Data Sheet

DBL® Irinotecan Injection Concentrate

Irinotecan hydrochloride injection 20mg/mL

DESCRIPTION

DBL® Irinotecan Injection Concentrate is an antineoplastic agent of the topoisomerase I inhibitor class.

Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata. It is a pale yellow to yellow crystalline powder, with the empirical formula C₃₃H₃₈N₄O₆.HCl.3H₂O and a molecular weight of 677.19. Irinotecan hydrochloride is slightly soluble in water and organic solvents.

The chemical name is (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)dione hydrochloride trihydrate

The chemical structure of irinotecan hydrochloride is shown below:

CAS No: CAS-136572-09-3

Irinotecan Injection Concentrate is supplied as a sterile, pale yellow, clear, aqueous solution of pH 3.5. It is intended for dilution with 5% Glucose Injection or 0.9% Sodium Chloride Injection prior to infusion. The 2 mL and 5 mL injections contain 40 mg and 100 mg of irinotecan hydrochloride trihydrate respectively. In addition to irinotecan hydrochloride trihydrate, the ingredients are sorbitol and lactic acid. Sodium hydroxide and hydrochloric acid are used for pH adjustment.

PHARMACOLOGY

Irinotecan hydrochloride is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan hydrochloride and its active metabolite SN-38 bind to the topoisomerase I - DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan hydrochloride is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan hydrochloride or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.

Irinotecan hydrochloride serves as a water-soluble precursor of the lipophilic metabolite SN-38 which is approximately 1000 times as potent as irinotecan hydrochloride as an inhibitor of topoisomerase I purified from human and rodent tumour cell lines. However, the precise contribution of SN-38 to the activity of irinotecan hydrochloride is unknown. Both irinotecan hydrochloride and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. An acidic pH promotes the formation of the lactone whereas a basic pH favours the hydroxy acid anion form.

Administration of irinotecan hydrochloride has resulted in antitumour activity in mice bearing cancers of rodent origin and human carcinoma xenografts of various histological types.

Irinotecan hydrochloride is a non-competitive inhibitor of acetylcholinesterase and a cholinergic syndrome is associated with its administration (see ADVERSE REACTIONS).

Pharmacokinetics

After intravenous infusion of irinotecan hydrochloride in humans with various cancers, irinotecan hydrochloride plasma concentrations decline in a multi-exponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. In a study where irinotecan hydrochloride was administered at doses of 100-750 mg/m² by 30 minute intravenous infusion every three weeks, the plasma terminal elimination half-life was 14.2 ± 7.7 hours for irinotecan hydrochloride and 13.8 ± 1.4 hours for SN-38.

Over the recommended dose range of 50 to 350 mg/m², the AUC of irinotecan hydrochloride increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90 minute infusion of irinotecan hydrochloride.

Pharmacokinetic parameters for irinotecan hydrochloride and SN-38 following a 90-minute infusion of irinotecan hydrochloride at dose levels of 125 and 340 mg/m² determined in two clinical studies in patients with solid tumours are summarised in Table 1.

Table 1 - Summary of mean (± standard deviation) irinotecan hydrochloride and SN-38 pharmacokinetic parameters in patients with solid tumors

C_max: Maximum plasma concentration
AUC_0-24: Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the 90-minute infusion
t_½: Terminal elimination half-life
V_area: Volume of distribution of terminal elimination phase
CL: Total systemic clearance
^a Plasma specimens collected for 24 hours following the end of the 90-minute infusion
^b Plasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer collection period, these values provide a more accurate reflection of the terminal elimination half-lives of irinotecan hydrochloride and SN-38

In vitro studies indicate that irinotecan hydrochloride exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan hydrochloride and SN-38 predominantly bind is albumin.

Metabolism

The metabolic conversion of irinotecan hydrochloride to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in the liver. SN-38 subsequently undergoes conjugation to form a glucuronide metabolite (SN-38 glucuronide).

Excretion

The disposition of irinotecan hydrochloride has not been fully elucidated in humans. In studies of patients with various cancers the urinary excretion of irinotecan hydrochloride was 11% to 20% of the administered dose; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan hydrochloride and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan hydrochloride in two patients ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).

Pharmacokinetics in Special Populations

Geriatric: In studies where irinotecan hydrochloride was administered weekly, the terminal half-life of irinotecan hydrochloride was 6.0 hours in patients who were 65 years or older, and 5.5 hours in patients younger than 65 years. Dose-normalised AUC0-24 for SN-38 in patients who were at least 65 years of age was 11% higher than in patients younger than 65 years. There are no kinetic data on the use of the once-every-three-week dosage schedule in elderly patients. A lower starting dose is recommended in patients 65 years and older based on clinical toxicity experienced with this dosage regimen (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: The influence of severe hepatic insufficiency on the pharmacokinetic characteristics of irinotecan hydrochloride and its metabolites has not been formally studied. Among patients with metastatic colorectal cancer and known hepatic tumour involvement (a majority of patients), irinotecan hydrochloride and SN-38 AUC values were somewhat higher than values for patients without liver metastases (see PRECAUTIONS).

Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics of irinotecan hydrochloride has not been evaluated.

