Lorviqua^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Pfizer Manufacturing Deutschland, GmbH (Germany)

ATC Code

L01ED05 (Lorlatinib)

Active Substance

Lorlatinib (Rec.INN registered by WHO)

Dosage Forms

	Lorviqua®	Film-coated tablets, 25 mg: 30, 90, or 120 pcs.
		Film-coated tablets, 100 mg: 10 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light pink in color, round, biconvex, engraved with “Pfizer” on one side, and “25” and “LLN” on the other side.

Excipients: microcrystalline cellulose*, calcium hydrogen phosphate, sodium starch glycolate, magnesium stearate.

* PH-102 or equivalent.

Film coating composition Opadry^® II 33G200010 Tan, Opadry^® II 33G200003 Lavender: hypromellose (2910), lactose monohydrate, macrogol 4000/PEG 3350, triacetin, titanium dioxide, iron oxide black, iron oxide red.

10 pcs. – blisters (3) – cardboard packs with first-opening control.
10 pcs. – blisters (9) – cardboard packs with first-opening control.
10 pcs. – blisters (12) – cardboard packs with first-opening control.

Film-coated tablets dark pink in color, oval, biconvex, engraved with “Pfizer” on one side and “LLN 100” on the other side.

Excipients: microcrystalline cellulose*, calcium hydrogen phosphate, sodium starch glycolate, magnesium stearate.

* PH-102 or equivalent.

Film coating composition Opadry^® II 33G200010 Tan, Opadry^® II 33G200003 Lavender: hypromellose (2910), lactose monohydrate, macrogol 4000/PEG 3350, triacetin, titanium dioxide, iron oxide black, iron oxide red.

10 pcs. – blisters (1) – cardboard packs with first-opening control.
10 pcs. – blisters (3) – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent, protein tyrosine kinase inhibitor

Pharmacological Action

Lorlatinib is a selective inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase receptors, capable of competing with ATP.

In preclinical studies, Lorlatinib inhibited the catalytic activity of non-mutated ALK and clinically significant non-mutated ALK kinases in recombinant enzymatic and cellular assays.

Lorlatinib demonstrated potent antitumor activity in mice with tumor xenografts expressing echinoderm microtubule-associated protein-like 4 (EML4) with ALK variant 1 (v1), including ALK L1196M, G1269A, G1202R, and I1171T mutations.

It is known that two of these ALK mutants, G1202R and I1171T, confer resistance to alectinib, brigatinib, ceritinib, and crizotinib.

Lorlatinib was also able to penetrate the blood-brain barrier.

Lorlatinib demonstrated activity in mice with orthotopic brain tumor implants of EML4-ALK or EML4-ALK L1196M.

Pharmacokinetics

C_max of lorlatinib in plasma is reached rapidly, with a median T_max of 1.2 hours after a single 100 mg dose and 2 hours after multiple daily 100 mg doses.

The mean absolute bioavailability was 80.8% (90% CI: 75.7%, 86.2%) relative to IV administration bioavailability.

Taking lorlatinib with a high-calorie, high-fat meal increased its exposure by 5% compared to taking it in the morning on an empty stomach.

Lorlatinib can be taken with or without food.

When taking lorlatinib 100 mg once daily in patients with malignant tumors, the geometric mean (% coefficient of variation /CV/) C_max in plasma was 577 (42) ng/mL, and the AUC₂₄ value reached 5650 (39) ng×h/mL.

The geometric mean (% CV) oral clearance was 17.7 (39) L/h.

In vitro, the binding of lorlatinib to human plasma proteins is 66%, with moderate binding to albumin or alpha₁-acid glycoprotein.

In humans, Lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways.

In vitro data indicate that Lorlatinib is metabolized primarily by CYP3A4 and UGT1A4 isoenzymes, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.

The main metabolite of lorlatinib in plasma was the benzoic acid metabolite of lorlatinib, formed by oxidative cleavage of the amide and aromatic ether bonds of lorlatinib, accounting for 21% of the total radioactivity.

The metabolite formed by oxidative cleavage has no pharmacological activity.

T_1/2 of lorlatinib from plasma after a single 100 mg dose was 23.6 hours.

After oral administration of radiolabeled lorlatinib 100 mg, an average of 47.7% of the radiolabel was excreted in urine and 40.9% in feces, with a total mean excretion of 88.6%.

Unchanged Lorlatinib was the main component in human plasma and feces, accounting for 44% and 9.1% of the total radioactivity, respectively.

Less than 1% of unchanged lorlatinib was detected in urine.

Furthermore, Lorlatinib is an inducer via interaction with the human pregnane X receptor (PXR) and the human constitutive androstane receptor (CAR).

After a single dose of lorlatinib, systemic exposure (AUC_inf) and C_max increased dose-dependently over the dose range of 10 to 200 mg.

