Drug Interactions
Adverse events due to CAMPTOSAR, such as myelosuppression and diarrhea, would be expected to be enhanced by combination with other anti-neoplastic agents having similar adverse effects.
Interaction between CAMPTOSAR and neuromuscular blocking agents cannot be ruled out. Since irinotecan has anticholinesterase activity, drugs with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized.
Appropriate starting dose for patients taking drugs shown or anticipated to alter the kinetics of CAMPTOSAR has not been formally defined. Co-administration of azole antifungals and irinotecan is contraindicated and patients should discontinue ketoconazole at least 1 week prior to starting CAMPTOSAR therapy (see Contraindications). Patients should not drink grapefruit juice during treatment. Consideration should be given to starting or substituting to non-enzyme-inducing anticonvulsants at least one week prior to initiation of CAMPTOSAR therapy in patients requiring anticonvulsant treatment. Co-administration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these drugs (see Warnings and Precautions).
Lymphocytopenia has been reported in patients receiving CAMPTOSAR. It is possible that the administration of dexamethasone as an anti-emetic prophylaxis may have enhanced the likelihood of this effect. However, in these reports, serious opportunistic infections were not observed and no complications were specifically attributed to lymphocytopenia.
Hyperglycemia has been reported in patients receiving CAMPTOSAR. This has usually been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of CAMPTOSAR. It is probable that dexamethasone, given as anti-emetic prophylaxis, contributed to hyperglycemia in some patients.
There are no known interactions between CAMPTOSAR and laboratory tests.
Exposure to the active metabolite SN-38 is reduced by approximately 40% in patients taking concomitant St. John’s wort and CAMPTOSAR. St. John’s wort should be discontinued at least 1 week prior to the first cycle of CAMPTOSAR (see Warnings and Precautions).
It would be expected that laxative use during CAMPTOSAR therapy may worsen the incidence or severity of diarrhea.
The use of diuretics should be carefully monitored because of the potential risk of dehydration secondary to vomiting and/or diarrhea induced by CAMPTOSAR. The physician may wish to withhold diuretics during CAMPTOSAR dosing, and certainly during periods of active vomiting or diarrhea.
The incidence of akathisia in clinical trials of the weekly dosage schedule was greater (8.5%, 4 of 47 patients) when prochlorperazine was administered on the same day as CAMPTOSAR than when these drugs were given on separate days (1.3%, 1 of 80 patients). However, the 8.5% incidence of akathisia is within the range reported for use of prochlorperazine when given as premedication for other chemotherapies.
CAMPTOSAR (irinotecan hydrochloride trihydrate) is metabolized by carboxyl esterase to an active metabolite, SN-38, and oxidized by CYP3A4 to two relatively inactive metabolites (APC and NPC). SN-38 is glucuronidated to an inactive conjugate (see Action and Clincial Pharmacology, Pharmacokinetics). Pharmacokinetic drug-drug and drug-herbal interactions have been shown in (Table 6). These have most often been attributed to inhibition or induction of CYP3A4, though multiple mechanisms have been suggested to contribute to the interactions (induction/inhibition of carboxyl esterase, UDP-glucuronyl transferase 1A1, and drug transporters).
In vitro drug interaction studies reveal that the metabolism of irinotecan to its active metabolite SN-38 by carboxylesterase enzymes is not inhibited by 5-fluorouracil (5-FU). Data from a phase 1 clinical study involving CAMPTOSAR, 5-FU, and leucovorin (LV) in 26 patients with solid tumours indicate that the disposition of irinotecan and its active metabolite SN-38 are not substantially altered when the drugs are co-administered. In vivo or in vitro drug interaction studies to evaluate the influence of irinotecan on the disposition of 5-FU and LV have not been conducted.
Co-administration with CYP3A4 inhibitors (eg. cimetidine, macrolide antibiotics [azithromycin, clarithromycin, erythromycin], azole antifungals [fluconazole, ketoconazole, itraconazole], grapefruit juice, CYP3A4-inhibitory calcium channel blockers such as verapamil, diltiazem, and nifedipine) can potentially lead to significantly increased formation of SN-38 and potential toxicity. This interaction has been documented in cancer patients with the co-administration of CAMPTOSAR and ketoconazole, a potent enzyme inhibitor, where the relative exposure to the CYP3A4-mediated metabolite APC was reduced by 87%, whereas the relative exposure to the active metabolite SN-38 increased by 100%.
Exposure to fluoroquinolones such as ciprofloxacin or norfloxacin may be increased in patients with compromised renal function due to dehydration or colorectal cancer complications. In these circumstances co-administration of CAMPTOSAR and CYP3A4-inhibitory fluoroquinolone antibiotics could potentially lead to increased SN-38 exposure and enhanced toxicity.
Similarly, co-administration of CAMPTOSAR with CYP3A4 inducers (eg. carbamazepine, phenobarbital, phenytoin, glucocorticoids, St. John’s Wort) leads to reduction in plasma levels of the active metabolite SN-38, which may have a deleterious impact on treatment outcome. This interaction has been documented in cancer patients with the co-administration of CAMPTOSAR with St. John’s Wort and with the co-administration of CAMPTOSAR with phenytoin.
