lorlatinib INDAR Lorviqua/Lornib/Lorbrexen Capsules PF-6463922

Lorlatinib (Lorbrena) Package Insert: Please read this package insert carefully and use the medication under the guidance of a physician.

Generic Name: Lorlatinib

Brand Name: Lorbrena

Full Name: Lorlatinib, Lorbrena

Specification: 100 mg × 30 Capsules

Manufacturer: Indar Pharmaceutical Pvt. Ltd.

Indications:

This product is a targeted therapy indicated for the treatment of patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC).

For ALK-positive NSCLC patients undergoing first-line treatment, the overall response rate is as high as 90%, with an intracranial response rate of up to 75%.

For ALK-positive patients who have previously received crizotinib, the overall response rate is 69%, with an intracranial response rate of 68%.

For ALK-positive patients who have previously received treatment with ALK inhibitors other than crizotinib, the overall response rate is 33%, with an intracranial response rate of 42%.

For ALK-positive patients who have previously received treatment with 2 to 3 different ALK inhibitors, the overall response rate is 39%, with an intracranial response rate of 48%.

Clinical results demonstrate that this product exhibits clinically significant activity in the treatment of both pulmonary tumors and brain metastases in patients with advanced ALK-positive and ROS1-positive NSCLC.

Dosage and Administration:

Standard Adult Dosage for Non-Small Cell Lung Cancer:

100 mg orally once daily. Continue treatment until disease progression or until unacceptable toxicity occurs.

May be taken with or without food. Adverse Reactions:

>10%:

Cardiovascular: Edema (57%)

Central Nervous System: Peripheral neuropathy (47%; Grade 3/4: 3%), Cognitive dysfunction (27% to 29%), Fatigue (26%), Mood disturbance (23% to 24%), Headache (18%), Dizziness (16%), Speech disorder (12% to 14%), Sleep disorder (10%)

Dermatologic: Rash (14%)

Endocrine & Metabolic: Hypercholesterolemia (96%), Hypertriglyceridemia (90%), Hyperglycemia (52%), Hypoproteinemia (33%), Weight gain (24%), Increased amylase (22%), Hyperkalemia (21%), Hypomagnesemia (21%), Hypophosphatemia (21%)

Gastrointestinal: Increased serum lipase (24%), Diarrhea (22%), Nausea (18%), Constipation (15%), Vomiting (12%)

Hematologic & Oncologic: Anemia (52%; Grade 3/4: 5%) %), Thrombocytopenia (23%; Grade 3/4: <1%), Lymphopenia (22%; Grade 3/4: 3%)

Hepatic: Increased serum aspartate aminotransferase (37%), Increased serum alanine aminotransferase (28%), Increased serum alkaline phosphatase (24%)

Neuromuscular and Skeletal: Arthralgia (23%), Myalgia (17%), Back pain (13%), Pain in extremity (13%)

Ophthalmic: Visual impairment (15%)

Respiratory: Dyspnea (27%), Cough (18%), Upper respiratory tract infection (12%)

Other: Pyrexia (12%)

1%-10%:

Cardiovascular: Atrioventricular (AV) block (1%)

Central Nervous System: Hallucinations (7%), Seizures (3%), Altered mental status (2%)

Respiratory: Pneumonia (3%), Interstitial lung disease (≤2%), Focal pneumonia (≤2%), Respiratory failure (1%)

Contraindications:

Concomitant use with strong CYP3A inducers.

Hypersensitivity to lorlatinib or to any of the excipients in the formulation.

Precautions:

Myelosuppression: Anemia (usually mild) commonly occurs with lorlatinib. Mild thrombocytopenia and lymphopenia also occur.

Cardiovascular Effects: PR interval prolongation and AV block (including Grade 3 events) have occurred rarely in patients receiving lorlatinib. Some patients required pacemaker placement. Monitor ECG prior to initiating lorlatinib treatment, and periodically thereafter. Withhold treatment, and resume at a reduced dose (if a pacemaker was not placed) or at the same dose (for patients with a pacemaker). Permanently discontinue treatment in patients without a pacemaker upon recurrence.