After multiple once-daily doses of lorlatinib, C_max increased proportionally with dose and AUC_tau increased slightly less than proportionally over the dose range of 10 to 200 mg once daily.

Additionally, at steady-state plasma concentrations of lorlatinib, the exposure level is lower than expected from single-dose pharmacokinetics, indicating a cumulative time-dependent self-induction effect.

Indications

Indicated as first-line therapy for the treatment of adult patients with ALK-positive advanced non-small cell lung cancer (NSCLC).

Indicated as monotherapy for the treatment of adult patients with ALK-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after the following: alectinib or ceritinib as first-line ALK tyrosine kinase inhibitor (TKI) therapy; or crizotinib and at least one other ALK TKI.

ICD codes

Dosage Regimen

Detection of ALK-positive NSCLC is necessary for patient selection for lorlatinib treatment.

Assessment of ALK-positive NSCLC should be performed by laboratories highly proficient in the specific technology used.

Incorrect test performance may lead to unreliable results.

Treatment with lorlatinib should be initiated and supervised by a physician experienced in the use of antineoplastic medicinal products.

The recommended dose is 100 mg orally once daily continuously.

Treatment with lorlatinib is recommended provided the patient is deriving clinical benefit from therapy without unacceptable toxicity.

Adverse Reactions

Blood and lymphatic system disorders very common – anemia.

Metabolism and nutrition disorders very common – hypercholesterolemia, hypertriglyceridemia, weight increased, lipase increased; common – hyperglycemia.

Psychiatric disorders very common – mood effects; common – psychotic disorders, mental status changes.

Nervous system disorders very common – cognitive impairment, peripheral neuropathy, headache; common – speech impairment.

Eye disorders: very common – vision impairment.

Cardiac disorders very common – hypertension; uncommon – PR interval prolongation on ECG.

Respiratory, thoracic and mediastinal disorders common – pneumonitis.

Gastrointestinal disorders very common – diarrhea, nausea, constipation.

Skin and subcutaneous tissue disorders very common – rash.

Musculoskeletal and connective tissue disorders very common – arthralgia, myalgia.

General disorders and administration site conditions very common – edema, fatigue.

Contraindications

Hypersensitivity to lorlatinib; concomitant use with strong CYP3A4/5 inducers; children and adolescents under 18 years of age; pregnancy, breastfeeding period.

With caution

P-glycoprotein substrates with a narrow therapeutic index (e.g., digoxin, dabigatran etexilate) should be used with caution in combination with lorlatinib due to the potential decrease in plasma concentrations of these substrates since Lorlatinib is a moderate inducer of P-glycoprotein.

Use with caution in combination with BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and OAT3 substrates, as clinically significant changes in plasma exposure of these substrates cannot be excluded.

Concomitant use of lorlatinib and CYP3A4/5 substrates with a narrow therapeutic index, such as hormonal contraceptives, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided, as Lorlatinib may decrease the concentrations of these drugs.

Not recommended for use in patients with moderate or severe hepatic impairment.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

During treatment with lorlatinib and for at least 14 weeks after the final dose, male patients with partners of childbearing potential should use effective contraception, including condoms, and male patients with pregnant partners should use condoms.

During treatment with lorlatinib, male reproductive function may be impaired.

Before starting treatment, men should receive counseling on effective fertility preservation.

Women of childbearing potential should be advised to avoid pregnancy while being treated with lorlatinib.

Female patients during treatment with lorlatinib require a highly effective non-hormonal method of contraception, as Lorlatinib may reduce the effectiveness of hormonal contraceptives.

If a hormonal method of contraception is unavoidable, a condom should be used in combination with the hormonal method.

Effective contraception should continue for at least 35 days after completion of therapy.

It is not known whether Lorlatinib affects female fertility.

Use in Hepatic Impairment

No dose adjustment is required for patients with mild hepatic impairment.

Information on the use of lorlatinib in patients with moderate or severe hepatic impairment is limited.

Lorlatinib is not recommended for use in patients with moderate or severe hepatic impairment.

Use in Renal Impairment

A dose reduction of lorlatinib is recommended for patients with severe renal impairment.

No dose adjustment is required for patients with mild or moderate renal impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Data on use in elderly patients over 65 years of age are limited.

Special Precautions

Cholesterol and triglyceride levels should be assessed before starting lorlatinib therapy, at 2, 4, and 8 weeks after starting lorlatinib therapy, and periodically thereafter.

Initiate or increase the dose of lipid-lowering medications if indicated.

For patients who experience CNS adverse reactions, dose modification or discontinuation of lorlatinib may be required.

ECG should be monitored before starting lorlatinib therapy and then monthly, especially in patients with conditions predisposing to clinically significant cardiac events.

Patients who develop AV block may require dose adjustment.

