Carohet 40 Mg/2 Ml/100 Mg/5 Ml/300 Mg/15 Ml Solution

CAROHET is indicated for the treatment of patients with advanced colorectal cancer with a WHO performance status of 2 or lower:

• In combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease,
• As a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen.

Posology

Recommended Dosage:

In monotherapy (for previously treated patient):

The recommended dosage of CAROHET is 350 mg/m2 administered as an intravenous infusion over a 30-to 90-minute period every three weeks.

In combination therapy (for previously untreated patient):

Safety and efficacy of CAROHET in combination with 5-fluorouracil (5FU) and folinic acid (FA) have been assessed with either of the following schedules:

CAROHET plus 5FU/FA in weekly schedule:

The recommended dose of CAROHET is 80 mg/m2 administered as a weekly intravenous infusion over a 30- to 90-minute period, followed by infusion with folinic acid and then by 5-fluorouracil over 6 weeks. This treatment is followed by one week rest.

The full dosage regimen is as follows:

CAROHET 80 mg/m2 as a 30- to 90-minute infusion on Day 1 and then weekly for 6 weeks. Folinic acid 500 mg/m2 i.v. as a 2-hour infusion, followed by 5-fluorouracil 2 000 mg/m2 i.v. as a 24-hour infusion, on Day 1 and then weekly for 6 weeks. The treatment is to be repeated every 7 weeks.

CAROHET plus 5FU/FA in every 2 weeks schedule:

The recommended dose of CAROHET is 180 mg/m2 administered once every 2 weeks as an intravenous infusion over a 30- to 90-minute period, followed by infusion with folinic acid and 5-fluorouracil.

The full dosage regimen is as follows:

CAROHET 180 mg/m2 i.v. as a 30- to 90-minute infusion on Day 1 only. Folinic acid 200 mg/m2 i.v. as a 2-hour infusion, followed by 5-fluorouracil 400 mg/m2 i.v. bolus, followed by 5-fluorouracil 600 mg/m2 i.v. as a 22-hour infusion. The folinic acid and 5-fluorouracil are repeated for two consecutive days. Repeat the cycle every two weeks.

Dosage Adjustments:

Delayed Dosing: CAROHET should not be administered until the neutrophil count remains above 1 500 cells/mm3. In patients who experienced severe neutropenia or severe gastrointestinal adverse events such as diarrhoea, nausea and vomiting, dosing of CAROHET should be delayed until there has been a full recovery of these effects, especially diarrhoea. CAROHET should be administered after appropriate recovery of all adverse events to grade 0 or 1 NCICTC grading (National Cancer Institute Common Toxicity Criteria) and when treatment-related diarrhoea is fully resolved. This must be strictly adhered to. At the start of a subsequent infusion of therapy, the dose of CAROHET, and 5FU when applicable, should be decreased according to the worst grade of adverse events observed in the prior infusion. Treatment should be delayed by 1 to 2 weeks to allow recovery from treatment-related adverse events.

With the following adverse events a dose reduction of 15 to 20 % should be applied for CAROHET and/or 5FU when applicable:

• haematological toxicity (neutropenia grade 4, febrile neutropenia (neutropenia grade 3-4 and fever grade 2-4), thrombocytopenia and leukopenia (grade 4),
• non-haematological toxicity (grade 3-4).

Treatment Duration: Treatment with CAROHET should be continued until there is an objective progression of the disease or an unacceptable toxicity.

Special populations:

Impaired hepatic function: Frequent monitoring of complete blood counts should be conducted in patients with impaired liver function. Patients with a bilirubin > 1,5 times the ULN (upper limit of the normal range) should not be treated with CAROHET. In patients with a bilirubin u2264 1,5 times the ULN range, a dose of 350 mg/m2 CAROHET is recommended. In patients with bilirubin > 1 and u2264 1,5 times the ULN, the risk of severe neutropenia is increased.

Elderly: The dose should be chosen carefully in this population due to their greater frequency of decreased hepatic, renal of cardiac function.

Paediatric population: The safety and efficacy of CAROHET in children have not been established.

Method of administration

CAROHET is administered intravenously.

