Excipients: croscarmellose sodium, microcrystalline cellulose, hypromellose, silica

Transcription

1 SCHEDULING STATUS S4 PROPRIETARY NAME AND DOSAGE FORM CAPECITABINE SPECPHARM 150 (film-coated tablet) CAPECITABINE SPECPHARM 500 (film-coated tablet) COMPOSITION Each 150 mg film-coated tablet contains 150 mg of capecitabine. Each 500 mg film-coated tablet contains 500 mg of capecitabine. Excipients: croscarmellose sodium, microcrystalline cellulose, hypromellose, silica colloidal anhydrous, magnesium stearate, titanium dioxide, talc, macrogol 400, red and yellow iron oxide. Sugar free. PHARMACOLOGICAL CLASSIFICATION A26 Cytostatic agents PHARMACOLOGICAL ACTION Pharmacodynamic properties Page 1 of 32

2 Capecitabine is a fluoropyrimidine carbamate which is an orally administered, tumour-activated and tumour-selective prodrug cytotoxic substance. Capecitabine is non-cytotoxic in vitro but in vivo it is converted to the cytotoxic moiety, 5-fluorouracil (5-FU), which is further metabolised. The formation of 5-FU is catalysed preferentially at the tumour site by the tumour associated angiogenic factor thymidine phosphorylase (dthdpase). Both normal and tumour cells metabolise 5-FU to 5- fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine-triphosphate (FUTP). The metabolites cause cell injury by two different mechanisms: 1. FdUMP and the folate cofactor, N methylenetetrahydrofolate, bind to thymidylate synthase (TS) and thus inhibits the formation of thymidylate from uracil. Thymidylate is a necessary precursor of thymidine triphosphate, which is essential for deoxyribonucleic acid (DNA) synthesis. A deficiency of thymidylate will inhibit cell division. 2. Nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during RNA synthesis. This metabolic error can interfere with RNA processing and protein synthesis. The metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thus interfering with the synthesis of DNA. The incorporation of 5-FU also leads to inhibition of RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be to create a thymidine deficiency that causes unbalanced growth and death of cells. The Page 2 of 32

3 effects of RNA and DNA inhibition are most prevalent on rapidly proliferating cells which metabolise 5-FU at a more rapid rate. Pharmacokinetic properties Absorption: After oral administration, capecitabine is well and extensively absorbed, followed by extensive conversion to the metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'- deoxy-5-fluorouridine (5'-DFUR). Administration with food decreases the rate of capecitabine absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC of the subsequent metabolite 5-FU. Distribution: Capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 54 %, 10 %, 62 % and 10 % protein bound, mainly to albumin. Metabolism: Capecitabine is first metabolised by hepatic carboxylesterase to 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, mainly located in the liver and tumour tissues. Further metabolism of 5'-DFUR then occurs by thymidine phosphorylase (dthdpase) to form 5-FU. The enzymes involved in the catalytic activation are found in tumour tissues but also in normal tissues at lower levels. The sequential enzymatic biotransformation of capecitabine to 5-FU leads to higher concentrations within tumour tissues. After conversion to 5-FU and anabolites of 5- FU, the metabolites of capecitabine become cytotoxic. 5-FU is further catabolised by Page 3 of 32

4 the enzyme dihydropyrimidine dehydrogenase (DPD) to dihydro-5-fluorouracil (FUH2), 5-fluoro-ureidopropionic acid (FUPA) and α-fluoro-β-alanine (FBAL) which is cleared in the urine. Dihydropyrimidine dehydrogenase (DPD) activity is the rate limiting step. Deficiency of DPD may lead to increased toxicity of capecitabine (see PHARMACOLOGICAL ACTION, Pharmacodynamics). Elimination: The elimination half-lives (t1/2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL are 0,85; 1,11; 0,66; 0,76 and 3,23 respectively. Capecitabine and its metabolites are mainly excreted in urine where 95,5 % of the administered capecitabine dose is recovered in urine. Faecal excretion is minimal at 2,6 %. The major metabolite excreted in urine is FBAL, which represents 57 % of the administered dose. About 3 % of the administered dose is excreted in urine unchanged. Pharmacokinetics in special populations: Gender, presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have no significant effect on the pharmacokinetics of 5'- DFUR, 5-FU and FBAL. Patients with hepatic impairment due to liver metastases: The bioavailability of capecitabine and exposure to 5-FU may be increased in cancer patients with mild to moderate liver impairment due to liver metastases, when compared to patients with Page 4 of 32