Pharmacokinetics in Combination Therapy: In a phase I clinical study involving irinotecan hydrochloride, fluorouracil (5-FU), and leucovorin (LV) in 26 patients with solid tumours the disposition of irinotecan hydrochloride was not substantially altered when the drugs were co-administered. However, C_max and AUC_0-24 of SN-38, the active metabolite, were reduced (by 14% and 8%, respectively) when irinotecan hydrochloride was followed by 5-FU and LV administration compared with when irinotecan hydrochloride was given alone. Formal in vivo or in vitro drug interaction studies to evaluate the influence of irinotecan hydrochloride on the disposition of 5-FU and LV have not been conducted.

CLINICAL TRIALS

Irinotecan hydrochloride has been studied in clinical trials in combination with 5-FU and LV as a first line agent in metastatic colorectal cancer and as a single agent used after failure of initial therapy. Weekly and once every 3 weeks dosage schedules were studied using irinotecan hydrochloride as the single agent. Weekly and once every 2 week schedules were studied with irinotecan hydrochloride used in combination treatment. Patients with a WHO performance status of 3 or 4 have not been studied in clinical trials (refer to Table 2).

Table 2: WHO scale for performance status

Combination therapy for first-line treatment of metastatic colorectal cancer

Two randomised, open-label, controlled, multinational, phase III clinical trials support the use of irinotecan hydrochloride as first-line treatment of patients with metastatic carcinoma of the colon or rectum. The dosing regimens of these studies are given in Table 3.

Table 3: Dosage regimen of the studies evaluating the first line treatment of metastatic colorectal cancer

^a Based on the Saltz, Mayo Clinic, de Gramont and Association of Medical Oncology of the German Cancer Society (AIO) dosing regimens

In both studies, concomitant medications such as anti-emetics, atropine and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. In study 2, if late diarrhoea persisted for greater than 24 hours despite loperamide, a 7 day course of fluoroquinolone antibiotic prophylaxis was given. Treatment with oral fluoroquinolone was initiated in patients whose diarrhoea persisted for greater than 24 hours despite loperamide or if they developed a fever in addition to diarrhoea. Treatment with oral fluoroquinolone was also initiated in patients who developed an absolute neutrophil count (ANC) < 0.5 x 10⁹/L, even in the absence of fever or diarrhoea. Patients also received treatment with intravenous antibiotics if they had persistent diarrhoea or fever or if ileus developed.

In both studies the combination of irinotecan hydrochloride/5-FU/LV therapy resulted in significant improvements in objective tumour response rate, time to tumour progression (TTP) and survival when compared with 5- FU/LV alone. These differences in survival were observed despite the use of post-study second-line therapy, including irinotecan-containing regimens in patients in the control arm. Patient characteristics and major efficacy results are shown in Table 4.

Table 4: Combination therapy in first line treatment of metastatic colorectal cancer: Study Results

^a Refer to Table 2
^b Confirmed = 4 to 6 weeks after first evidence of objective response

Improvement was noted when response rates and time to tumour progression were examined across all demographic and disease-related subgroups (as categorised by age, gender, ethnic origin, performance status, extent of organ involvement with cancer, time from diagnosis of cancer, prior adjuvant therapy, and baseline laboratory abnormalities), with irinotecan hydrochloride-based combination therapy relative to 5-FU/LV.

The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was used in both studies. While there was no statistical evidence that there were significant differences between irinotecan hydrochloride/5-FU/LV combination and 5-FU/LV alone with regard to quality of life (QOL) improvement, descriptive evidence suggested a general trend favouring QOL improvement or less-worsening in favour of the irinotecan hydrochloride combination regimen.

Single Agent Treatment in Recurrent or Progressive Metastatic Colorectal Cancer After 5-FU Based Treatment: Weekly Dosage Schedule

Three multicentre, open-label, phase II studies, all utilising repeated cycles of once weekly treatment with irinotecan hydrochloride for 4 consecutive weeks, followed by a two week rest period were conducted in a total of 304 patients in the United States. These studies were designed to evaluate tumour response rate and toxicity with irinotecan hydrochloride in patients with metastatic colorectal cancer that recurred or progressed following a prior 5-FU based chemotherapeutic regimen. Starting doses of irinotecan hydrochloride in these trials were 100, 125 or 150 mg/m², with 150 mg/m² proving to be poorly tolerated due to unacceptably high rates of grade 4 late diarrhoea and febrile neutropenia. The results of the studies are shown in Table 5.

Table 5: Phase II clinical studies with the once weekly dosage schedule

^a The initial dose in Study C was 125 mg/m² but was reduced to 100 mg/m² because the toxicity at the starting dose was perceived to be greater than seen in previous studies. Results are analysed separately for the two starting doses
^b Nine patients received 150 mg/m² as a starting dose; 2 (22.2%) responded to irinotecan hydrochloride
^c Relative dose intensity for irinotecan hydrochloride based on planned dose intensity of 100, 83.3 and 66.7 mg/m²/wk corresponding with 150, 125 and 100 mg/m² starting doses respectively
^d There were 2 complete responses and 38 partial responses

Of the 304 patients treated in the phase II studies, response rates to irinotecan hydrochloride were similar in males and females and among patients younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum, and in patients with single and multiple metastatic sites. Response rate was 18.5% in patients with a WHO performance status of 0, and 8.2% in patients with a performance status of 1 or 2.

The response rates with irinotecan hydrochloride were unaffected by whether or not patients had responded to prior 5-FU based treatment given for metastatic disease. Patients who had received previous irradiation to the pelvis also responded to irinotecan hydrochloride at approximately the same rate as those who had not previously received irradiation.