Precautions to be taken before handling or administering the product. u2018For instructions on dilution of the product before administration, see section 6.6.u2019

• Patients with a history of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate or to any of the excipients listed in section 6.1.
• Chronic inflammatory bowel disease, and/or bowel obstruction or ileus. Patients should not be treated with CAROHET until resolution of the ileus.
• Pregnancy and lactation. Women of childbearing age receiving CAROHET should be advised to avoid becoming pregnant and to inform the treating medical practitioner immediately should this occur (see section 4.6).
• Bilirubin > 1,5 times the upper limit of the normal range.
• Severe bone marrow failure.
• WHO performance status > 2.
• Concomitant administration of azole antifungals, St. Johnu2019s Wort (see section 4.5).
• Live attenuated vaccines (see section 4.5).

CAROHET should be used in patients with a WHO good performance status of less than 2 (see section 4.3).

The use of CAROHET should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered to patients under the supervision of a medical practitioner with experience in anticancer chemotherapy. It is strongly recommended that CAROHET be administered only in healthcare institutions with adequately equipped facilities, including an intensive care unit.

Premedication with anti-emetic medicines are recommended in order to reduce nausea and vomiting associated with CAROHET treatment. This treatment should be started at least 30 minutes before the infusion. In all instances where the use of CAROHET is considered for chemotherapy, it is especially important to ensure that the patient understands the need for sufficiently prolonged antidiarrhoeal treatment and abundant fluid intake. In rare cases where it is predictable that the patient would comply poorly with the guidances for the management of side effects, a strict follow-up of the patient by the treating medical practitioner or hospitalisation is recommended.

Given the nature and frequency of adverse events, the expected benefit must be balanced in case of risk factors, especially WHO Performance status u2265 2 (or Karnofsky Index < 50).

Delayed diarrhoea: Apart from the diarrhoea shortly after the infusion of CAROHET, patients should be aware of the high risk of delayed diarrhoea occurring more than 24 hours after the administration of CAROHET and at any time before the next cycle. In monotherapy, the median time of onset of the first liquid stool was on day 5 after the infusion of CAROHET. Patients should quickly inform their medical practitioner of its occurrence and start appropriate therapy immediately.

Patients with an increased risk of diarrhoea:

• Patients who had a previous abdominal/pelvic radiotherapy,
• Patients with baseline leukocytosis and
• Patients with performance status u2265 2

If not properly treated, diarrhoea can be life-threatening, especially if the patient is concomitantly neutropenic. As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and an appropriate antidiarrhoeal therapy must be initiated immediately. This antidiarrhoeal treatment will be prescribed by the department where CAROHET has been administered. After discharge from the hospital, the patients should obtain the prescribed medicines so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their medical practitioner or the department administering CAROHET that diarrhoea is occurring.

The currently recommended antidiarrhoeal treatment is loperamide 4 mg for the first intake and then 2 mg every 2 hours. This therapy should continue for 12 hours after the last liquid stool and should not be modified. In no case should loperamide be administered for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours.

In addition to the antidiarrhoeal treatment, a prophylactic broad spectrum antibiotic should be given when diarrhoea is associated with severe neutropenia (neutrophil count < 500 cells/mm3).

In addition to the antibiotic treatment, hospitalisation is recommended for management of the diarrhoea in the following cases:

• Diarrhoea associated with fever,
• Severe diarrhoea (requiring intravenous hydration),
• Diarrhoea persisting beyond 48 hours following the initiation of high-dose loperamide therapy.

Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea at previous cycles. In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles (see section 4.2).

Renal impairment: No specific pharmacokinetic studies have been performed in patients with renal impairment.

Haematology: Weekly monitoring of complete blood cell counts should be performed during CAROHET treatment. Patients should be aware of the risk of infection and the significance of a fever. Febrile neutropenia (temperature > 38 u00baC and neutrophil count u2264 1 000 cells/mm3) should be urgently treated in the hospital with broad spectrum intravenous antibiotics. CAROHET administration should be delayed until the neutrophil count is u2265 1 500 cells/mm3. In patients who experienced severe asymptomatic neutropenia (< 500 cells/mm3), fever or infections associated with neutropenia, the dose of CAROHET should be reduced. In patients who experienced severe haematologic events, a dose reduction is recommended for subsequent administration (see section 4.2).