5 no liver impairment. There are no pharmacokinetic data on patients with severe hepatic impairment. Patients with renal impairment: In cancer patients with mild to severe renal impairment, there is no evidence of an effect of creatinine decreased clearance on the pharmacokinetics of intact capecitabine and 5-FU. Creatinine clearance influences the systemic exposure to 5'-DFUR (35 % increase in AUC when creatinine clearance decreases by 50 %) and to FBAL (114 % increase in AUC when creatinine clearance decreases by 50 %). FBAL is a metabolite without antiproliferative activity. Elderly: Age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increases with age (20 % increase in age results in a 15 % increase in the AUC of FBAL). This increase is likely due to a change in renal function. INDICATIONS Breast cancer: Metastatic breast cancer (combination therapy): CAPECITABINE SPECPHARM in combination with docetaxel, is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy which should have included an anthracycline. Metastatic breast cancer (monotherapy): CAPECITABINE SPECPHARM is indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and Page 5 of 32

6 an anthracycline-containing chemotherapy treatment or when further anthracycline treatment is not indicated. Colorectal cancer: Colon cancer: CAPECITABINE SPECPHARM is indicated in patients with Dukes C colon cancer, as an adjuvant treatment post-surgery. Metastatic colorectal cancer: CAPECITABINE SPECPHARM is indicated in patients with metastatic colorectal adenocarcinoma. The benefit relates to time to progression, while overall survival was not influenced. Gastric cancer: CAPECITABINE SPECPHARM is indicated for the treatment of patients with advanced gastric adenocarcinoma, as first line treatment, in combination with other anti-chemotherapeutic treatment. The benefit relates to time to progression, while overall survival was not influenced. CONTRAINDICATIONS CAPECITABINE SPECPHARM is contraindicated in patients with: - a known hypersensitivity to capecitabine or to any of its excipients. - a history of severe and unexpected reactions to fluoropyrimidine therapy, or with a known hypersensitivity to fluorouracil, a capecitabine metabolite. Page 6 of 32

7 - a known dihydropyrimidine dehydrogenase (DPD) deficiency. - severe leukopenia, neutropenia or thrombocytopenia. - severe hepatic impairment. - severe renal impairment (creatinine clearance < 30 ml/min). - CAPECITABINE SPECPHARM should not be given with sorivudine or any of its chemical analogues, such as brivudine, (See INTERACTIONS). - If patients have contraindications to any of the medicines in the combination regimen, that medicine should not be used. WARNINGS AND SPECIAL PRECAUTIONS Warfarin interaction: CAPECITABINE SPECPHARM may alter the coagulation parameters and/ or bleeding by increasing prothrombin time and INR in patients who were stabilised on anticoagulants when CAPECITABINE SPECPHARM is introduced. (See INTERACTIONS) The concomitant use of CAPECITABINE SPECPHARM with oral coumarinderivative anticoagulant therapy requires that patients have their anticoagulant response (International Normalised Ratio (INR) or prothrombin time) monitored frequently to facilitate adequate anticoagulant dose adjustment. Sorivudine and analogues: CAPECITABINE SPECPHARM must not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine (See Page 7 of 32

8 INTERACTIONS). Sorivudine and its analogues inhibit dihydropyrimidine dehydrogenase and lead to an increase in CAPECITABINE SPECPHARM toxicity. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. (See INTERACTIONS). Dose limiting toxicities: CAPECITABINE SPECPHARM may cause diarrhoea (sometimes severe), abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction), palmar-plantar erythrodysaesthesia (See SIDE EFFECTS). Most of these reactions are reversible when doses of CAPECITABINE SPECPHARM are reduced or withheld. Diarrhoea: Patients with severe diarrhoea should be monitored, given fluids and electrolyte replacement if they become dehydrated. Standard antidiarrhoeals may be used (e.g. loperamide). Grade 2 diarrhoea is defined as an increase of 4 6 stools/ day or nocturnal stools. Grade 3 diarrhoea is an increase of 7 to 9 stools/ day or incontinence and malabsorption. Grade 4 diarrhoea is an increase of 10 stools/ day or grossly bloody diarrhoea or the need for parenteral support. Dose reduction should be applied as needed. Dehydration: Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhoea could rapidly become dehydrated. Page 8 of 32

