Palbociclib Pfizer 75 Mg/100 Mg/125 Mg Capsules

PALBOCICLIB PFIZER is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination:

• with letrozole as initial endocrine-based therapy in postmenopausal women
• with fulvestrant in women with disease progression who have received prior endocrine therapy

Treatment with PALBOCICLIB PFIZER should be conducted by a medical practitioner experienced in the use of anticancer therapies.

Posology

The recommended starting dose of PALBOCICLIB PFIZER is a 125 mg capsule taken orally once daily with food for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days.

When co-administered with PALBOCICLIB PFIZER, the recommended dose of letrozole is 2,5 mg taken orally once daily continuously throughout the 28-day cycle. Please refer to the full prescribing information of letrozole.

When co-administered with PALBOCICLIB PFIZER, the recommended dose of fulvestrant is 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter. Please refer to the full prescribing information of fulvestrant.

Patients should be encouraged to take their dose at approximately the same time each day. Continue the treatment as long as the patient is deriving clinical benefit from therapy. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. PALBOCICLIB PFIZER capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.

Prior to the start of, and throughout treatment with the combination PALBOCICLIB PFIZER plus fulvestrant, pre/perimenopausal women should be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to local clinical practice.

Dose modifications

Dose modification of PALBOCICLIB PFIZER is recommended based on individual safety and tolerability. Management of some adverse reactions may require temporary dosing interruptions/cycle delays, and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 3, 4 and 5 (see sections 4.4 and 4.8).

Table 1. PALBOCICLIB PFIZER Recommended dose modifications for adverse events

* If further dose reduction below 75 mg/day is required, discontinue the treatment.

Table 2. PALBOCICLIB PFIZER Dose modification and management u2013 haematologic toxicities

Monitor complete blood counts prior to the start of PALBOCICLIB PFIZER therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle and as clinically indicated.

CTCAE Grade

Dose Modifications

Grade 1 or 2: No dose adjustment is required.

Grade 3: Day 1 of cycle: Withhold PALBOCICLIB PFIZER, until recovery to Grade u2264 2, and repeat complete blood count monitoring within 1 week. When recovered to Grade u2264 2, start the next cycle at the same dose. Day 15 of first 2 cycles: If Grade 3 on Day 15, continue PALBOCICLIB PFIZER at the current dose to complete cycle and repeat complete blood count on Day 22. If Grade 4 on Day 22, see Grade 4 dose modification guidelines below.

Consider dose reduction in cases of prolonged (> 1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of the subsequent cycles.

Grade 3 ANC (< 1 000 to 500/mm3) + fever u2265 38,5u00baC and/or infection: At any time: Withhold PALBOCICLIB PFIZER until recovery to Grade u2264 2. Resume at the next lower dose.

Grade 4: At any time: Withhold PALBOCICLIB PFIZER until recovery to Grade u2264 2. Resume at the next lower dose.

Grading according to CTCAE 4,0 (Grade 1: ANC < LLN u2013 1 500/mm3; Grade 2: ANC 1 000 - <1 500/mm3; Grade 3: ANC 500 - < 1 000/mm3; Grade 4: ANC < 500/mm3). ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events; LLN = lower limit of normal.

Table applies to all haematologic adverse reactions except lymphopenia (unless associated with clinical events, e.g. opportunistic infections).

ANC: Grade 1: ANC < LLN u2013 1 500/mm3; Grade 2: ANC 1 000 - < 1 500/mm3; Grade 3: ANC 500 - < 1 000/mm3; Grade 4: ANC < 500/mm3.

Table 3. PALBOCICLIB PFIZER Dose modification and management u2013 non-haematologic toxicities

CTCAE Grade

Dose modifications

Grade 1 or 2: No dose adjustment is required.

Grade u2265 3 non-haematologic toxicity: Withhold until symptoms resolve (if persisting despite medical treatment) to: u2022 Grade u2264 1; u2022 Grade u2264 2 (if not considered a safety risk for the patient) Resume at the next lower dose.

Grading according to CTCAE 4,0 CTCAE = Common Terminology Criteria for Adverse Events. No dose modifications are required on the basis of patientu2019s age, sex or body weight (see section 5.2).

Permanently discontinue PALBOCICLIB PFIZER in patients with severe interstitial lung disease (ILD) or pneumonitis (see section 4.4).

Special populations

Elderly population

No dose adjustment is necessary in patients u2265 65 years of age (see section 5.2).

