LORBRENA (lorlatinib) 4 Dosage And Administration | Pfizer Medical Information

4.1 Dosing Considerations

Strong cytochrome P-450 (CYP)3A inhibitors: Concurrent use of LORBRENA (lorlatinib) with strong CYP3A inhibitors may increase lorlatinib plasma concentrations. Concomitant use of LORBRENA with strong CYP3A inhibitors should be avoided. An alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered (see 9 DRUG INTERACTIONS). If a strong CYP3A inhibitor must be co administered concomitantly, the LORBRENA dose of 100 mg once daily should be reduced to once daily 75 mg dose (see 9 DRUG INTERACTIONS and 10 CLINICAL PHARMACOLOGY). If concurrent use of a strong CYP3A inhibitor is discontinued, LORBRENA should be resumed at the dose used prior to the initiation of the strong CYP3A inhibitor and after a washout period of 3 to 5 half lives of the CYP3A inhibitor.
Dosing modification for Fluconazole: Avoid concomitant use of LORBRENA with fluconazole, based on Physiologically-Based Pharmacokinetic (PBPK) simulation. If concomitant use is unavoidable, reduce the starting dose of LORBRENA to 75 mg once daily.
Strong CYP3A inducers: LORBRENA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA.
Moderate CYP3A inducers: Avoid concomitant use with moderate CYP3A inducers as they may reduce lorlatinib plasma concentrations. If concomitant use is unavoidable, increase the starting dose of LORBRENA to 125 mg once daily.
Hepatic impairment: A formal hepatic impairment study has not been conducted with lorlatinib. No dose adjustments are recommended for patients with mild hepatic impairment. Limited information is available for LORBRENA in patients with moderate or severe hepatic impairment (see 10 CLINICAL PHARMACOLOGY).
Renal impairment: No dose adjustment is needed for patients with mild or moderate impairment [absolute estimated glomerular filtration rate ≥ 30 mL/min). Reduce the dose when administering LORBRENA in patients with severe renal impairment (absolute eGFR < 30 mL/min) from 100 mg to 75 mg orally once daily (see 10 CLINICAL PHARMACOLOGY). Lorlatinb is not recommended for patients requiring hemodialysis as information for use in these patients is very limited.

4.2 Recommended Dose and Dosage Adjustment

Recommended Dose:

The recommended dose of LORBRENA is 100 mg taken orally once daily continuously. Continue treatment with LORBRENA until disease progression or unacceptable toxicity.

LORBRENA may be taken with or without food (see 10 CLINICAL PHARMACOLOGY).

Pediatric patients (<8 years):

The safety and efficacy of LORBRENA in pediatric patients have not been established. Health Canada has not authorized an indication for pediatric use.

Geriatrics (≥ 65 years):

No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients (see 10 CLINICAL PHARMACOLOGY).

Dose Modifications:

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. Dose reduction levels are summarized below.

First dose reduction: LORBRENA 75 mg taken orally once daily
Second dose reduction: LORBRENA 50 mg taken orally once daily

LORBRENA should be permanently discontinued if the patient is unable to tolerate LORBRENA 50 mg taken orally once daily.

Dose modification recommendations for toxicities are provided in Table 1. Dose modification recommendations for patients who develop first-degree, second-degree, or complete atrioventricular (AV) block are provided in Table 2.