9 Dehydration may lead to acute renal failure, especially in patients where renal function is already compromised or when CAPECITABINE SPECPHARM is taken concomitantly with known nephrotoxic medicines. Patients who show signs of dehydration should have their treatment with CAPECITABINE SPECPHARM interrupted until they are rehydrated. Cutaneous: CAPECITABINE SPECPHARM can cause hand-foot syndrome which is a cutaneous toxicity defined by Grades according to its severity. (See SIDE EFFECTS). Grade 1 is defined by numbness, dysaesthesia, paraesthesia, tingling erythema of the hands and/ or feet and/ or discomfort which does not affect a patients daily activities. Grade 2 hand and foot syndrome is defined as painful erythema and swelling of the hands and/ or feet or discomfort which affects a patients daily living. Grade 3 hand and foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/ or feet and/ or a severe discomfort that causes the patient to be unable to work or perform activities of daily living. If Grade 2 or 3 hand and foot syndrome occurs, CAPECITABINE SPECPHARM should be interrupted until the syndrome resolves or decreases in intensity to Grade 1. (See DOSAGE AND DIRECTIONS FOR USE) Cardiotoxicity: CAPECITABINE SPECPHARM may cause cardiotoxicity associated with fluoropyrimidine therapy. This includes myocardial infarction, angina pectoris, dysrhythmias (including ventricular fibrillation, torsade de pointes and bradycardia), Page 9 of 32

10 cardiogenic shock, heart failure, cardiomyopathy, sudden death and electrocardiographic changes, including QT prolongation. Caution must be exercised in patients with a history of cardiac disease, dysrhythmias and angina pectoris. Calcium imbalances: Hypocalcaemia or hypercalcaemia may occur in patients taking CAPECITABINE SPECPHARM. Caution should be exercised in patients with pre-existing hypocalcaemia or hypercalcaemia. Diabetes mellitus or electrolyte disturbances: CAPECITABINE SPECPHARM should be used with caution in patients who have diabetes mellitus or electrolyte disturbances as these conditions may be aggravated during treatment with CAPECITABINE SPECPHARM. Hepatic impairment: CAPECITABINE SPECPHARM can induce hyperbilirubinaemia and treatment with CAPECITABINE SPECPHARM should be interrupted in patients where bilirubin increases to > 3,0 x ULN (Upper limit of normal) or if hepatic aminotransferases (ALT, AST) increase to > 2,5 x ULN. Treatment with CAPECITABINE SPECPHARM monotherapy may be resumed when bilirubin decreases to 3,0 x ULN or hepatic aminotransferases decrease to 2,5 x ULN. Patients with mild to moderate hepatic impairment should be carefully monitored when taking CAPECITABINE SPECPHARM. The effect of hepatic impairment that is Page 10 of 32

11 not a result of liver metastases or severe hepatic impairment on the disposition of CAPECITABINE SPECPHARM is not known. (See DOSAGE AND DIRECTIONS FOR USE: Special Populations) Renal insufficiency: CAPECITABINE SPECPHARM is contraindicated in patients with severe renal impairment where the creatinine clearance is < 30 ml/ min and caution must be exercised in patients with impaired renal function. The incidence of treatment related Grade 3 or 4 side effects is higher in patients with moderate renal impairment (creatinine clearance between 30 to 50 ml/ min) and a dose reduction to 75 % of the starting dose is recommended for patients on monotherapy and combination therapy. Careful monitoring and prompt treatment interruption is recommended if a patient develops a Grade 2,3 or 4 side effect after their dose of CAPECITABINE SPECPHARM has been adjusted. (See Table 4, DOSAGE AND DIRECTIONS FOR USE.) Dihydropyrimidine dehydrogenase (DPD) deficiency: CAPECITABINE SPECPHARM is contraindicated in DPD deficiency (See CONTRAINDICATIONS). CAPECITABINE SPECPHARM may cause severe toxicity (e.g. stomatitis, diarrhoea, neutropenia and neurotoxicity) which is associated with 5-fluorouracil and may be caused by a deficiency in DPD activity. A link between lowered levels of DPD and increased and potentially fatal toxic effects due to 5-FU cannot be excluded. Page 11 of 32

