DRUG INTERACTIONS

 CYP3A Inducers:                                                                                          Contraindicated with strong CYP3A inducers. Avoid concomitant use with moderate CYP3A  inducers

CYP3A Inhibitors:                                                                                                       Avoid concomitant use with strong CYP3A inhibitors; reduce LORBRENA dose if concomitant use cannot be avoided.

CYP3A Substrates:                                                                                                       Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures. 

BRIEF SUMMARY

LORATINIB- (Nov 2018)

Indn-         To treat patients with anaplastic  lymphoma kinase(ALK) -positive metastic non-small cell lung cancer

Comp-           Tablets: 25 mg or 100 mg. The recommended dosage is 100 mg orally once daily. 

ADR-    Most common adverse reactions (incidence =20%) are edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. 

CI-   Concomitant use with strong CYP3A inducers. 

Pat Infm-

Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers Inform patients of the potential risk of hepatoxicity with the concomitant use of strong CYP3A 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)

Central Nervous System (CNS) Effects                                                                     Advise patients to notify their healthcare provider if they experience new or worsening CNS symptoms.

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  48

 ADVERSE REACTIONS

 Most common adverse reactions (incidence =20%) are edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. 

 Hyperlipidemia:

Initiate or increase the dose of lipid-lowering agents. Withhold and resume LORBRENA at same or reduced dose based on severity. 

Atrioventricular Block: Withhold and resume LORBRENA at same or reduced dose based on severity. 

Interstitial Lung Disease/Pneumonitis: Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity. 

 Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus. Advise males and females of reproductive potential to use an effective non-hormonal method of contraception. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers Inform patients of the potential risk of hepatoxicity with the concomitant use of strong CYP3A 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)

Central Nervous System (CNS) Effects                                                                     Advise patients to notify their healthcare provider if they experience new or worsening CNS symptoms.

Hyperlipidemia                                                                                                           Inform patients that serum cholesterol and triglycerides will be monitored during treatment. Advise patients that initiation or an increase in the dose of lipid-lowering agents may be required 

Atrioventricular (AV) Block                                                                                       Inform patients of the risks of AV block. Advise patients to contact their healthcare provider immediately to report new or worsening cardiac symptoms.

Interstitial Lung Disease (ILD)/Pneumonitis                                                              Inform patients of the risks of severe ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms.

Embryo-Fetal Toxicity                                                                                                      Advise females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

Use in Specific Populations                                                                                      Advise females of reproductive potential to use effective non-hormonal contraception during treatment with LORBRENA 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 with LORBRENA and for at least 3 months after the final dose.

Lactation                                                                                                                          Advise women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose.

Infertility                                                                                                                     Advise males of reproductive potential that LORBRENA may transiently impair fertility  This product’s label may have been updated.

For full prescribing information, please visit www.LORBRENA.com. LAB-1162-0.11

Product of Pfizer USA

 CLINICAL PHARMACOLOGY

1 Mechanism of Action

Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK.

Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.

Lorlatinib also demonstrated anti-tumor activity and prolonged survival in mice implanted intracranially with EML4-ALK-driven tumor cell lines. The overall antitumor activity of lorlatinib in in vivo models was dose-dependent and correlated with inhibition of ALK phosphorylation.

2 Pharmacodynamics

Exposure-Response Relationships                                                                         Based on the data from Study, 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.

Cardiac Electrophysiology                                                                                              In 295 patients who received LORBRENA at the recommended dosage of 100 mg once daily and had an ECG measurement in Study, the maximum mean change from baseline for PR interval was 16.4 ms . (2-sided 90% upper confidence interval [CI] 19.4 ms).

3 .Pharmacokinetics                                                                                                 Steady-state lorlatinib maximum plasma concentration (Cmax) increases proportionally and AUC increased slightly less than proportionally over the dose range of 10 mg to 200 mg orally once daily (0.1 to 2 times the recommended dosage).

At the recommended dosage, the mean (coefficient of variation [CV] %) Cmax was 577 ng/mL (42%) and the AUC0-24h was 5650 ng h/mL (39%) in patients with cancer. Lorlatinib oral clearance increased at steady-state compared to single dose, indicating autoinduction.

Absorption                                                                                                                       The median lorlatinib Tmax was 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady state. The mean absolute bioavailability is 81% (90% CI 75.7%, 86.2%) after oral administration compared to intravenous administration.