The prescribing information of concomitant medications should also be consulted to identify potential interactions.
Information for the Patient
Camptosar
Special Handling Instructions
As with other potentially toxic anti-cancer agents, care should be exercised in the handling and preparation of infusion solutions containing CAMPTOSAR (irinotecan hydrochloride trihydrate). Preparation of CAMPTOSAR should be done in a vertical laminar flow hood. The use of gloves, safety glasses and protective clothing is recommended. If CAMPTOSAR solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If CAMPTOSAR contacts the mucous membranes, flush thoroughly with water. All waste material that has come in contact with CAMPTOSAR should be properly segregated, sealed and incinerated.
Dosage and Administration
Dosing of patients is not recommended with (see Warnings and Precautions):
-
serum bilirubin >35 µmol/L, transaminase >3 times ULN if no liver metastases, or transaminase >5 times ULN with liver metastases
-
ECOG performance status 3 or 4
Recommended laboratory tests (see Warnings and Precautions) before/during therapy:
-
white blood cell count with differential, hemoglobin and platelet count before each dose
-
liver function before initiation of treatment and monthly or as clinically indicated
Dose reduction may be considered for patients (see Warnings and Precautions):
-
aged ≥70 years
-
with prior pelvic/abdominal radiotherapy
-
with performance status of 2
-
with moderately elevated bilirubin levels (17-35 µmol/L)
-
with Gilbert’s syndrome
Dose schedules, dose modifications and dose delay:
-
patients should be carefully monitored for toxicity and assessed prior to each treatment
-
dosage schedule and dose modifications for combination therapy are summarized in Table 7 and Table 8 and for single agent therapy in Table 9 and Table 10.
-
dose modifications should be based on the worst preceding toxicity. Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. Patients experiencing clinically significant (defined as grade ≥2) diarrhea, abdominal cramping, or neutropenia on the day of treatment administration should have treatment delayed until they recover and subsequent doses should be decreased.
-
a new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicity. If the patient has not recovered, consideration should be given to discontinuing therapy.
-
provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.
It is recommended that patients receive premedication with antiemetic agents. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. Besides the dosage modification, prompt use of oral loperamide is recommended in order to control and treat the diarrhea (see Warnings and Precautions, Gastrointestinal).
| Weekly Regimen a | 125 mg/m2 IV over 90 min once-weekly (days 1, 8, 15, 22) followed by a 2-week rest |
| Starting Dose and Modified Dose Levels (mg/m2) |
| Starting Dose | Dose Level-1 | Dose Level-2 |
| 125 | 100 | 75 |
| Once-every-3-week Regimen b | 350 mg/m2 IV over 90 min, once weekly every 3 weeks |
| Starting Dose and Modified Dose Levels (mg/m2) |
| Starting Dose | Dose Level-1 | Dose Level-2 |
| 350 | 300 | 250 |
a. Subsequent doses may be adjusted as high as 150 mg/m
2 or to as low as 50 mg/m
2 in 25 to 50 mg/m
2 decrements depending upon individual patient tolerance.
b. Subsequent doses may be adjusted as low as 200 mg/m
2 in 50 mg/m
2 decrements depending upon individual patient tolerance.
Recommended Dose Modifications for Single-Agent Schedulesa
| Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1.5×109/L, and the platelet count has recovered to ≥100×109/L, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing therapy. |
Toxicity
NCI Gradeb (value) | During a Cycle of Therapy | At the Start of Subsequent Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cyclec |
| Weekly | Weekly | Once Every 3 Weeks |
| No Toxicity | Maintain dose level | ↑25 mg/m2 up to a maximum dose of 150 mg/m2 | Maintain dose level |
| Neutropenia |
| 1 (1500 to 1999/mm3) | Maintain dose level | Maintain dose level | Maintain dose level |
| 2 (1000 to 1499/mm3) | ↓25 mg/m2 | Maintain dose level | Maintain dose level |
| 3 (500 to 999/mm3) | Omit dose, then ↓25 mg/m2 when resolved to ≤grade 2 | ↓25 mg/m2 | ↓50 mg/m2 |
| 4 (<500/mm3) | Omit dose, then ↓50 mg/m2 when resolved to ≤grade 2 | ↓50 mg/m2 | ↓50 mg/m2 |
| Neutropenic Fever (grade 4 neutropenia & ≥grade 2 fever) | Omit dose, then ↓50 mg/m2 when resolved | ↓50 mg/m2 | ↓50 mg/m2 |
| Other Hematologic Toxicities | Dose modifications for leukopenia, thrombocytopenia and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. |
| Diarrhea |
1 (2–3 stools/day
>pretxc) | Maintain dose level | Maintain dose level | Maintain dose level |
2 (4–6 stools/day
>pretxc) | ↓25 mg/m2 | Maintain, if the only grade 2 toxicity | Maintain dose level |
3 (7–9 stools/day
>pretxc) | Omit dose, then ↓25 mg/m2 when resolved to ≤grade 2 | ↓25 mg/m2, if the only grade 3 toxicity | ↓50 mg/m2 |
4 (≥10 stools/day
>pretxc) | Omit dose, then ↓50 mg/m2 when resolved to ≤grade 2 | ↓50 mg/m2 | ↓50 mg/m2 |
| Other Nonhematologic Toxicities d |
| Grade 1 | Maintain dose level | Maintain dose level | Maintain dose level |
| Grade 2 | ↓25 mg/m2 | ↓25 mg/m2 | ↓50 mg/m2 |
| Grade 3 | Omit dose, then ↓25 mg/m2 when resolved to ≤grade 2 | ↓25 mg/m2 | ↓50 mg/m2 |
| Grade 4 | Omit dose, then ↓50 mg/m2 when resolved to ≤grade 2 | ↓50 mg/m2 | ↓50 mg/m2 |
a. National Cancer Institute Common Toxicity Criteria.