12 Effects on the ability to drive and use machines: CAPECITABINE SPECPHARM may cause dizziness, fatigue and nausea which may have an influence on the ability to drive and use machines. INTERACTIONS Cytochrome P450: CAPECITABINE SPECPHARM may increase the prothrombin time and/ or INR in patients taking warfarin concomitantly (See blocked warning). It is thought that CAPECITABINE SPECPHARM down-regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin-derivative anticoagulants concomitantly with CAPECITABINE SPECPHARM should be monitored regularly for changes in their coagulation parameters (PT or INR) and the anticoagulant dose adjusted accordingly. (See WARNINGS & SPECIAL PRECAUTIONS) Phenytoin: Caution should be exercised when CAPECITABINE SPECPHARM is coadministered with 2C9 substrates (e.g. phenytoin). Increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication may occur with concomitant use of CAPECITABINE SPECPHARM and phenytoin. Patients taking this combination of medicines should be regularly monitored for increased phenytoin plasma concentrations. Folinic acid/ Folic acid: Folinic acid has an effect on the pharmacodynamics and may increase the toxicity of CAPECITABINE SPECPHARM. The dose of CAPECITABINE SPECPHARM may require adjustment when taken concomitantly Page 12 of 32

13 with folic acid. Caution should be taken with patients taking folic acid supplementation for folate deficiency due to the similarity between folinic acid and folic acid. Sorivudine and analogues: CAPECITABINE SPECPHARM must not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine (See CONTRAINDICATIONS). Sorivudine and its analogues inhibit dihydropyrimidine dehydrogenase and lead to an increase in CAPECITABINE SPECPHARM toxicity. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. There should be at least a 4-week waiting period between end of treatment with sorivudine or its chemically related analogues such as brivudine and start of CAPECITABINE SPECPHARM therapy. Allopurinol: Concomitant use of allopurinol with CAPECITABINE SPECPHARM should be avoided since interactions with allopurinol may occur for 5-FU; with possible decreased efficacy of 5-FU. Interferon alpha: The Maximum Tolerated Dose (MTD) of CAPECITABINE SPECPHARM is mg/m 2 per day when combined with interferon alpha-2a (3 MIU/m 2 per day) compared to mg/m 2 per day when CAPECITABINE SPECPHARM is used alone. Radiotherapy: The MTD of CAPECITABINE SPECPHARM as monotherapy using the intermittent regimen is 3000 mg/m 2 per day, however, when CAPECITABINE Page 13 of 32

14 SPECPHARM is combined with radiotherapy for rectal cancer, the MTD of CAPECITABINE SPECPHARM is 2000 mg/m 2 per day using either a continuous schedule or given daily Monday through Friday during a 6-week course of radiotherapy. Oxaliplatin: CAPECITABINE SPECPHARM taken concomitantly with oxaliplatin or in combination with oxaliplatin and bevacizumab shows no clinically significant differences in exposure to CAPECITABINE SPECPHARM or its metabolites, free platinum or total platinum. Bevacizumab: Bevacizumab does not affect the pharmacokinetic parameters of CAPECITABINE SPECPHARM or its metabolites in the presence of oxaliplatin. Antacid: Aluminium hydroxide and magnesium hydroxide-containing antacids may cause a small increase in plasma concentrations of CAPECITABINE SPECPHARM and one metabolite (5'-DFCR); with no effect on the 3 major metabolites (5'-DFUR, 5-FU and FBAL). Food: It is recommended that CAPECITABINE SPECPHARM be taken with food. Administration with food decreases the rate of CAPECITABINE SPECPHARM absorption. (See DOSAGE & DIRECTIONS FOR USE) Combination therapy: Page 14 of 32

