Lynparza

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Olaparib may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• diarrhea
• heartburn
• headache
• decreased appetite
• muscle, joint, or back pain
• stomach pain or discomfort
• taste changes
• anxiety
• depression
• dry skin
• itching
• rash
• difficulty falling asleep or staying asleep
• sore throat, runny nose, or other cold symptoms
• pain urinating

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• fever, cough, or wheezing
• shortness of breath
• weakness
• extreme tiredness
• weight loss
• numbness, tingling, or burning sensation in the hands or feet
• unusual bruising or bleeding
• pale skin
• blood in urine or stool

Olaparib may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Oral Administration

To avoid substitution errors and overdose, do not substitute olaparib tablets with olaparib capsules on a mg-to-mg basis due to differences in the dosing and bioavailability of each formulation

Tablets or capsules: May take with or without food

Swallow tablets whole; do not chew, crush, dissolve or divide

Swallow capsules whole; do not chew, dissolve, or open

Do not take capsules that appear deformed or show evidence of leakage

Missed dose: Instruct patient to take their next dose at its scheduled time

Olaparib is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Olaparib is used to treat advanced ovarian cancer in women with a certain abnormal inherited gene. Olaparib is usually given after at least 3 other cancer medicines have been tried without success.

Olaparib was approved by the US Food and Drug Administration (FDA) on an "accelerated" basis. In clinical studies, olaparib produced complete or partial response in many women. However, further studies are needed to determine if this medicine can lengthen survival time.

Olaparib may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use olaparib if you are allergic to it.

To make sure olaparib is safe for you, tell your doctor if you have:

• liver disease;
• kidney disease; or
• lung disease or breathing problems.

Do not use olaparib if you are pregnant. It could harm the unborn baby. Tell your doctor if you become pregnant during treatment. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 1 month after your treatment ends.

It is not known whether olaparib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

• Astrazeneca

Take Lynparza exactly as prescribed.

Lynparza comes in capsule form and is taken 2 times every day. Do not chew, divide, or break Lynparza capsules. Swallow capsules whole.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take 2 doses of Lynparza at the same time.

Your doctor will perform a blood test to make sure olaparib is the right treatment for your condition.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Do not crush, chew, dissolve, or break an olaparib capsule or tablet. Swallow the pill whole.

If your doctor changes your brand, strength, or type of olaparib, your dosage needs may change. Ask your pharmacist if you have any questions about the olaparib pills you receive at the pharmacy.

Olaparib capsules must not be used as a substitute for olaparib tablets. These two pill forms are not taken in the same dosage amounts.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Olaparib can lower blood cells that help your body fight infections and help your blood to clot. You will need weekly or monthly blood tests. You may also need chest x-rays to be sure this medicine is not causing harmful effects on your lungs. Your cancer treatments may be delayed based on the results of these tests.

Store at room temperature away from moisture and heat.

Do not use any olaparib capsule that has been exposed to high heat (higher than 104 degrees).

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Contraindications

• Manufacturer states none known.1

Warnings/Precautions

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)

MDS and AML reported in <1% of olaparib-treated patients; most cases (77%) were fatal.1 5 All patients with MDS/AML had received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents.1 The duration of olaparib therapy in patients who developed MDS/AML ranged from <6 months to >2 years.1

Monitor CBC at baseline and monthly thereafter.1 Delay initiation of olaparib until patients have recovered from hematologic toxicity caused by previous chemotherapy (≤grade 1).1

If prolonged hematologic toxicity occurs during therapy, interrupt therapy and monitor CBC weekly until recovery to ≤grade 1.1

If myelosuppression persists for >4 weeks following interruption of therapy, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.1 If MDS/AML is confirmed, discontinue olaparib.1

Pneumonitis

Pneumonitis, sometimes fatal, reported in <1% of patients.1 12

If patient develops new or worsening pulmonary symptoms (see Advice to Patients) or a radiologic abnormality occurs, interrupt therapy and initiate prompt diagnostic evaluation.1 12 If pneumonitis is confirmed, discontinue olaparib and treat appropriately.1 12

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; teratogenicity, embryotoxicity, fetotoxicity, and embryolethality demonstrated in animals.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use highly effective contraceptive methods while receiving olaparib and for ≥1 month after the drug is discontinued.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard and risk for loss of the pregnancy.1

Specific Populations

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether olaparib is distributed into milk.1 Discontinue nursing or the drug.1

Safety, efficacy, and pharmacokinetics not established in pediatric patients.1 12