Overall, across the pivotal studies, stable disease was documented in 148 (48.7%) of the 304 patients in the intent to treat population and in 145 (55.6%) of the 261 patients in the evaluable population. Consistent with the results in Study C, a somewhat greater percentage of patients who were treated with the 125 mg/m² starting dose (53.4%; 103/193) than with the 100 mg/m² starting dose (39.2%; 40/102) had stable disease during therapy.

Once Every 3 Week Dosage Schedule

Two phase III, multicentre, randomised studies were conducted with a three weekly dosage regimen in patients with metastatic colorectal cancer whose disease had recurred or progressed following 5-FU therapy (n = 535). Second-line irinotecan hydrochloride was compared with best supportive care in one study and with infusional 5-FU-based therapy in the second study. The primary endpoint in both studies was survival. Parameters of clinical benefit and quality of life were also assessed. The starting dose was 350 mg/m² infused intravenously over 90 minutes to a maximum total dose of 700 mg. For patients 70 years or older and for patients with a WHO performance status of 2 the starting dose was reduced to 300 mg/m². Anti-emetics, atropine and loperamide were provided as supportive care and late diarrhoea persisting for greater than 24 hours despite loperamide was treated with a 7-day course of a fluoroquinolone antibiotic.

A significant survival advantage for irinotecan hydrochloride over best supportive care or infusional 5-FU-based therapy was demonstrated. When adjusted for baseline patient characteristics (e.g. performance status), survival among patients treated with irinotecan hydrochloride remained significantly longer than in the control populations (p = 0.001 for Study 1 and p = 0.017 for Study 2). Clinical benefit in Study 1, as measured by pain-free survival and survival without weight loss were significantly longer for patients treated with irinotecan hydrochloride than for patients in the best supportive care group (p, 0.01 and p, 0.05 respectively). The results are summarised in Table 6.

Table 6: Phase III clinical studies with the once every 3 week dosage schedule

^a One of the following 5-FU regimens was used:
(i) Leucovorin 200 mg/m² iv over 2 hours; followed by 5-FU 400 mg/m² iv bolus; followed by 5-FU 600 mg/m² continuous iv infusion over 22 hours on days 1 and 2 every 2 weeks.
(ii) 5-FU 250-300 mg/m²/day protracted continuous iv infusion until toxicity.
(iii) 5-FU 2.6-3 g/m²/day iv over 24 hours every week for 6 weeks with or without leucovorin 20-500 mg/m²/day every week iv for 6 weeks with a 2 week rest between cycles
^b Study 1 < 6 months; Study 2 < 3 months
^c Relative dose intensity for irinotecan hydrochloride based on planned dose intensity of 116.7 mg/m²/week. Dose intensity in patients receiving 5-FU in Study 2 varied depending upon type of regimen
** Cannot be estimated due to small sample size

In the two phase III studies, quality of life was assessed using the European Organisation on Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire. In Study 1, the global quality of life scores were significantly higher for patients treated with irinotecan hydrochloride than for those who received best supportive care (p=0.0013). In Study 2, the global quality of life scores were similar for patients who received either irinotecan hydrochloride or infusional 5-FU.

Other studies

A Japanese open-label, uncontrolled, late phase II study in patients with non-small-cell lung cancer enrolled a total of 153 patients. In this study, pneumonitis occurred in 6.2% (9/146) of the patients. One patient died of interstitial pneumonitis. Irinotecan hydrochloride was given at a dose of 100 mg/m² intravenously once weekly. Dosage adjustments were made according to toxicity and the duration of treatment was until disease progression or unacceptable toxicity occurred (with each patient to receive at least three doses).

INDICATIONS

DBL® Irinotecan Injection Concentrate is indicated for the first line treatment of patients with metastatic carcinoma of the colon or rectum, in combination with 5FU/leucovorin. Irinotecan Injection Concentrate is also indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial therapy.

CONTRAINDICATIONS

Irinotecan Injection Concentrate is contraindicated in patients with a known hypersensitivity to the drug or its excipients. Irinotecan Injection Concentrate antigenicity has not been observed in clinical trials, but irinotecan hydrochloride antigenicity occurred in tests for passive cutaneous anaphylaxis in guinea pigs and rabbits, and in tests for active systemic anaphylaxis in guinea pigs. In these tests, both animal species produced antibodies against irinotecan hydrochloride, and some deaths occurred in guinea pigs sensitised to irinotecan hydrochloride.

Irinotecan Injection Concentrate is contraindicated in women who intend to become pregnant (see Carcinogenicity and mutagenicity, and Effects on fertility).

Irinotecan Injection Concentrate is contraindicated in pregnancy and lactation (see Use in pregnancy and Use in lactation).

PRECAUTIONS

Irinotecan Injection Concentrate should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Irinotecan Injection Concentrate is administered by intravenous infusion. Care should be taken to avoid extravasation and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and application of ice are recommended.

Except in a well-designed clinical study, Irinotecan Injection Concentrate should not be used in combination with the "Mayo Clinic" regimen of 5-FU/LV (administration for 4-5 consecutive days every 4 weeks; refer to Table 3) because of reports of increased toxicity, including toxic deaths. Irinotecan Injection Concentrate should be used as recommended in DOSAGE AND ADMINISTRATION.

Thromboembolic events including angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischaemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis and vascular disorder have been observed rarely in patients receiving irinotecan hydrochloride. The specific cause of these events has not been determined.