Hepatic impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of PALBOCICLIB PFIZER is 75 mg once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days (see section 4.1 and section 5.2).

Renal impairment

No dose adjustment is required for patients with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] u2265 15 mL/min). Insufficient data are available in patients requiring haemodialysis to provide any dosing recommendation in this patient population.

Paediatric population

The safety and efficacy of PALBOCICLIB PFIZER in children and adolescents u2264 18 years of age have not been established.

• Hypersensitivity to palbociclib or any of the excipients of PALBOCICLIB PFIZER (listed in section 6.1).

Neutropenia

Decreased neutrophil counts have been observed in clinical studies with PALBOCICLIB PFIZER. In patients receiving PALBOCICLIB PFIZER in combination with letrozole (Study 1 and 2) or fulvestrant (Study 3), Grade 3 and Grade 4 decreased neutrophil counts were reported in 56,1 % and 10,6 % of patients, respectively. The median time to first episode of any grade neutropenia was 15 days (12 - 700 days) and the median duration of Grade u2265 3 neutropenia was 7 days across 3 randomised clinical studies. Monitor complete blood count prior to starting PALBOCICLIB PFIZER therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle and as clinically indicated. Treatment interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia (see section 4.2).

Interstitial lung disease/pneumonitis

Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors, including PALBOCICLIB PFIZER when taken in combination with endocrine therapy. Across clinical trials, 1,4 % of PALBOCICLIB PFIZER-treated patients had ILD/pneumonitis of any grade, 0,1 % had Grade 3, and no Grade 4 or fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting (see section 4.8), with fatalities reported. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnoea). In patients who have new or worsening respiratory symptoms and are suspected to have developed ILD/pneumonitis, interrupt PALBOCICLIB PFIZER immediately and evaluate the patient. Permanently discontinue PALBOCICLIB PFIZER in patients with severe ILD or pneumonitis (see section 4.2).

Infections

Since PALBOCICLIB PFIZER has myelosuppressive properties, it may predispose to infections. Infections of any grade have been reported at a higher rate in patients treated with PALBOCICLIB PFIZER plus letrozole or fulvestrant (54,8 %) compared to patients treated in the respective comparator arms (36,9 %). Grades 3 and 4 infections occurred in 4,4 % and 0,7 %, respectively, in patients treated with PALBOCICLIB PFIZER in either combination compared to patients treated in the respective comparator arms (2,5 % and 0 %, respectively). Monitor patients for signs and symptoms of infection and treat as medically appropriate (see section 4.8). Healthcare providers should inform patients to promptly report any episodes of fever.

Venous thromboembolism

Venous thromboembolic events were reported in patients treated with PALBOCICLIB PFIZER (see section 4.8). Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism and treated as medically appropriate.

Excipients with known effect

PALBOCICLIB PFIZER contains lactose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take PALBOCICLIB PFIZER. PALBOCICLIB PFIZER may have an effect on the glycaemic control of patients with diabetes mellitus.

PALBOCICLIB PFIZER is primarily metabolised by CYP3A and sulphotransferase (SULT) enzyme SULT2A1. In vivo, PALBOCICLIB PFIZER is a time-dependent inhibitor of CYP3A.

Medicines that may increase PALBOCICLIB PFIZER plasma concentrations

Effect of CYP3A inhibitors

Data from a drug-drug interaction (DDI) study in healthy subjects indicate that co-administration of multiple 200 mg doses of itraconazole with a single 125 mg dose of PALBOCICLIB PFIZER increased PALBOCICLIB PFIZER total exposure area under the plasma concentration-time curve from zero to infinity (AUC 0-inf) and the maximum observed plasma concentration (C max) by approximately 87 % and 34 %, respectively, relative to a single 125 mg dose of PALBOCICLIB PFIZER given alone. The concomitant use of strong CYP3A inhibitors including, but not limited to: amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided.