In clinical studies in patients with advanced solid tumors (the majority [69%] had ovarian cancer), 20% of patients were ≥65 years of age.1 Safety profile was similar regardless of patient age, except for an increased incidence of ≥grade 3 adverse reactions in geriatric patients relative to younger adults.1

Safety, efficacy, and pharmacokinetics not studied in patients with hepatic impairment.1

Patients with serum bilirubin concentrations >1.5 times ULN and ALT and/or AST concentrations ≥2.5 times ULN in the absence of liver metastases or ALT and/or AST concentrations >5 times ULN in the presence of liver metastases were excluded from clinical trials.1

Increased exposure observed in patients with mild renal impairment (Clcr of 50–80 mL/minute).1 (See Absorption under Pharmacokinetics.)

Not studied in patients with moderate or severe renal impairment (Clcr <50 mL/minute) or in those receiving dialysis.1

Common Adverse Effects

Adverse effects: Fatigue (including asthenia),1 2 nausea,1 2 abdominal pain or discomfort,1 2 vomiting,1 2 diarrhea,1 2 nasopharyngitis or pharyngitis,1 dyspepsia,1 back pain,1 headache,1 dermatitis or rash,1 decreased appetite,1 myalgia,1 arthralgia or musculoskeletal pain,1 cough,1 dysgeusia.1 2

Laboratory abnormalities: Anemia,1 2 elevated mean corpuscular volume (MCV),1 lymphopenia,1 thrombocytopenia,1 elevated Scr concentrations,1 neutropenia.1

Patient Selection

Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see http://www.fda.gov/companiondiagnostics.

Important Administration Instructions

Lynparza is also available as 100 mg and 150 mg tablets. DO NOT substitute Lynparza capsules (50 mg) with Lynparza tablets (100 mg and 150 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Refer to the full prescribing information for Lynparza tablets for specific tablet dosing.

Recommended Dosing

The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken orally twice daily with or without food, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.

If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time.

Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2)].

Dose Adjustments for Adverse Reactions

To manage adverse reactions, consider dose interruption of treatment or dose reduction.

The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.

If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.

Dose Modifications for Use with CYP3A Inhibitors

Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2)].

Dose Modifications for Patients with Renal Impairment

Patients with mild renal impairment (CLcr 51-80 mL/min as estimated by Cockcroft-Gault) do not require an adjustment in Lynparza dosing. In patients with moderate renal impairment (CLcr 31-50 mL/min) the recommended dose reduction is to 300 mg (six 50 mg capsules) taken twice daily, for a total daily dose of 600 mg. The pharmacokinetics of olaparib have not been evaluated in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Mechanism of Action

Lynparza is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.

Pharmacokinetics

Absorption

Following oral administration of olaparib via the capsule formulation, absorption is rapid with peak plasma concentrations typically achieved between 1 to 3 hours after dosing. On multiple dosing there is no marked accumulation (accumulation ratio of 1.4 – 1.5 for twice daily dosing), with steady state exposures achieved within 3 to 4 days.

Limited data suggest that the systemic exposure (AUC) of olaparib increases less than proportionally with dose over the dose range of 100 to 400 mg, but the PK data were variable across trials.

Co-administration with a high fat meal slowed the rate (Tmax delayed by 2 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 20%).

Distribution

Olaparib had a mean (± standard deviation) apparent volume of distribution at steady state of 167 ± 196 L after a single 400 mg dose of olaparib. The in vitro protein binding of olaparib at plasma concentrations achieved following dosing at 400 mg twice daily is approximately 82%.

Metabolism

In vitro, CYP3A4 was shown to be the enzyme primarily responsible for the metabolism of olaparib.

Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating radioactivity in plasma (70%). It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.

Excretion

A mean (± standard deviation) terminal plasma half-life of 11.9 ± 4.8 hours and apparent plasma clearance of 8.6 ± 7.1 L/h were observed after a single 400 mg dose of olaparib.

Following a single dose of 14C-olaparib, 86% of the dosed radioactivity was recovered within a 7-day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites.

Drug Interactions

Based on the data from a drug-interaction trial (N=57), the AUC and Cmax of olaparib increased by 2.7- and 1.4-fold, respectively, when olaparib was administered in combination with itraconazole, a strong CYP3A inhibitor. Simulations suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 2.2- and 1.2-fold, respectively.