Use with caution in the following circumstances

Physicians should exercise particular caution in monitoring the effects of irinotecan hydrochloride in patients with poor performance status. Patients with poor performance status are at increased risk of irinotecan-related adverse events. In patients receiving either irinotecan hydrochloride/5-FU/LV or 5-FU/LV in clinical trials comparing these agents, higher rates of hospitalisation, neutropenic fever, thromboembolism, first-cycle treatment discontinuation and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance of 0 or 1. Patients with performance status of 3 or 4 should not receive irinotecan hydrochloride.

Physicians should exercise particular caution in monitoring the effects of irinotecan hydrochloride in patients who have previously received pelvic/abdominal irradiation (see ADVERSE REACTIONS).

Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of irinotecan hydrochloride. The concurrent administration with irradiation has not been adequately studied and is not recommended.

The use of irinotecan hydrochloride in patients with significant hepatic dysfunction has not been established. In clinical trials, irinotecan hydrochloride was not administered to patients with serum bilirubin >34 mmol/L or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis. However, in clinical trials of the single agent weekly dosage schedule, it has been noted that patients with even modest elevations in total baseline serum bilirubin levels (17-34 mmol/L) have had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 17 mmol/L (50% versus 17.7%; p<0.001). Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert's syndrome, may also be at greater risk of myelosuppression when receiving therapy with irinotecan hydrochloride. An association between bilirubin elevations and an increased risk of late diarrhoea has not been observed in studies of the weekly dosage schedule.

Irinotecan hydrochloride has cholinergic effects and should be used with caution in patients with asthma or cardiovascular diseases, and in patients with mechanical intestinal or urinary obstruction.

Before administration

Careful monitoring of the white blood cell count with differential, haemoglobin and platelet count is recommended before each dose of irinotecan hydrochloride.

Patients should be advised of the expected toxic effects of irinotecan hydrochloride, particularly of gastrointestinal complications such as nausea, vomiting, abdominal cramping, diarrhoea and infection.

Irinotecan hydrochloride is emetigenic. It is recommended that patients receive premedication with anti-emetic agents. In clinical studies with the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of anti-emetic agent, such as a 5-HT₃ blocker (e.g. ondansetron or granisetron). Anti-emetic agents should be given on the day of treatment, starting at least 30 minutes before administration of Irinotecan Injection Concentrate. Physicians should also consider providing patients with an anti-emetic regimen (e.g. prochlorperazine) for subsequent use as needed.

Patients should be advised to consult their physician if any of the following occur after treatment with Irinotecan Injection Concentrate: diarrhoea for the first time; inability to control diarrhoea within 24 hours; vomiting; fever or evidence of infection; symptoms of dehydration, such as faintness, light-headedness or dizziness; bloody or black stools; inability to take fluids by mouth due to nausea or vomiting. Patients should also be alerted to the possibility of alopecia. Laxatives should be avoided (see Interactions with other drugs) and patients should contact their physician to discuss any laxative use.

Recommended actions in the case of adverse effects

Diarrhoea: Irinotecan hydrochloride can induce both an early and a late form of diarrhoea that appear to be mediated by different mechanisms. Both forms of diarrhoea may be severe.

Early diarrhoea (occurring during or shortly after infusion of irinotecan hydrochloride) is cholinergic in nature. It is usually transient and only infrequently is severe. It may be accompanied by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, bradycardia and intestinal hyperperistalsis that can cause abdominal cramping. Administration of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered (unless clinically contraindicated) in patients experiencing cholinergic symptoms occurring during or shortly after infusion of irinotecan hydrochloride.

Late diarrhoea (generally occurring more than 24 hours after administration of irinotecan hydrochloride) can be prolonged, may lead to dehydration, electrolyte imbalance or infection and can be life-threatening. Late diarrhoea should be treated promptly with loperamide. Patients should be instructed to have loperamide readily available and begin treatment at the first episode of poorly formed or loose stools, or the earliest onset of bowel movements more frequent than normally expected for the patient. One dosage regimen for loperamide used in clinical trials consisted of 4 mg at the first onset of late diarrhoea, and then 2 mg every 2 hours until the patient was diarrhoea-free for at least 12 hours. During the night, the patient may take 4 mg of loperamide every 4 hours. Premedication with loperamide is not recommended.

Patients with diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated and should be given antibiotics if they develop ileus, fever or severe neutropenia. After the first treatment, subsequent chemotherapy should be delayed until patients are diarrhoea-free (return to pre-treatment bowel function) for at least 24 hours without the need for antidiarrhoea medication. If NCI grade 2, 3 or 4 diarrhoea occurs, subsequent doses of irinotecan hydrochloride should be reduced within the current cycle (see DOSAGE AND ADMINISTRATION).

Neutropenia: Deaths due to sepsis following severe neutropenia have been reported in patients treated with irinotecan hydrochloride. Neutropenic complications should be managed promptly with antibiotic support. Therapy with irinotecan hydrochloride should be temporarily omitted if neutropenic fever occurs or if the absolute neutrophil count drops below 1.5 x 10⁹/L. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥ 1.5 x 10⁹/L. After the patient recovers, subsequent doses of irinotecan hydrochloride should be reduced depending upon the level of neutropenia observed (see DOSAGE AND ADMINISTRATION). Routine administration of a colony-stimulating factor (CSF) is not necessary but physicians may consider CSF use in individual patients experiencing problems related to neutropenia.

