Palbonix palbociclib composition

[Drug Name]

Generic Name: Palbociclib Capsules

Brand Name: Palbociclib Capsules

[Main Ingredients] The main active ingredient of this product is palbociclib. Its chemical name is: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one. Molecular Weight: 447.54. Excipients: Microcrystalline cellulose, Lactose monohydrate, Sodium starch glycolate, Colloidal silicon dioxide, Magnesium stearate.

[Indications/Therapeutic Uses] This product is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. It should be used in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women.

[Description] This product is a capsule; the contents consist of an off-white to yellow powder.

[Specification] 100 mg × 21 capsules

[Dosage and Administration] Treatment with this product should be initiated and supervised by a physician experienced in the use of anticancer therapies. Recommended Dosage: The recommended dose of palbociclib is 125 mg, taken orally once daily for 21 consecutive days, followed by 7 days off treatment (a 3/1 dosing schedule), constituting a complete 28-day treatment cycle. Treatment should be continued as long as the patient continues to derive clinical benefit from therapy or until unacceptable toxicity occurs. When used in combination with letrozole, the recommended dose of letrozole is 2.5 mg, taken orally once daily, administered continuously throughout the entire 28-day treatment cycle. For specific details, please refer to the approved prescribing information for letrozole. Method of Administration: Oral use. Palbociclib should be taken with food; it is recommended to take it with a meal to ensure consistent exposure to palbociclib (see [Pharmacokinetics]). Palbociclib must not be taken with grapefruit or grapefruit juice (see [Drug Interactions]). Palbociclib capsules should be swallowed whole (do not chew, crush, or open the capsules prior to swallowing). If a capsule appears damaged, cracked, or otherwise compromised, it must not be taken. Patients should be encouraged to take the medication at approximately the same time each day. If a patient vomits or misses a dose, they should not take an additional dose on that day. The next scheduled dose should be taken as usual. Dose Adjustment: It is recommended to adjust the dosage of palbociclib based on individual safety and tolerability.

**Method of Administration**

Oral use. Palbociclib should be taken with food; preferably, it should be taken with a meal to ensure consistent exposure.

Palbociclib must not be taken with grapefruit or grapefruit juice.

Palbociclib capsules should be swallowed whole (do not chew, crush, or open the capsules prior to swallowing).

If a capsule appears damaged, cracked, or otherwise compromised, it must not be taken.

Patients should be encouraged to take the medication at approximately the same time each day.

If a patient vomits or misses a dose, they should not take an additional dose on that day. The next scheduled dose should be taken as usual.

**[Dose Adjustment]**

It is recommended to adjust the dosage of palbociclib based on individual safety and tolerability.

Management of certain adverse reactions may require temporary interruption/delay of dosing, dose reduction, and/or permanent discontinuation of treatment; please refer to the guidelines provided in Tables 1, 2, and 3 for dose adjustment protocols.

Complete blood counts (CBC) should be monitored prior to initiating palbociclib therapy, at the beginning of each treatment cycle, on Day 15 of the first two cycles, and as clinically indicated.

For patients who experience Grade 1 or 2 neutropenia during the first 6 treatment cycles, subsequent CBC monitoring should be performed every 3 months, prior to the start of each cycle, and as clinically indicated. It is recommended that palbociclib be administered only when the Absolute Neutrophil Count (ANC) is ≥ 1,000/mm³ and the platelet count is ≥ 50,000/mm³.

**Special Populations**

**Geriatric Patients:** No dose adjustment is required for patients aged ≥ 65 years.

**Pediatric Patients:** The safety and efficacy of palbociclib in children and adolescents aged ≤ 18 years have not been established. No data are available. Hepatic Impairment: No dose adjustment of palbociclib is required for patients with mild or moderate hepatic impairment (Child-Pugh Class A and B).

For patients with severe hepatic impairment (Child-Pugh Class C), the recommended dose is 75 mg once daily, administered on a 3/1 dosing schedule (see [Precautions] and [Pharmacokinetics]).

Renal Impairment: No dose adjustment of palbociclib is required for patients with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] ≥ 15 mL/min).

There are insufficient data for patients requiring hemodialysis to provide any dose adjustment recommendations for this population.

Dose Adjustment When Used Concurrently with Strong CYP3A Inhibitors

Avoid the concomitant use of strong CYP3A inhibitors; consider substituting with other concomitant medications that have no or only weak CYP3A inhibitory effects. If patients must be co-administered a strong CYP3A inhibitor, reduce the palbociclib dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the palbociclib dose to the dose used prior to the initiation of the strong CYP3A inhibitor (after 3 to 5 half-lives of the inhibitor).

