|S4| PALBOCICLIB PFIZER 75 mg Capsules (52/26/0041), PALBOCICLIB PFIZER 100 mg Capsules (52/26/0042), PALBOCICLIB PFIZER 125 mg Capsules (52/26/0043). COMPOSITION: Each PALBOCICLIB PFIZER 75 mg capsule contains 75 mg palbociclib and 55,78 mg lactose monohydrate. Each PALBOCICLIB PFIZER 100 mg capsule contains 100 mg palbociclib and 74,37 mg lactose monohydrate. Each PALBOCICLIB PFIZER 125 mg capsule contains 125 mg palbociclib and 92,96 mg lactose monohydrate. PHARMACOLOGICAL CLASSIFICATION : Antineoplastic medicines, protein kinase inhibitors. INDICATIONS: 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 or with fulvestrant in women with disease progression who have received prior endocrine therapy. DOSAGE AND DIRECTIONS FOR USE: Treatment with PALBOCICLIB PFIZER should be conducted by a medical practitioner experienced in the use of anticancer therapies. 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 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. Recommended dose-125 mg/day, first dose reduction-100 mg/day, second dose reduction-75 mg/day and if further dose reduction below 75 mg/day is required, discontinue the treatment. Dose modification and management - 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. For full information regarding the dose modification please refer to package insert. Dose modification and management - non-haematologic toxicities. Based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4. If Grade 1 or 2-no dose adjustment is required. Grade ≥ 3 non-haematologic toxicity (if persisting despite medical treatment) withhold until symptoms resolve to: Grade ≤ 1; Grade ≤ 2 (if not considered a safety risk for the patient) resume at the next lower dose. No dose modifications are required on the basis of patient’s age, sex or body weight. Permanently discontinue PALBOCICLIB PFIZER in patients with severe interstitial lung disease (ILD) or pneumonitis. Contraindications: Hypersensitivity to palbociclib or any of the excipients of PALBOCICLIB PFIZER. Special populations: Elderly population. No dose adjustment is necessary in patients ≥ 65 years of age. 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. Renal impairment. No dose adjustment is required for patients with mild, moderate, or severe renal impairment (creatinine clearance [ CrCl] ≥ 15 mL/min). Insufficient data are available in patients requiring haemodialysis to provide any dosing recommendation in this patient population. Paediatric populations: The safety and efficacy of PALBOCICLIB PFIZER in children and adolescents ≤ 18 years of age have not been established. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: Neutropenia:. Decreased neutrophil counts have been observed in clinical studies with PALBOCICLIB PFIZER. The median time to first episode of any grade neutropenia was 15 days (12 - 700 days) and the median duration of Grade ≥ 3 neutropenia was 7 days. 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. 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, and no Grade 4 or fatal cases. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. 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. 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 compared to patients treated in the respective comparator arms. Monitor patients for signs and symptoms of infection and treat as medically appropriate. Healthcare providers should inform patients to promptly report any episodes of fever. 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. Interaction with other medicines and other forms of interaction: 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: itraconazole. 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: rifampicin and modafinil. The concomitant use of strong CYP3A inducers including, but not limited to carbamazepine, enzalutamide, felbamate, nevirapine, phenobarbital, phenytoin,  primidone, rifabutin, rifampicin, rifapentin, and St. John’s wort, should be avoided. 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. No clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on PALBOCICLIB PFIZER exposure. However, PPI use under fasted conditions decreased PALBOCICLIB PFIZER AUC0-inf and C_max. Therefore, PALBOCICLIB PFIZER should be taken with food. 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 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 coadministered. 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 coadministered. 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: 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, Pgp and BCRP mediated transport are unlikely to affect the extent of oral absorption of palbociclib at therapeutic doses. FERTILITY, PREGNANCY AND LACTATION: 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. PALBOCICLIB PFIZER is not recommended during pregnancy and in women of childbearing potential not using contraception. 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: No clinical data 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. SIDE-EFFECTS: Undesirable effects: Based on System Organ Class and Council for International Organizations of Medical Sciences frequency category (Very common ≥ 1/10 and Common ≥ 1/1 00 to <1/10) are included here (please refer to full package insert for further information). Infections and Infestations. Very common: Infections. Blood and lymphatic system bdisorders. 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, maculopapular 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. Postmarketing adverse events: Respiratory, thoracic and mediastinal disorders: ILD/pneumonitis. 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 “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF TREATMENT: Overdose: There is no known antidote for PALBOCICLIB PFIZER. The treatment of PALBOCICLIB PFIZER overdose should consist of general supportive measures.  NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: Pfizer Laboratories (Pty) Ltd. Reg. No. 1954/000781/07. 85 Bute Lane, Sandton, 2196, South Africa. Tel: +27(0)11 320 6000 / 0860 734937 (toll free South Africa). PI Ref: 10/11/2020. For full prescribing information refer to the package insert. PP-PLBZAF-0006