b. All dose modifications should be based on the worst preceding toxicity.
c. Pretreatment.
d. Excludes alopecia, anorexia, asthenia.
| Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1.5×109/L, and the platelet count has recovered to ≥100×109/L, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing therapy. |
Toxicity
NCI CTC gradea (Value) | During a Cycle of Therapy | At the Start of Subsequent Cycles of Therapyb |
| No Toxicity | Maintain dose level | Maintain dose level |
| Neutropenia |
| 1 (1500 to 1999/mm3) | Maintain dose level | Maintain dose level |
| 2 (1000 to 1499/mm3) | ↓1 dose level | Maintain dose level |
| 3 (500 to 999/mm3) | Omit dose until resolved to ≤grade 2 then ↓1 dose level | ↓1 dose level |
| 4 (<500/mm3) | Omit dose until resolved to ≤grade 2 then ↓2 dose levels | ↓2 dose levels |
| Neutropenic fever (grade 4 neutropenia & ≥grade 2 fever) | Omit dose until resolved then ↓2 dose levels | ↓2 dose levels |
| Other Hematologic Toxicities | Dose modifications for leukopenia or thrombocytopenia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. |
| Diarrhea |
| 1 (2–3 stools/day >pretxc) | Delay dose until resolved to baseline then give same dose | Maintain dose level |
| 2 (4–6 stools/day >pretxc) | Omit dose until resolved to baseline then ↓1 dose level | Maintain dose level |
| 3 (7–9 stools/day >pretxc) | Omit dose until resolved to baseline then ↓1 dose level | ↓1 dose level |
| 4 (≥10 stools/day >pretxc) | Omit dose until resolved to baseline then ↓2 dose levels | ↓2 dose levels |
| Other Nonhematologic Toxicities d |
| 1 | Maintain dose level | Maintain dose level |
| 2 | Omit dose, then ↓1 dose level when resolved to ≤grade 1 | Maintain dose level |
| 3 | Omit dose, then ↓1 dose level when resolved to ≤grade 2 | ↓1 dose level |
| 4 | Omit dose, then ↓2 dose levels when resolved to ≤grade 2 | ↓2 dose levels |
| | For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR | For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR |
a. National Cancer Institute Common Toxicity Criteria.
b. Relative to the starting dose used in the previous cycle.
c. Pretreatment.
d. Excludes alopecia, anorexia, asthenia.
The CAMPTOSAR vial is for single use only. Unused portions must be discarded. CAMPTOSAR must be diluted prior to infusion, using 5% Dextrose Injection (preferred) or 0.9% Sodium Chloride Injection to a final concentration range of 0.12 to 3.0 mg/mL. Other drugs should not be added to the infusion solution.
The infusion solutions, when packaged in low-density polyethylene (LDPE) or polyvinyl chloride (PVC) containers, are physically and chemically stable for up to 28 days at controlled room temperature (15 to 30°C) or at refrigerated temperatures (2 to 8°C), if protected from light. If stored at room temperature (15 to 30°C) but exposed to light, the infusion solutions are physically and chemically stable for 72 hours (3 days). Freezing CAMPTOSAR and admixtures of CAMPTOSAR may result in precipitation of the drug and should be avoided.
Because of possible microbial contamination during dilution, it is recommended that the admixture be prepared immediately prior to use and infusion commenced as soon as practicable after preparation. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, or 6 hours at 15 to 30°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.
Adverse Reactions
Nausea, vomiting and diarrhea are common adverse events following treatment with CAMPTOSAR (irinotecan hydrochloride trihydrate) and can be severe. When observed, nausea and vomiting usually occur during or shortly after infusion of CAMPTOSAR. In the clinical studies testing the every 3-week-dosage schedule, the median time to the onset of late diarrhea was 5 days after CAMPTOSAR infusion. In the clinical studies evaluating the weekly dosage schedule, the median time to onset of late diarrhea was 11 days following administration of CAMPTOSAR. All grade late diarrhea occurred in approximately 80% in this patient population. For patients on the 125 mg/m2 weekly dose, the median duration of any grade late diarrhea was 3 days. The median duration was 7 days for those patients reporting grades 3 or 4 late diarrhea on this same weekly dose.