[Adverse Reactions]

This prescribing information describes adverse reactions observed in clinical trials that were judged to be possibly caused by palbociclib, along with their approximate incidence rates. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates observed in another clinical trial and may not reflect the rates observed in clinical practice.

Summary of Safety Profile

The overall safety profile of palbociclib is based on pooled data from 872 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received palbociclib in combination with endocrine therapy (527 patients with letrozole and 345 patients with fulvestrant) in randomized studies [including Study PALOMA-1 (A5481003), Study PALOMA-2 (A5481008), and Study PALOMA-3 (A5481023)]. In clinical studies, the most common (≥20%) adverse reactions of any grade reported in patients receiving palbociclib were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, and diarrhea.

The most common (≥2%) Grade ≥3 adverse reactions associated with palbociclib were neutropenia, leukopenia, anemia, fatigue, and infections.

In Study PALOMA-2, the safety of palbociclib (125 mg/day) in combination with letrozole (2.5 mg/day) was evaluated against placebo in combination with letrozole. The median duration of treatment was 19.8 months for the palbociclib-plus-letrozole arm and 13.8 months for the placebo-plus-letrozole arm. Among patients receiving palbociclib plus letrozole, 36% required dose reduction due to adverse reactions of any grade. Permanent discontinuation due to adverse reactions occurred in 43/444 (9.7%) patients receiving palbociclib plus letrozole and in 13/222 (5.9%) patients receiving placebo plus letrozole. Adverse reactions leading to permanent discontinuation in patients receiving palbociclib plus letrozole included neutropenia (1.1%) and alanine aminotransferase increased (0.7%).

List of Adverse Reactions

Table 4 reports adverse reactions from the pooled dataset of three randomized studies [Study PALOMA-1 (A5481003), Study PALOMA-2 (A5481008), and Study PALOMA-3 (A5481023)]. In the pooled dataset, the median duration of palbociclib treatment was 12.7 months.

Table 5 reports laboratory abnormalities from the pooled dataset of the three randomized studies. Adverse reactions are listed by System Organ Class and frequency of occurrence. Frequency of occurrence is defined as: very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1,000 to <1/100).

In the PALOMA-2 and PALOMA-3 studies, 200 Asian patients were enrolled. Among Asian patients receiving palbociclib, the reported incidence of Grade 3 or 4 neutropenia and leukopenia was higher than that in non-Asian patients; consequently, the frequency of dose interruptions, dose reductions, and cycle delays was also slightly higher in Asian patients compared to non-Asian patients. However, overall safety was manageable through protocol-specified dose adjustments, and Asian patients demonstrated a median duration of treatment similar to that of non-Asian patients. Based on a cumulative analysis of existing palbociclib dose-exposure, safety, and efficacy data, a starting dose of 125 mg once daily is appropriate for Asian patients.

Palbociclib dosage should be adjusted strictly in accordance with the prescribing information, based on the individual patient's safety and tolerability.

Description of Selected Adverse Reactions

Overall, across the three randomized studies, 703 patients (80.6%) receiving palbociclib—regardless of the combination regimen—reported neutropenia of any grade; of these, 482 patients (55.3%) and 88 patients (10.1%) reported Grade 3 and Grade 4 neutropenia, respectively (see Table 4). Across the three randomized clinical studies, the median time to the first onset of neutropenia of any grade was 15 days (range: 12–700 days), and the median duration of Grade ≥3 neutropenia was 7 days. Febrile neutropenia was reported in 0.9% of patients receiving palbociclib in combination with fulvestrant, and in 2.1% of patients receiving palbociclib in combination with letrozole. Across the overall clinical study population, febrile neutropenia was reported in approximately 2% of patients treated with palbociclib. [Contraindications] Contraindicated in patients with known hypersensitivity to the active ingredient or to any of the excipients listed in the [Ingredients] section.

Concomitant use of products containing St. John’s wort (*Hypericum perforatum*) is contraindicated.

[Precautions]

[Pre/Perimenopausal Women]

Given the mechanism of action of aromatase inhibitors, pre/perimenopausal women receiving combination therapy with palbociclib and an aromatase inhibitor must undergo ovarian ablation or suppression using a Luteinizing Hormone-Releasing Hormone (LHRH) agonist.

In studies evaluating palbociclib in combination with fulvestrant in pre/perimenopausal women, palbociclib was administered only in combination with an LHRH agonist.

[Severe Visceral Disease (Metastases)]

The efficacy and safety of palbociclib have not been studied in patients with severe visceral disease (metastases).