Medicines that may decrease PALBOCICLIB PFIZER plasma concentrations

Effect of CYP3A inducers

Data from a DDI study in healthy subjects indicate that co-administration of multiple 600 mg doses of rifampicin, a strong CYP3A inducer, with a single 125 mg dose of PALBOCICLIB PFIZER decreased PALBOCICLIB PFIZER AUC 0-inf and C max by 85 % and 70 %, respectively, relative to a single 125 mg dose of PALBOCICLIB PFIZER given alone. Data from a DDI study in healthy subjects indicate that co-administration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg dose of PALBOCICLIB PFIZER decreased palbociclib AUC 0-inf and C max by 32 % and 11 %, respectively, relative to a single 125 mg dose of PALBOCICLIB PFIZER given alone. The concomitant use of strong CYP3A inducers including, but not limited to carbamazepine, enzalutamide, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampicin, rifapentin, and St. Johnu2019s wort, should be avoided. Co-administration of a moderate CYP3A inducer (modafinil) decreased the plasma exposure of palbociclib in healthy subjects by 32 %. Moderate CYP3A inducers (e.g. bosentan, efavirenz, etravirine, modafinil, and nafcillin) can be used concurrently with PALBOCICLIB PFIZER when unavoidable. No dosing adjustments are required.

Effect of acid reducing medicines

Data from a DDI study in healthy subjects indicated that co-administration of a single 125 mg dose of PALBOCICLIB PFIZER with multiple doses of the PPI rabeprazole under fed conditions decreased PALBOCICLIB PFIZER C max by 41 % but had limited impact on AUC 0-inf (13 % decrease) compared with a single 125 mg dose of PALBOCICLIB PFIZER administered alone. Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on PALBOCICLIB PFIZER exposure. Data from another DDI study in healthy subjects indicated that co-administration of a single dose of PALBOCICLIB PFIZER with multiple doses of the PPI rabeprazole under fasted conditions decreased PALBOCICLIB PFIZER AUC 0-inf and C max by 62 % and 80 %, respectively, when compared with a single dose of PALBOCICLIB PFIZER administered alone. Therefore, PALBOCICLIB PFIZER should be taken with food (see section 4.2).

Effects of PALBOCICLIB PFIZER on other medicines

PALBOCICLIB PFIZER, 125 mg daily dosing, is a weak time-dependent inhibitor of CYP3A at steady state in humans. In a DDI study in healthy subjects, co-administration of midazolam with multiple doses of PALBOCICLIB PFIZER increased the midazolam AUC 0-inf and C max values by 61 % and 37 %, respectively, as compared with administration of midazolam alone. In vitro, PALBOCICLIB PFIZER is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations.

Letrozole

Data from a clinical study in patients with breast cancer showed that there was no drug interaction between PALBOCICLIB PFIZER and letrozole when the two medicines were co-administered.

Fulvestrant

Data from a clinical study in patients with breast cancer showed that there was no clinically relevant interaction between PALBOCICLIB PFIZER and fulvestrant when the 2 medicines were co-administered.

Goserelin

Data from a clinical study in patients with breast cancer showed that there was no clinically relevant interaction between PALBOCICLIB PFIZER and goserelin when the 2 medicines were co-administered.

Tamoxifen

Data from a DDI study in healthy male subjects indicated that palbociclib exposures were comparable when a single dose of PALBOCICLIB PFIZER was co-administered with multiple doses of tamoxifen and when PALBOCICLIB PFIZER was given alone.

In vitro studies with transporters Based on in vitro data, PALBOCICLIB PFIZER is predicted to inhibit intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) mediated transport. Therefore, administration of PALBOCICLIB PFIZER with medicines that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g., pravastatin, rosuvastatin, fluvastatin, sulfasalazine) may increase their therapeutic effect and adverse reactions. Based on in vitro data, PALBOCICLIB PFIZER may inhibit the uptake transporter organic cationic transporter OCT1 and then may increase the exposure of medicine substrates of this transporter (e.g., metformin). Drug-drug interaction between PALBOCICLIB PFIZER and statins Concomitant use of PALBOCICLIB PFIZER with statins which are substrates of CYP3A4 and/or BCRP may increase the risk of rhabdomyolysis due to increased statin plasma concentration. Cases of rhabdomyolysis including fatal cases have been reported following coadministration of PALBOCICLIB PFIZER with simvastatin or atorvastatin.

Pregnancy

There are no adequate and well-controlled studies using PALBOCICLIB PFIZER in pregnant women. Based on findings in animals and mechanism of action, PALBOCICLIB PFIZER can cause foetal harm when administered to a pregnant woman. In animal studies, PALBOCICLIB PFIZER was teratogenic and foetotoxic at maternally toxic doses. PALBOCICLIB PFIZER is not recommended during pregnancy and in women of childbearing potential not using contraception (see section 5.3). Females of childbearing potential or their male partners who are receiving PALBOCICLIB PFIZER, should use adequate contraceptive methods during therapy and for at least 21 days or 97 days after completing therapy for females and males, respectively.