Results from a retrospective analysis have shown that the frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥65 years than in patients <65 years of age. However, results from a prospective study treating patients with metastatic colorectal cancer refractory to one 5-FU-based chemotherapeutic regimen, on a 125 mg/m2 weekly dosage schedule (4 weeks on, 2 weeks off) did not demonstrate any statistically significant difference in the rate of treatment-emergent grade 3-4 late diarrhea in patients ≥65 years of age versus patients <65 years of age. It should be noted however, that a statistically significant increase in the incidence of treatment-emergent early diarrhea in patients ≥65 years of age versus patients <65 years of age was found. Furthermore, a 10% reduction in median relative weekly dose intensity was required in patients ≥65 years versus patients <65 years in order to achieve tolerability. In the early Japanese trials, there is some information that patients with considerable ascites or pleural effusions were at increased risk for neutropenia or diarrhea.
The following events have been identified during postmarketing use of CAMPTOSAR in clinical practice.
Infrequent cases of colitis, including typhlitis, ulcerative and ischemic colitis, have been observed. This can be complicated by ileus or what was described as toxic megacolon, ulceration, bleeding, obstruction, and infection. Rare cases of intestinal perforation have been reported. Cases of ileus without preceding colitis have also been observed. Patients experiencing ileus should receive prompt antibiotic support (see Warnings and Precautions). Hiccups have also been reported.
Rare cases of hyponatremia mostly related to diarrhea and vomiting have been reported.
Increases in serum levels of transaminases (i.e., AST and ALT), GGT and bilirubin in the absence of progressive liver metastasis have been observed; rare cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have been observed.
Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea and/or vomiting, or sepsis (see Warnings and Precautions).
Early effects such as muscular contraction or cramps and paresthesia have been reported.
Severe pulmonary events are infrequent. Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects such as dyspnea have been reported (see Warnings and Precautions).
Myocardial ischemic events, with some cases resulting in fatality, have been observed in patients treated with CAMPTOSAR, the majority of whom had underlying cardiac disease, other known risk factors for cardiac disease and/or were treated with other concomitant cytotoxic chemotherapy (see Warnings and Precautions).
Percent of Patients Experiencing Grade 3 and 4 Adverse Events in Comparative Studies of Once-Every-3-Week CAMPTOSAR Therapya
| Adverse Event | Study V301 | Study V302 |
CAMPTOSAR
n=189 | BSCb
n=90 | CAMPTOSAR
n=127 | 5-FUc
n=129 |
| Total Grade 3/4 Adverse Events | 79.4 | 66.7 | 69.3 | 54.3 |
| Gastrointestinal |
| Diarrhea | 21.7 | 5.6 | 22.0 | 10.9 |
| Vomiting | 13.8 | 7.8 | 14.2 | 4.7 |
| Nausea | 13.8 | 3.3 | 11.0 | 3.9 |
| Abdominal Pain | 13.8 | 15.6 | 8.7 | 7.8 |
| Constipation | 9.5 | 7.8 | 7.9 | 6.2 |
| Anorexia | 5.3 | 6.7 | 5.5 | 3.9 |
| Mucositis | 1.6 | 1.1 | 2.4 | 5.4 |
| Hematologic |
| Leukopenia/Neutropenia | 22.2 | 0 | 14.2 | 2.3 |
| Anemia | 7.4 | 6.7 | 6.3 | 3.1 |
| Hemorrhage | 5.3 | 3.3 | 0.8 | 3.1 |
| Thrombocytopenia | 1.1 | 0 | 3.9 | 1.6 |
| Infection |
| without grade 3/4 neutropenia | 8.5 | 3.3 | 0.8 | 3.9 |
| with grade 3/4 neutropenia | 1.1 | 0 | 1.6 | 0 |
| Fever |
| without grade 3/4 neutropenia | 2.1 | 1.1 | 1.6 | 0 |
| with grade 3/4 neutropenia | 2.1 | 0 | 3.9 | 1.6 |
| Body as a Whole |
| Pain | 18.5 | 22.2 | 16.5 | 13.2 |
| Asthenia | 14.8 | 18.9 | 13.4 | 11.6 |
| Cholinergic Syndrome | 12.2 | 0 | 1.6 | 0 |
| Metabolic and Nutritional |
| Hepaticd | 8.5 | 6.7 | 8.7 | 6.2 |
| Dermatologic |
| Hand and Foot Syndrome | 1.6 | 0 | 0.8 | 4.7 |
| Cutaneous Signse | | | | 3.1 |
| Respiratory f | 10.1 | 7.8 | 4.7 | 7 |
| Neurologic g | 12.2 | 13.3 | 8.7 | 3.9 |
| Cardiovascular h | 8.5 | 3.3 | 3.9 | 1.6 |
| Other i | 31.7 | 27.8 | 11.8 | 14 |
a. Severity of adverse events based on NCI CTC (version 1.0).