15 CAPECITABINE SPECPHARM has no effect on the pharmacokinetics of either docetaxel or paclitaxel (Cmax and AUC). Docetaxel and paclitaxel have no effect on the pharmacokinetics of 5'-DFUR. PREGNANCY AND LACTATION Pregnancy CAPECITABINE SPECPHARM is teratogenic and should not be taken during pregnancy as the possibility exists that foetal harm may occur. Women of childbearing potential Women of childbearing potential should be advised to avoid becoming pregnant while taking CAPECITABINE SPECPHARM as there is a risk of potential hazard to the foetus. An effective contraception method should be used during treatment with CAPECITABINE SPECPHARM. Lactation It is not known whether CAPECITABINE SPECPHARM is excreted in human milk, however, because of the potential for serious side effects in breastfed infants, it is recommended that breastfeeding be discontinued when taking CAPECITABINE SPECPHARM. Fertility The effect of CAPECITABINE SPECPHARM on fertility is not known. Page 15 of 32

16 DOSAGE AND DIRECTIONS FOR USE CAPECITABINE SPECPHARM should only be prescribed by a qualified medical practitioner who is experienced in the use of antineoplastic medicines. CAPECITABINE SPECPHARM Tablets should be swallowed with water within 30 minutes after a meal. Treatment with CAPECITABINE SPECPHARM should be discontinued if progressive disease or intolerable toxicity occurs. Adults: Monotherapy - Management of colon, colorectal and breast cancer: The recommended monotherapy dose of CAPECITABINE SPECPHARM is mg/m 2 taken twice daily, in the morning and evening (equivalent to mg/m 2 total daily dose) for 14 days followed by a 7 day rest period. Adjuvant treatment in patients with Stage III colon cancer is recommended for a maximum of six months. Combination therapy - Colorectal and Gastric cancer: In combination treatment, the starting dose of CAPECITABINE SPECPHARM should be reduced to mg/m 2 when taken twice daily for 14 days followed by a 7 day rest period. For the Dose Reduction Schedule for CAPECITABINE SPECPHARM, please refer to Table 1 below. Page 16 of 32

17 The starting dose of CAPECITABINE SPECPHARM will not change with the inclusion of biological medicines in a combination regimen. According to the cisplatin prescribing information, premedication to maintain adequate hydration and antiemesis should be started prior to cisplatin administration for patients receiving CAPECITABINE SPECPHARM with cisplatin in combination. Combination therapy - Breast cancer: In combination with docetaxel for locally advanced or metastatic breast cancer, the recommended dose of CAPECITABINE SPECPHARM is mg/m 2 twice daily for 14 days followed by a 7 day rest period, combined with docetaxel at 75 mg/m 2 as a 1 hour intravenous infusion every 3 weeks. According to the docetaxel prescribing information, premedication with an oral corticosteroid such as dexamethasone should be started prior to docetaxel administration for patients receiving CAPECITABINE SPECPHARM with docetaxel in combination. The dose of CAPECITABINE SPECPHARM is calculated according to body surface area of the patient. Page 17 of 32

18 Table 1: Standard and reduced dose calculations according to body surface area for a starting dose of CAPECITABINE SPECPHARM of mg/m 2 Table 1: Dose level mg/m 2 (twice daily) Full dose Number of 150 mg Reduced Reduced dose mg/m 2 Tablets and/ or 500 mg dose (75 %) (50 %) Tablets per 950 mg/m mg/m 2 Body Surface Area (m 2 ) administration (each administration to be given morning and evening) Dose per Dose per Dose per administration 150 mg 500 mg administration administration (mg) (mg) (mg) 1, ,27 1, ,39 1, ,53 1, ,67 1, ,79 1, ,93 2, ,07 2, , Page 18 of 32