Colitis/Ileus: Cases of colitis have been reported. In some cases, colitis was complicated by ulceration, bleeding, ileus and infection. Cases of ileus without preceding colitis have also been reported. Patients experiencing ileus should receive prompt antibiotic support.

Carcinogenicity and mutagenicity

Long-term carcinogenicity studies with irinotecan hydrochloride were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan hydrochloride once per week for 13 weeks (AUC about 1.3 times the values of patients administered 125 mg/m²) and were then allowed to recover for 91 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas.

Irinotecan hydrochloride was clastogenic both in vitro (Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan hydrochloride or SN-38 was mutagenic in the in vitro Ames assay.

Effects on fertility

No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan hydrochloride in doses of up to 6 mg/kg/day to rats. Atrophy of male reproductive organs was observed after multiple daily irinotecan hydrochloride doses both in rodents at 20 mg/kg (AUC approximately the same value as in patients administered 125 mg/m² weekly) and dogs at 0.4 mg/kg (AUC about 1/15th the value in patients administered 125 mg/m² weekly).

Use in pregnancy

Category D

Irinotecan hydrochloride may cause foetal harm when administered to a pregnant woman. Administration of 6 mg/kg/day intravenous irinotecan hydrochloride to rats (AUC about 0.2 times the corresponding values in patients administered 125 mg/m²) and rabbits (about one-half the recommended human weekly starting dose on a mg/m² basis) during the period of organogenesis, is embryotoxic as characterised by increased post-implantation loss and decreased numbers of live foetuses. Irinotecan hydrochloride was teratogenic in rats at doses greater than 1.2 mg/kg/day (AUC about 1/40th the corresponding values in patients administered 125 mg/m²) and in rabbits at 6.0 mg/kg/day. Teratogenic effects included a variety of external, visceral, and skeletal abnormalities.

There are no adequate and well-controlled studies of irinotecan hydrochloride in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be informed about the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with irinotecan hydrochloride.

Use in lactation

Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabelled irinotecan hydrochloride and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. Irinotecan hydrochloride has been shown to impair learning ability and cause a delay in postnatal development in rats. As many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that breastfeeding be discontinued when receiving therapy with irinotecan hydrochloride.

Use in children

The safety and effectiveness of irinotecan hydrochloride in children have not been established.

Use in elderly

Physicians should exercise particular caution in monitoring the effects of irinotecan hydrochloride in elderly patients. A reduction in the starting dose of Irinotecan Injection Concentrate may be considered for patients over 65 years of age (see DOSAGE AND ADMINISTRATION).

Interactions with other drugs

Possible pharmacokinetic interactions of irinotecan hydrochloride with other concomitantly administered medications have not been formally investigated. The adverse effects of irinotecan hydrochloride, such as myelosuppression and diarrhoea, would be expected to be exacerbated by other antineoplastic agents having similar adverse events.

Lymphocytopenia has been reported in patients receiving irinotecan hydrochloride and it is possible that the administration of dexamethasone as anti-emetic prophylaxis may have enhanced the likelihood of this effect. However, serious opportunistic infections have not been observed and no complications have specifically been attributed to the lymphocytopenia.

Hyperglycaemia has also been reported in patients receiving irinotecan hydrochloride. Usually this has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of irinotecan hydrochloride. It is probable that the administration of dexamethasone contributed to hyperglycaemia in some patients.

The incidence of akathisia in clinical trials of the single agent weekly dosage schedule was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as irinotecan hydrochloride than when these drugs were given on separate days (1.3%, 1/80 patients). However, the 8.5% incidence of akathisia is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies.

It would be expected that the incidence or severity of diarrhoea would be worsened by laxative use during therapy with irinotecan hydrochloride, but this has not been studied.

In view of the potential risk of dehydration secondary to vomiting and/or diarrhoea, the physician may wish to withhold diuretics during dosing with irinotecan hydrochloride and, certainly, during periods of active vomiting or diarrhoea.

Effects on Laboratory Tests

There are no known interactions between irinotecan hydrochloride and laboratory tests.

ADVERSE REACTIONS

Combination Therapy in First Line Treatment of Metastatic Colorectal Cancer

In the two phase III studies, a total of 955 patients with metastatic colorectal cancer received irinotecan hydrochloride in combination with 5-FU/LV, 5-FU/LV alone, or irinotecan hydrochloride alone (see Table 3, CLINICAL TRIALS). In these studies, 370 patients received irinotecan hydrochloride in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients received irinotecan hydrochloride alone.

Fifty-nine (6.1%) patients died within 30 days of last study treatment: 27 (7.3%) received irinotecan hydrochloride in combination with 5-FU/LV, 19 (5.3%) received 5-FU/LV alone, and 13 (5.8%) received irinotecan hydrochloride alone. Deaths potentially related to treatment occurred in 3 (0.7%) patients who received irinotecan hydrochloride in combination with 5-FU/LV (2 neutropenic fever/sepsis, 1 treatment toxicity), 3 (0.7%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis,1 CNS bleeding during thrombocytopenia, 1 unknown) and 2 (0.9%) patients who received irinotecan hydrochloride alone (2 neutropenic fever). Deaths within 60 days of study treatment were reported for 18 (4.9%) patients who received irinotecan hydrochloride in combination with 5-FU/LV, 18 (5.0%) patients who received 5-FU/LV alone and 15 (6.7%) patients who received irinotecan hydrochloride alone. Discontinuations due to adverse events were reported for 26 (7.0%) patients who received irinotecan hydrochloride in combination with 5-FU/LV, 15 (4.1%) patients who received 5-FU/LV alone, and 26 (11.7%) patients who received irinotecan hydrochloride alone.