b. BSC=best supportive care.
c. One of the following 5-FU regimens were used: (1) Leucovorin, 200 mg/m
2 iv over 2 hr; followed by 5-FU, 400 mg/m
2 iv bolus; followed by 5-FU, 600 mg/m
2 continuous iv infusion over 22 hr on days 1 and 2 every 2 wk. (2) 5-FU, 250 to 300 mg/m
2/day protracted continuous iv infusion until toxicity. (3) 5-FU, 2 to 3 g/m
2/day iv over 24 hr every wk for 6 wk with or without leucovorin, 20 to 500 mg/m
2/day every wk iv for 6 wk with 2-wk rest between cycles.
d. Hepatic includes events such as ascites and jaundice.
e. Cutaneous signs include events such as rash.
f. Respiratory includes events such as dyspnea and cough.
g. Neurologic includes events such as somnolence.
h. Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction.
i. Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss.
Severe pulmonary events are infrequent. Early effects such as dyspnea have been reported (see Warnings and Precautions). In the clinical studies evaluating the weekly dosage schedule, over half the patients with dyspnea had lung metastases. The extent to which malignant pulmonary involvement or other pre-existing lung disease may have contributed to dyspnea in these patients is unknown.
Potentially life threatening interstitial disease presenting with dyspnea, fever and pulmonary infiltrates (reticulonodular pattern on chest x-ray) is uncommon during CAMPTOSAR therapy. Usually seen in Japanese studies the contribution of CAMPTOSAR to these events was difficult to assess because these patients also had lung tumours and some had pre-existing non-malignant pulmonary disease.
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed (see Warnings and Precautions).
In a study to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in patients treated with CAMPTOSAR and infusional 5-FU/LV at doses of 180 mg/m2, 1 out of 22 patients with the UGT1A1 *28/*28 genotype had grade 4 neutropenia, versus 6 out of 114 patients with the UGT1A1 *1/*28 and 2 out of 114 for patients with the UGT1A1 *1/*1 genotype.
Insomnia and dizziness can occur, but are not usually considered to be directly related to the administration of CAMPTOSAR. Dizziness may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration (see Warnings and Precautions).
Alopecia has been reported during treatment with CAMPTOSAR. Rashes have also been reported but did not result in discontinuation of treatment.
Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhea. 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 irinotecan dose levels. The timing of the symptoms is most consistent with the occurrence of peak irinotecan serum levels during parental administration.
Asthenia, fever, and abdominal pain are generally the most common events of this type.
In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 liver enzyme abnormalities were observed in less than 10% of patients. These events typically occur in patients with known hepatic metastases.
Vasodilation (flushing) may occur during administration of CAMPTOSAR. Bradycardia may also occur, but has not required intervention. These effects have been attributed to the cholinergic syndrome sometimes observed during or shortly after infusion of CAMPTOSAR. All thromboembolic events, when considered together, have commonly been observed in patients receiving CAMPTOSAR (see Warnings and Precautions, Cardiovascular). The specific cause of these events has not been determined.
Indications and Clinical Use
Evidence from clinical and pharmacokinetic studies suggests that patients 65 years of age or older should be closely monitored because of a greater risk of late diarrhea in this population. Specific dosing recommendations may apply to this population depending upon the regimen used (see Warnings and Precautions, General, Geriatrics and Dosage and Administration).
The safety and effectiveness of CAMPTOSAR in the pediatric population have not been established (see Warnings and Precautions).
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
Single doses of up to 750 mg/m2 of CAMPTOSAR (irinotecan hydrochloride trihydrate) have been given in some trials and there have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea. There is no known antidote for overdosage of CAMPTOSAR. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications. Complete blood count (CBC), platelets, electrolytes, liver and renal function should be monitored in cases of overdosage and patients should be monitored for signs and symptoms of respiratory distress.
Dosage Forms, Composition and Packaging
Each mL of sterile, clear, light yellow aqueous solution contains: irinotecan HCl trihydrate 20 mg. Nonmedicinal ingredients: lactic acid, sorbitol and water for injection. Sodium hydroxide and/or hydrochloric acid may be used to adjust the pH to 3.0 to 3.8. Single use vials of 2, 5 and 15 mL.
Warnings and Precautions
Increases in serum creatinine or blood urea nitrogen have been observed. Rare cases of renal impairment and acute renal failure have been identified. These events have generally been attributed to complications of infection or to dehydration related to nausea, vomiting and/or diarrhea, which are common and sometimes severe adverse events following CAMPTOSAR treatment. Rare instances of renal dysfunction due to tumour lysis syndrome have also been reported.
The influence of renal insufficiency on the pharmacokinetics of CAMPTOSAR has not been evaluated.
The co-administration of CAMPTOSAR with CYP3A4 inducers (eg. St. John’s Wort, phenytoin, phenobarbital, carbamazepine, glucocorticoids, rifampin) leads to a reduction in the plasma concentration of the active metabolite SN-38, which could potentially lead to a reduction of efficacy (see Drug Interactions).