19 Table 2: Standard and reduced dose calculations according to body surface area for a starting dose of CAPECITABINE SPECPHARM of mg/m 2 Table 1: Dose level mg/m 2 (twice daily) Full dose Number of 150 mg Reduced Reduced mg/m 2 Tablets and/ or 500 mg dose (75 %) dose (50 %) Tablets per 750 mg/m mg/m 2 Body Surface Area (m 2 ) administration (each administration to be given morning and evening) Dose per Dose per Dose per administration 150 mg 500 mg administration administration (mg) (mg) (mg) 1, ,27 1, ,39 1, ,53 1, ,67 1, ,79 1, ,93 2, ,07 2, , Dose adjustments during treatment: Patients taking CAPECITABINE SPECPHARM should be monitored for signs of toxicity. Toxicity due to CAPECITABINE SPECPHARM may be managed by Page 19 of 32

20 symptomatic treatment and/ or adjustment of the CAPECITABINE SPECPHARM dose (treatment interruption or dose reduction). Dosage modifications are not recommended for Grade 1 events. Treatment with CAPECITABINE SPECPHARM should be interrupted with occurrence of Grade 2 or 3 side effects. Once the side effect has resolved or decreased in intensity to Grade 1, treatment with CAPECITABINE SPECPHARM may then be restarted at full dose or adjusted according to Table 3 below. If a Grade 4 experience occurs, treatment should be discontinued or interrupted until resolved or decreased to Grade 1, and treatment can then be restarted at 50 % of the original dose. Patients taking CAPECITABINE SPECPHARM should be informed of the need to interrupt treatment immediately if moderate or worse toxicity occurs. Doses of CAPECITABINE SPECPHARM omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles. Once the dose has been reduced it should not be increased at a later time. (See SIDE EFFECTS) Table 3 shows the recommended dose modifications following toxicity with CAPECITABINE SPECPHARM. Page 20 of 32

21 Table 3: CAPECITABINE SPECPHARM dose reduction schedule following toxicity (3-weekly cycle or continuous treatment) Toxicity NCIC Grades* Dose changes within a treatment cycle Dose adjustment for next cycle dose (% of starting dose) Grade 1 Maintain dose level Maintain dose level Grade 2 1 st appearance Interrupt until resolved to Grade % 2 nd appearance Interrupt until resolved to Grade % 3 rd appearance Interrupt until resolved to Grade % 4 th appearance Discontinue treatment permanently Not applicable Grade 3 1 st appearance Interrupt until resolved to Grade % 2 nd appearance Interrupt until resolved to Grade % 3 rd appearance Discontinue treatment permanently Not applicable Grade 4 1 st appearance Discontinue treatment permanently or if in patient s best interest to continue, interrupt until resolved to Grade % 2 nd appearance Discontinue treatment permanently Not applicable * According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria (version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US National Cancer Institute, version 4.0 Page 21 of 32

22 Haematology: Patients with baseline neutrophil counts of < 1,5 x 10 9 /l and/ or thrombocyte counts of < 100 x 10 9 /l should not be treated with CAPECITABINE SPECPHARM. If during a treatment cycle laboratory assessments show that the neutrophil count of a patient drops below 1,0 x 10 9 /l or the platelet count drops below 75 x 10 9 /l, treatment with CAPECITABINE SPECPHARM should be interrupted. Page 22 of 32

23 SIDE EFFECTS The following side effects may be experienced in patients taking CAPECITABINE SPECPHARM as monotherapy: Body system Infections and infestations Neoplasms benign and malignant (including cysts and polyps) Blood and the lymphatic system disorders Immune system disorders Metabolism and nutrition disorders Frequent All Grades Herpes viral infection, nasopharyngitis, lower respiratory tract infection Neutropenia, anaemia Anorexia, dehydration, decreased weight Less frequent All Grades Sepsis, urinary tract infection, cellulitis, tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, herpes infection, infection, tooth abscess Lipoma Febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, haemolytic anaemia, International Normalised Ratio (INR) increased/ prothrombin time prolonged Hypersensitivity Diabetes, hypokalaemia, appetite disorder, Page 23 of 32

