Alecensa^® (Capsules) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

Excella, GmbH & Co. KG (Germany)

Labeled By

DELPHARM MILANO, S.r.l. (Italy)

Quality Control Release

F.Hoffmann-La Roche, Ltd (Switzerland)

ATC Code

L01ED03 (Alectinib)

Active Substance

Alectinib (Rec.INN registered by WHO)

Dosage Form

Alecensa®

Capsules 150 mg: 224 pcs.

Dosage Form, Packaging, and Composition

Capsules hard, size 1, body and cap from white to yellowish-white; the capsule body is imprinted with “150 mg” in black, the capsule cap is imprinted with “ALE” in black; capsule contents – powder or agglomerated powder from white to light yellow.

Excipients: lactose monohydrate, hydroxypropylcellulose (hyprolose), sodium lauryl sulfate, magnesium stearate, calcium carboxymethylcellulose (carmellose calcium); capsule shell – hypromellose, carrageenan, potassium chloride, titanium dioxide (E171), corn starch, carnauba wax; capsule printing ink – iron oxide red (E172), iron oxide yellow (E172), FD&C Blue No.2 aluminum lake (E132), carnauba wax, white shellac, glyceryl monooleate, 1-butanol, anhydrous ethyl alcohol.

8 pcs. – blister packs (7) – cardboard packs with first-opening control in the form of an affixed hologram (intermediate packaging) (4) – cardboard packs with first-opening control in the form of perforation (consumer packaging).

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent – protein kinase inhibitor

Pharmacological Action

Alectinib blocks the action of the enzyme – anaplastic lymphoma kinase (ALK-tyrosine kinase). Abnormal forms of this enzyme (resulting from a defect in the gene that produces this enzyme) promote tumor cell growth. Alectinib may slow or stop tumor cell growth.

In preclinical studies, inhibition of ALK tyrosine kinase activity led to blockade of downstream signaling pathways, including STAT3 (signal transducer and activator of transcription 3) and PI3K/AKT (phosphoinositide 3-kinase/protein kinase B), and induced apoptosis of tumor cells.

Pharmacokinetics

After oral administration of alectinib in patients with ALK-positive NSCLC at a dose of 600 mg twice daily after food, rapid absorption was observed. T_max – approximately from 4 to 6 h.

The geometric mean (coefficient of variation, %) values for C_max, C_min, and AUC_0-12h at steady state for alectinib were approximately 665 ng/ml (44.3%), 572 ng/ml (47.8%), and 7430 ng×h/ml (45.7%), respectively. The geometric mean values for C_max, C_min, and AUC_0-12h at steady state for M4 were approximately 246 ng/ml (45.4%), 222 ng/ml (46.6%), and 2810 ng×h/ml (45.9%), respectively.

When alectinib is administered at a dose of 600 mg twice daily, steady state for alectinib is reached within 7 days and remains unchanged, with a geometric mean accumulation ratio of 5.6 according to population pharmacokinetic analysis. Population pharmacokinetic analysis showed dose proportionality for alectinib in the range from 300 mg to 900 mg after food.

In healthy volunteers, the absolute bioavailability of alectinib administered after food was 36.9% (33.9-40.3%).

After a single oral dose of alectinib 600 mg, administration with a high-fat, high-calorie meal increased drug exposure 3-fold compared to administration under fasting conditions (geometric mean ratio of combined values for alectinib and M4 – C_max: 3.31 [2.79-3.93], AUC_inf: 3.11 [2.73-3.55]).

Alectinib and M4 are highly bound to human plasma proteins (>99%) independent of the active substance concentration. In vitro, the mean blood-to-plasma concentration ratio in humans is 2.64 and 2.50 for alectinib and M4, respectively (at clinically relevant concentrations).

The geometric mean V_ss of alectinib after intravenous administration was 475 L, indicating wide distribution of alectinib in tissues.

In vitro metabolism studies showed that the CYP3A4 isoenzyme is the main CYP (cytochrome P450) isoenzyme mediating the metabolism of alectinib and M4, and it was determined that this isoenzyme accounts for 40-50% of metabolism in human hepatocytes. According to mass balance study results, Alectinib and M4 were the main circulating substances in plasma, their total content was 76% of the total radioactivity in plasma. The geometric mean metabolite/parent ratio at steady state was 0.399.

In healthy volunteers after a single oral dose of ¹⁴C-labeled alectinib, the majority of radioactivity was recovered in feces (mean recovery 97.8%, range 95.6-100%), with minimal recovery in urine (mean recovery 0.46%, range 0.30-0.60%). The proportion of unchanged alectinib in feces was 84% of the administered dose, and the proportion of M4 was 5.8%.