Table 7 lists the grade 3 and 4 clinically relevant adverse events reported in the combination treatment arms of the two phase III studies.

Table 7: Percent (%) of Patients Experiencing Clinically Relevant Grade 3 & 4 Adverse Events in Phase III Studies of Combination Therapies^a

^a Severity of adverse events based on National Cancer Institute's Common Toxicity Criteria (NCI CTC) (version 1.0)
^b Number of patients in the as-treated population for each group
^c Number of patients treated in the de Gramont regimen (B2/C2 treatment arms of Table 3)
The most clinically significant adverse events for patients receiving irinotecan hydrochloride-based therapy were diarrhoea, nausea, vomiting, neutropenia, and alopecia (complete hair loss = Grade 2). The most clinically significant adverse events for patients receiving 5-FU/LV therapy were diarrhoea, neutropenia, neutropenic fever, and mucositis. In Study 1, grade 4 neutropenia, neutropenic fever (defined as ≥ grade 2 fever and grade 4 neutropenia), and mucositis were observed less often with irinotecan hydrochloride/5-FU/LV than with administration of 5-FU/LV.

Single Agent Therapy in Recurrent or Progressive Metastatic Colorectal Cancer

Information on adverse reactions for irinotecan hydrochloride as single agent therapy is available from 304 patients with metastatic carcinoma of the colon or rectum treated in phase II trials with the once weekly dosage schedule, 316 patients treated with the once-every-3-week dosage schedule and over 1100 patients with a variety of tumour types treated in Japan. In general the types of toxicities observed were similar. 4.3% of patients treated with the weekly dosage schedule and 8% of patients treated with the once-every-3-week dosage schedule discontinued treatment with irinotecan hydrochloride because of medical events. Seventeen of the 304 patients treated with the weekly dosage schedule died within 30 days of the administration of irinotecan hydrochloride and in five cases (1.6%), the deaths were potentially drug-related. Eleven patients treated with irinotecan hydrochloride in the once-every-3-week dosage schedule died within 30 days of treatment and in three cases (1%), the deaths were potentially related to treatment with irinotecan hydrochloride. The main causes of the deaths potentially related to treatment were neutropenic infection, Grade 4 diarrhoea and asthenia.

The frequency of the most common adverse events reported from the single agent second line studies is presented in Table 8 below. Additional information on adverse events follows the table, organised by body system category.

Table 8: Adverse events reported from the second line single agent therapy in 304 patients^a

^a Severity of adverse events based on NCI CTC (version 1.0)
^b Combined results for leucopenia/neutropenia are presented for the once-every-3-week dosage schedule
^c In this study, 22.2% of patients treated with best supportive care experienced NCI Grade 3/4 pain
^d In this study, 13.2% of patients treated with infusional 5-FU experienced NCI Grade 3/4 pain
^e Complete hair loss = NCI grade 2

Gastrointestinal

Nausea, vomiting and diarrhoea are common adverse events following treatment with irinotecan hydrochloride and can be severe. Among those patients treated at the 125 mg/m² single agent weekly dose, the median duration of any grade of late diarrhoea was 3 days, and for grade 3 or 4 late diarrhoea was 7 days. The frequency of grade 3 and 4 late diarrhoea was significantly greater in patients 65 years or older (39.8% versus 23.4%, p=0.0025).

Abdominal pain and cramping are associated with early-onset diarrhoea (diarrhoea which occurs within 24 hours of drug administration). In studies it has been found that atropine is useful in ameliorating these events. Colonic ulceration, sometimes with gastrointestinal bleeding, ileus and infection, has been observed in association with administration of irinotecan hydrochloride

Haematological

Irinotecan hydrochloride commonly causes neutropenia, leucopenia (including lymphocytopenia) and anaemia. Serious thrombocytopenia is uncommon. In clinical studies with the single agent weekly dosage schedule, one death due to neutropenic sepsis without fever was judged to be potentially drug-related (0.3%, 1/304). Blood transfusions were given to 9.9% of patients. When evaluated in the trials of single agent weekly administration, the frequency of grade 3 or 4 neutropenia was significantly higher in patients who had received previous pelvic/abdominal irradiation (48.1% versus 24.1%, p=0.0356). In these same studies, patients with total baseline serum bilirubin levels of 17 mmol/L or more also had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 17 mmol/L (50% versus 17.7%, p<0.001).

Cholinergic symptoms

Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhoea. If these symptoms occur, they manifest during or shortly after drug infusion. They are thought to be related to the anticholinesterase activity of the irinotecan parent compound and are more likely to occur at higher doses. The timing of the symptoms is most consistent with the occurrence of peak irinotecan hydrochloride serum levels during parenteral administration.

Metabolic and nutritional

In the clinical studies evaluating the single agent weekly dosage schedule, NCI grade 3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients. These events typically occur in patients with known hepatic metastases. The dehydration observed in 14.8% of patients in these studies was as a consequence of diarrhoea, nausea and vomiting. Increases in serum creatinine or blood urea nitrogen, generally attributable to complications of infection or to dehydration related to nausea, vomiting or diarrhoea have been observed. There have been cases of acute renal failure. Rare instances of renal dysfunction due to tumour lysis syndrome have also been reported. For the once-every-3-week dosage schedule, hepatic events, such as ascites and jaundice of NCI Grade 3/4 severity occurred in 8.5% of patients in one study and 8.7% of patients in another study.