Breastfeeding

No studies have been conducted in humans to assess the effect of PALBOCICLIB PFIZER on milk production, its presence in breast milk, or its effects on the breastfed child. It is unknown whether PALBOCICLIB PFIZER is excreted in human milk. Patients receiving PALBOCICLIB PFIZER should not breastfeed.

Fertility

There were no effects on oestrous cycle (female rats) or mating and fertility in rats in nonclinical studies. However, no clinical data have been obtained on fertility in human females. Based on nonclinical safety findings in male reproductive tissues, male fertility may be compromised by treatment with PALBOCICLIB PFIZER. Men should consider sperm preservation prior to beginning therapy with PALBOCICLIB PFIZER (see section 5.3).

No studies on the effects of PALBOCICLIB PFIZER on the ability to drive or operate machinery have been conducted. However, patients experiencing fatigue and dizziness while taking PALBOCICLIB PFIZER should exercise caution when driving or operating machinery.

Summary of the safety profile

The overall safety profile of PALBOCICLIB PFIZER is based on pooled data from 872 patients who received palbociclib in combination with endocrine therapy (N = 527 in combination with letrozole and N = 345 in combination with fulvestrant) in randomised clinical studies in HR-positive, HER2-negative advanced or metastatic breast cancer.

Table 4 presents the adverse drug reactions for palbociclib from the pooled dataset of 3 randomised studies within each system organ class by decreasing medical seriousness.

Table 4. Side effects by SOC and CIOMS frequency category (Very common u2265 1/10, Common u2265 1/100 to <1/10) uncommon (u2265 1/1 000 to < 1/100), rare (u2265 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data).

Infections and Infestations

Very common Infections

Blood and lymphatic system disorders

Very common Neutropenia (neutropenia, decreased neutrophil count), leukopenia (leukopenia, decreased white blood cell count), anaemia (anaemia, decreased haemoglobin, decreased haematocrit), thrombocytopenia (thrombocytopenia, decreased platelet count)

Common Febrile neutropenia

Metabolism and nutrition disorders

Very common Decreased appetite

Nervous system disorders

Common Dysgeusia

Eye disorders

Common Blurred vision, increased lacrimation, dry eye

Respiratory, thoracic and mediastinal disorders

Common Epistaxis

Gastrointestinal disorders

Very common Stomatitis (aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis), nausea, diarrhoea, vomiting

Skin and subcutaneous tissue disorders

Very common Rash (rash, maculo-papular rash, pruritic rash, erythematous rash, papular rash, dermatitis, acneiform dermatitis, toxic skin eruption), alopecia

Common Dry skin

General disorders and administration site conditions

Very common Fatigue, asthenia, pyrexia

Investigations

Common Increased alanine aminotransferase, increased aspartate aminotransferase, increased blood creatinine

The most common (u2265 20 %) adverse drug reactions of any grade reported in patients receiving palbociclib in randomised clinical trials were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, alopecia, and diarrhoea.

Dose reductions due to any adverse reaction occurred in 34,4 % of patients receiving PALBOCICLIB PFIZER in any combination in randomised clinical studies, Study 1, Study 2, and Study 3. Permanent discontinuation associated with an adverse drug reaction occurred in 4,1 % of patients receiving PALBOCICLIB PFIZER in any combination in randomised clinical trials Study 1, Study 2, and Study 3.

The most frequently (u2265 1 %) reported serious adverse drug reactions in patients receiving palbociclib plus letrozole (Study 1 and Study 2) were infections (4,6 %) and febrile neutropenia (1,3 %). The most frequently (u2265 1 %) reported serious adverse drug reactions in patients receiving palbociclib plus fulvestrant (Study 3) were infections (4,1 %), pyrexia (1,4 %), and neutropenia (1,2 %).

Post-marketing adverse events

System organ class Side effect

Vascular disorders Venous thromboembolism

Respiratory, thoracic and mediastinal disorders ILD/pneumonitis

Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome, Cutaneous lupus erythematosus, Erythema multiforme

ILD/Pneumonitis includes any reported Preferred Terms that are part of the Standardized MedDRA Query Interstitial Lung Disease (narrow).

Venous thromboembolism includes the following PTs: pulmonary embolism, embolism, deep vein thrombosis, peripheral embolism, thrombosis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Report any suspected adverse drug reactions associated with the use of the medicine directly to Pfizer via [email protected].

There is no known antidote for PALBOCICLIB PFIZER. The treatment of PALBOCICLIB PFIZER overdose should consist of general supportive measures.