Albocif (Capsules) Instructions for Use

Marketing Authorization Holder

R-Pharm JSC (Russia)

Manufactured By

Ortat, JSC (Russia)

ATC Code

L01EF01 (Palbociclib)

Active Substance

Palbociclib (Rec.INN registered by WHO)

Dosage Forms

	Albocif	Capsules 75 mg
		Capsules 100 mg
		Capsules 125 mg

Dosage Form, Packaging, and Composition

Capsules

21 pcs. – bottles – cardboard packs (21 pcs.) – By prescription

Capsules

21 pcs. – bottles – cardboard packs (21 pcs.) – By prescription

Capsules

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
21 pcs. – bottles – cardboard packs (21 pcs.) – By prescription
7 pcs. – blister packs (3 pcs.) – cardboard packs (21 pcs.) – By prescription

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Groups

• Antineoplastic agents, protein kinase inhibitors, cyclin-dependent kinase (CDK) inhibitors
• Antineoplastic agents; protein kinase inhibitors; cyclin-dependent kinase (CDK) inhibitors

Pharmacological Action

Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 kinases are components of downstream signaling pathways that activate cell proliferation. In vitro, Palbociclib reduced the proliferation of estrogen receptor-positive (ER+) breast cancer cell lines by blocking the progression of cells from the G1 phase to the S phase of the cell cycle.

Combined treatment of breast cancer cell lines with palbociclib and antiestrogens led to a reduction in retinoblastoma protein (Rb) phosphorylation and, consequently, to a decrease in E2F expression and signaling, and to a marked growth blockade compared to treatment of cell lines with each drug separately.

Combined treatment of ER-positive breast cancer cell lines with palbociclib and antiestrogens in vitro led to accelerated cell senescence compared to treatment with each substance separately, which persisted for up to 6 days after cessation of exposure and was more pronounced with continued antiestrogen treatment.

In vivo studies using xenograft models derived from patient ER-positive breast cancer cells showed that the combination of palbociclib and letrozole enhanced inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to monotherapy with each drug separately.

Pharmacokinetics

After oral administration, the mean C_max of palbociclib is generally reached within 6-12 hours ( T_max). At a dose of 125 mg, the mean absolute bioavailability is 46%. Overall, AUC and C_max increase proportionally with the dose in the range from 25 mg to 225 mg. Steady state was reached within 8 days after repeated once-daily administration of the drug.

Upon repeated once-daily administration of palbociclib, accumulation of palbociclib occurs, with a median accumulation ratio of 2.4 (range 1.5-4.2).

Compared to morning fasting intake, the mean AUC_inf and C_max of palbociclib in the population increased by 21% and 38%, respectively, when taken with a high-calorie, high-fat meal (approximately 800 to 1000 calories, of which 150, 250, and 500-600 calories came from protein, carbohydrates, and fat, respectively); by 12% and 27%, respectively, when taken with a low-calorie, low-fat meal (approximately 400 to 500 calories, of which 120, 250, and 28-35 calories came from protein, carbohydrates, and fat, respectively); and by 13% and 24%, respectively, when a normal-calorie, moderate-fat meal (approximately 500 to 700 calories, of which 75-105, 250-350, and 175-245 calories came from protein, carbohydrates, and fat, respectively) was taken 1 hour before and 2 hours after palbociclib intake.

The binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence observed in the concentration range of 500-5000 ng/mL. The mean unbound fraction (fu) of palbociclib in human plasma in vivo gradually increased with worsening liver function. No obvious trend was observed regarding the change in the mean fu of palbociclib in human plasma in vivo with worsening renal function. The geometric mean apparent volume of distribution ( V_z/F) was 2583 L with a coefficient of variation (CV) of 26%.

In vitro and in vivo studies indicate that in humans, Palbociclib undergoes biotransformation in the liver. After a single oral dose of 125 mg of [¹⁴C]-labeled palbociclib, the main pathways of palbociclib metabolism included oxidation and sulfonation, with minor pathways being acylation and glucuronidation. Palbociclib was the main compound released from the drug formulation and circulating in plasma (23%). The main circulating metabolite was the glucuronide conjugate of palbociclib, although it accounted for only 1.5% of the administered dose in excreta. Palbociclib was extensively metabolized, with the unchanged drug accounting for 2.3% and 6.9% of the radioactivity in feces and urine, respectively. The main drug metabolite found in feces was the sulfamic acid conjugate of palbociclib, which accounted for 26% of the administered dose. Studies in human hepatocytes, liver cytosol and S9 fractions, and with recombinant SULT enzymes indicated that CYP3A and SULT2A1 enzymes are primarily involved in the metabolism of palbociclib.