24 Body system Frequent All Grades Less frequent All Grades malnutrition, hypertriglyceridaemia Psychiatric disorders Insomnia, depression Confusional state, panic attack, depressed mood, decreased libido Nervous system disorders Eye disorders Ear and labyrinth disorders Cardiac disorders Headache, lethargy, dizziness, paraesthesia, dysgeusia Increased lacrimation, conjunctivitis, eye irritation Aphasia, memory impairment, ataxia, syncope, balance disorder, sensory disorder, peripheral neuropathy Reduced visual acuity, diplopia, lacrimal duct stenosis, corneal deposits, keratitis, punctate keratitis Vertigo, ear pain Unstable angina, angina pectoris, myocardial ischaemia, atrial fibrillation, dysrhythmia, tachycardia, sinus tachycardia, palpitations, ventricular fibrillation, QT prolongation, Torsade de pointes, bradycardia, vasospasm Vascular disorders Thrombophlebitis Deep vein thrombosis, hypertension, petechiae, Page 24 of 32

25 Body system Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Hepatobiliary disorders Skin and subcutaneous tissue disorders Frequent All Grades Dyspnoea, epistaxis, cough, rhinorrhoea Diarrhoea, vomiting, nausea, stomatitis, abdominal pain, gastrointestinal haemorrhage, constipation, upper abdominal pain, dyspepsia, flatulence, dry mouth Hyperbilirubinaemia, liver function test abnormalities Palmar-plantar erythrodysaesthesia syndrome, rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, rash macular, skin desquamation, dermatitis, pigmentation disorder, nail disorder Less frequent All Grades hypotension, hot flush, peripheral coldness Pulmonary embolism, pneumothorax, haemoptysis, asthma, dyspnoea (exertional) Intestinal obstruction, ascites, enteritis, gastritis, dysphagia, abdominal pain lower, oesophagitis, abdominal discomfort, gastro-oesophageal reflux disease, colitis, blood in stool Jaundice, hepatic failure, cholestatic hepatitis Blister, skin ulcer, rash, urticaria, photosensitivity reaction, palmar erythema, swelling face, purpura, radiation recall syndrome, cutaneous lupus erythematosus, Stevens- Johnson syndrome and Toxic epidermal necrolysis Page 25 of 32

26 Body system Musculoskeletal, connective tissue and bone disorders Renal and urinary disorders Reproductive system and breast disorders General disorders and administrative site conditions Frequent All Grades Pain in extremity, back pain, arthralgia Fatigue, asthenia, pyrexia, oedema peripheral, malaise, chest pain Less frequent All Grades Joint swelling, bone pain, facial pain, musculoskeletal stiffness, muscular weakness Hydronephrosis, urinary incontinence, haematuria, nocturia, increased blood creatinine, acute renal failure secondary to dehydration Vaginal haemorrhage Oedema, chills, influenzalike illness, rigors, increased body temperature Page 26 of 32

27 The following laboratory abnormalities may occur in patients taking CAPECITABINE SPECPHARM as monotherapy. Grade of abnormality Frequent Less frequent Patients with Grade 1 to 4 abnormality Patients with Grade 3 or 4 Patients with Grade 4 haemoglobin, neutrophils/ granulocytes, platelets, lymphocytes, sodium, potassium, or calcium, bilirubin, alkaline phosphatase, ALT (SGPT), AST (SGOT) lymphocytes, bilirubin, haemoglobin, neutrophils/ granulocytes, platelets, calcium, alkaline phosphatase, ALT (SGPT) neutrophils/ granulocytes, lymphocytes, calcium, bilirubin sodium, potassium, calcium, AST (SGOT) haemoglobin, platelets, sodium, potassium, calcium, alkaline phosphatase, ALT (SGPT), AST (SGOT) The following side effects may be experienced in patients taking CAPECITABINE SPECPHARM in combination with different chemotherapy regimens such as cisplatin, docetaxel, oxaliplatin, bevacizumab, irinotecan and epirubicin, in addition to the side effects seen with CAPECITABINE SPECPHARM as monotherapy or seen occurring at a higher frequency compared to CAPECITABINE SPECPHARM monotherapy. Page 27 of 32