There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea, complete blood cell counts should be performed.

Liver Impairment: Liver function tests should be performed at baseline and before each cycle. Patients with impaired liver function (bilirubin > 1,0 and u2264 1,5 times the upper limit of the normal range [ULN] and transaminases 5 times ULN) are at greater risk of developing severe neutropenia or febrile neutropenia and should be closely monitored, including complete blood counts. CAROHET should not be used in patients with a bilirubin > 1,5 times the ULN and the patients with bilirubin > ULN should be followed with caution. In patients with a bilirubin of < 1,5 times ULN a dose of 350 mg/m2 is recommended once every 3 weeks (see section 4.2).

Nausea and vomiting: Prophylactic treatment with an anti-emetic is recommended before each treatment with CAROHET. Nausea and vomiting have been frequently reported. Patients with vomiting associated with delayed diarrhoea should be hospitalised as soon as possible for treatment.

Acute cholinergic syndrome: If an acute cholinergic syndrome appears (defined as early diarrhoea and a group of symptoms such as sweating, abdominal cramping, lacrimation, myosis and salivation), atropine sulphate (0,25 mg subcutaneously) should be administered unless clinically contraindicated (see section 4.8). These symptoms may disappear after atropine administration. Caution should be exercised in patients with asthma. In patients who experienced an acute cholinergic syndrome, the use of prophylactic atropine sulphate is recommended with subsequent doses of CAROHET.

Immunosuppressant effects/increased susceptibility to infections: Administration of live or live-attenuated vaccines in patients immunocompromised by CAROHET, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving CAROHET. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Respiratory disorders: Interstitial pulmonary disease presenting as pulmonary infiltrates may occur less frequently during CAROHET therapy. Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include the use of pneumotoxic medicines, radiation therapy and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during CAROHET therapy.

Extravasation: While CAROHET is not a known vesicant, care should be taken to avoid extravasation and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site and application of ice is recommended.

Elderly: Due to the greater frequency of decreased hepatic, renal or cardiac function in an elderly patient, dose selection with CAROHET should be cautious in this population.

Chronic inflammatory bowel disease and/or bowel obstruction: Patients must not be treated with CAROHET until resolution of the bowel obstruction (see section 4.3).

Pharmacokinetic parameters of irinotecan combined with 5-fluorouracil-folinic acid are comparable to those observed in monotherapy.

Neuromuscular blocking medicines: Interaction between CAROHET and neuromuscular blocking medicines cannot be ruled out. Medicines with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarising medicines may be antagonised. Excess acetylcholine may impair the muscle relaxant action of the non-depolarising medicines and may impair the return of normal muscle tone at the end of anaesthesia.

Antineoplastic medicines: The adverse effects of CAROHET, such as myelosuppression and diarrhoea, is expected to be exacerbated by other antineoplastic medicines having a similar adverse-effect profile.

Dexamethasone: Lymphocytopenia has been reported in patients receiving CAROHET, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of lymphocytopenia. Hyperglycaemia has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of CAROHET. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycaemia in some patients.

Laxatives: Laxative use during therapy with CAROHET is expected to worsen the incidence or severity of diarrhoea.

Diuretics: Dehydration secondary to vomiting and/or diarrhoea may be induced by CAROHET. The medical practitioner may wish to withhold diuretics during dosing with CAROHET and during periods of active vomiting or diarrhoea.

Anticonvulsants: Concomitant administration of CYP3A enzyme-inducing anticonvulsant medicines (e.g., carbamazepine, phenobarbitone or phenytoin) leads to reduced exposure to the active metabolite SN-38. Consideration should be given to starting or substituting non-enzyme inducing anticonvulsants at least one week prior to initiation of CAROHET therapy in patients requiring anticonvulsant treatment.

Azole antifungals: CAROHET clearance is greatly reduced in patients receiving concomitant azole antifungals, leading to increased exposure to the active metabolite, SN-38. Azole antifungals should be discontinued at least 1 week prior to starting CAROHET therapy and should not be administered during CAROHET therapy (see section 4.3).