In patients with advanced breast cancer, the geometric mean apparent oral clearance ( CL/F) of palbociclib was 63.1 L/h (CV 29%), and the mean (± standard deviation) plasma T_1/2 was 29 h ± 5 h. In 6 healthy male volunteers after a single oral dose of [¹⁴C]-labeled palbociclib, a median of 91.6% of the total administered radioactive dose was excreted over 15 days; the main route of elimination was fecal excretion (74.1% of the dose), and 17.5% was urinary excretion. Most of the active substance was excreted as metabolites.

Indications

Treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine therapy in postmenopausal women, or with fulvestrant in women with disease progression after endocrine therapy.

ICD codes

Dosage Regimen

Take the capsules orally at a dose of 125 mg once daily for 21 consecutive days, followed by a 7-day treatment break to complete a 28-day cycle.

Administer the recommended dose of the concomitant aromatase inhibitor at the same time.

Take capsules with food to improve bioavailability and reduce variability; avoid grapefruit or grapefruit juice.

Do not crush, chew, or open the capsules; swallow them whole.

If a dose is vomited, or if a dose is missed, do not take an additional dose; resume the usual dosing schedule with the next capsule.

Perform complete blood count (CBC) monitoring prior to therapy initiation, at the start of each cycle, on day 15 of the first two cycles, and as clinically indicated.

For patients with moderate hepatic impairment (Child-Pugh class B), reduce the starting dose to 75 mg once daily.

Avoid use in patients with severe hepatic impairment (Child-Pugh class C).

For hematologic toxicities, manage according to severity with temporary interruption, dose reduction, or delay in starting the next cycle.

For Grade 3 adverse reactions (except neutropenia), consider interruption until resolution to Grade ≤1, then resume at the same dose; if recurrence occurs, interrupt until resolution and reduce the dose to 100 mg.

For Grade 4 adverse reactions, interrupt until resolution to Grade ≤1, then reduce the dose to 100 mg; if Grade 4 recurrence occurs, further reduce to 75 mg or discontinue.

For Grade 3 neutropenia, interrupt therapy until resolution to Grade ≤2, then resume at the same dose.

For Grade 3 neutropenia with fever or infection, or for Grade 4 neutropenia, interrupt therapy until resolution to Grade ≤2, then reduce the dose to 100 mg.

For subsequent episodes of Grade 3 neutropenia with fever/infection or Grade 4 neutropenia, interrupt therapy until resolution and further reduce the dose to 75 mg; discontinue if toxicity persists at 75 mg.

Avoid concomitant use of strong CYP3A inhibitors; if co-administration is unavoidable, reduce the palbociclib dose to 75 mg.

If the strong inhibitor is discontinued, increase the palbociclib dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the inhibitor.

Avoid concomitant use of strong CYP3A inducers; if co-administration is unavoidable, consider increasing the palbociclib dose in 25 mg increments, not to exceed 175 mg daily, based on tolerability.

Adverse Reactions

Infections and infestations: infections.

Blood and lymphatic system disorders: neutropenia, leukopenia, anemia, thrombocytopenia.

Metabolism and nutrition disorders: decreased appetite.

Nervous system disorders: dysgeusia.

Gastrointestinal disorders: stomatitis, nausea, diarrhea, vomiting.

Skin and subcutaneous tissue disorders: alopecia, rash, dry skin.

General disorders and administration site conditions: fatigue, asthenia, pyrexia.

Investigations: decreased white blood cell count, decreased neutrophil count, anemia, decreased platelet count, increased AST and ALT activity.

Contraindications

Childhood, hypersensitivity to palbociclib.

Use in Pregnancy and Lactation

Use during pregnancy and in women of childbearing potential not using contraception is not recommended.

There is no information on the penetration of palbociclib into breast milk and its effect on the development of the breastfed infant. Breastfeeding should be discontinued during treatment and for 3 weeks after receiving the last dose of the drug.

Women of childbearing potential should have a pregnancy test performed before starting therapy with Palbociclib.