28 Body system Infections and infestations Blood and the lymphatic system disorders Immune system disorders Metabolism and nutrition disorders Psychiatric disorders Nervous system disorders Frequent All Grades Herpes zoster, urinary tract infection, oral candidiasis, upper respiratory tract infection, rhinitis, influenza, oral herpes Neutropenia, bone marrow depression Hypersensitivity Decreased appetite, hypokalaemia, hyponatraemia, hypomagnesaemia, hypocalcaemia, hyperglycaemia Sleep disorder, anxiety Paraesthesia, dysaesthesia, peripheral neuropathy, peripheral sensory neuropathy, dysgeusia, headache, neurotoxicity, tremor, neuralgia, hypersensitivity reaction, hypoesthesia Frequent Grades 3 4 Infection leucopenia, anaemia, neutropenic fever, thrombocytopenia, febrile neutropenia Page 28 of 32

29 Body system Eye disorders Ear and labyrinth disorders Cardiac disorders Vascular disorders Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Frequent All Grades Increased lacrimation, visual disorders, dry eye, eye pain, visual impairment, blurred vision Tinnitus, hypoacusis Atrial fibrillation, cardiac ischaemia/ infarction Lower limb oedema, hypertension, thrombosis, flushing, hypotension, hypertensive crisis, hot flush, phlebitis Sore throat, dysaesthesia pharynx, hiccups, pharyngolaryngeal pain, dysphonia Constipation, dyspepsia, upper gastrointestinal haemorrhage, mouth ulceration, gastritis, abdominal distension, gastroesophageal reflux disease, oral pain, dysphagia, rectal haemorrhage, lower abdominal pain, oral dysaesthesia, paraesthesia Frequent Grades 3 4 Embolism Page 29 of 32

30 Body system Hepatobiliary disorders Skin and subcutaneous tissue disorders Musculoskeletal, connective tissue and bone disorders Renal and urinary disorders General disorders and administrative site conditions Injury, poisoning and procedural complications Frequent All Grades oral, hypoesthesia oral, abdominal discomfort Abnormal hepatic function Alopecia, nail disorder, hyperhidrosis, erythematous rash, urticaria, night sweats Myalgia, arthralgia, pain in extremity, pain in jaw, muscle spasms, trismus, muscular weakness Haematuria, proteinuria, decreased creatinine renal clearance, dysuria Pyrexia, weakness, temperature intolerance, mucosal inflammation, pain in limb, pain, chills, chest pain, influenza-like illness, infusion related reaction, injection site reaction, infusion site pain, injection site pain Confusion Frequent Grades 3 4 Lethargy, fever KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT Page 30 of 32

31 Acute overdosage with CAPECITABINE SPECPHARM can manifest with symptoms such as nausea, vomiting, diarrhoea, mucositis, gastrointestinal irritation and bleeding, and bone marrow depression. In the event of overdosage with CAPECITABINE SPECPHARM, treatment should include customary therapeutic and supportive medical interventions aimed at correcting the clinical manifestations and preventing their possible complications. IDENTIFICATION CAPECITABINE SPECPHARM 150 mg film-coated tablets are light-peach, oval, film-coated tablets embossed with 150 on one side and with dimensions of 11,4 mm x 5,9 mm. CAPECITABINE SPECPHARM 500 mg film-coated tablets are peach, oblong, capsule-shaped, film-coated tablets embossed with 500 on one side and with dimensions 17,1 mm x 8,1 mm PRESENTATION CAPECITABINE SPECPHARM 150 mg film-coated tablets are packed in aluminium with transparent PVC/PVDC blister packs or in aluminium with transparent PVC/PE/PVDC blister packs of 60 or 120 tablets. CAPECITABINE SPECPHARM 500 mg film-coated tablets are packed in aluminium with transparent PVC/PVDC blister packs or in aluminium with transparent PVC/PE/PVDC blister packs of 60 or 120 tablets. Page 31 of 32

32 The blisters are packed in a cardboard carton. Keep blisters in the outer carton until required for use. Not all pack sizes may be marketed. STORAGE INSTRUCTIONS Store at or below 25 C. Store in the original package. KEEP OUT OF REACH OF CHILDREN REGISTRATION NUMBER CAPECITABINE SPECPHARM 150: 49/26/1045 CAPECITABINE SPECPHARM 500: 49/26/1046 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION Specpharm (Pty) Ltd. Cnr 15 th & Pharmaceutical Road Halfway House, Midrand DATE OF PUBLICATION OF THE PACKAGE INSERT 9 June 2016 Page 32 of 32