDA Updates (2023–2024):
• Expanded indication for BRCA-mutated metastatic prostate cancer.
• Reinforced warnings for MDS/AML and pneumonitis in prescribing information.
• Guideline Endorsements:
• NCCN, ESMO, and ASCO recommend Olaparib for maintenance and treatment settings in BRCA-mutated cancers.
• HRR gene panel testing is encouraged prior to initiation.
• Ongoing Trials:
• Combinations with immune checkpoint inhibitors and anti-angiogenic agents are being evaluated for broader solid tumor indications.

• Storage Temperature:
• Store at 20°C to 25°C (68°F to 77°F).
• Excursion permitted to 15°C to 30°C (59°F to 86°F).
• Humidity & Light:
• Protect from moisture and direct light.
• Keep in original container until use.
• Handling Precautions:
• Do not crush, chew, or split tablets.
• Wash hands before and after handling.
• Dispose of unused medication properly, per local regulations.