The appropriate starting dose of CAMPTOSAR when co-administered with CYP3A4 inducers has not been determined.
The concurrent administration of CAMPTOSAR with irradiation is not recommended.
Carcinogenicity studies have not been conducted. Rats administered 2 mg/kg or 25 mg/kg irinotecan IV once weekly for 13 weeks and allowed to recover for 91 weeks had a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan and SN-38 were not mutagenic in bacterial in vitro assays (Ames assay). Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Therefore, irinotecan may be able to induce chromosomal damage in human spermatozoa. For this reason, males undergoing CAMPTOSAR treatment should discuss effective contraceptive methods with their doctors.
Physicians should exercise particular caution in monitoring the effects of CAMPTOSAR in patients with poor performance status. Patients with performance status of 3 or 4 should not receive CAMPTOSAR. In patients receiving either CAMPTOSAR /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 status of 0 or 1. Close monitoring is recommended in patients who have previously received pelvic/abdominal irradiation and in the elderly as these patients may be less tolerant of the toxic effects of the drug. The use of CAMPTOSAR has not been established in patients with significant hepatic dysfunction (see Warnings and Precautions, Hepatic/Biliary/Pancreatic). There are known and suspected drug-drug interactions (see Contraindications, Drug Interactions below, and Drug Interactions).
Cases of colitis complicated by ulceration, bleeding, ileus, and infection have been observed. Cases of ileus without preceding colitis have also been reported. Patients experiencing ileus should receive prompt antibiotic support (see Drug Interactions) and must not be treated with irinotecan until resolution of the bowel obstruction.
Co-administration of CAMPTOSAR with azole antifungals (ketoconazole, fluconazole, itraconazole) is contraindicated (see Contraindications).
Co-administration of CAMPTOSAR with other CYP3A4 inhibitors (eg., cimetidine, fluoroquinolone antibiotics [ciprofloxacin and norfloxacin in patients with compromised renal function], macrolide antibiotics (azithromycin, clarithromycin, erythromycin), atazanavir sulfate, grapefruit juice, and CYP3A4-inhibitory calcium channel blockers (verapamil, diltiazem, and nifedipine) could lead to an increase in the relative exposure to the active metabolite SN-38 and therefore possibly increased toxicity (see Drug Interactions and Dosage and Administration).
The appropriate starting dose of CAMPTOSAR when co-administered with CYP3A4 inhibitors has not been determined.
Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during CAMPTOSAR therapy (see Adverse Reactions). Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.
The safety and effectiveness of CAMPTOSAR in the pediatric population have not been established.
CAMPTOSAR has been shown to be embryotoxic in rats and rabbits at a dose of 6 mg/kg/day. It is teratogenic in rats at doses greater than 1.2 mg/kg/day, and in rabbits at 6 mg/kg/day. Treatment-related changes in the fetuses included external and visceral abnormalities, skeletal variations and abnormalities. CAMPTOSAR may cause fetal harm when administered to a pregnant woman. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving CAMPTOSAR.
Patients greater than 65 years of age should be closely monitored because of a greater risk of late diarrhea in this population (see Adverse Reactions). The starting dose of CAMPTOSAR in patients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m2 (see Dosage and Administration).
Increases in serum levels of liver enzymes and bilirubin have been reported in clinical trials and in the post-market period (see Adverse Reactions, Adverse Drug Reaction Overview).
The use of CAMPTOSAR in patients with significant hepatic dysfunction has not been established. CAMPTOSAR was not administered to patients with serum bilirubin >35 µmol/L, or transaminase >3 times the upper limit of normal if no liver metastases, or transaminase >5 times the upper limit of normal with liver metastases (see Dosage and Administration).
In clinical trials of weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (17-35 µmol/L) had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 hematologic toxicities including neutropenia than those with bilirubin levels that were less than 17 µmol/L. Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may also be at greater risk of myelosuppression when receiving therapy with CAMPTOSAR. An association between baseline bilirubin elevations and an increased risk of late diarrhea has not been observed in studies of the weekly dosage schedule (see Dosage and Administration).
CAMPTOSAR commonly causes neutropenia, leukopenia, and anemia, any of which may be severe and therefore should not be used in patients with severe bone marrow failure. Therapy with CAMPTOSAR should be temporarily omitted if neutropenic fever occurs or if the absolute neutrophil count drops below 1.5×109/L. After the patient recovers to an absolute neutrophil count ≥1.5×109/L, subsequent doses of CAMPTOSAR should be reduced depending upon the level of neutropenia observed (see Dosage and Administration). Severe neutropenia resulting in deaths due to sepsis have been reported in patients treated with CAMPTOSAR. Neutropenic complications should be managed promptly with antibiotic support (see Drug Interactions). Routine administration of colony stimulating factor is not necessary; however, physicians should consider the use of colony-stimulating factors in patients experiencing clinically significant neutropenia (≥grade 2).