Women of childbearing potential taking the drug, or their male partners, should use effective contraceptive measures during therapy and for at least 3 weeks or 3 months after the last dose of palbociclib for women and men, respectively.

Special Precautions

Before starting therapy, at the beginning of each cycle, on day 15 of the first 2 cycles, and as clinically indicated, complete blood count monitoring should be performed. If grade 3 or 4 neutropenia develops, it is recommended to temporarily discontinue therapy, reduce the dose of palbociclib, or delay the new therapy cycle to a later time.

Treating physicians should inform patients of the need to promptly report any cases of fever.

Effect on ability to drive and operate machinery

Patients experiencing fatigue during treatment should be cautious when driving and operating machinery.

Drug Interactions

Palbociclib is metabolized primarily by the CYP3A isoenzyme and sulfotransferase SULT2A1. Palbociclib, when taken daily at a dose of 125 mg and at steady state in humans, has a weak, time-dependent inhibitory effect on CYP3A. In vitro, Palbociclib at clinically significant concentrations is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or an inducer of CYP1A2, 2B6, 2C8 and 3A4.

In healthy volunteers (n=12), with simultaneous multiple administration of a potent CYP3A isoenzyme inhibitor (itraconazole 200 mg/day) and a single 125 mg dose of palbociclib, an increase in the AUC_inf and C_max of palbociclib in plasma by 87% and 34%, respectively, was observed compared to a single dose of palbociclib 125 mg alone. Concurrent use of palbociclib and potent CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole) should be avoided. Consumption of grapefruit or grapefruit juice should be avoided during therapy with palbociclib. If concomitant use of palbociclib with potent CYP3A isoenzyme inhibitors is necessary, the dose of palbociclib should be reduced.

In healthy volunteers (n=15), concomitant administration of multiple doses of a potent CYP3A isoenzyme inducer (rifampin 600 mg/day) with a single 125 mg dose of palbociclib resulted in an 85% and 70% decrease in the AUC_inf and C_max of palbociclib in plasma, respectively, compared to monotherapy with a single 125 mg dose of palbociclib.

In healthy volunteers (n=14), a single dose of palbociclib 125 mg against the background of multiple doses of the moderate CYP3A inducer modafinil 400 mg/day resulted in an approximate 32% and 11% decrease in the AUC_inf and C_max of palbociclib, respectively, compared to a single dose of palbociclib 125 mg alone.

Concomitant use of potent CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, enzalutamide, and St. John’s wort preparations) should be avoided.

Palbociclib, when taken daily at a dose of 125 mg and at steady-state concentration in humans, has a weak, time-dependent inhibitory effect on CYP3A. Concomitant administration of midazolam against the background of multiple doses of palbociclib in healthy volunteers (n=26) increased the AUC_inf and C_max of midazolam in plasma by 61% and 37%, respectively, compared to midazolam monotherapy.

A dose reduction of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may be required, as Palbociclib may increase their exposure.

In a drug interaction study involving healthy volunteers, a single dose of palbociclib 125 mg against the background of multiple doses of the proton pump inhibitor (PPI) rabeprazole with food led to a 41% decrease in the C_max of palbociclib and a moderate change in AUC_inf (as a 13% decrease) compared to a single dose of palbociclib as monotherapy. Given the less pronounced effect of H₂-receptor antagonists and local antacids on gastric pH compared to PPIs, it is believed that the effect of these classes of acid-reducing drugs on palbociclib exposure when combined with food intake will be minimal. When combined with food intake, no clinically significant effect of PPIs, H₂-receptor antagonists, or local antacids on palbociclib exposure is observed. In another study involving healthy volunteers, a single dose of palbociclib on an empty stomach against the background of multiple doses of the PPI rabeprazole resulted in a 62% and 80% decrease in the AUC_inf and C_max of palbociclib, respectively, compared to a single dose of palbociclib alone.

In vitro studies have shown that at clinically significant concentrations, Palbociclib has a low potential to inhibit the activity of the drug transporters organic anion transporter OAT1, OAT3, organic cation transporter (OCT)2, and organic anion transporting polypeptide OATP1B1, OATP1B3. In vitro, Palbociclib has the potential to inhibit OCT1 at clinically significant concentrations as well as the potential to inhibit the activity of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in the gastrointestinal tract at the proposed dose.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.