Based on data from Study B7461001, exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure. In 295 patients who received lorlatinib at the recommended dosage of 100 mg once daily and had an ECG measurement in the same Study B7461001, the maximum mean change from baseline for their PR interval was 16.4 ms (2-sided 90% upper confidence interval [CI] 19.4 ms). Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation ≥200 ms after starting use with lorlatinib. The prolongation of PR interval occurred in a concentration-dependent manner and atrioventricular block occurred in 1% of patients. Finally, in 275 patients who received lorlatinib at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected.

Use in Cancer

Lorlatinib is approved to treat adults with:

• Non-small cell lung cancer that is ALK-positive and has metastasized (spread to other parts of the body).
• Lorlatinib is an anaplastic lymphoma kinase inhibitor used to treat anaplastic lymphoma kinase positive metastatic non small cell lung cancer.

Lorlatinib is also being studied in the treatment of other types of cancer.

Contraindications

• Lorlatinib must not be combined with strong inducers (i.e. activators) of the liver enzymes CYP3A4/5 if it can be avoided, as serious cases of liver toxicity have been observed under combination with the CYP3A4/5 inducer rifampicin
• high cholesterol
• high amount of triglyceride in the blood
• suicidal thoughts
• high blood pressure
• atrioventricular block, a type of slow heart rhythm disorder
• a type of inflammation of the lung called interstitial pneumonitis
• seizures
• pregnancy
• a patient who is producing milk and breastfeeding
• chronic kidney disease stage 4 (severe)
• chronic kidney disease stage 5 (failure)

Dosage

Strengths: 25 mg; 100 mg

Non-Small Cell Lung Cancer

• 100 mg orally once a day
• Select patients for the treatment of metastatic non-small cell lung cancer (NSCLC) based on the presence of ALK positivity in tumor specimens.
• Therapy should be continued until disease progresses or unacceptable toxicity.
• For the treatment of adult patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test

Renal Dose Adjustments

• Mild or moderate renal dysfunction (CrCl 30 to 89 mL/min): No adjustment is recommended.
• Severe renal dysfunction (CrCl 15 to less than 30 mL/min): 75 mg orally once a day

Liver Dose Adjustments

• Mild liver dysfunction (total bilirubin less than or equal to the upper limit of normal (ULN) with AST greater than ULN or total bilirubin greater than 1 to 1.5 x ULN with any AST): No adjustment recommended.
• Moderate or severe live dysfunction: Data not available

Dose Adjustments

Dose Modifications for Adverse Reactions:

• First dose reduction: 75 orally once a day
• Second dose reduction: 50 mg orally once a day
• Permanently discontinue therapy in patients who are unable to tolerate 50 mg orally once daily.

Central Nervous System Adverse Effects:

• Grade 1: Continue at the same dose or withhold the dose until recovery to baseline; resume at the same dose or at reduced dose.
• Grade 2 or 3: Withhold dose until recovery to Grade 0 or 1; resume at a reduced dose.
• Grade 4: Permanently discontinue therapy.

Hyperlipidemia:

Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia: Withhold until recovery to Grade 2 or less; resume at the same dose. If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume at a reduced dose.

Atrioventricular (AV) Block:

• Second-degree AV block: Withhold until PR interval is less than 200 ms; resume at a reduced dose.
• The first occurrence of complete AV block: Withhold until pacemaker placed OR PR interval is less than 200 ms; if a pacemaker is placed, resume at same dose; if no pacemaker is placed, resume at a reduced dose.
• Recurrent complete AV block: Place pacemaker or permanently discontinue this drug.

Interstitial Lung Disease (ILD)/Pneumonitis:

• Any Grade treatment-related ILD/pneumonitis: Permanently discontinue this drug.

Hypertension:

• Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 100 mmHg; medical intervention indicated; more than one antihypertensive drug, or more intensive therapy than previously used indicated): Withhold until hypertension has recovered to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume at the same dose.
• If Grade 3 hypertension recurs, withhold until recovery to Grade 1 or less, and resume at a reduced dose. Permanently discontinue, if adequate hypertension control cannot be achieved with optimal medical management.

Grade 4 (life-threatening consequences, urgent intervention indicated): Withhold until recovery to Grade 1 or less, and resume at a reduced dose or permanently discontinue. Permanently discontinue, if Grade 4 hypertension recurs.

Hyperglycemia:

Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4: Withhold until hyperglycemia is adequately controlled, then resume at the next lower dosage. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue

Other Adverse Reactions:

• Grade 1 or 2: Continue at the same or reduced dose.
• Grade 3 or 4: Withhold until symptoms resolve to Grade 2 or less or baseline; resume at a reduced dose.

Concomitant Use of Strong CYP450 3A Inducers:

• This drug is contraindicated in patients taking strong CYP450 3A inducers. Discontinue strong CYP450 3A inducers for 3 plasma half-lives prior to initiating this drug.

Concomitant Use of Moderate CYP450 3A Inducers:

• Avoid concomitant use of this drug with moderate CYP450 3A inducers.
• If concomitant use with moderate CYP450 3A inducers is unavoidable, increase the dose of this drug to 125 mg once a day.