Dermatological

Alopecia has been reported during treatment with irinotecan hydrochloride. Rashes have also been reported but did not result in discontinuation of treatment.

Respiratory

Severe pulmonary events are infrequent. Over half the patients with dyspnoea in the clinical studies evaluating the single agent weekly dosage schedule had lung metastases; the extent to which malignant pulmonary involvement or other pre-existing lung disease may have contributed to dyspnoea in these patients is unknown. For the once-every-3-week dosage schedule, respiratory events, such as dyspnoea and cough of NCI Grade 3/4 severity occurred in 10.1% of patients in one study and 4.7% of patients in another study.

A potentially life-threatening pulmonary syndrome, consisting of dyspnoea, fever and a reticulonodular pattern on chest x-ray was observed in a small percentage of patients in early Japanese studies. The contribution of irinotecan hydrochloride to these preliminary events was difficult to assess because these patients also had lung tumours and some had pre-existing nonmalignant pulmonary disease. As a result of these observations, however, clinical studies in the USA enrolled few patients with compromised pulmonary function, significant ascites, or pleural effusions.

Neurological

Insomnia and dizziness were observed in 19.4% and 14.8% respectively of patients studied in clinical trials of the single agent weekly dosage schedule but were not usually considered to be directly related to the administration of irinotecan hydrochloride. Dizziness may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration.

Cardiovascular

Vasodilation (flushing) may occur during administration of irinotecan hydrochloride. Irinotecan hydrochloride has anti-cholinesterase activity. As such, there are possible cardiovascular effects due to its administration. These include sudden death, blackout and bradycardia. Patients should be monitored for cholinergic effects during administration of irinotecan hydrochloride, and atropine should be readily available for treatment of these effects. There were no cases of sudden death reported in the Phase II clinical studies of the single agent weekly dosage schedule involving 304 patients. In these studies, two patients (0.7%) suffered syncope and one patient (0.3%) suffered bradycardia.

Thromboembolic events including angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis and vascular disorder have been observed rarely in patients receiving irinotecan hydrochloride. The specific cause of these events has not been determined.

Other

Other NCI grade 3 or 4 drug-related adverse events observed in 1-10% of patients in clinical trials included mucositis, bilirubinaemia and hypovolaemia. In fewer than 1% of patients, NCI grade 3 or 4 rectal disorder, gastrointestinal monilia, hypokalaemia, hypomagnesaemia, increased GGTP, malaise, sepsis and abnormal gait were observed.

Post-marketing Surveillance

Cases of 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. There have been rare cases of renal impairment and acute renal failure, generally in patients who became infected and/or volume depleted from severe gastrointestinal toxicities. Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have also been reported.

DOSAGE AND ADMINISTRATION

It is recommended that patients receive premedication with anti-emetic agents. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms (see PRECAUTIONS).

Combination Therapy in First Line Treatment of Metastatic Colorectal Cancer

Irinotecan Injection Concentrate should be administered as an intravenous infusion (IV) over 90 minutes (see Preparation of Infusion Solution). For all regimens, the dose of LV should be administered immediately after Irinotecan Injection Concentrate, with the administration of 5-FU to follow immediately after the administration of LV. The recommended regimens are shown in Table 9.

Table 9: Combination Agent Dosage Regimens & Dose Modifications^a

^a Dose reductions beyond dose level -2 by decrements of ~20% may be warranted for patients continuing to experience toxicity. Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
^b Refer to Table 10
^c Infusion follows bolus administration

Dosing for patients with bilirubin >34 mmol/L cannot be recommended since such patients were not included in clinical trials.

Dose Modifications

Patients should be carefully monitored for toxicity and assessed prior to each treatment, especially during the first cycle of therapy. Doses of Irinotecan Injection Concentrate and 5-FU should be modified as necessary to accommodate individual patient tolerance to treatment. Based on the recommended dose levels described in Table 9, subsequent doses should be adjusted as suggested in Table 10, which shows the recommended dose modifications for combination schedules. All dose modifications should be based on the worst preceding toxicity. Patients should be diarrhoea free (return to pre treatment bowel function) without requiring antidiarrhoeal medications for at least 24 hours before receiving the next chemotherapy administration.

A new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less, the granulocyte count has recovered to ≥ 1.5 x 10⁹/L, the platelet count has recovered to ≥ 100 x 10⁹/L and treatment-related diarrhoea is fully resolved. Treatment should be delayed for 1 to 2 weeks to allow recovery from treatment-related toxicity. If the patient has not recovered after a 2 week delay, consideration should be given to discontinuing therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of Irinotecan Injection Concentrate /5-FU/LV may be continued indefinitely as long as patients continue to experience clinical benefit.

Table 10: Recommended dose modifications during a cycle of therapy with the Irinotecan Injection Concentrate /5-FU/LV combination and at the start of each subsequent cycle of therapy:

^a Severity of adverse events based on NCI CTC (version 2.0)
^b Relative to the starting dose used in the previous cycle
^c For mucositis/stomatitis decrease only 5-FU, not Irinotecan Injection Concentrate 

Single Agent Therapy in Recurrent or Progressive Metastatic Colorectal Cancer

Irinotecan Injection Concentrate should be administered as an intravenous infusion (see Preparation of Infusion Solution) over 90 minutes in a recommended weekly or once every 3 week dosage schedule as shown below in Table 11.