In one study an increased risk of neutropenia was observed in patients homozygous for the UGT1A1*28 allele, who received single-agent CAMPTOSAR at a dose of 350 mg/m2. Individuals with certain genetic polymorphisms in the UGT1A1 gene (eg. UGT1A1 *28/*28 genotype) have reduced UGT1A1 activity, which in turn increases the concentration of SN-38, the active metabolite of irinotecan (see Action and Clinical Pharmacology, Pharmacokinetics).
Patients with the UGT1A1*28 allele, treated with combination regimens that deliver doses of CAMPTOSAR in the range of 100-180 mg/m2, in combination with 5-FU/LV, the risk of grade 4 neutropenia was lower than in studies where CAMPTOSAR was administered at doses of 300-350 mg/m2 as a single agent (see Adverse Reactions, Hematology).
As in the case with all patients, dose modification should be considered based on individual patient tolerance to treatment (see Dosage and Administration).
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been reported (see Adverse Reactions).
Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents including irinotecan, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving irinotecan. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Careful monitoring of white blood cell count with differential, hemoglobin and platelet count is recommended before each dose of CAMPTOSAR. Liver function should be monitored before initiation of treatment and monthly, or as clinically indicated. (See Adverse Reactions, Adverse Drug Reaction Overview.)
Hyperglycemia has been reported in patients receiving CAMPTOSAR. This has usually been observed in patients with a history of diabetes or evidence of glucose intolerance prior to administration of CAMPTOSAR (see also Drug Interactions, Drug-Drug Interactions, Dexamethasone).
At the initiation of chemotherapy, patients should be given a sufficient supply of loperamide and instructed on its appropriate use. The prompt use of oral loperamide for controlling and treating the diarrhea is recommended and is higher than the usual dosage recommendation. Pre-treatment with loperamide before the onset of late diarrhea is not recommended. Instead, at the first episode of late-onset diarrhea (ie. poorly formed stools or more frequent bowel movement), patients are to take 4 mg loperamide, followed by 2 mg loperamide every two hours until they are free of diarrhea for at least 12 hours. During the night, the dose of loperamide may be 4 mg administered every 4 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus.
CAMPTOSAR is administered by intravenous infusion. Care should be taken to avoid extravasation. The infusion site should be monitored for signs of inflammation or other adverse effects. If extravasation occurs, flushing the site with sterile water and/or applying ice to the area are recommended.
CAMPTOSAR is emetogenic (see Adverse Reactions). Pre-medication with anti-emetic agents is recommended for patients receiving CAMPTOSAR. In clinical studies with the weekly dosage schedule, this pre-medication has mostly consisted of 10 mg dexamethasone given in conjunction with another type of anti-emetic agent. Anti-emetic agents should be given on the day of treatment, starting at least 30 minutes before administration of CAMPTOSAR. Physicians should also consider providing patients with an anti-emetic regimen for subsequent use as needed.
In rats, radioactivity appeared in the milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. It is not known whether irinotecan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving therapy with CAMPTOSAR.
CAMPTOSAR can induce both an early (occurring during or shortly after infusion of CAMPTOSAR) and a late (generally occurring more than 24 hours after CAMPTOSAR administration) form of diarrhea that appear to be mediated by different mechanisms.
Early onset diarrhea 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, and intestinal hyperperistalsis that can cause abdominal cramping. Early diarrhea may be alleviated by the use of atropine. Prophylactic or therapeutic administration of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered (unless contraindicated) (see Dosage and Administration).
Late onset diarrhea can be prolonged, may lead to dehydration, electrolyte imbalance, or infection, and can be life-threatening. The mechanism of action of late onset diarrhea is unknown. All grade late onset diarrhea occurred in 80% of patients and late diarrhea should be treated promptly with loperamide. Patients with diarrhea should be carefully monitored, and given fluid and electrolyte replacement if they become dehydrated. Patients should be given antibiotic support (see Drug Interactions) if they develop ileus, fever, or severe neutropenia. After the first treatment, subsequent chemotherapy should be delayed until patients return to pre-treatment bowel function for at least 24 hours without need for antidiarrhea medication. Patients experiencing clinically significant (grade ≥2) late diarrhea, should have subsequent doses of CAMPTOSAR decreased (see Dosage and Administration).
All thromboembolic events (includes 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) when considered together, have been commonly observed in patients receiving CAMPTOSAR. The specific cause of these events has not been determined. See also Adverse Reactions, Clinical Trial Adverse Drug Reactions.
Myocardial ischemic events have been uncommonly observed in patients receiving CAMPTOSAR. In some cases, a causal association with administration of CAMPTOSAR could not be excluded. See Adverse Reactions, Post-Market Adverse Drug Reactions.
Storage and Stability
Store at controlled room temperature (15 to 30°C). Protect from light. CAMPTOSAR (irinotecan hydrochloride trihydrate) is available in an amber-coloured polypropylene vial or in an amber glass vial that is packaged in plastic blister to protect from breakage. It is recommended that the vial remain in the carton until time of use. The CAMPTOSAR glass vial should be inspected for damage and visible signs of leaks before removing the plastic blister. If there are signs of breakage or leakage from the vial, do not open the plastic blister. Incinerate the unopened package.