Effect of Food                                                                                                 Administration of LORBRENA with a high fat, high calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) had no clinically meaningful effect on lorlatinib pharmacokinetics.

Distribution                                                                                                                       In vitro, lorlatinib was 66% bound to plasma proteins at a concentration of 2.4 µM. The blood-to-plasma ratio was 0.99. The mean (CV%) steady state volume of distribution (Vss) was 305 L (28%) following a single intravenous dose.

Elimination                                                                                                                        The mean plasma half-life (t½) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of LORBRENA. The mean oral clearance (CL/F) was 11 L/h (35%) following a single oral 100 mg dose and increased to 18 L/h (39%) at steady state, suggesting autoinduction.

Metabolism                                                                                                                        In vitro, lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3. In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity in a human [14C] mass balance study. The oxidative cleavage metabolite, M8, is pharmacologically inactive.

Excretion                                                                                                               Following a single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (<1% as unchanged) and 41% in feces (about 9% as unchanged).

Specific Populations                                                                                                       No clinically meaningful differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment (CLcr 30 to 89 mL/min), mild hepatic impairment (total bilirubin = ULN and AST > ULN or total bilirubin > 1.5 × ULN and any AST), or metabolizer phenotypes for CYP3A5 and CYP2C19.

The effect of moderate to severe hepatic impairment or severe renal impairment on lorlatinib pharmacokinetics is unknown.

Drug Interaction Studies                                                                                         Clinical Studies Effect of CYP3A Inducers on Lorlatinib: Twelve healthy subjects received rifampin, a strong CYP3A inducer that also activates PXR, 600 mg once daily for 8 days (Days 1 to 8) and a single oral 100 mg dose of LORBRENA on Day 8.

The coadministration of rifampin with LORBRENA reduced the mean lorlatinib AUCinf by 85% and Cmax by 76%. Grade 2 to 4 increases in ALT or AST occurred within 3 days. Grade 4 ALT or AST elevations occurred in 50%, Grade 3 ALT or AST elevations in 33%, and Grade 2 ALT or AST elevations occurred in 8% of subjects. ALT and AST returned to within normal limits within 7 to 34 days (median 15 days).

The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity with the concomitant use of moderate CYP3A inducers is unknown 

Effect of Strong CYP3A Inhibitors on Lorlatinib: Itraconazole, a strong CYP3A inhibitor, increased AUCinf by 42% and increased Cmax by 24% of a single oral 100 mg dose of LORBRENA 

Effect of Lorlatinib on CYP3A Substrates: LORBRENA 150 mg orally once daily for 15 days decreased AUCinf by 64% and Cmax by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate) 

Effect of Acid-Reducing Agents on Lorlatinib: Concomitant use of a proton pump inhibitor, rabeprazole, did not have a clinically meaningful effect on lorlatinib pharmacokinetics. In Vitro Studies Effect of Lorlatinib on CYP Enzymes: In vitro studies indicate that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A and that it activates PXR, with the net effect in vivo being induction.

 USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary                                                                                     Based on findings from animal studies and its mechanism of action, 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.

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.

2. Lactation Risk Summary                                                                                       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. 

Females and Males of Reproductive Potential Pregnancy Testing                              Verify pregnancy status in females of reproductive potential prior to initiating LORBRENA 

Contraception                                                                                                         LORBRENA can cause embryo-fetal harm when administered to a pregnant woman 

Females                                                                                                                    Advise female patients of reproductive potential  to use effective non-hormonal contraception during treatment with LORBRENA and for at least 6 months after the final dose.

Males                                                                                                                          Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENA and for at least 3 months after the final dose 

Infertility Males                                                                                                          Based on findings from animal studies, LORBRENA may transiently impair male fertility 

4. Pediatric Use                                                                                                              The safety and effectiveness of LORBRENA in pediatric patients have not been established.

5. Geriatric Use                                                                                                                  Of the 295 patients in a Study who received 100 mg LORBRENA orally once daily, 18% of patients were aged 65 years or older. Although data are limited, no clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.

6. Hepatic Impairment                                                                                                     No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin = upper limit of normal [ULN] with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST). The recommended dose of LORBRENA has not been established for patients with moderate or severe hepatic impairment.

7. Renal Impairment                                                                                                        No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). The recommended dose of LORBRENA has not been established for patients with severe renal impairment