Table 1. LORBRENA Dose Modifications and Management Recommendations for Adverse Reactions
Adverse Reaction	LORBRENA Dosing
Abbreviations: CNS=central nervous system; CTCAE=Common Terminology Criteria for Adverse Events; HMG CoA=3-hydroxy-3-methylglutaryl coenzyme A; DBP=diastolic blood pressure; SBP= systolic blood pressure; ULN=upper limit of normal. a Lipid‑lowering therapy may include: HMG CoA reductase inhibitor, nicotinic acid, fibric acid, or ethyl esters of omega-3 fatty acids. b Examples of CNS effects comprise psychotic effects (including hallucination) and hallucination and changes in cognition, mood, mental status or speech (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS). c Grade categories are based on CTCAE classifications.
Hypercholesterolemia or Hypertriglyceridemia
Mild hypercholesterolemia (cholesterol between ULN and 300 mg/dL or between ULN and 7.75 mmol/L) OR Mild hypertriglyceridemia (triglycerides between 150 and 300 mg/dL or 1.71 and 3.42 mmol/L)	Introduce or modify lipid-lowering therapy^a in accordance with respective prescribing information; continue LORBRENA at same dose.
Moderate hypercholesterolemia (cholesterol between 301 and 400 mg/dL or between 7.76 and 10.34 mmol/L) OR Moderate hypertriglyceridemia (triglycerides between 301 and 500 mg/dL or 3.43 and 5.7 mmol/L)
Severe hypercholesterolemia (cholesterol between 401 and 500 mg/dL or between 10.35 and 12.92 mmol/L) OR Severe hypertriglyceridemia (triglycerides between 501 and 1000 mg/dL or 5.71 and 11.4 mmol/L)	Introduce the use of lipid-lowering therapy;^a if currently on lipid-lowering therapy, increase the dose of this therapy^a in accordance with respective prescribing information; or change to a new lipid‑lowering therapy. Continue LORBRENA at the same dose without interruption.
Grade 4 hypercholesterolemia (cholesterol over 500 mg/dL or over 12.92 mmol/L) OR Grade 4 hypertriglyceridemia (triglycerides over 1000 mg/dL or over 11.4 mmol/L)	Introduce the use of lipid-lowering therapy^a or increase the dose of this therapy^a in accordance with respective prescribing information or change to a new lipid‑lowering therapy. Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to moderate or mild severity grade. Re-challenge at same LORBRENA dose while maximizing lipid‑lowering therapy^a in accordance with respective prescribing information. If severe hypercholesterolemia and/or hypertriglyceridemia recurs despite maximal lipid‑lowering therapy^a in accordance with respective prescribing information, reduce LORBRENA by 1 dose level.
Central nervous system (CNS) effects^b,c
Grade 1: Mild	Continue at the same dose or withhold dose until recovery to baseline. Then resume LORBRENA at the same dose or reduce by 1 dose level.
Grade 2: Moderate OR Grade 3: Severe	Withhold dose until toxicity is less than or equal to Grade 1. Then resume LORBRENA at 1 reduced dose level.
Grade 4: Life-threatening/Urgent intervention indicated	Permanently discontinue LORBRENA.
Interstitial Lung Disease (ILD)/Pneumonitis
Any Grade treatment–related ILD/Pneumonitis	Permanently discontinue LORBRENA.
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 LORBRENA until hypertension has recovered to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENA at the same dose. If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade 1 or less, and resume at a reduced dose. If adequate hypertension control cannot be achieved with optimal medical management, permanently discontinue LORBRENA.
Grade 4 (life-threatening consequences, urgent intervention indicated)	Withhold LORBRENA until recovery to Grade 1 or less, and resume at a reduced dose or permanently discontinue LORBRENA. If Grade 4 hypertension recurs, permanently discontinue LORBRENA.
Hyperglycemia
Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4	Withhold LORBRENA until hyperglycemia is adequately controlled, then resume LORBRENA at the next lower dosage. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue LORBRENA.
Other adverse reactions^c
Grade 1 OR Grade 2	Consider no dose modification or reduce by 1 dose level, as clinically indicated.
Greater than or equal to Grade 3	Withhold LORBRENA until symptoms resolve to less than or equal to Grade 2 or baseline. Then resume LORBRENA at 1 reduced dose level.

Table 2. Recommended LORBRENA Dose Modifications - PR Interval Prolongation/Atrioventricular Block
Event	LORBRENA Dosing
Abbreviations: AV=atrioventricular; ECG=electrocardiogram.
Event	Asymptomatic	Symptomatic
First-degree AV block	Continue LORBRENA at the same dose without interruption. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely.	Withhold LORBRENA. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If symptoms resolve, resume LORBRENA at same dose or at 1 reduced dose level.
Second-degree AV block	Withhold LORBRENA. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If subsequent ECG does not show second‑degree block, resume LORBRENA at same dose or 1 reduced dose level.	Withhold LORBRENA. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Refer for cardiac observation and monitoring. Consider pacemaker placement if symptomatic AV block persists. If symptoms and the second‑degree block resolve or if patients revert to asymptomatic first‑degree AV block, resume LORBRENA at 1 reduced dose level.
Complete AV Block	Withhold LORBRENA dose. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Refer for cardiac observation and monitoring. Temporary pacemaker placement may be indicated for severe symptoms associated with AV block. If AV block does not resolve, placement of a permanent pacemaker may be considered. If pacemaker placed, may resume LORBRENA at full dose. If no pacemaker placed, resume LORBRENA at 1 reduced dose level only when symptoms resolve AND PR interval is less than 200 msec.

4.4 Administration

Patients should be encouraged to take their dose of LORBRENA at approximately the same time each day. Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

4.5 Missed Dose

If a dose of LORBRENA is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.