St. Johnu2019s Wort (Hypericum perforatum): Exposure to the active metabolite of CAROHET is reduced in patients taking concomitant St. Johnu2019s Wort. St. Johnu2019s Wort should be discontinued at least 1 week prior to the first cycle of CAROHET and should not be administered during CAROHET therapy (see section 4.3).

Atazanavir sulphate: Coadministration of atazanavir sulphate, a CYP3A4 and UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the active metabolite of CAROHET. Atazanavir should not be used with CAROHET.

Bevacizumab: In one study, irinotecan plasma concentrations were similar in patients receiving CAROHET/5-FU/FA alone and in combination with bevacizumab. Concentrations of SN-38, the active metabolite of irinotecan, were analysed in a subset of patients. Concentrations of SN-38 were on average 33 % higher in patients receiving CAROHET/5-FU/FA in combination with bevacizumab compared with CAROHET/5-FU/FA alone. Due to high inter-patient variability and limited sampling, it is uncertain if the increase in SN-38 levels observed was due to bevacizumab. There was a small increase in diarrhoea and leukopenia adverse events. More dose reductions of CAROHET were reported for patients receiving CAROHET/5-FU/FA in combination with bevacizumab.

Vaccines: Yellow fever vaccine: There is a risk of fatal generalised reaction to vaccines. Concomitant use with CAROHET (see section 4.4).

Vitamin K antagonists: Increased risk of haemorrhage and thrombotic events in tumoural diseases. If vitamin K antagonists are indicated, an increased frequency in the monitoring of INR (International Normalised Ratio) is required. Loperamide should not be given prophylactically.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with CAROHET (see section 4.3). Women of childbearing potential and men have to use effective contraception during and up to 1 month and 3 months after treatment respectively.

Pregnancy

CAROHET is contraindicated during pregnancy as it may cause foetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of CAROHET in pregnant women. If CAROHET is used during pregnancy, or if the patient becomes pregnant, while receiving CAROHET, the patient should be apprised of the potential hazard to the foetus.

Breastfeeding

CAROHET is contraindicated during lactation. Patients receiving CAROHET should not breastfeed their infants.

Fertility

There are no human data on the effect of irinotecan on fertility.

Patients should be warned about the potential for dizziness or visual disturbances, and advised not to drive or operate machinery if these symptoms occur.

The intensity of the major toxicities encountered with CAROHET (e.g., leukoneutropenia and diarrhoea) are related to the exposure (AUC) to parent substance and metabolite SN-38. Significant correlations were observed between haematological toxicity (decrease in white blood cells and neutrophils at nadir) or diarrhoea intensity and both irinotecan and metabolite SN-38 AUC values in monotherapy.

Tabulated summary of adverse reactions

SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION

Infections and Infestations Frequency Infection Less frequent Sepsis

Blood and lymphatic system disorders Frequent Leukopenia, *neutropenia, anaemia, Thrombocytopenia Frequency unknown Peripheral thrombocytopenia with antiplatelet antibodies has been reported

Immune system disorders Less frequent Hypersensitivity reactions, including anaphylactic, anaphylactoid reactions.

Endocrine disorders Less frequent Diaphoresis, increased salvation

Metabolism and nutrition disorders Frequent Decrease weight, dehydration, hypovolaemia, decrease or loss of appetite Less frequent hypokalaemia, hypomagnesaemia

Nervous system disorders Less frequent Paraesthesia, abnormal gait, confusion, headache, dizziness.

Eye disorders Less frequent Increased lacrimation, myosis Frequency unknown Conjunctivitis, visual disturbance

Cardiac disorders Less frequent Hypotension, syncope, bradycardia

Vascular disorders Frequent Venous and arterial thromboembolic events which includes (angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep vein thrombophlebitis, heart arrest, myocardial infarct, myocardial ischaemia, peripheral vascular disorder, pulmonary embolus, sudden death,

Less frequent Hypertension, flushing Frequency unknown Vasodilation

Respiratory, thoracic and mediastinal disorders Frequent: Dyspnoea Less frequent: Rhinitis, Upper respiratory tract infection, interstitial pneumonia (see section 4.4)