In patients with cardiac risk factors and in patients with diseases that may affect LVEF, cardiac monitoring, including assessment of LVEF at baseline and during treatment, should be considered.

In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring, including assessment of LVEF, should be considered.

The risk of developing pancreatitis should be considered in patients receiving Lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsic mechanism.

Patients should be monitored for elevated lipase and amylase levels before starting lorlatinib therapy and then regularly, as clinically indicated.

All patients with worsening respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever) should be promptly investigated for ILD/pneumonitis.

Lorlatinib should be interrupted and/or permanently discontinued based on severity.

Blood pressure should be controlled before starting lorlatinib.

Blood pressure should be monitored 2 weeks after starting the drug and then at least monthly during treatment.

Lorlatinib should be interrupted and resumed at a reduced dose or permanently discontinued depending on severity.

Fasting serum glucose level should be determined before starting lorlatinib and monitored periodically thereafter.

Lorlatinib should be interrupted and resumed at a reduced dose or permanently discontinued depending on severity.

Effect on ability to drive and use machines

Lorlatinib has a moderate influence on the ability to drive and use machines.

Caution should be exercised when driving or operating machinery as patients may experience CNS adverse reactions.

Drug Interactions

In vitro data indicate that Lorlatinib is metabolized primarily by CYP3A4 and UGT1A4 isoenzymes, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.

Concomitant use of lorlatinib and strong CYP3A4/5 inducers (e.g., rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin, and St. John’s wort preparations) may lead to decreased plasma concentrations of lorlatinib.

Use of strong CYP3A4/5 inducers with lorlatinib is contraindicated.

Concomitant use of lorlatinib with CYP3A4/5 substrates with a narrow therapeutic index, including those such as alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided, as the concentration of these drugs may be decreased under the influence of lorlatinib.

In healthy volunteers, itraconazole, a strong CYP3A4/5 inhibitor, at a dose of 200 mg once daily for 5 days, increased the mean AUC of lorlatinib after a single oral 100 mg dose by 42% and the C_max value by 24%.

When lorlatinib is used concomitantly with strong CYP3A4/5 inhibitors (such as boceprevir, cobicistat, itraconazole, ketoconazole, posaconazole, troleandomycin, voriconazole, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir and ritonavir in combination with elvitegravir, indinavir, lopinavir, or tipranavir), the plasma concentration of lorlatinib may increase.

Grapefruit products may also increase the plasma concentration of lorlatinib and should be avoided.

Consider concomitant use of an alternative medicinal product with less potential for CYP3A4/5 inhibition.

If concomitant use of a strong CYP3A4/5 inhibitor is necessary, a dose reduction of lorlatinib is recommended.

Lorlatinib is a weak inducer of CYP2B6, and no dose adjustment is required when lorlatinib is used in combination with drugs that are primarily metabolized by CYP2B6.

Use of lorlatinib 100 mg once daily for 15 days led to a decrease in AUC_inf and C_max of tolbutamide (a sensitive CYP2C9 substrate) after a single oral 500 mg dose by 43% and 15%, respectively.

Thus, Lorlatinib is a weak inducer of CYP2C9, and no dose adjustment is required for drugs that are primarily metabolized by CYP2C9.

However, patients receiving concomitant treatment with drugs with a narrow therapeutic range metabolized by CYP2C9 (e.g., coumarin anticoagulants) should be monitored.

Use of lorlatinib 100 mg once daily for 15 days led to a decrease in AUC_inf and C_max of acetaminophen after a single oral 500 mg dose (a UGT, SULT, and CYP1A2, 2A6, 2D6, and 3A4 substrate) by 45% and 28%, respectively.

Thus, Lorlatinib is a weak inducer of UGT, and no dose adjustment is required for drugs that are primarily metabolized by UGT.

However, patients receiving concomitant treatment with drugs with a narrow therapeutic range metabolized by UGT should be monitored.

Use of lorlatinib 100 mg once daily for 15 days led to a decrease in AUC_inf and C_max of fexofenadine after a single 60 mg oral dose [a sensitive P-glycoprotein (Pgp) substrate] by 67% and 63%, respectively.

Thus, Lorlatinib is a moderate inducer of Pgp.

Drugs with a narrow therapeutic range that are Pgp substrates (e.g., digoxin, dabigatran etexilate) should be used with caution in combination with lorlatinib due to the likelihood of decreased plasma concentrations of these substrates.

In vitro studies have shown that Lorlatinib can potentially inhibit BCRP (in the gastrointestinal tract), OATP1B1, OATP1B3, OCT1, MATE1, and OAT3 at clinically relevant concentrations.

Lorlatinib should be used with caution in combination with substrates of BCRP, OATP1B1, OATP1B3, OCT1, MATE1, and OAT3, as clinically significant changes in the plasma exposure of these substrates cannot be excluded.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.