Action and Clinical Pharmacology
Irinotecan clearance is diminished in patients with hepatic dysfunction while relative exposure to the active metabolite SN-38 is increased. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in serum total bilirubin and transaminase concentrations (see Dosage and Administration and Warnings and Precautions).
CAMPTOSAR (irinotecan hydrochloride trihydrate) is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan is a semi-synthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks.
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38, which is formed from irinotecan primarily by liver carboxylesterase enzymes. The SN-38 metabolite is approximately 1000 times more potent than irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumour cell lines. The precise contribution of SN-38 to the activity of CAMPTOSAR in humans has not been completely defined. Both irinotecan 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.
In one pharmacokinetic study of patients administered a starting dose of irinotecan 125mg/m2, the terminal half-life of irinotecan was statistically significantly longer in patients who were 65 years or older compared to patients younger than 65 years (6.0 hours versus 5.5 hours, respectively). Dose-normalized AUC0-24 was 14.8% higher, Cmax was 11.3% higher and clearance was 17.5% lower in patients 65 years and older compared with patients younger than 65 years. Also, dose normalized AUC0-24 of SN-38 was 11.2% higher in subjects age 65 years and over compared to subjects less than 65 years, but this result was not statistically significant.
In a different pharmacokinetic study that was prospectively designed to investigate the effect of age on irinotecan toxicity, no statistically significant differences in irinotecan pharmacokinetics were seen in patients ≥65 years compared to those <65 years administered a single 125 mg/m2 irinotecan dose. Irinotecan Cmax and AUC0-24 were, respectively, 0.7% and 0.3% lower in patients ≥65 years compared to patients who were <65 years. Values for SN-38 Cmax and AUC0-24 were, respectively, 1.8% lower and 0.8% higher in patients ≥65 years compared to patients <65 years and values for SN-38 glucuronide Cmax and AUC0-24 were, respectively, 1.0% and 3.1% lower in patients ≥65 years compared to patients who were <65 years.
The reason for the conflicting results between the two pharmacokinetic results is not known. Clinically, however, particular caution should be exercised when administering irinotecan to elderly patients as these patients may be less tolerant of the toxic effects of the drug. See Warnings and Precautions and Adverse Reactions, Adverse Drug Reaction Overview.
Over the recommended dose range of 50 to 350 mg/m2, the AUC of irinotecan increases linearly with dose. The AUC of SN-38 increases less than proportionally with dose. Irinotecan exhibits moderate plasma protein binding (30 to 68% bound). SN-38 is approximately 95% bound to human plasma proteins, mainly albumin.
The complete disposition of irinotecan in humans has not been fully elucidated. The metabolic conversion of irinotecan to SN-38 is mediated by carboxylesterase enzymes primarily in the liver. SN-38 subsequently undergoes conjugation by UDP-glucuronyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite (SN-38 glucuronide). UGT1A1 enzyme activity is reduced in individuals with certain genetic polymorphisms, such as UGT1A1*28. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele (also known as UGT1A1 7/7).
In a prospective study, in which irinotecan was administered as a single-agent (350 mg/m2) on a once every 3 week schedule, patients homozygous for the UGT1A1*28 allele (UGT1A1 7/7) had higher systemic exposures to SN-38 than those who were homozygous for the wild-type UGT1A1 allele (UGT1A1 *1/*1) (see Warnings and Precautions, Hematologic and Adverse Reactions, Hematology). The urinary excretion of irinotecan (11 to 20%), SN-38 (<1%), and SN-38 glucuronide (3%) is low.
Irinotecan is oxidized by cytochrome P450 isozyme 3A4 (CYP3A4) to yield two relatively inactive metabolites, APC (7-ethyl-l0-[4-N-(5-aminopentanoic acid)-l-piperidino]-carbonyloxycamptothecin) and the minor metabolite, NPC (7-ethyl-l0-(4 amino-1-piperidino)carbonyloxycamptothecin). See Figure 1.
The influence of renal insufficiency on the pharmacokinetics of irinotecan has not been formally studied.
There is no clinically important gender influence on the pharmacokinetics of irinotecan; the influence of race has not been studied.
Contraindications
CAMPTOSAR (irinotecan hydrochloride trihydrate) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.
Co-administration of CAMPTOSAR with azole antifungals (ketoconazole, fluconazole, itraconazole), known CYP3A4 inhibitors, is contraindicated because this can lead to an increase in the relative exposure to the active metabolite SN-38 and can therefore possibly lead to increased toxicity.
In patients receiving concomitant CAMPTOSAR and ketoconazole, exposure to SN-38 was increased by approximately 110%. Patients should discontinue ketoconazole at least 1 week prior to starting irinotecan therapy. See Warnings and Precautions regarding potential drug-drug interactions with other CYP3A4 inhibitors and inducers.
Patients with hereditary fructose intolerance should not be given CAMPTOSAR, as this product contains sorbitol.
