lorlatinib (Rx)

All grades of severity listed unless otherwise specified

>10%

Hypercholesterolemia (96%)

Hypertriglyceridemia (90%)

Edema (57%)

Hyperglycemia (52%)

Anemia (52%)

Peripheral neuropathy (47%)

Increased AST (37%)

Hypoalbuminemia (33%)

Increased ALT (28%)

Cognitive effects (27%)

Dyspnea (27%)

Fatigue (26%)

Weight gain (24%)

Increased lipase (24%)

Increased alkaline phosphatase (24%)

Thrombocytopenia (23%)

Arthralgia (23%)

Mood effects (23%)

Diarrhea (22%)

Increased amylase (22%)

Lymphopenia (22%)

Hyperkalemia (21%)

Hypomagnesemia (21%)

Headache (18%)

Cough (18%)

Nausea (18%)

Myalgia (17%)

Dizziness (16%)

Vision disorder (15%)

Constipation (15%)

Rash (14%)

Back pain (13%)

Pain in extremity (13%)

Vomiting (12%)

Speech effects (12%)

Pyrexia (12%)

Upper respiratory tract infection (12%)

Grades 3 or 4

• Hypercholesterolemia (18%)
• Hypertriglyceridemia (18%)

1-10% (All Grades)

Sleep effects (10%)

Hallucinations (7%)

Pneumonia (3.4%)

Dyspnea (2.7%)

Pyrexia (2%)

Mental status changes (1.4%)

Respiratory failure (1.4%)

1-10% (Grades 3 or 4)

Dyspnea (5.4%)

Hyperglycemia (5%)

Hypophosphatemia (4.8%)

Anemia (4.8%)

Increased amylase (3.9%)

Lymphopenia (3.4%)

Peripheral neuropathy (2.7%)

Increased AST/ALT (2.1%)

Cognitive effects (2%)

Mood effects (1.7%)

Vomiting (1%)

Increased alkaline phosphatase (1%)

Hypokalemia (1%)

Hypoalbuminemia (1%)

<1% (Grades 3 or 4)

Vision disorder

Nausea

Diarrhea

Headache

Dizziness

Speech effects

Arthralgia

Myalgia

Back pain

Pain in extremity

Fatigue

Pyrexia

Rash

Thrombocytopenia

Contraindications

Coadministration with strong CYP3A inducers due to potential for serious hepatotoxicity

Cautions

Increased serum cholesterol and triglycerides may occur; initiate or increase dose of lipid-lowering agents in patients with hyperlipidemia; monitor serum cholesterol and triglycerides

PR interval prolongation and AV block reported; monitor ECG before initiating treatment and periodically thereafter

Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis can occur

Hypertension reported; median time to onset was 6.4 months (1 day to 2.8 years), and 2.3% of patients temporarily discontinued for hypertension; control blood pressure before initiating; monitor blood pressure after 2 weeks and at least monthly thereafter during treatment

Hyperglycemia can occur; median time to onset of hyperglycemia was 4.8 months (1 day to 2.9 years), and 0.8% of patients temporarily discontinued for hyperglycemia; assess fasting serum glucose prior to initiating and monitor periodically thereafter

Fetal harm may occur

Risk of serious hepatotoxicity with concomitant use of strong CYP3A inducers

• Serious hepatotoxicity occurred in healthy patients received a single dose of lorlatinib with multiple daily doses of rifampin (a strong CYP3A4 inducer)
• ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days; median time to recovery for Grade ≥3 was 18 days and for Grade 2 was 7 days

CNS effects

• A broad spectrum of CNS effects may occur
• These include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep
• Median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years)

Drug interactions overview

• CYP3A4 substrate; moderate CYP3A4 inducer and CYP2B6 inducer
• Inhibitor of P-gp and organic cation transporter (OCT)1, organic anion transporter (OAT)3, multidrug and toxin extrusion (MATE)1, and intestinal breast cancer resistance protein (BCRP)

• CYP3A4 inducers

  • Strong and moderate CYP3A inducers decrease lorlatinib plasma concentrations
  • Coadministration with strong CYP3A4 inducers are contraindicated and avoid use with moderate CYP3A4 inducers

• CYP3A4 inhibitors

  • Avoid coadministration
  • Strong CYP3A inhibitors increased lorlatinib plasma concentrations

• CYP3A substrates

  • Coadministration with certain CYP3A substrates decreases concentration of CYP3A substrates, which may reduce the efficacy of these substrates
  • Avoid use with CYP3A substrates with narrow therapeutic index; if coadministration unavoidable, increase dose of CYP3A substrate in accordance to prescribing information

• Fluconazole

  • Avoid coadministration
  • Fluconazole may increase lorlatinib plasma concentrations and risk of adverse reactions

Pregnancy

Based on findings from animal studies and its mechanism of action, embryo-fetal harm may occur when administered to a pregnant woman

No available data on use in pregnant women

Advise pregnant women of the potential risk to fetus

Verify pregnancy status in females of reproductive potential before initiating treatment

Animal data

• Administration of lorlatinib to pregnant rats and rabbits by oral gavage during organogenesis resulted in malformations, increased postimplantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at 100 mg qDay

Contraception

• Female patients of reproductive potential: Use effective nonhormonal contraception during treatment and for at least 6 months after final dose, because lorlatinib can render hormonal contraceptives ineffective
• Males: Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after final dose

Infertility

• Based on animal studies, male fertility may transiently be impaired

Lactation

No data on presence of lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production

Because of potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment and for 7 days after final dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

ALK/ROS1 tyrosine kinase inhibitor

ALK and ROS1 kinases promote tumor progression in ALK/ROS1 positive lung cancer; lorlatinib binds to and inhibits both kinases, which leads to a disruption of the ALK- and ROS1-mediated signaling; this disruption can subsequently inhibit tumor cell growth in ALK- and ROS1-overexpressing tumor cells

Absorption

Peak plasma concentration: 577 ng/mL

Peak plasma time: 1.2 hr (single 100-mg dose); 2 hr (100 mg qDay at steady-state)

AUC: 5650 ng·hr/mL

Bioavailability: 81%

Distribution

Vd (steady-state): 305 L

Protein bound: 66%

Metabolism

Metabolized primarily by CYP3A4 and UGT1A4; minor contributions by CYP2C8, CYP2C19, CYP3A5, and UGT1A3

Oxidative cleavage metabolite, M8, is pharmacologically inactive

Elimination

Half-life (single 100-mg dose): 24 hr

Oral clearance: 11 L/hr (single100-mg dose); 18 L/hr (steady-state)

Excretion (single 100-mg dose): Urine (48% [<1% unchanged]); feces (41% [~9% unchanged])

Oral Administration

Swallow tablets whole

Do not chew, crush, or split tablets

Do not ingest if tablets are broken, cracked, or otherwise not intact

Administer at same time each day

Missed dose

• If a dose is missed, then administer dose unless next dose is due within 4 hr
• Do not take 2 doses at the same time
• Do not take an additional dose if vomiting occurs after administration; continue with next scheduled dose

Storage

Tablets: Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)