According to population pharmacokinetic analysis data, the apparent clearance of alectinib was 81.9 L/h, and for M4 it was 217 L/h. The individually calculated geometric mean T_1/2 of alectinib was 32.5 h, and for M4 it was 30.7 h.

Indications

Monotherapy for locally advanced or metastatic non-small cell lung cancer with tumor expression of anaplastic lymphoma kinase (ALK-positive) in adults over 18 years of age.

ICD codes

Dosage Regimen

The recommended dose is 600 mg (four 150 mg capsules) taken orally twice daily, approximately every 12 hours, for a total daily dose of 1200 mg.

Always administer Alecensa capsules with food. Swallow capsules whole with water; do not open or dissolve the contents.

Continue treatment until disease progression or unacceptable toxicity occurs.

If a dose is missed, do not take it if the next dose is due within 6 hours. If vomiting occurs after taking a dose, do not take an additional dose; continue with the next scheduled dose.

For severe hepatic impairment (Child-Pugh Class C), reduce the total daily dose to 450 mg twice daily.

Manage adverse reactions through temporary dose interruptions, dose reductions, or permanent discontinuation. The first dose reduction is to 450 mg twice daily; the second dose reduction is to 300 mg twice daily.

Permanently discontinue Alecensa if unable to tolerate 300 mg twice daily.

Adverse Reactions

From the hematopoietic system very common – anemia, hemolytic anemia, which may cause increased fatigue, weakness, or shortness of breath.

From the nervous system common – dysgeusia (taste perception disorder).

From the organ of vision very common – vision disorders.

From the cardiovascular system: very common – bradycardia, which may cause fainting, dizziness, arterial hypotension.

From the respiratory system common – interstitial lung disease/pneumonitis.

From the digestive system: very common – constipation, nausea, diarrhea, vomiting; common – stomatitis.

From the liver and biliary tract very common – increased bilirubin concentration, increased AST activity, increased ALT activity; uncommon – drug-induced liver injury.

From the skin and subcutaneous tissues very common – rash, photosensitivity reaction.

From the musculoskeletal system very common – myalgia, increased blood CPK activity.

From the urinary system: common – increased blood creatinine concentration, acute renal failure.

Other very common – edema; common – weight gain

Contraindications

Hypersensitivity to alectinib, pregnancy, breastfeeding period, age under 18 years (efficacy and safety have not been studied).

With caution

Severe renal impairment.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Patients with baseline severe hepatic impairment (Child-Pugh class C) require dose regimen adjustment.

Use in Renal Impairment

No dose adjustment is required in patients with mild to moderate renal impairment. The use of alectinib in patients with severe renal impairment has not been studied, however, since Alectinib is minimally excreted by the kidneys, no dose adjustment is required in such patients.

Pediatric Use

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

Geriatric Use

No dose adjustment of alectinib is required in elderly/geriatric patients (≥65 years).

Special Precautions

Treatment with alectinib should be immediately interrupted in patients diagnosed with ILD/pneumonitis and therapy should be permanently discontinued if other potential causes of ILD/pneumonitis are not identified.

During treatment, liver function parameters, including ALT, AST, and total bilirubin, should be monitored at baseline and then every 2 weeks for the first 3 months of treatment. Periodic monitoring should then be continued, as abnormalities may occur after 3 months of treatment. Patients who experienced elevated transaminase levels and bilirubin concentration require more frequent monitoring. Depending on the severity of the adverse reaction, treatment should be either interrupted and then resumed at a reduced dose, or alectinib therapy should be permanently discontinued.

Patients should be advised to report any cases of unexplained muscle pain, tenderness, or weakness. CPK activity should be assessed every 2 weeks during the first month of therapy and as clinically indicated in those patients who report symptoms.

Heart rate and blood pressure should be monitored as clinically indicated. In case of asymptomatic bradycardia, no dose adjustment is required. If symptomatic bradycardia or life-threatening conditions develop, the effect of concomitant medications known to cause bradycardia, as well as the effect of antihypertensive medications, should be assessed. The dose of alectinib should be adjusted.

Patients should be advised to avoid prolonged sun exposure while taking alectinib and for at least 7 days after discontinuation of therapy. Broad-spectrum UV (UVA/UVB) sunscreen and lip balm with SPF (sun protection factor) ≥50 should also be used to protect against possible sunburn.

Overdose

In vitro, Alectinib and M4 are inhibitors of P-glycoprotein and BCRP. Thus, Alectinib and M4 may contribute to increased plasma concentrations of P-glycoprotein or BCRP substrates when co-administered (an increase in exposure of more than two-fold is not expected). Appropriate monitoring is recommended for patients who are concurrently taking Alectinib and P-glycoprotein or BCRP substrates with a narrow therapeutic index (e.g., digoxin, dabigatran, methotrexate).

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.