[Hematologic Toxicity]

Neutropenia was the most frequently reported adverse reaction in clinical studies. Febrile neutropenia was reported in approximately 2% of patients treated with palbociclib in clinical studies, and one fatal case of neutropenic sepsis was reported.

Complete blood counts should be monitored prior to the start of palbociclib therapy, at the beginning of each cycle, on Day 15 of the first two cycles, and as clinically indicated. For patients who develop Grade 3 or 4 neutropenia, dose interruption, dose reduction, or delayed initiation of the treatment cycle is recommended, along with close monitoring. Physicians should advise patients to report any febrile episodes immediately.

[Infections] Due to its myelosuppressive properties, palbociclib may predispose patients to infections. Several randomized studies reported a higher incidence of infections in patients in the palbociclib arm compared to their respective control arms. Grade 3 and 4 infections occurred in 4.5% and 0.7% of patients, respectively, receiving any palbociclib combination regimen. Patients should be monitored for signs and symptoms of infection and treated as appropriate. Patients should immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness, or an increased tendency for bleeding and/or bruising.

[Hepatic Impairment] Palbociclib should be used with caution in patients with moderate or severe hepatic impairment, and patients should be closely monitored for signs of toxicity.

[Renal Impairment] Palbociclib should be used with caution in patients with moderate or severe renal impairment, and patients should be closely monitored for signs of toxicity.

[Concomitant Treatment with CYP3A4 Inhibitors or Inducers]

Strong CYP3A4 inhibitors may lead to increased toxicity. Concomitant use with strong CYP3A inhibitors should be avoided during palbociclib treatment. Concomitant use should be considered only after a careful assessment of the potential benefits and risks. If concomitant use with strong CYP3A inhibitors cannot be avoided, the palbociclib dose should be reduced to 75 mg once daily. Upon discontinuation of the strong inhibitor, the palbociclib dose (after 3 to 5 half-lives of the inhibitor) should be increased to the dose used prior to the initiation of the strong CYP3A inhibitor. Concomitant use with CYP3A inducers may lead to decreased exposure to palbociclib, thereby posing a risk of reduced efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. No dose adjustment is required when palbociclib is used concomitantly with moderate CYP3A inducers.

[Women of Childbearing Potential or Their Partners] Women of childbearing potential or their male partners must use a highly effective method of contraception during palbociclib treatment.

[Lactose] Palbociclib contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take palbociclib. Effects on Ability to Drive and Use Machines: Palbociclib has negligible influence on the ability to drive and use machines. However, palbociclib may cause fatigue; therefore, patients should exercise caution when driving or operating machinery. [Use in Pregnant and Lactating Women] Women of Childbearing Potential/Contraception: Women of childbearing potential receiving treatment with this product, or their male partners, should use adequate contraceptive measures (e.g., double-barrier contraception) during treatment and for at least 3 weeks (for women) or 14 weeks (for men) after completing treatment.

[Pregnancy] There are limited or no data regarding the use of palbociclib in pregnant women. Animal studies have shown palbociclib to be reproductively toxic. Palbociclib is not recommended for use in pregnant women or in women of childbearing potential who are not using contraception.

[Lactation] Studies have not been conducted in humans or animals to evaluate the effect of palbociclib on milk production, its presence in breast milk, or its effects on the breastfed infant. It is not known whether palbociclib is excreted in human milk. Patients receiving palbociclib treatment should not breastfeed.

[Fertility] In non-clinical reproductive toxicity studies, no effects were observed on the estrous cycle (in females) or on mating and fertility (in males and females) in rats. Clinical data regarding the effects on human fertility are not available. Based on changes observed in male reproductive organs in non-clinical safety studies (degeneration of seminiferous tubules in the testes, reduced sperm in the epididymis, decreased sperm motility and density, and reduced prostatic secretion), palbociclib treatment may impair fertility in males. Therefore, males should consider sperm preservation prior to initiating palbociclib treatment.

[Pediatric Use] The safety and efficacy of palbociclib in pediatric and adolescent patients aged 18 years and younger have not been established. No data are available.

[Geriatric Use] Of the 444 patients treated with palbociclib in the PALOMA-2 study, 181 (41%) were aged ≥65 years, and 48 (11%) were aged ≥75 years. No differences in the safety or efficacy of palbociclib were observed between these patients and younger patients. No dose adjustment for palbociclib is required for patients aged 65 years and older. Specifications & Parameters

Product Name: Palbociclib 100mg (21 Capsules/Box) — Palbonix 100mg — Manufactured by BEACON (Bangladesh)

Common Name: Palbociclib