Gastrointestinal disorders Frequent Late diarrhoea, nausea, vomiting, early diarrhoea, abdominal cramping/pain, anorexia, stomatitis, constipation, mucositis, episodes of dehydration commonly associated with diarrhoea (see section 4.4) Less frequent Rectal disorder, gi monilia, intestinal obstruction, ileus or gastrointestinal haemorrhage, intestinal perforation, transient increase in amylase and lipase, anorexia, mucositis, abdominal enlargement, bloated feeling or gas, Clostridium difficile induced pseudo-membranous colitis, indigestion

Hepato-biliary disorders Frequent Hyperbilirubinaemia

Skin and subcutaneous tissue disorders Frequent Alopecia Less frequent Rash, cutaneous signs such as dry skin, pruritus, skin discolouration Frequency unknown Sweating

Musculoskeletal and connective tissue disorders Less frequent Muscular contraction or cramps

Renal and urinary disorders Less frequent Urinary tract infection, renal insufficiency

Reproductive system and breast disorders Less frequent Breast pain

General disorders and administration site conditions Frequent Asthenia, fever, pain, neutropenic fever, mucosal inflammation Less frequent Chills, malaise, infusion site reactions, extravasation, tumour lysis syndrome Frequency unknown transient speech disorders

Investigations Frequent Increased serum creatinine, Monotherapy: transient and mild to moderate increases in serum levels of either transaminases, alkaline phosphatise, bilirubin and creatinine. Less frequent Increased serum alkaline phosphate, increased GGTP (gamma-glutamyl transpeptidase), increase in amylase, increase in lipase

Post marketing surveillance Infections and infestations Pseudomembranous colitis one of which has been documented bacteriologically ( Clostridium difficile ) u2022 Sepsis u2022 Fungal infections* u2022 Viral infections u2020

Blood and lymphatic system disorders One case of peripheral thrombocytopenia with antiplatelet antibodies has been reported.

Immune system disorders: Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been reported.

Metabolism and nutrition disorders u2022 Dehydration (due to diarrhoea and vomiting) u2022 Hypovolaemia u2022 Nervous system disorders: Speech disorders, generally transient in nature, have been reported; in some cases the event was attributed to the cholinergic syndrome observed during or shortly after infusion of CAROHET.

Cardiac disorders: Myocardial ischaemic events have been observed following CAROHET therapy.

Vascular disorders u2022 Hypotension

Respiratory, thoracic and mediastinal disorders: Interstitial pulmonary disease presenting as pulmonary infiltrates may occur during CAROHET therapy. Early effects such as dyspnoea have been reported. Hiccups have also been reported.

Gastrointestinal disorders: Cases of intestinal obstruction, ileus, megacolon, or gastrointestinal haemorrhage, and rare cases of colitis, including typhlitis, ischaemic and ulcerative colitis have been reported. In some cases, colitis was complicated by ulceration, bleeding, ileus or infection. Cases of ileus without preceding colitis have also been reported. Cases of intestinal perforation have been reported. Cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have been reported.

Hypovolaemia: There have been cases of renal impairment and acute renal failure, generally in patients who became infected and/or volume depleted from severe gastrointestinal toxicities. Cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting or sepsis.

Hepato-biliary disorders u2022 Steatohepatitis

u2022 Hepatic steatosis

Skin and subcutaneous tissue disorders u2022 Skin reaction

Musculoskeletal and connective tissue disorders: Muscular contraction or cramps and paraesthesia have been reported.

Renal and urinary disorders u2022 Renal impairment and acute renal failure generally in patients who become infected and/or volume depleted from severe gastrointestinal toxicities

u2022 Renal insufficiency

General disorders and administration site conditions u2022 Infusion site reaction

Investigations Cases of hyponatraemia mostly related with diarrhoea and vomiting have been reported. Increases in serum transaminases (AST, ALT) in the absence of progressive liver metastasis have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of CAROHET is important. It allows continued monitoring of the benefit/risk balance of the CAROHET. Healthcare professionals 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 or to the Holder of certificate of registration through the mail: [email protected].

There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal.

Symptoms: The most significant adverse reactions reported were severe neutropenia and diarrhoea.

Treatment: There is no known antidote for CAROHET. It is recommended that the patients be hospitalised for close monitoring of vital functions and treatment of observed effects. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious complications.