Palbociclib 125 Mg/75 mg/100 mg Capsules

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

Posology

The recommended starting dose of PALBOCICLIB CIPLA 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 CIPLA, 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 CIPLA the recommended dose of fulvestrant is 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter. Please refer to the Professional 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 CIPLA 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 CIPLA 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 CIPLA is recommended based on individual safety and tolerability. Management of some adverse reactions may require temporary dose interruptions/ cycle delays, and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2, and 3 (see sections 4.4 and 4.8).

• Hypersensitivity to the active substance, palbociclib or to any of the excipients listed in section 6.1.
• Use of preparations containing St. John's Wort (see section 4.5).

Neutropenia

Decreased neutrophil counts have been observed in clinical studies with PALBOCICLIB CIPLA. In patients receiving PALBOCICLIB CIPLA 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 CIPLA 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).

Pre/perimenopausal women

Ovarian ablation or suppression with an LHRH agonist is mandatory when pre/perimenopausal women are administered PALBOCICLIB CIPLA in combination with an aromatase inhibitor, due to the mechanism of action of aromatase inhibitors. Palbociclib in combination with fulvestrant in pre/perimenopausal women has only been studied in combination with an LHRH agonist.

Critical visceral disease

The efficacy and safety of palbociclib have not been studied in patients with critical visceral disease (see section 5.1).

Haematological disorders

Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Appropriate monitoring should be performed (see sections 4.2 and 4.8).

Interstitial lung disease/pneumonitis (ILD)

Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with cyclin-dependent kinase (CDK 4/6) inhibitors, including PALBOCICLIB CIPLA when taken in combination with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.4 % of PALBOCICLIB CIPLA-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, with fatalities reported (see section 4.8). 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 CIPLA immediately and evaluate the patient. Permanently discontinue PALBOCICLIB CIPLA in patients with severe ILD or pneumonitis (see section 4.2).

Infections

Since PALBOCICLIB CIPLA has myelosuppressive properties, it may predispose patients to infections. Infections of any grade have been reported at a higher rate in patients treated with PALBOCICLIB CIPLA in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 4,4 % and 0,7 % of patients treated with PALBOCICLIB CIPLA in any combination (see section 4.8). Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see section 4.2). Medical practitioners should inform patients to promptly report any episodes of fever.

Hepatic impairment

Administer PALBOCICLIB CIPLA with caution to patients with moderate or severe hepatic impairment, with close monitoring of signs of toxicity (see sections 4.2 and 5.2).

Renal impairment

Administer PALBOCICLIB CIPLA with caution to patients with moderate or severe renal impairment, with close monitoring of signs of toxicity (see sections 4.2 and 5.2).

Concomitant treatment with inhibitors or inducers of CYP3A4

Strong inhibitors of CYP3A4 may lead to increased toxicity (see section 4.5). Concomitant use of strong CYP3A inhibitors during treatment with palbociclib should be avoided. Co-administration should only be considered after careful evaluation of the potential benefits and risks. If co-administration with a strong CYP3A inhibitor is unavoidable, reduce the PALBOCICLIB CIPLA dose to 75 mg once daily. When the strong inhibitor is discontinued, increase the PALBOCICLIB CIPLA dose (after 3 u2013 5 half u2013 lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see section 4.5). Concomitant use of palbociclib with strong CYP3A4 inducers should be avoided since coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently a risk for lack of efficacy. No dose adjustments are required for co-administration of palbociclib with moderate CYP3A inducers (see section 4.5).

Women of childbearing potential or their partners

Women of childbearing potential or their male partners must use a highly effective method of contraception while taking PALBOCICLIB CIPLA (see section 4.6).

Lactose Monohydrate

PALBOCICLIB CIPLA contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency, or glucose-galactose malabsorption should not take this medicine. PALBOCICLIB CIPLA may have an effect on the glycaemic control of patients with diabetes mellitus.

Sodium

This medicine contains less than 1 mmol (23 mg) sodium per capsule, that is to say essentially 'sodium-free'.

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

Effects of other medicines on the pharmacokinetics of palbociclib

Effect of CYP3A inhibitors

Coadministration of multiple 200 mg doses of itraconazole with a single 125 mg palbociclib dose increased palbociclib total exposure (AUC inf) and the peak concentration (C max) by approximately 87 % and 34 %, respectively, relative to a single 125 mg palbociclib dose given alone. The concomitant use of strong CYP3A inhibitors including, but not limited to: amprenavir, boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4). No dose adjustments are needed for mild and moderate CYP3A inhibitors.

Medicines that may decrease PALBOCICLIB CIPLA plasma concentrations.

Effect of CYP3A inducers

Coadministration of multiple 600 mg doses of rifampicin with a single 125 mg palbociclib dose decreased palbociclib AUC inf and C max by 85 % and 70 %, respectively, relative to a single 125 mg palbociclib dose given alone. The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampicin, rifapentine, and St. John's Wort should be avoided (see sections 4.3 and 4.4). Coadministration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg PALBOCICLIB CIPLA dose decreased palbociclib AUC inf and C max by 32 % and 11 %, respectively, relative to a single 125 mg PALBOCICLIB CIPLA dose given alone. No dose adjustments are required for moderate CYP3A inducers (see section 4.4).