Dose Modification for Strong CYP450 3A Inhibitors:

• Avoid concomitant use of this drug with strong CYP450 3A inhibitors. If concomitant use with a strong CYP450 3A inhibitor cannot be avoided, reduce the starting dose of this drug from 100 mg once a day to 75 mg orally once a day.
• In patients who have had a reduction to 75 mg orally once a day due to adverse reactions and who initiate a strong CYP450 3A inhibitor, reduce the dose of this drug to 50 mg orally once a day.
• If concomitant use of a strong CYP450 3A inhibitor is discontinued, increase the dose of this drug (after 3 plasma half-lives of the strong CYP450 3A inhibitor) to the dose that was used before starting the strong inhibitor.

Administration advice:

• This drug may be taken with or without food.
• Swallow tablets whole, do not chew, crush or split.
• Do not ingest if tablets are broken, cracked, or otherwise not intact.
• If a dose is missed, take the missed dose unless the next dose is due within 4 hours; do not take 2 doses at the same time to make up for a missed dose.
• Do not take an additional dose if vomiting occurs but continue with the next scheduled dose

Monitoring:

• Monitor blood pressure after 2 weeks and then at least monthly during treatment.
• Monitor serum cholesterol and triglycerides before initiating treatment, after 1 and 2 months during treatment, and periodically thereafter.
• Monitor ECG prior to initiating treatment and periodically thereafter.
• Obtain fasting serum glucose prior to initiating treatment and monitor periodically thereafter.

Patient advice:

• Advise the patient to read the FDA-approved patient labeling (Patient Information).
• Inform patients of the potential risk of hepatotoxicity with the concomitant use of strong CYP450 3A inducers.
• Advise patients to inform their healthcare providers of all medications they are taking, including prescription medicines, over-the-counter drugs, vitamins, and herbal products (e.g., St. John’s wort).
• Advise patients to notify their healthcare provider if they experience new or worsening CNS symptoms.
• Advise patients that initiation or an increase in the dose of lipid-lowering agents may be required, depending on measured readings.
• Advise patients to contact their healthcare provider immediately to report new or worsening cardiac symptoms.
• Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms.
• Advise patients of the risks of hypertension and to promptly report signs or symptoms of hypertension to their healthcare provider and that antihypertension medications may need to be initiated or adjusted during treatment.
• Advise patients with newly occurring hyperglycemia during treatment that antihyperglycemic medications may need to be initiated.
• Inform patients with diabetes mellitus or glucose intolerance to monitor glucose levels periodically and that antihyperglycemic medications may need to be adjusted during treatment , depending on reading.
• Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
• Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for at least 6 months after the final dose.
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose
• Advise women not to breastfeed during treatment and for 7 days after the final dose.
• Advise males of reproductive potential that this drug may transiently impair fertility.

Side Effects

The Most Common

• weight gain
• muscle, joint, or back pain
• diarrhea
• constipation
• nausea
• vomiting
• tiredness
• headache
• vision changes
• rash or itching
• swelling in your arms, legs, hands and feet
• difficulty breathing
• shortness of breath, cough, or fever
• numbness and tingling feeling in your joints or arms and legs
• difficulty thinking or confusion
• seizures
• seeing things or hearing voices that do not exist
• changes in mood, feeling sad or anxious
• problems with speech
• difficulty falling asleep or staying asleep
• unusual dreams or nightmares
• headache, dizziness, blurred vision, feeling faint, chest pain, or shortness of breath
• feeling more hungry or thirsty than usual, increased urination, extreme tiredness, weakness, confusion, or breath that smells fruity

More common

• Actions that are out of control
• aggression
• agitation
• anxiety
• black, tarry stools
• bleeding gums
• blood in the urine or stools
• blurred vision or other changes in vision
• body aches or pain
• burning, crawling, itching, numbness, prickling, “pins and needles”, tingling, or painful sensations
• changes in behavior
• chills
• cough
• defects in intelligence, short-term memory, learning ability, and attention
• difficult or labored breathing
• difficulty in breathing
• discouragement
• dizziness
• dry mouth
• ear congestion
• false or unusual sense of well-being
• feeling sad or empty
• fever
• flushed, dry skin
• fruit-like breath odor
• headache
• hoarseness
• increased hunger
• increased thirst
• increased urination
• irritability
• lack of appetite
• loss of interest or pleasure
• loss of voice
• lower back or side pain
• nausea
• nervousness
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• runny or stuffy nose
• seeing, hearing, or feeling things that are not there
• skin rash
• slow or fast heartbeat
• sneezing
• sore throat
• stomach pain
• sweating
• swelling
• talking, feeling, and acting with excitement
• thoughts of killing oneself
• tightness in the chest
• trouble concentrating
• trouble sleeping
• trouble breathing
• unexplained weight loss
• unsteadiness or awkwardness
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• weakness in the arms, hands, legs, or feet

Rare

• Abnormal dreams
• back pain
• constipation
• difficulty in moving
• difficulty in speaking
• drowsiness
• joint pain
• muscle aches, cramps, pains, or stiffness
• pain in the arms or legs
• sleep talking
• swollen joints

Drug Interaction

Pregnancy and Lactation

Pregnancy

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], LORBRENA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on LORBRENA use in pregnant women. Administration of lorlatinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at the recommended dose of
100 mg once daily based on AUC (see Data). Advise a pregnant woman of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

Lactation

There are no data on the 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 the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose.