Ibrance 75 mg, 100 mg, 125 mg Capsules

IBRANCE 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 IBRANCE should be conducted by a medical practitioner experienced in the use of anticancer therapies.

Posology

The recommended starting dose of IBRANCE 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 IBRANCE, 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 IBRANCE, 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. IBRANCE 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 IBRANCE 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 IBRANCE 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. IBRANCE Recommended dose modifications for adverse events

Dose Level Dose Recommended dose 125 mg/day First dose reduction 100 mg/day Second dose reduction 75 mg/day* * If further dose reduction below 75 mg/day is required, discontinue the treatment.

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

Neutropenia

Decreased neutrophil counts have been observed in clinical studies with IBRANCE. In patients receiving IBRANCE 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 IBRANCE 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 IBRANCE when taken in combination with endocrine therapy. Across clinical trials, 1,4 % of IBRANCE-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 IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis (see section 4.2).

Infections

Since IBRANCE has myelosuppressive properties, it may predispose to infections. Infections of any grade have been reported at a higher rate in patients treated with IBRANCE 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 IBRANCE 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 IBRANCE (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

IBRANCE 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 IBRANCE. IBRANCE may have an effect on the glycaemic control of patients with diabetes mellitus.

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

Medicines that may increase IBRANCE 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 IBRANCE increased IBRANCE 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 IBRANCE 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 IBRANCE 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 IBRANCE decreased IBRANCE AUC 0-inf and C max by 85 % and 70 %, respectively, relative to a single 125 mg dose of IBRANCE 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 IBRANCE decreased palbociclib AUC 0-inf and C max by 32 % and 11 %, respectively, relative to a single 125 mg dose of IBRANCE 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 IBRANCE 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 IBRANCE with multiple doses of the PPI rabeprazole under fed conditions decreased IBRANCE C max by 41 % but had limited impact on AUC 0-inf (13 % decrease) compared with a single 125 mg dose of IBRANCE 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 IBRANCE exposure. Data from another DDI study in healthy subjects indicated that co-administration of a single dose of IBRANCE with multiple doses of the PPI rabeprazole under fasted conditions decreased IBRANCE AUC 0-inf and C max by 62 % and 80 %, respectively, when compared with a single dose of IBRANCE administered alone. Therefore, IBRANCE should be taken with food (see section 4.2).

Effects of IBRANCE on other medicines

IBRANCE, 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 IBRANCE increased the midazolam AUC 0-inf and C max values by 61 % and 37 %, respectively, as compared with administration of midazolam alone. In vitro, IBRANCE 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 IBRANCE 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 IBRANCE 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 IBRANCE 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 IBRANCE was co-administered with multiple doses of tamoxifen and when IBRANCE was given alone. In vitro studies with transporters In vitro evaluations indicate that palbociclib has a low potential to inhibit the activities of drug transporters P-glycoprotein (P-gp, systemically), breast cancer resistance protein (BCRP, systemically), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1, OATP1B3, and bile salt export pump (BSEP) at clinically relevant concentrations. In vitro, palbociclib has the potential to inhibit OCT1 at clinically relevant concentrations, as well as the potential to inhibit P-gp or BCRP in the gastrointestinal tract at the proposed clinical dose. Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of palbociclib at therapeutic doses.

Pregnancy

There are no adequate and well-controlled studies using IBRANCE in pregnant women. Based on findings in animals and mechanism of action, IBRANCE can cause foetal harm when administered to a pregnant woman. In animal studies, IBRANCE was teratogenic and foetotoxic at maternally toxic doses. IBRANCE 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 IBRANCE, 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 IBRANCE on milk production, its presence in breast milk, or its effects on the breastfed child. It is unknown whether IBRANCE is excreted in human milk. Patients receiving IBRANCE 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 IBRANCE. Men should consider sperm preservation prior to beginning therapy with IBRANCE (see section 5.3).

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

Summary of the safety profile

The overall safety profile of IBRANCE 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).

System organ class Frequency Side effect

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

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 IBRANCE 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 IBRANCE 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

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 asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

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