Table 11: Single-Agent Regimens of Irinotecan Injection Concentrate and Dose Modifications

^a Subsequent doses may be adjusted as high as 150 mg/m² or as low as 50 mg/m² in 25 to 50 mg/m² decrements depending on individual patient tolerance
^b Subsequent doses may be adjusted as low as 200 mg/m² in 50 mg/m² decrements depending on individual patient tolerance
^c Refer to Table 12

A reduction in the starting dose by one level of Irinotecan Injection Concentrate may be considered for patients with any of the following circumstances: over 65 years, prior pelvic/abdominal radiotherapy, performance status of 2 or moderately increased bilirubin levels (17 - 34 micromol/L). Dosing for patients with bilirubin >34 mmol/L cannot be recommended since such patients were not included in clinical trials.

Dose Modifications

Patients should be carefully monitored for toxicity and doses of Irinotecan Injection Concentrate should be modified as necessary to accommodate individual patient tolerance to treatment. Based on recommended dose-levels described in Table 11, subsequent doses of Irinotecan Injection Concentrate should be adjusted as suggested in Table 12. All dose modifications should be based on the worst preceding toxicity.

A new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less, the granulocyte count has recovered to ≥ 1.5 x 10⁹/L, the platelet count has recovered to ≥ 100 x 10⁹/L and treatment-related diarrhoea is fully resolved. Treatment may be delayed for 1 to 2 weeks to allow recovery from treatment-related toxicity. If the patient has not recovered, consideration should be given to discontinuing Irinotecan Injection Concentrate therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of Irinotecan Injection Concentrate may be continued indefinitely as long as patients continue to experience clinical benefit.

Table 12: Recommended dose modifications during a cycle of therapy with the weekly dosage schedule and at the start of each subsequent cycle of therapy with both dosage schedules

^a Severity of adverse events based on NCI CTC (version 2.0)

Preparation and Administration Precautions

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from Irinotecan Injection Concentrate. The use of gloves is recommended. If a solution of Irinotecan Injection Concentrate contacts the skin, wash the skin immediately and thoroughly with soap and water. If Irinotecan Injection Concentrate contacts the mucous membranes, flush thoroughly with water.

Irinotecan Injection Concentrate contains no antimicrobial agent. It is for single use in one patient only. Discard any residue.

Preparation of Infusion Solution

The vial should be inspected for damage and visible signs of leaks. If damaged, incinerate the unopened package.

Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe. If particulate matter is seen, do not use the contents.

Irinotecan Injection Concentrate must be diluted prior to infusion. Irinotecan Injection Concentrate should be diluted in 5% Glucose Injection (preferred) or 0.9% Sodium Chloride Injection to a final concentration range of 0.12 to 2.8 mg/mL. Other drugs should not be added to the infusion solution. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.

Solutions diluted in 0.9% Sodium Chloride Injection in infusion bags are physically and chemically stable for up to 24 hours at 25°C when exposed to light, and up to 7 days when stored refrigerated (2 to 8°C) in the dark. Refrigeration of admixtures using 0.9% sodium chloride injection is not recommended due to a low and sporadic incidence of visible particles. Solutions diluted in 5% Glucose Injection in infusion bags are physically and chemically stable for 48 hours at 25°C when exposed to light, and to 7 days when stored refrigerated (2 to 8°C) in the dark. To reduce microbiological hazard, use as soon as practicable after preparation. If storage is necessary, hold at 2° to 8°C for not more than 24 hours.

Do not freeze admixtures of Irinotecan Injection Concentrate as this may result in precipitation of the drug.

Pharmaceutical Precautions

The following protective recommendations are given due to the toxic nature of this substance:

• Personnel should be trained in good technique for handling.
• Pregnant staff should be excluded from working with this drug.
• Personnel handling Irinotecan Injection Concentrate should wear protective clothing: goggles, gowns and disposable gloves and masks.
• A designated area should be defined for reconstitution (preferably under a laminar flow containment system). The work surface should be protected by disposable plastic backed absorbent paper.
• All items used for administration of cleaning, including gloves, should be placed in high-risk, waste-disposal bags for high temperature incineration.
• Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water.
• All cleaning materials should be disposed of as indicated previously.
• Accidental contact with the eyes or skin should be treated immediately. Copious lavage with water is appropriate treatment for contact with the eyes, whereas water or soap and water, or sodium bicarbonate solution may be used on the skin; medical attention should be sought.

OVERDOSAGE

Symptoms

In humans, at single doses up to 750 mg/m², adverse events were similar to those reported with the recommended dosage regimens. In rodents, lethality was observed after single intravenous irinotecan hydrochloride doses of approximately 111 mg/kg in mice and 73 mg/kg in rats. Death was preceded by cyanosis, tremors, respiratory distress and convulsions.

Treatment

There is no known antidote for overdosage of irinotecan hydrochloride. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious complications.

PRESENTATION

Irinotecan Injection Concentrate is supplied in single use, amber glass vials containing 20 mg/mL of irinotecan hydrochloride trihydrate,

Product Pack Size

40 mg/2 mL 1 vial

100 mg/5 mL 1 vial

STORAGE

Store below 30°C. Protect from light.

MEDICINE CLASSIFICATION

Prescription Medicine

NAME AND ADDRESS

Hospira NZ Limited
23 Haining Street
Te Aro
Wellington
New Zealand

DATE OF PREPARATION

1 January 2008