Based on the data from a drug-interaction trial (N=22), the AUC and Cmax of olaparib decreased by 87% and 71%, respectively, when olaparib was administered in combination with rifampicin, a strong CYP3A inducer. Simulations suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by approximately 50% and 30%, respectively.

In vitro studies have shown that olaparib is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6. Simulations suggested that olaparib may not affect the exposure of a CYP3A substrate in humans. It cannot be excluded that olaparib may induce CYP2C9 and CYP2C19. In vitro studies also indicated that olaparib is a substrate of P-gp and an inhibitor of P-gp (MDR1), BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown. The potential for olaparib to induce P-gp has not been evaluated.

Pharmacokinetics in Specific Populations

Hepatic Impairment

In a hepatic impairment trial, the mean AUC increased by 15% and the mean Cmax by 13% when olaparib was dosed in patients with mild hepatic impairment (Child-Pugh classification A; N=9) compared with patients with normal hepatic function (N=13). Mild hepatic impairment had no effect on the protein binding of olaparib and therefore total plasma exposure was representative of free drug. There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment

In a dedicated renal impairment trial, the mean AUC and Cmax of olaparib both increased by 1.2-fold, when olaparib was dosed in patients with mild renal impairment (CLcr = 51-80 mL/min defined by the Cockcroft-Gault equation; N=13) and by 1.4- and 1.3-fold, respectively, when olaparib was dosed in patients with moderate renal impairment (CLcr = 31-50 mL/min; N=13), compared to those with normal renal function (CLcr ≥81 mL/min; N=12). There was no evidence of a relationship between the extent of plasma protein binding of olaparib and creatinine clearance. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤ 30 mL/min).

How Supplied

Lynparza 50 mg is a white, opaque, hard capsule, marked in black ink with: “OLAPARIB 50 mg” on the cap and AstraZeneca logo on the body; available in:

Storage

Store at 25ºC (77ºF), excursions permitted to 15ºC-30ºC (59ºF-86ºF) [see USP Controlled Room Temperature]

Lynparza should not be exposed to temperatures greater than 40ºC or 104ºF. Do not take Lynparza if it is suspected of having been exposed to temperatures greater than 40ºC or 104ºF.

NDC 0310-0657-58

Lynparza™

olaparib

50 mg capsules

Oral use

112 Capsules

Rx only

AstraZeneca

Applies to olaparib: oral capsule, oral tablet

Oncologic

Uncommon (0.1% to 1%): Myelodysplastic syndrome/Acute Myeloid Leukemia[Ref]

Hematologic

Very common (10% or more): Decreased hemoglobin (up to 90%), elevated mean corpuscular volume (up to 85%), decreased lymphocytes (up to 56%), anemia (up to 34%), decreased absolute neutrophil count (up to 32%), decreased platelets (up to 30%)
Common (1% to 10%): Leukopenia[Ref]

Respiratory

Very common (10% or more): Nasopharyngitis/pharyngitis/upper respiratory infection (up to 43%), cough (up to 21%), dyspnea
Common (1% to 10%): Pulmonary embolism
Uncommon (0.1% to 1%): Pneumonitis[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 75%), abdominal pain/discomfort (up to 47%), vomiting (up to 43%), diarrhea (up to 31%), dyspepsia (up to 25%), constipation
Common (1% to 10%): Stomatitis[Ref]

Other

Very common (10% or more): Fatigue/asthenia/lethargy (up to 68%), peripheral edema
Common (1% to 10%): Pyrexia[Ref]

Renal

Very common (10% or more): Increased creatinine (up to 30%)[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia/musculoskeletal pain (up to 32%), myalgia (up to 25%), back pain (up to 25%)[Ref]

Cardiovascular

Common (1% to 10%): Hypertension, hot flush, venous thrombosis[Ref]

Dermatologic

Very common (10% or more): Dermatitis/rash (up to 25%)
Common (1% to 10%): Dry skin, eczema, pruritus[Ref]

Genitourinary

Very common (10% or more): Urinary tract infection
Common (1% to 10%): Dysuria, urinary incontinence, vulvovaginal disorder[Ref]

Metabolic

Very common (10% or more): Decreased appetite (up to 25%)
Common (1% to 10%): Hypomagnesemia, hyperglycemia[Ref]

Nervous system

Very common (10% or more): Headache (up to 25%), dysgeusia (up to 21%), dizziness
Common (1% to 10%): Peripheral neuropathy[Ref]

Psychiatric

Common (1% to 10%): Anxiety, depression, insomnia[Ref]

Some side effects of Lynparza may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.