Central Nervous System Effects: CNS effects (including seizures, hallucinations, and changes in cognitive function, mood [including suicidal ideation], speech, mental status, and sleep) may occur in patients receiving lorlatinib. Overall, central nervous system (CNS) effects were observed in slightly more than half of the patients treated with lorlatinib. In one study, nearly one-third of patients receiving lorlatinib (at any dose) experienced cognitive effects; a small subset of these events were severe (Grade 3 or 4). Nearly one-quarter of patients experienced mood-related effects; severe events were rare. Speech-related effects, hallucinations, and changes in mental status were also reported, including rare severe events. Seizures have been observed, sometimes in conjunction with other neurological findings. Changes in sleep patterns have also been reported. The median time to onset for any CNS reaction was 1.2 months (range: 1 day to 1.7 years). Depending on severity, CNS adverse events may require treatment interruption, dose reduction, or permanent discontinuation.

Hepatotoxicity: Severe hepatotoxicity occurred in the majority of healthy subjects who received a dose of lorlatinib in combination with multiple doses of rifampin (a strong CYP3A inducer). Grade 3 or 4 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were common, and Grade 2 elevations were also reported. ALT or AST levels rose within 3 days and returned to the normal range within 15 days (range: 7 to 34 days); the median time to recovery was 7 days for subjects with Grade 2 ALT or AST elevations, and 18 days for subjects with Grade 3 or 4 ALT or AST elevations. Lorlatinib is contraindicated in patients taking strong CYP3A inducers. Prior to initiating lorlatinib treatment, discontinue strong CYP3A inducers for at least 3 plasma half-lives of the strong CYP3A inducer. Avoid the concomitant use of lorlatinib with moderate CYP3A inducers; if concomitant use with moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin at least 3 times—at 48 hours after initiating lorlatinib, and during the first week of lorlatinib treatment. Discontinue lorlatinib or the CYP3A inducer for persistent Grade 2 or higher hepatotoxicity, based on the relative importance of each drug. Hyperlipidemia: Patients treated with Lorlatinib may experience elevations in serum cholesterol and triglycerides. Grade 3 or 4 elevations in total cholesterol and triglycerides have been reported. The median time to onset (for both hypercholesterolemia and hypertriglyceridemia) is 15 days. Typically, within 21 days of initiating Lorlatinib treatment, most patients with hypercholesterolemia and hypertriglyceridemia require the initiation of lipid-lowering therapy. Assess serum cholesterol and triglycerides prior to initiating Lorlatinib; monitor serum cholesterol and triglycerides periodically at 1 and 2 months after starting Lorlatinib. Initiate lipid-lowering agents (or increase their dosage) for patients with hyperlipidemia. Depending on the severity, hyperlipidemia may require interruption or dose reduction of Lorlatinib treatment.

Pulmonary Toxicity: Lorlatinib use may be associated with rare, severe, or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis, including Grade 3 and 4 events. Promptly evaluate new or worsening respiratory symptoms suggestive of ILD/pneumonitis (e.g., dyspnea, cough, fever). If ILD/pneumonitis is suspected, immediately withhold Lorlatinib; permanently discontinue Lorlatinib for any grade of ILD/pneumonitis that is considered related to the drug.

Drug-Drug Interactions: Significant interactions may exist that require dosage or frequency adjustments, additional monitoring, or the selection of alternative therapies.

ALK-Positive Status: Lorlatinib is approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are positive for Anaplastic Lymphoma Kinase (ALK) gene abnormalities.