Effect of acid reducing medicines

Under fed conditions (intake of a moderate-fat meal), coadministration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg PALBOCICLIB CIPLA decreased palbociclib C max by 41 % but had limited impact on AUC inf (13 % decrease) compared with a single dose of 125 mg PALBOCICLIB CIPLA administered alone. Under fasting conditions, the coadministration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg PALBOCICLIB CIPLA decreased palbociclib AUC inf and C max by 62 % and 80 %, respectively. Therefore, PALBOCICLIB CIPLA should be taken with food, preferably a meal (see sections 4.2 and 5.2). Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, no clinically relevant effect of H2-receptor antagonists or local antacids on palbociclib exposure is expected when PALBOCICLIB CIPLA is taken with food.

Effects of palbociclib on the pharmacokinetics of other medicines

Palbociclib is a weak, time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady state in humans. Coadministration of multiple doses of palbociclib with midazolam increased the midazolam AUCinf and C max values by 61 % and 37 %, respectively, as compared with administration of midazolam alone. In vitro, palcociclib 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. The dose of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced when co-administered with PALBOCICLIB CIPLA as PALBOCICLIB CIPLA may increase their exposure.

Drug-drug interaction between palbociclib and letrozole

Data from the drug-drug interaction (DDI) evaluation portion of a clinical study in patients with breast cancer showed that there was no drug interaction between palbociclib and letrozole when the 2 medicines were co-administered.

Effect of tamoxifen on palbociclib exposure

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

Drug-drug interaction between palbociclib and fulvestrant

Data available in patients with breast cancer showed that there was no clinically relevant drug interaction between palbociclib and fulvestrant when the two medicines were co-administered.

Drug-drug interaction between palbociclib and oral contraceptives

There is no date available on DDI studies of palbociclib with oral contraceptives (see section 4.6).

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.

Women of childbearing potential/Contraception

Females of childbearing potential who are receiving this medicine, or their male partners should use adequate contraceptive methods (e.g., double-barrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively.

Pregnancy

There are no adequate and well-controlled studies using PALBOCICLIB CIPLA in pregnant women. Based on findings in animals and mechanism of action, PALBOCICLIB CIPLA can cause foetal harm when administered to a pregnant woman. In animal studies, PALBOCICLIB CIPLA was teratogenic and foetotoxic at maternally toxic doses.

Breastfeeding

It is unknown whether palbociclib is excreted in human milk as no studies have been conducted in humans or animals to assess the effect of palbociclib on milk production, its presence in breast milk, or its effects on the breast-fed child. Patients receiving PALBOCICLIB CIPLA should not breast feed.

Fertility

No clinical data have been obtained on fertility in humans. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in nonclinical safety studies, male fertility may be compromised by treatment with PALBOCICLIB CIPLA. Thus, men may consider sperm preservation prior to beginning therapy with PALBOCICLIB CIPLA.

PALBOCICLIB CIPLA has minor influence on the ability to drive and use machines. However, PALBOCICLIB CIPLA may cause fatigue and patients should exercise caution when driving or using machines.

Infections and infestations

Frequent: Infections b

Blood and lymphatic system disorders

Frequent: Neutropenia c (neutropenia, decreased neutrophil count), Leukopeniad (leukopenia, decreased white blood cell count), Anaemia e (anaemia, decreased haemoglobin, decreased haematocrit), Thrombocytopenia f (thrombocytopenia, decreased platelet count), Febrile neutropenia

Metabolism and nutrition disorders

Frequent: Decreased appetite

Nervous system disorders

Frequent: Dysgeusia

Eye disorders

Frequent: Vision blurred, Lacrimation increased, Dry eye

Respiratory, thoracic and mediastinal disorders

Frequent: Epistaxis

Gastrointestinal disorders

Frequent: Stomatitis g (aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis), Nausea, Diarrhoea, Vomiting

Skin and subcutaneous tissue disorders

Frequent: Rash h (rash, maculo-papular rash, pruritic rash, erythematous rash, papular rash, dermatitis, acneiform dermatitis, toxic skin eruption), Alopecia, Dry skin

General disorders and administration site conditions

Frequent: Fatigue, Asthenia, Pyrexia

Investigations

Frequent: Increased alanine aminotransferase, increased aspartate aminotransferase

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease; N/n=number of patients; N/A=not applicable.

a Preferred Terms (PTs) are listed according to MedDRA 17.1.

b Infections includes all PTs that are part of the System Organ Class Infections and infestations.

c Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased.

d Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased.

e Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased.

f Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased.

g Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis.

h Rash includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash papular, Dermatitis, Dermatitis acneiform, Toxic skin eruption.

Post-marketing adverse events

Respiratory, thoracic and mediastinal disorders ILD/pneumonitis*

Skin and subcutaneous tissue disorders Cutaneous lupus erythematosus

* ILD/pneumonitis includes any reported PTs that are part of the Standardised MedDRA Query Interstitial Lung Disease (narrow)

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. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8 and to Cipla Medpro (Pty) Ltd at [email protected] or telephone 080 222 6662 (toll free).

There is no antidote for PALBOCICLIB CIPLA. In the event of a PALBOCICLIB CIPLA overdose, both gastrointestinal (e.g., nausea, vomiting) and haematological (e.g., neutropenia) toxicity may occur and general supportive care should be provided.