Pregnancy: Based on its mechanism of action and data from animal reproduction studies, Lorlatinib may cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment. Females of reproductive potential should avoid pregnancy and use effective non-hormonal contraception during treatment and for at least 6 months after the last dose of Lorlatinib. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose of Lorlatinib. Storage:

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Mechanism of Action:

Lorlatinib is a novel, third-generation tyrosine kinase inhibitor (TKI) that targets Anaplastic Lymphoma Kinase (ALK) and the receptor tyrosine kinase c-ros oncogene 1 (ROS1).

Safety and Efficacy:

Studies have demonstrated that patients with advanced non-small cell lung cancer (NSCLC) who are positive for ALK (Anaplastic Lymphoma Kinase) or ROS1 (receptor tyrosine kinase c-ros oncogene 1)—including those with brain metastases—exhibit a clinical therapeutic response to Lorlatinib. In a Phase 1 clinical trial, patients who were either treatment-naïve or had experienced disease progression following treatment with a single tyrosine kinase inhibitor achieved an overall response rate of 46% after receiving dose-escalation therapy with this drug. The median progression-free survival was 1.4 months, and a reduction in the volume of brain metastases was observed.

On April 27, 2017, Pfizer announced that its next-generation ALK/ROS1 inhibitor, Lorlatinib, had been granted Breakthrough Therapy Designation by the FDA for the treatment of ALK-positive, metastatic NSCLC (non-small cell lung cancer) in patients whose disease has progressed following prior treatment with one or more ALK inhibitors. This designation was granted based on efficacy and safety data derived from an ongoing Phase 1/2 clinical study. On October 17, 2017, Pfizer announced the complete Phase II clinical trial data for Lorlatinib at the 2017 World Conference on Lung Cancer (WCLC):

For ALK-positive, treatment-naïve NSCLC (non-small cell lung cancer) patients, the ORR (Objective Response Rate) reached as high as 90%, with an intracranial ORR of 75%;

For ALK-positive patients previously treated with Crizotinib, the ORR was 69%, with an intracranial ORR of 68%;

For ALK-positive patients previously treated with ALK inhibitors other than Crizotinib, the ORR was 33%, with an intracranial ORR of 42%;

For ALK-positive patients previously treated with 2 to 3 different ALK inhibitors, the ORR was 39%, with an intracranial ORR of 48%;

For ROS1-positive patients who had undergone prior treatment, the ORR was 36%, with an intracranial ORR of 56%.

The trial results demonstrated that this drug exhibits clinically significant activity in treating both pulmonary tumors and brain metastases in patients with advanced ALK-positive and ROS1-positive NSCLC.

**Product Specifications**

**Product Name:** LORLANDR 100 — Lorlatinib 100mg × 30 Capsules (INDAR; Synonyms: Lorviqua/Lornib/Lorbrexen Capsules; PF-6463922)

**Common Name:** Lorlatinib

**Active Ingredient:** Lorlatinib

**Dosage Form:** Capsules

**Specification:** 100mg × 30 Capsules

**Manufacturer:** Indar Pharmaceutical Pvt. Ltd.

**Indications:** This product is a targeted therapy indicated for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). For ALK-positive NSCLC patients undergoing first-line treatment, this product demonstrates an overall response rate of up to 90% and an intracranial response rate of up to 75%;

For ALK-positive patients who have previously received crizotinib, the overall response rate is 69%, and the intracranial response rate reaches 68%;

For ALK-positive patients who have previously received treatment with ALK inhibitors other than crizotinib, the overall response rate is 33%, and the intracranial response rate reaches 42%;

For ALK-positive patients who have previously received treatment with 2 to 3 different ALK inhibitors, the overall response rate is 39%, and the intracranial response rate reaches 48%;

Clinical results indicate that this product demonstrates clinically meaningful activity in the treatment of both pulmonary tumors and brain metastases in patients with advanced ALK-positive and ROS1-positive NSCLC.

Dosage and Administration: Usual Adult Dosage for Non-Small Cell Lung Cancer

100 mg orally once daily. Continue treatment until disease progression or unacceptable toxicity occurs.

May be taken with or without food.